Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N[C:9]([O:11][CH2:12][CH3:13])=[O:10])C1C=CC=CC=1.[F:14][C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([F:35])[C:21]=1[C:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:24][CH:23]=1)[NH2:18].[Li]CCCC.[C:41](OC[C@@H]1OC1)(=[O:45])CCC>C1COCC1>[OH:45][CH2:41][C@@H:12]1[O:11][C:9](=[O:10])[N:18]([C:17]2[CH:19]=[C:20]([F:35])[C:21]([C:22]3[CH2:27][CH2:26][N:25]([CH2:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:24][CH:23]=3)=[C:15]([F:14])[CH:16]=2)[CH2:13]1
Reactant: CCCC(=O)OC[C@H]1CO1
Reactant: CCOC(=O)NCc1ccccc1
Reactant: Nc1cc(F)c(C2=CCN(Cc3ccccc3)CC2)c(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1O[C@@H](CO)CN1c1cc(F)c(C2=CCN(Cc3ccccc3)CC2)c(F)c1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
The benzylurethane from Reference Example 3 (5.54 g, 12.76 mmol ) in 50 ml dry THF was cooled to −70° C. under nitrogen and 8.80 ml of 1.6M nBuLi in hexanes (14.08 mmol ) added dropwise at the same temperature. After 20 minutes at the same temperature a solution of (R)-glycidyl butyrate (2.00 g, 13.88 mmol in 5 ml THF) was added dropwise and the mixture stirred for 30 minutes at −70° C., and then stirred to ambient temperature overnight. After quenching with 100 ml 10% ammonium chloride, the mixture was extracted with EtOAc and usual work-up to give an oily solid, which was purified by flash chromatography (Merck C60 silica, 5% MeOH/dichloromethane eluant) to give a crystalline solid (4.40 g, 86%). MS: ESP+ (M+H)=401.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([CH2:39][CH:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)[C:36]([OH:38])=O)=[CH:31][C:30]=1[N+:45]([O-:47])=[O:46].[NH2:48][C:49]1[CH:54]=[CH:53][C:52]([Br:55])=[CH:51][N:50]=1>C(Cl)Cl>[Br:55][C:52]1[CH:53]=[CH:54][C:49]([NH:48][C:36](=[O:38])[CH:35]([C:32]2[CH:33]=[CH:34][C:29]([Cl:28])=[C:30]([N+:45]([O-:47])=[O:46])[CH:31]=2)[CH2:39][CH:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)=[N:50][CH:51]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Br)cn1)C(CC1CCCC1)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 56.8 %

Procedure:
A solution of triphenylphosphine (241 mg, 0.92 mmol) in methylene chloride (3 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (164 mg, 0.92 mmol). The reaction mixture was stirred at 0° C. for 10 min and then treated with 2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 64, 250 mg, 0.84 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-amino-5-bromopyridine (320 mg, 1.85 mmol). The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230–400 mesh, 3/1 hexanes/ethyl acetate) to afford N-(5-bromo-pyridin-2-yl)-2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-propionamide (216 mg, 57%) as a pale yellow solid: mp 128–130° C.; EI-HRMS m/e calcd for C19H19BrClN3O3 (M+) 451.0298, found 451.0300.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]([NH:16][C:17]2[NH:21][N:20]=[N:19][N:18]=2)=[O:15])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([CH3:12])=[C:7]([CH3:13])[CH:6]=2.[Na].[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][OH:27]>>[ClH:1].[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][O:27][C:2]1[C:3]([C:14]([NH:16][C:17]2[NH:21][N:20]=[N:19][N:18]=2)=[O:15])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([CH3:12])=[C:7]([CH3:13])[CH:6]=2
Reactant: CN(C)CCO
Reactant: Cc1cc2nc(Cl)c(C(=O)Nc3nnn[nH]3)nc2cc1C
Agent: [Na]
Product: Cc1cc2nc(OCCN(C)C)c(C(=O)Nc3nnn[nH]3)nc2cc1C
Product: Cl

