Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([C:11]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N+:27]([C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)([O-:29])=[O:28]>[N+](C1C=CC=CC=1)([O-])=O>[N+:27]([C:30]1[CH:38]=[CH:37][C:33]([C:34]([C:8]2[CH:7]=[CH:6][C:5]([C:11]3([C:21]4[CH:22]=[CH:23][C:24]([C:34](=[O:35])[C:33]5[CH:32]=[CH:31][C:30]([N+:27]([O-:29])=[O:28])=[CH:38][CH:37]=5)=[CH:25][CH:26]=4)[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12]3)=[CH:10][CH:9]=2)=[O:35])=[CH:32][CH:31]=1)([O-:29])=[O:28]
Reactant: CCCCC1CCC(c2ccccc2)(c2ccccc2)CC1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCCC1CCC(c2ccc(C(=O)c3ccc([N+](=O)[O-])cc3)cc2)(c2ccc(C(=O)c3ccc([N+](=O)[O-])cc3)cc2)CC1
Temperature: 67 °C
Yield: 74.9 %

Procedure:
Aluminum chloride 101.22 g and nitrobenzene 200 ml were mixed, the mixture was poured and dissolved in para-nitrobenzoyl chloride 57.10 g on ice cooling. Then, a solution of 1,1-diphenyl-4-butylcyclohexane 30.0 g in nitrobenzene 50 ml was added dropwise for 30 minutes. 30 minutes after adding, the ice bath was removed and the mixture was slowly heated to 67° C. for four hours in a mantle heater. The finish of the reaction was confirmed by liquid chromatography, and then the reaction solution was poured into ice 1.5 liters to extract with chloroform 1.0 liter. The solution was washed with a 6N-HCl solution, an aqueous solution of sodium bicarbonate, an aqueous solution of sodium chloride and water. After chloroform was removed with a rotary evaporator, nitrobenzene was removed by steam distillation. The residue was dissolved in toluene, and the solution was purified with a silica gel column to obtain 1,1-bis[4-(4-nitrobenzoyl)phenyl]-4-butylcyclohexane 45.40 g.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C([O:13][CH2:14][CH2:15][N:16]1[C:28]2[CH2:27][CH2:26][CH2:25][CH:24]([C:29]([OH:31])=[O:30])[C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][C:21]=2[O:32][CH3:33])C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[OH:13][CH2:14][CH2:15][N:16]1[C:28]2[CH2:27][CH2:26][CH2:25][CH:24]([C:29]([OH:31])=[O:30])[C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][C:21]=2[O:32][CH3:33]
Reactant: [H][H]
Reactant: COc1cccc2c1c1c(n2CCOCc2ccccc2)CCCC1C(=O)O
Agent: [Pd]
Solvent: CCNCC
Solvent: CO
Product: COc1cccc2c1c1c(n2CCO)CCCC1C(=O)O
Yield: 75.9 %

Procedure:
9-(2-Benzyloxy-ethyl)-5-methoxy-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamine (10) (1.0 g, 2.1 mmol) in methanol (50 ml) was shaken with 10% palladium on charcoal (300 mg), and hydrogen gas excess for 18 h at 55° C. The reaction was then filtered through a pad of celite and the filtrate concentrated in vacuo to give 578 mg (100%) 9-(2-hydroxyethyl)-5-methoxy-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamine (11) as a foam. The structure was confirmed by 13C NMR (75 MHz; CDCl3): δC 13.0, 14.4, 20.0, 22.0, 28.0, 36.4, 40.6, 42.0, 54.7, 60.6, 99.2, 102.6, 107.0, 116.7, 121.1, 136.1, 137.5, 138.0 153.5, and 175.7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[C:43]([CH3:58])=[C:44]([C:48]([N:50]2[CH2:55][CH2:54][N:53]([CH2:56][CH3:57])[CH2:52][CH2:51]2)=[O:49])[CH:45]=[CH:46][CH:47]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[C:43]([CH3:58])=[C:44]([C:48]([N:50]6[CH2:51][CH2:52][N:53]([CH2:56][CH3:57])[CH2:54][CH2:55]6)=[O:49])[CH:45]=[CH:46][CH:47]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: CCN1CCN(C(=O)c2cccc(Br)c2C)CC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: CCN1CCN(C(=O)c2cccc(N3CCc4c(-c5cnc(N(Cc6ccc(OC)cc6)Cc6ccc(OC)cc6)nc5)nc(N5CCOCC5)nc43)c2C)CC1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and (3-bromo-2-methyl-phenyl)-(4-ethyl-piperazin-1-yl)-methanone (156 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of [3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methyl-phenyl]-(4-ethyl-piperazin-1-yl)-methanone was obtained, and then the PMB groups were removed according to Deprotection method 3, to obtain the desired compound (D-158) as a pale yellow powder (53 mg, 54%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:14]([O-:16])=[O:15])=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=O.C([O-])(=O)C.[NH4+].[N+:22]([CH3:25])([O-:24])=[O:23]>C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3]1[C:4]([N+:14]([O-:16])=[O:15])=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=[CH:25][N+:22]([O-:24])=[O:23]
