Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]2[C:22]([CH3:23])=[CH:21][C:20]3[C:19]([CH3:25])([CH3:24])[CH:18]([O:26][C:27](=[O:29])[CH3:28])[CH2:17][C:16]([CH3:31])([CH3:30])[C:15]=3[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].[Br:33]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:32])[C:5]1[CH:6]=[CH:7][C:8](/[CH:11]=[CH:12]/[C:13]2[C:22]([CH2:23][Br:33])=[CH:21][C:20]3[C:19]([CH3:25])([CH3:24])[CH:18]([O:26][C:27](=[O:29])[CH3:28])[CH2:17][C:16]([CH3:31])([CH3:30])[C:15]=3[CH:14]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(/C=C/c2cc3c(cc2C)C(C)(C)C(OC(C)=O)CC3(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(/C=C/c2cc3c(cc2CBr)C(C)(C)C(OC(C)=O)CC3(C)C)cc1
Temperature: 25 °C
Yield: 55.8 %

Procedure:
A solution of 0.68 g (1.57 mmol) of Ethyl-4-[(E)-2-(5,5,8,8-Tetramethyl-3-methyl-6-acetoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoate, 0.36 g (2.03 mmol) of N-bromosuccinimide and 0.019 g (0.078 mmol) of benzoyl peroxide in 15 mL of carbon tetrachloride was heated at reflux. After 3 hours the reaction was cooled to room temperature, washed with 10% aqueous sodium bisulfite and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution, hexane-5% ethyl acetate/hexane) to give 0.45 g (56%) of Ethyl-4-[(E)-2-(5,5,8,8-Tetramethyl-3-bromomethyl-6-acetoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoate (M+=512).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:20][C:21]4[N:22]([C:24](Br)=[CH:25][N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:20][C:21]4[N:22]([C:24]([C:14]5[CH:15]=[CH:16][CH:17]=[C:12]([C:8]#[N:7])[CH:13]=5)=[CH:25][N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nn4c(Br)cnc4cc3-c3ccccc3)cc2)CCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nn4c(-c5cccc(C#N)c5)cnc4cc3-c3ccccc3)cc2)CCC1
Temperature: 100 °C
Yield: 74.5 %

Procedure:
311 mg (0.6 mmol) {1-[4-(3-Bromo-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, intermediate example Int-2-1, were dissolved in 6.2 mL THF. After addition of 6 mL (3 mmol) of 3-(cyanophenyl)zinc iodide (0.5M solution in THF) and 23 mg (0.03 mmol) bis(diphenylphosphino)ferrocenedichloropalladium(II) the reaction mixture was heated for 40′ in the microwave at 100° C. Additional 6 mL (3 mmol) of 3-(cyanophenyl)zinc iodide (0.5M solution in THF) and 46 mg (0.06 mmol) catalysator were added and the mixture was heated in the microwave for an additional hour at 100° C. The reaction mixture was poured on water (100 mL) and extracted twice with ethyl acetate (100 mL each). The combined organic extracts were washed with water and dried over sodium sulfate. After filtration and evaporation of the solvent the residue was purified by chromatography on silicagel (eluents: dichloromethane/methanol) yielding 121 mg of the desired compound which however were strongly contaminated.
Reaction SMILES: Cl.[F:2][C@@:3]12[C@:16]3([CH3:17])[C:11](=[CH:12][C:13](=[O:18])[CH:14]=[CH:15]3)[C@@H:10]([F:19])[CH2:9][C@H:8]1[C@@H:7]1[CH2:20][C@@H:21]3[C@:25]([C:26](=[O:30])[CH2:27][S:28][CH3:29])([C@@:6]1([CH3:31])[CH2:5][C@@H:4]2[OH:32])[CH2:24][NH:23][CH2:22]3.[Cl:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]Br>C(Cl)Cl>[Cl:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][N:23]1[CH2:24][C@:25]2([C:26](=[O:30])[CH2:27][S:28][CH3:29])[C@@H:21]([CH2:20][C@H:7]3[C@H:8]4[C@@:3]([F:2])([C@:16]5([CH3:17])[C:11]([C@@H:10]([F:19])[CH2:9]4)=[CH:12][C:13](=[O:18])[CH:14]=[CH:15]5)[C@@H:4]([OH:32])[CH2:5][C@@:6]32[CH3:31])[CH2:22]1
Reactant: Clc1cccc(CBr)c1
Reactant: CSCC(=O)[C@@]12CNC[C@@H]1C[C@H]1[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]12C
Agent: Cl
Solvent: ClCCl
Product: CSCC(=O)[C@@]12CN(Cc3cccc(Cl)c3)C[C@@H]1C[C@H]1[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]12C
Yield: 29.6 %