Procedure:
3-Chloro-6,7-dimethyl-N(1H-tetrazol-5-yl)-2-quinoxalinecarboxamide (Example 14) (3 g) was added to a solution of sodium (0.46 g) in 2-dimethylaminoethanol (20 ml) and the mixture was heated at 100° in an atmosphere of nitrogen for 5.5 hours and evaporated. The residue was dissolved in water and the solution was acidified with dilute hydrochloric acid. The solid was crystallised from dimethylformamide and had m.p. 247°-248° (d) (15%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[NH:16][C:15]([C:17]3([CH3:21])[CH2:20][O:19][CH2:18]3)=[N:14][C:13]=2[CH3:22])=[CH:7][C:3]=1[C:4](O)=[O:5].CC1NC(C2C=C(C=CC=2C)C(O)=O)=C(C)N=1.Cl.[F:41][C:42]1([C:46]2[CH:53]=[CH:52][C:49]([C:50]#[N:51])=[CH:48][CH:47]=2)[CH2:45][NH:44][CH2:43]1.Cl.N1CC(C2C=CC(C#N)=CC=2)C1>>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[NH:16][C:15]([C:17]3([CH3:21])[CH2:20][O:19][CH2:18]3)=[N:14][C:13]=2[CH3:22])=[CH:7][C:3]=1[C:4]([N:44]1[CH2:43][C:42]([C:46]2[CH:47]=[CH:48][C:49]([C:50]#[N:51])=[CH:52][CH:53]=2)([F:41])[CH2:45]1)=[O:5]
Reactant: Cc1cc(C)c(-c2[nH]c(C3(C)COC3)nc2C)cc1C(=O)O
Reactant: N#Cc1ccc(C2(F)CNC2)cc1
Agent: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Agent: Cl
Agent: N#Cc1ccc(C2CNC2)cc1
Product: Cc1cc(C)c(-c2[nH]c(C3(C)COC3)nc2C)cc1C(=O)N1CC(F)(c2ccc(C#N)cc2)C1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5, except 2,4-dimethyl-5-(4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)benzoic acid (compound 175.4) was used in place of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7) and 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4) was used in place of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 459 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 11.73 (br, 1H), 7.95 (d, J=8.0 Hz, 2H), 7.76 (d, J=8.4 Hz, 2H), 7.25 and 7.24 (2 singlets, Ar—H, 1H), 7.19 and 7.16 (2 singlets, Ar—H, 1H), 4.94-4.86 (m, 2H), 4.57-4.35 (m, 6H), 2.36 and 2.34 (2 singlets, CH3, 3H), 2.29 and 2.19 (2 singlets, CH3, 3H), 2.14 and 2.00 (2 singlets, CH1, 3H), 1.67 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[C:10](=[O:19])[NH:9][N:8]=1.Br[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[C:30]([O:29][C:27]([CH2:26][N:9]1[N:8]=[C:7]([NH:6][CH2:5][C:4]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:2]([Cl:1])[CH:3]=2)[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[C:10]1=[O:19])=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1ccc(CNc2n[nH]c(=O)c3ccc(C#N)cc23)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2nn(CC(=O)OC(C)(C)C)c(=O)c3ccc(C#N)cc23)cc1Cl
Temperature: 80 °C
Reaction time: 4 h
Yield: 153.6 %

Procedure:
4-(3-Chloro-4-methoxybenzyl)amino-6-cyanol-1(2H)-phthalazinone (0.20 g) prepared in Example 21 was dissolved in 5 ml of N-methyl-2-pyrrolidinone, followed by the addition of 0.14 g of t-butyl bromoacetate and 0.24 g of potassium carbonate. The obtained mixture was stirred at 80° C. for 4 hours and poured into water, followed by extraction with ethyl acetate. The organic phase was washed with water twice and with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and freed from the solvent by vacuum distillation. The title compound (0.41 g) was obtained as a yellow crystal.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[CH:18]3[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]3)[CH:14]=1)[CH:7]=[CH:6]2.N.[Cl:22]CCl>>[ClH:22].[N:15]12[CH2:16][CH2:17][CH:18]([CH2:19][CH2:20]1)[C:13]([C:8]1[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=1)[CH:4]=[C:3]([OH:2])[CH:12]=[CH:11]3)=[CH:14]2
Reactant: ClCCl
Reactant: COc1ccc2cc(C3=CN4CCC3CC4)ccc2c1
Agent: N
Product: Cl
Product: Oc1ccc2cc(C3=CN4CCC3CC4)ccc2c1
Temperature: -10 °C
Reaction time: 48 h