Reactant: COc1cc(C=O)c([N+](=O)[O-])c(OC)c1O
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)OC(C)=O
Product: COc1cc(C=C[N+](=O)[O-])c([N+](=O)[O-])c(OC)c1O
Yield: 58.5 %

Procedure:
A suspension of 20 g (0.088 mole) of 3,5-dimethoxy-4-hydroxy-2-nitrobenzaldehyde and 21 g (0.27 mole) of dry ammonium acetate in 400 cm3 of acetic anhydride and 15.8 g (0.26 mole) of nitromethane is heated under reflux for 2 hours. The reaction mixture is cooled, then the precipitate is filtered off. After washing with water, recrystallization from an ethanol-water mixture and drying under vacuum, 13.9 g of the desired product is obtained in the form of orangish-yellow crystals (yield=58%).
Reaction SMILES: [H-].[Na+].[C:3](OC)(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].C([Li])CCC.[C:16]1([CH2:22][CH2:23][C:24](=[O:33])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.O>[OH:6][C:5]1[CH2:7][C:24]([CH2:23][CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:33][C:3](=[O:8])[CH:4]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=C(CCc1ccccc1)CCc1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1C=C(O)CC(CCc2ccccc2)(CCc2ccccc2)O1
Reaction time: 0.17 h

Procedure:
Freshly distilled THF (25 mL) was cooled in an ice bath under a nitrogen atmosphere, then charged with 660 mg (16.5 mmol) sodium hydride (60% dispersion). This suspension was treated with 1.89 g (16.3 mmol) methyl acetoacetate dropwise, and the reaction was stirred for 10 minutes. n-Butyllithium (10.3 mL of 1.6 M in hexanes; 16.5 mmol) was dripped in and the reaction was stirred 30 minutes. At this time 3.10 g (13 mmol) of 1,5-diphenyl-3-pentanone (Ram and Spicer, Tetrahedrom Lett., 1988, 29 (31), 3741) in 20 mL THF was added dropwise over 15 minutes. After 4 hours 100 mL H2O was added and the reaction stirred overnight. The reaction was extracted with diethyl ether, and the organics set aside. The aqueous layer was chilled, treated with 50% HOAc until a precipitate formed, and then extracted with EtOAc. These organics were washed with saturated brine, dried (Na2SO4), and concentrated. 1H NMR (DMSO-d6) δ 2.0 (d of d, 4 H), 2.65 (m, 6 H), 5.0 (s, 1 H), 7.15-7.35 (m, 10 H), 11.4 (bs, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:10][CH:9]1[C:11]1[CH:12]=[CH:13][C:14]([CH3:21])=[C:15]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:16]=1.[C:26]1([SH:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[O:5][CH2:6][CH2:7][NH:8][CH2:10][CH:9]([C:11]1[CH:12]=[CH:13][C:14]([CH3:21])=[C:15]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:16]=1)[S:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccccc1OCCN1CC1c1ccc(C)c(S(N)(=O)=O)c1
Reactant: Sc1ccccc1
Solvent: CO
Product: COc1ccccc1OCCNCC(Sc1ccccc1)c1ccc(C)c(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
In 50 ml of methanol was dissolved 2.5 g of 5-{1-[2-(2-methoxyphenoxy)ethyl]aziridin-2-yl}-2-methylbenzenesulfonamide and after adding 1 g of thiophenol to the solution and stirring overnight the mixture at room temperature, methanol was distilled off. The residue was applied to a silica gel column chromatography and the product was eluted by a mixed solvent of chloroform and methanol (9:1 by volume ratio) to provide 2.4 g of 5-{2-[2-(2-methoxyphenoxy)ethylamino]-1-phenylthioethyl}-2-methylbenzenesulfonamide as a viscous oily material.