Procedure:
A solution of compound 186 (103 mg, 0.211 mmol), 3-chorobenzylbromide (66.0 μl, 0.317 mmol) and TEA (88 μl, 0.633 mmol) in DCM (10 ml) is stirred under nitrogen at RT for 16 hours. The solution is diluted with DCM and washed with brine, dried over Na2SO4 and filtered. The solvent is evaporated and the crude is purified by silica gel chromatography (eluent: DCM/MeOH 99/1). Trituration with petroleum ether affords the title compound (36 mg, 29.6% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[N:12]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([CH:27]=1)[C:24](O)=[O:25].Cl.CN(C)CCCN=C=NCC.N1(C2C=CN=CC=2)CCCC1.C(N(CC)CC)C>ClCCl>[Br:17][C:13]1[N:12]=[C:11]([NH:10][C@H:8]([C:4]2[CH:3]=[C:2]([NH:1][C:24](=[O:25])[C:23]3[CH:27]=[C:19]([CH3:18])[CH:20]=[N:21][CH:22]=3)[CH:7]=[CH:6][CH:5]=2)[CH3:9])[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cncc(C(=O)O)c1
Reactant: C[C@H](Nc1cccc(Br)n1)c1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cncc(C(=O)Nc2cccc([C@H](C)Nc3cccc(Br)n3)c2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 62.8 %

Procedure:
A mixture of N-[(1S)-1-(3-aminophenyl)ethyl]-6-bromopyridin-2-amine (70 mg, 0.24 mmol), 5-methylnicotinic acid (39 mg, 0.29 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (69 mg, 0.36 mmol), 4-pyrrolidinopyridine (7 mg, 0.05 mmol) and triethylamine (0.08 mL, 0.58 mmol) in dichloromethane (3 mL) was stirred at room temperature for 17 hours. After this time the mixture was diluted with dichloromethane (20 mL), washed successively with saturated aqueous sodium hydrogen carbonate (2×15 mL) and brine (15 mL), dried (Na2SO4) and concentrated under reduced pressure to give a dark yellow oil which was purified by flash chromatography (silica, ethyl acetate/hexanes) to give N-(3-{(1S)-1-[(6-bromopyridin-2-yl)amino]ethyl}phenyl)-5-methylnicotinamide (62 mg, 63%) as a pale yellow foam.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=3)=[CH:10][C:9]=2[CH3:27])[CH2:7][CH2:6]1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:25][CH:26]=3)=[CH:10][C:9]=2[CH3:27])[CH2:7][CH2:6]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCC(C)(C)C)CC3)c(C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(CCc2ccc(C(=O)O)cc2)ccc1C1(OCC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.7 %

Procedure:
Using General Procedure I; a solution of ethyl 4-[4-[1-(2,2-dimethylpropyloxy)-cyclopropyl]-3-methyl-phenylethynyl]-benzoate (Compound 87, 60.0 mg, 0.15 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 24.0 mg (43%) of the title compound as a colorless solid.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=O)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][N:26]=[CH:25]2.[OH-].[Na+]>C(Cl)Cl.CN(C)C1C=CN=CC=1.N1C=CC=CC=1.C(N(CC)CC)C>[CH2:5]([N:12]1[CH2:13][CH2:14][CH:15]([C:18]([NH:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][N:26]=[CH:25]3)=[O:20])[CH2:16][CH2:17]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: O=C(O)C1CCN(Cc2ccccc2)CC1
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc2[nH]ncc2c1)C1CCN(Cc2ccccc2)CC1
Yield: 29.8 %

Procedure:
Thionyl chloride (10.5 ml) was added to 1-benzyl-4-piperidinecarboxylic acid (4.85 g, 22.1 mmol), and the resulting mixture was refluxed for 2 hours. The reaction solution was distilled under reduced pressure to remove the solvent. To a solution of the resulting residue in methylene chloride (65 ml) were added 5-aminoindazole (4.41 g, 33.2 mmol), triethylamine (1.8 ml), pyridine (30 ml) and a catalytic amount of 4-dimethylaminopyridine at 0° C., and then stirred at room temperature for 3 hours. Then, the reaction solution was poured into a 1N-aqueous sodium hydroxide solution and extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol=20/1) to obtain 1-benzyl-N-(1H-indazol-5-yl)-4-piperidinecarboxamide (2.2 g, 30%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[NH2:16]>C(OCC)(=O)C>[CH3:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])[CH:17]=[C:18]([CH3:20])[CH:19]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: Cc1cc(C)cc(N)c1
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(Nc2cc(O)ccc2[N+](=O)[O-])c1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
5.4 g of 3-fluoro-4-nitrophenol and 4.3 ml of 3,5-dimethylaniline were mixed and stirred for 6 hours at 120° C. After cooling, it was taken up in ethyl acetate and water and extracted three times with 1N aqueous hydrochloric acid. The combined aqueous phases were extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, concentrated by evaporation in a vacuum, and the residue was crystallized.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:20]=[CH:19][C:18]3[N:17]([CH3:21])[C:16]4[CH2:22][CH:23]5[NH:27][CH:26]([C:15]=4[C:14]=3[C:13]=2C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[ClH:35]>C(OCC)C>[ClH:35].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[C:16]2[CH2:22][CH:23]4[NH:27][CH:26]([C:15]3=2)[CH2:25][CH2:24]4)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(S(=O)(=O)c2ccc3c(c2C(=O)OC(C)(C)C)c2c(n3C)CC3CCC2N3)c1
Agent: Cl
Solvent: CCOCC
Product: COc1cccc(S(=O)(=O)c2ccc3c(c2)c2c(n3C)CC3CCC2N3)c1

Procedure:
The product of step A was subjected to Boc-deprotection with 2 M HCl in diethyl ether following the procedure of Example 28, step B. The crude material was purified by flash column chromatography (SiO2, 95:5 dichloromethane/methanol). The free base was dissolved in methanol (0.5 mL) and treated with 1.25 M HCl in methanol (1.5 mL). The solution was concentrated in vacuo to give 2-(3-methoxyphenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole hydrochloride (19 mg, 85%, AUC HPLC >99%) as an off-white solid: mp 186-190° C.; 1H NMR (CD3OD, 300 MHz) δ 8.27 (d, J=1.8 Hz 1H), 7.73 (dd, J=8.7, 1.8 Hz, 1H), 7.58 (d, J=8.7 Hz, 1H), 7.41-7.51 (m, 3H), 7.10-7.17 (m, 1H), 5.30 (d, J=4.8 Hz, 1H), 4.51-4.58 (m, 1H), 3.82 (s, 3H), 3.70 (s, 3H), 3.48 (dd, J=17.4, 4.5 Hz 1H), 2.25-2.47 (m, 3H), 2.16-2.23 (m, 1H), 1.94-2.23 (m, 1H). ESI MS m/z 383 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:27][CH2:26][N:25]4[C@H:20]([CH2:21][O:22][CH2:23][CH2:24]4)[CH2:19]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>CCOC(C)=O.[Pd]>[CH2:21]1[C@@H:20]2[CH2:19][N:18]([CH:15]3[CH2:14][CH2:13][N:12]([C:5]4[CH:6]=[CH:7][C:8]([NH2:9])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH2:17][CH2:16]3)[CH2:27][CH2:26][N:25]2[CH2:24][CH2:23][O:22]1
Reactant: COc1cc(N2CCC(N3CCN4CCOC[C@@H]4C3)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(N2CCC(N3CCN4CCOC[C@@H]4C3)CC2)ccc1N
Reaction time: 8 h
Yield: 88.9 %