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([NH2:23])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:6][CH:5]=1.Cl.C[CH:26]([NH2:41])[C:27]1C=[CH:31][C:30](CCC2C=CC=CC=2)=[CH:29][CH:28]=1>>[ClH:1].[CH3:2][CH:3]([N:23]=[C:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:41]1)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:6][CH:5]=1
Reactant: CCCCCCCCCCCCCc1ccc(C(C)N)cc1
Reactant: CC(N)c1ccc(CCc2ccccc2)cc1
Agent: Cl
Product: CCCCCCCCCCCCCc1ccc(C(C)N=C2CCCCCN2)cc1

Procedure:
Following essentially the same procedure described in Example 7 but substituting α-methyl-p-tridecylbenzylamine hydrochloride for the α-methyl-p-phenethylbenzylamine hydrochloride above, results in the formation of 2-(α-methyl-p-tridecylbenzylimino)hexahydroazepine hydrochloride having a M.P. 183°-5° C.
Reaction SMILES: O[CH2:2][CH:3]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[CH2:5][N:4]1[C:11]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[N:20]1[N:24]=[CH:23][CH:22]=[N:21]1)=[O:12].[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:19][C:17]1[CH:16]=[CH:15][C:14]([N:20]2[N:21]=[CH:22][CH:23]=[N:24]2)=[C:13]([CH:18]=1)[C:11]([N:4]1[CH2:5][CH:6]2[CH2:10][CH2:9][CH2:8][CH:7]2[CH:3]1[CH2:2][N:29]1[C:25](=[O:35])[C:26]2[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:28]1=[O:30])=[O:12]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CC3CCCC3C2CO)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CC3CCCC3C2CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0° C. solution of (1-(hydroxymethyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (1 equiv.), phthalimide (2 equiv.) and PPh3 (3 equiv.) in THF (0.5M in amine) was added with DIAD (5 equiv.) dropwise. The resulting suspension was allowed to warm to rt gradually, stirred overnight, and then concentrated in vacuo to a brown oil. The reaction mixture was diluted with EtOAc and washed with water, brine, dried (MgSO4), and concentrated. The crude residue was purified by chromatography on silica gel (EtOAc/hex) to give the title compound as a clear oil. MS (ESI) 456 (M+H).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][CH:13]=2)=[O:11])[CH2:5][CH2:4]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:15]=3[NH:14][CH:13]=2)=[O:11])[CH2:5][CH2:4]1)(=[O:35])[CH3:34]
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-Cyclopropylmethoxy-5-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide hydrochloride (example A160) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=1[O:4][CH2:5][CH:6]1[O:8][CH2:7]1.[NH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]([CH3:31])[CH2:26][C:27](=[O:30])[NH:28][N:29]=2)=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=1[O:4][CH2:5][CH:6]([OH:8])[CH2:7][NH:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:25]([CH3:31])[CH2:26][C:27](=[O:30])[NH:28][N:29]=2)=[CH:22][CH:23]=1
Reactant: CC1CC(=O)NN=C1c1ccc(OCCN)cc1
Reactant: Cc1ccc(Cl)c(OCC2CO2)c1
Product: Cc1ccc(Cl)c(OCC(O)CNCCOc2ccc(C3=NNC(=O)CC3C)cc2)c1

Procedure:
Prepared analogously to Example 1 from 1-(2-chloro-5-methylphenoxy)-2,3-epoxypropane and 6-[4-(2-aminoethoxy)phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH2:8](O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>S(Cl)(Cl)=O>[CH2:8]([O:6][C:5](=[O:7])[CH2:4][CH2:3][CH2:2][Br:1])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)CCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: O=C(CCCBr)OCc1ccccc1
Temperature: -50 °C
Reaction time: 4 h

Procedure:
4-bromobutyric acid (10.6 g, 60 mmole) was dissolved in thionyl chloride (20 mml), and the reaction was kept for 4 hr. The solution was evaporated and coevaporated with toluene several times. The residue was redissolved in dichloromethane (120 ml), and then benzyl alcohol (4.14 ml, 40 mmole) was added. The solution was cooled down to −50° C. and triethylamine (10 ml, 72 mmole) was added. The reaction mixture was slowly warmed to room temperature. After 3 hr, the reaction mixture was poured into sodium bicarbonate aqueous solution and the organic phase was washed with water and dried, giving the titled product, 6.8 g.
Reaction SMILES: [C:1]1([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([OH:17])=[CH:9][C:8]2=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C2C(=CC=CC=2)C=C[C:20]1=[O:29]>>[C:1]1([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([OH:17])=[C:9]([CH:20]=[O:29])[C:8]2=[O:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1cc(O)c2ccccc2n1-c1ccccc1
Reactant: O=c1ccc2ccccc2[nH]1
Product: O=Cc1c(O)c2ccccc2n(-c2ccccc2)c1=O

Procedure:
Following the procedure set forth in Preparation B, 1- phenyl-4-hydroxy-2(1H)-quinolinone was converted to 1 -phenyl-3-formyl-4-hydroxy-(2(1H)-quinolinone. That the expected product was obtained was confirmed by the spectral data: MS: m/e 265 (M·+); NMR (DMSO): δ10.08 (s, 1H, CHO) ppm.
Reaction SMILES: CO[C:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][CH2:4]2.C([Br:14])(=O)C>O>[Br:14][C:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][CH2:4]2
Reactant: CC(=O)Br
Reactant: COC12CCC(CC1)CC2
Solvent: O
Product: BrC12CCC(CC1)CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
To a stirred mixture of 1-methoxybicyclo[2.2.2]octane (4.0 g, 28 mmol) and acetyl bromide (6.2 g, 50.4 mmol) was added 10 drops of stannic chloride at 0° C. After stirring for 0.5 h, the temperature was allowed to rise to 20-25° C. and stirring was continued at the same temperature for 3 h. After cooling to 0° C., water (30 mL) was added and the mixture was stirred for 10 min. Then the mixture was poured into water (150 mL) and extracted with ether (100 mL×3). The ether layers were combined, washed with aqueous sodium bicarbonate and water, and dried over sodium sulfate. The solvent was removed under reduced pressure to produce 1-bromobicyclo[2.2.2]octane (4.0 g, 75%), which was used for next step without purification. 1H NMR (CDCl3) δ 2.23 (m, 6H), 1.95 (m, 1H), 1.81-1.63 (m, 6H), 1.52 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[N:12][C:13]([CH:16]([NH:18][C:19]([C:21]3[CH:25]=[CH:24][O:23][CH:22]=3)=O)[CH3:17])=[CH:14][N:15]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O>ClCCCl>[O:23]1[CH:24]=[CH:25][C:21]([C:19]2[N:12]3[C:13]([CH:14]=[N:15][C:10]([NH:9][C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)=[N:11]3)=[C:16]([CH3:17])[N:18]=2)=[CH:22]1
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccoc3)nn2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COc1ccc(Nc2ncc3c(C)nc(-c4ccoc4)n3n2)cc1
Yield: 53.5 %

Procedure:
Applying the Cyclization Procedure 1, using N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]-3-furancarboxamide (Intermediate 58) (110 mg, 0.32 mmol), 1,2-dichloroethane (5 mL) and phosphorus oxychloride (0.20 mL, 2.14 mmol), to afford 7-(3-furanyl)-5-methyl-N-[4-(methyloxy)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (55 mg) as a yellow solid. MS m/z 322 (M+1).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([OH:12])=O)[N:8]=1)=[O:2].[NH2:25][CH:26]1[C:46](=[O:47])[N:28]2[C:29]([C:43]([OH:45])=[O:44])=[C:30]([CH2:33][S:34][C:35]3[N:39]([CH2:40][CH:41]=[CH2:42])[N:38]=[N:37][N:36]=3)[CH2:31][S:32][C@H:27]12>>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([NH:25][CH:26]2[C:46](=[O:47])[N:28]3[C:29]([C:43]([OH:45])=[O:44])=[C:30]([CH2:33][S:34][C:35]4[N:39]([CH2:40][CH:41]=[CH2:42])[N:38]=[N:37][N:36]=4)[CH2:31][S:32][C@H:27]23)=[O:12])[N:8]=1)=[O:2]