Procedure:
To (9aS)-8-{1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinyl}octahydropyrazino[2,1-c][1,4]-oxazine (0.516 g, 1.35 mmol) in EtOAc (50 mL) was added Pd on carbon. The mixture was stirred under H2 (1 atm) overnight. The mixture was filtered through Celite® to provide the title compound of step I (0.417 g, 1.20 mmol, 89%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44-1.56 (m, 2H), 1.77-1.88 (m, 2H), 2.10-2.22 (m, 2H), 2.42 (s, 4H), 2.48 (s, 5H), 2.58 (d, J=12.1 Hz, 1H), 2.69 (d, J=9.9 Hz, 1H), 3.04 (t, J=10.4 Hz, 1H), 3.37-3.47 (m, 3H), 3.59 (d, J=11.4 Hz, 1H), 3.66-3.73 (m, 5H), 6.25 (dd, J=8.3, 2.1 Hz, 1H), 6.43-6.51 (m, 2H).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:27])[C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[C:17]([N+:24]([O-])=O)[CH:16]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:28]1([C:34]2[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[O:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:15]3[CH:20]=[CH:19][C:18]4[NH:21][C:38]([C:37]5[CH:36]=[CH:35][C:34]([N:28]6[CH2:33][CH2:32][O:31][CH2:30][CH2:29]6)=[CH:41][CH:40]=5)=[N:24][C:17]=4[CH:16]=3)=[O:27])=[CH:9][CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Reactant: O=C(Nc1ccc(N2CCOCC2)cc1)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Product: O=C(Nc1ccc(N2CCOCC2)cc1)c1ccc2[nH]c(-c3ccc(N4CCOCC4)cc3)nc2c1

Procedure:
Compound 211 was prepared according to the procedure similar to that described in Scheme III from N-(4-morpholinylphenyl)-3,4-dinitrobenzamide and 4-morpholinylbenzaldehyde. [M+H]+ calcd for C28H29N5O3: 484.23; found: 483.92.
Reaction SMILES: BrC1C(OC)=C(C=CC=1C[S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1C)C(OCC)=O.[Br:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:35]Br)=[C:29]([CH:34]=1)[C:30]([O:32][CH3:33])=[O:31].C1(S)C=CC=CC=1>>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:35][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:29]([CH:34]=1)[C:30]([O:32][CH3:33])=[O:31]
Reactant: CCOC(=O)c1ccc(CSc2ccccc2C)c(Br)c1OC
Reactant: COC(=O)c1cc(Br)ccc1CBr
Agent: Sc1ccccc1
Product: COC(=O)c1cc(Br)ccc1CSc1ccccc1

Procedure:
Prepared by proceeding in a similar manner to Intermediate 77, starting from methyl 5-bromo-2-bromomethylbenzoate (prepared according to Lartia et al, J Org Chem, 2008, 73, 1732) and thiophenol.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]([CH2:14][CH2:15][CH2:16][N:17]=[C:18]=[S:19])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:22]1([C:28]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:29]2[CH:33]=[C:32]([CH2:34][CH2:35][CH2:36][NH2:37])[N:31]=[CH:30]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[C:44]1([C:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:29]2[CH:33]=[C:32]([CH2:34][CH2:35][CH2:36][NH:37][C:18]([NH:17][CH2:16][CH2:15][CH2:14][N:7]([CH2:6][C:5]3[CH:20]=[CH:21][C:2]([Br:1])=[CH:3][CH:4]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)=[S:19])[N:31]=[CH:30]2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: S=C=NCCCN(Cc1ccc(Br)cc1)c1ccccn1
Reactant: NCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: ClC(Cl)Cl
Product: S=C(NCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NCCCN(Cc1ccc(Br)cc1)c1ccccn1
Yield: 78.9 %

Procedure:
N-(4-bromobenzyl)-N-(3-isothiocyanatopropyl)-N-(pyridin-2-yl)amine(1 g, 2.76 mmol) and 3-(1-triphenylmethylimidazol-4-yl)propylamine (1.014 g, 2.76 mmol) were dissolved in chloroform (10 ml) and heated at reflux for 4 h. The solvent was removed by evaporation in vacuo and the residue (3.09 g) purified by column chromatography on silica gel (400 ml) using ethyl acetate/methanol/triethylamine 9:0.5:0.5 as eluent affording 1.59 g (80%) of pure 1-[3-(1-triphenylmethylimidazol-4-yl)propyl]-3-[3-[N-(4-bromobenzyl)-N-(pyridin-2-yl)amino]propyl]thiourea.
Reaction SMILES: [Na].[NH2:2][C:3]1[C:12]2[N:11]=[CH:10][C:9](=[O:13])[N:8]([C@@H:14]3[O:28][C@H:27]([CH2:29][O:30]C(=O)C4C=CC(Cl)=CC=4)[C@@H:16]([O:17]C(=O)C4C=CC(Cl)=CC=4)[CH2:15]3)[C:7]=2[N:6]=[C:5]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:4]=1.CC(O)=O>CO>[NH2:2][C:3]1[C:12]2[N:11]=[CH:10][C:9](=[O:13])[N:8]([C@@H:14]3[O:28][C@H:27]([CH2:29][OH:30])[C@@H:16]([OH:17])[CH2:15]3)[C:7]=2[N:6]=[C:5]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:4]=1
Reactant: Nc1nc(-c2ccccc2)nc2c1ncc(=O)n2[C@H]1C[C@H](OC(=O)c2ccc(Cl)cc2)[C@@H](COC(=O)c2ccc(Cl)cc2)O1
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1nc(-c2ccccc2)nc2c1ncc(=O)n2[C@H]1C[C@H](O)[C@@H](CO)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a solution of 10 mg of sodium in 50 mL of anhydrous methanol was added 0.632 g (1 mmol) of 4-amino-2-phenyl-8-[2-deoxy-3,5-di-O-(4-chlorophenyl)-βD-ribofuranosyl]pteridine-7-one (4). The solution was stirred at room temperature for 1 hour. The solution was then neutralized by the addition of AcOH and then evaporated. The residue was recrystallized from methanol / H2O to give 5 as 0.323 g (91% yield) of colorless crystals (m.p. 169°-172° C.).
Reaction SMILES: [Br:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:6](=[O:25])[NH:5][C:4]=2[CH:3]=1.Cl[CH2:27][C:28]1[O:32][N:31]=[C:30]([CH2:33][O:34][CH3:35])[N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][CH2:13]3)[C:6](=[O:25])[N:5]([CH2:27][C:28]3[O:32][N:31]=[C:30]([CH2:33][O:34][CH3:35])[N:29]=3)[C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(Br)sc3c2=O)CC1
Reactant: COCc1noc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(Br)cc32)n1

Procedure:
According to the procedure describe for compound B99 of tert-butyl 4-(6-bromo-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (10.00 g; compound B53) is reacted with 5-(chloromethyl)-3-(methoxymethyl)-1,2,4-oxadiazole (3.78 g, D14) in the presence of potassium carbonate (3.21 g) in DMF (93 ml) to afford the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5](I)=[CH:4][CH:3]=1.[CH:11]1(B(O)O)[CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([CH:11]2[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: COc1nc(Br)ccc1I
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1nc(Br)ccc1C1CC1
Temperature: 110 °C
Reaction time: 4.5 h
Yield: 107.6 %