Reactant: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)NCCON=C(C(=O)O)c1csc(NC=O)n1
Product: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCNC(=O)OC(C)(C)C)c3csc(NC=O)n3)[C@H]2SC1
Yield: 95.4 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetic acid (syn isomer, 2 g.) and 7-amino-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (2 g.) were treated in a similar manner to that of Example 20-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 3.7 g.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:36]([C:38]1[C:39]([N:47]2[CH2:52][CH2:51][CH:50]([N:53]3[CH2:58][CH2:57][N:56]([S:59]([CH3:62])(=[O:61])=[O:60])[CH2:55][CH2:54]3)[CH2:49][CH2:48]2)=[CH:40][C:41]([O:45][CH3:46])=[C:42]([CH:44]=1)[NH2:43])[CH3:37].Cl.N>C(O)C(F)(F)F.CO>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:43][C:42]3[CH:44]=[C:38]([CH2:36][CH3:37])[C:39]([N:47]4[CH2:48][CH2:49][CH:50]([N:53]5[CH2:54][CH2:55][N:56]([S:59]([CH3:62])(=[O:61])=[O:60])[CH2:57][CH2:58]5)[CH2:51][CH2:52]4)=[CH:40][C:41]=3[O:45][CH3:46])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: CCc1cc(N)c(OC)cc1N1CCC(N2CCN(S(C)(=O)=O)CC2)CC1
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: Cl
Agent: N
Solvent: OCC(F)(F)F
Solvent: CO
Product: CCc1cc(Nc2nccc(-c3c(-c4ccc(OC)c(C(=O)Nc5c(F)cccc5F)c4)nc4ccccn34)n2)c(OC)cc1N1CCC(N2CCN(S(C)(=O)=O)CC2)CC1
Temperature: 85 °C
Yield: 70.7 %

Procedure:
A mixture of 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (23.0 g, 46.8 mmol), 5-ethyl-2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (Example 206, Step B) (18.6 g, 46.8 mmol) and HCl (4N,1,4-Dioxane, 23.4 mL, 93.6 mmol) in trifluoroethanol (200 mL) was heated in a sealed vessel at 85° C. for 48 h. After cooling to rt, the reaction mixture was treated with an excess of 7N NH3 in MeOH and then subjected to filtration. The filtrate was concentrated onto silica gel and purified by flash chromatography. The chromatographed product was dissolved in DCM and treated with an excess of diethyl ether. The resultant bright yellow precipitate was collected by filtration and then recrystallized from DCM and EtOH to afford the title compound N-(2,6-difluorophenyl)-5-(3-{2-[(5-ethyl-2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)-2-(methyloxy)benzamide (28.2 g, 67%).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:22][O:23][CH2:24]Cl.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:22][O:23][CH3:24])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)c2ccccc12
Reactant: COCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1ccc(F)c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1.91 g of 4-fluoro-1-hydroxynaphthalene in 40 ml of dry dichloromethane in an ice/salt bath was added by syringe 2.64 ml of diisopropylethylamine followed by 1.11 ml of methoxymethylchloride. The mixture was stirred at 0° C. for 0.5 h, allowed to warm to ambient temperature and stirred for 14 h. The reaction mixture was poured into saturated sodium bicarbonate, extracted with dichloromethane, dried (sodium sulphate), filtered and concentrated to a yellow oil. The material was purified by flash chromatography on silica gel eluting with toluene/heptanes to provide 1.98 g of 4-fluoro-1-methoxymethoxynaphthalene.