Procedure:
Palladium acetate (36 mg) was added to a suspension of 6-bromo-3-iodo-2-methoxypyridine (1.0 g), cyclopropylboronic acid (547 mg), triphenylphosphine (84 mg) and potassium carbonate (1.32 g) in toluene (20 mL) and water (1 mL), and the mixture was stirred at 110° C. for 4.5 hours. Water and ethyl acetate were added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1→96:4) to give the title compound as a colorless oil (782 mg).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.[NH2:8][C:9]1[N:10]=[C:11]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[N:21]=2)=[N:13][C:14]=1Br.O>C(Cl)(Cl)Cl.CC(C)=O>[NH2:8][C:9]1[N:10]=[C:11]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:12]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[N:21]=2)=[N:13][C:14]=1[N:3]1[CH:7]=[CH:6][CH:5]=[N:4]1
Reactant: CC(C)n1nc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)n1nc(-c2nc(-n3cccn3)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 27.5 °C
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
To a suspension of NaH (60% in oil suspension) (23.3 mg) in 1,2-dimethyl-2-imidazolidinone (0.3 ml) was added 1H-pyrazole (42.3 mg) and the mixture was stirred at 25-30° C. for 30 minutes. After addition of 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (150 mg), the mixture was heated at 120-125° C. for 15 hours. To the reaction mixture was added water (3 ml) to give a precipitate. The precipitate was dissolved in CHCl3, dried over MgSO4 and concentrated under reduced pressure to give a solid. The solid was suspended in acetone and collected by filtration to give 6-[5-amino-3-phenyl-6-(1H-pyrazol-1-yl)-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (66 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@:9]([CH3:16])([CH:11]([O:14][CH3:15])[O:12][CH3:13])[C@@H:8]3[O:17][C@@H:7]3[C:6]=2[CH:18]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH2:27][C:28]2[N:29]=[N:30][N:31]([CH3:33])[N:32]=2)=[CH:22][CH:21]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@:9]([CH3:16])([CH:11]([O:14][CH3:15])[O:12][CH3:13])[C@H:8]([OH:17])[C@@H:7]([N:26]([C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)[CH2:27][C:28]3[N:29]=[N:30][N:31]([CH3:33])[N:32]=3)[C:6]=2[CH:18]=1
Reactant: Cn1nnc(CNc2ccc(Cl)cc2)n1
Reactant: COC(OC)[C@@]1(C)Oc2ccc(Br)cc2[C@H]2O[C@H]21
Product: COC(OC)[C@@]1(C)Oc2ccc(Br)cc2[C@H](N(Cc2nnn(C)n2)c2ccc(Cl)cc2)[C@H]1O
Yield: 17 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using (2S,3R,4R)-6-bromo-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran (192 mg, 0.61 mmol) and N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine (136 mg, 0.60 mmol). The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=1:2), to give desired compound (55 mg, yield: 17%).
Reaction SMILES: C(O[CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:29])[C:19]([C:23]3[N:24]=[C:25]([NH2:28])[S:26][CH:27]=3)=[N:20][O:21][CH3:22])[C:15](=[O:30])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=O)C.[C:31]([O-:34])(=[S:33])[CH3:32].[K+].P(O)(O)([O-])=O.[Na+].O>C(O)=O>[C:31]([S:33][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:29])[C:19]([C:23]3[N:24]=[C:25]([NH2:28])[S:26][CH:27]=3)=[N:20][O:21][CH3:22])[C:15](=[O:30])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:34])[CH3:32]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Reactant: CC([O-])=S
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSC(C)=O)CS[C@H]12)c1csc(N)n1
Reaction time: 0.08 h

Procedure:
A solution of the syn isomer of 4.55 g of 3-acetoxymethyl-7-[{2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl}amino]-ceph-3-eme-4-carboxylic acid, 1.7 g of potassium thioacetate, 2 g of deshydrated monosodium phosphate 1.05 g sodium acid carbonate and 20 ml of distilled water was heated at 70° C. for 90 minutes and the mixture was acidified with 2 ml of formic acid and was extracted 4 times with 60 ml of methyl acetate (insolubles vacuum filtered). The organic solution was washed with water and evaporated to dryness. The residue was dissolved in 20 ml of acetone containing 10% of water and 0.5 g of activated carbon were added thereto. The mixture was stirred for 5 minutes and was vacuum filtered and the filter was washed with acetone containing 10% of water. The filter was evaporated to dryness and the residue was treated with absolute ethanol and was vacuum filtered. The product was washed with alcohol and then with ether to obtain 1.9 g of the pure syn isomer of 3-acetylthiomethyl-7-[{2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl}amino]-ceph-3-eme-4-carboxylic acid which was identical to the product of Example 6.