Reaction SMILES: [OH-].[K+].[O:3]=[C:4]1[N:8]2[CH:9]([C:14]([O:16]C)=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][C:7]2=[N:6][O:5]1.C(OCC)C.Cl>C1COCC1>[O:3]=[C:4]1[N:8]2[CH:9]([C:14]([OH:16])=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][C:7]2=[N:6][O:5]1
Reactant: COC(=O)C1CCCCc2noc(=O)n21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)C1CCCCc2noc(=O)n21
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
Potassium hydroxide (0.47 g, 8.39 mmol) was dissolved in 10 mL of 50% aqueous THF. To this was added a solution of the product of Example 4 in 6 mL THF and the reaction mixture was stirred for 2 h at 25° C. Diethylether (20 mL) was then added and the reaction mixture was made acidic by adding 10 mL of 1N HCl. The organic layer was separated, dried over magnesium sulfate, filtered and all solvent evaporated to give 0.43 g (52% yield) of the title product. The structure of the compound was characterized by 1H and 13C NMR.
Reaction SMILES: [F:1][CH:2]([F:27])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:22][C:21]([CH2:23]O)=[N:20][CH:19]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:26])[CH3:25])=[O:4].[N:28]1C=CC=C[CH:29]=1.C(N(C(C)C)CC)(C)C.Cl>C(Cl)Cl.C([O-])(O)=O.[Na+]>[F:1][CH:2]([F:27])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:22][C:21]([CH2:23][NH:28][CH3:29])=[N:20][CH:19]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:25])[CH3:26])=[O:4]
Reactant: c1ccncc1
Reactant: CC1(C)O[C@H](c2ccc(-c3cnc(CO)s3)cc2)[C@@H](CF)N1C(=O)C(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNCc1ncc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
Mesyl anhydride (860 mg, 4.9 mmol) is added to 2,2-difluoro-1-((4S,5R)-4-(fluoromethyl)-5-(4-(2-(hydroxymethyl)thiazol-5-yl)phenyl)-2,2-dimethyl-oxazolidin-3-yl)ethanone (1.4 g, 3.5 mmol) in CH2Cl2 (35 mL). Pyridine (0.5 mL, 5.9 mmol) is added and stirred at room temperature for 1 hour. The reaction is diluted with CH2Cl2 (35 mL) and washed with water and brine. The organic phase is dried (Na2SO4) and concentrated under vacuum. The crude mesylate is dissolved in acetonitrile (10 mL) and transferred to a scintillation vial. Diisopropylethylamine (0.65 mL, 3.7 mmol) and metyhlamine HCl (130 mg, 1.9 mmol) are added and the reaction mixture is heated to 55° C. for 18 hours. The reaction mixture is cooled and diluted with saturated NaHCO3 (75 mL). The reaction mixture is extracted with CH2Cl2 (2×75 mL) and the combined organic phase is dried (Na2SO4) and concentrated under vacuum to afford the title compound (475 mg): m/z (Cl) M+H 414.