Procedure:
A mixture of 3-(6-methoxy-naphthalen-2-yl)-1-aza-bicyclo[2.2.2]oct-2-ene (0.80 g, 2.10 mmol) and dichloromethane (25 ml) was cooled to −10° C. Borontribromide (10 eq) solved in dichloromethane (21.0 ml, 21.0 mmol) was added dropwise at −10° C. The mixture was allowed to stir for 48 h. Concentrated ammonia (20 ml) was added. The phases were separated and the aqueous phase was extracted with dichloromethane (2×20 ml). The combined organic phase was dried and evaporated. The free base of the title compound was precipitated to the hydrochloric acid salt by addition of hydrogen chloride solved in ethanol. Yield 20 mg (3%). Mp 227-230° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:12][CH:13]3[CH2:17][CH2:16][C:15](=[O:18])[NH:14]3)C(=O)[NH:10][C:5]2=[N:4][CH:3]=1.BrC1C(N)=NC=C(Br)N=1.Cl.NCC1NC(=O)CC1.C(N(C(C)C)CC)(C)C>CS(C)=O>[NH2:10][C:5]1[C:6]([NH:8][CH2:12][CH:13]2[NH:14][C:15](=[O:18])[CH2:16][CH2:17]2)=[N:7][C:2]([Br:1])=[CH:3][N:4]=1
Reactant: O=C1CCC(Cn2c(=O)[nH]c3ncc(Br)nc32)N1
Agent: Cl
Agent: NCC1CCC(=O)N1
Agent: Nc1ncc(Br)nc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Nc1ncc(Br)nc1NCC1CCC(=O)N1

Procedure:
6-Bromo-1-((5-oxopyrrolidin-2-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one. 3,5-Dibromopyrazin-2-amine (253 mg, 1 mmol), 5-(aminomethyl)pyrrolidin-2-one hydrochloride (150 mg, 1 mmol), diisopropylethylamine (0.5 mL), and dimethylsulfoxide (2 mL) were heated in a Biotage Emrys Optimizer microwave reactor at 150° C. for 2 h to afford crude 5-((3-amino-6-bromopyrazin-2-ylamino)methyl)pyrrolidin-2-one. MS (ESI) m/z 286.0 [M]+, 288.0 [M+2]+. 1,1′-Carbonyldiimidazole (243 mg, 1.5 mmol) was added to the reaction mixture and the solution was heated again in a Biotage Emrys Optimizer microwave reactor at 150° C. for 10 min. The product was purified by reverse-phase semi-preparatory HPLC (10-70% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). The product fractions were concentrated and then triturated with ether to give a white solid. MS (ESI) m/z 312.0 [M]+, 314.0 [M+2]+.
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>O>[NH:18]([C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccccc1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Agent: Cl
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Nc1ccccc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 4-Chloro-3-nitro-5-sulphamyl-benzoic acid (8.4 g), aniline (8.4 g), and water (40 ml) was stirred at 80° C for 2 hours. After the addition of 1N hydrochloric acid (50 ml) and cooling, the precipitated 4-anilino-3-nitro-5-sulphamyl-benzoic acid was collected by suction, washed with water, and recrystallized from aqueous ethanol. The melting point was 261°-262° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:30]=[CH:29][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:28])[C:15]([CH3:27])([CH2:24][CH2:25][CH3:26])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:31](Cl)([CH3:34])(=[O:33])=[O:32].N1C=CC=CC=1>CC(C)=O>[OH:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:27])([CH2:24][CH2:25][CH3:26])[C:14](=[O:28])[C:13]=1[C:8]1[NH:7][C:6]2[CH:29]=[CH:30][C:3]([NH:2][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Yield: 89.4 %

Procedure:
A solution of Example 32B (0.050 g, 0.112 mmol), mesyl chloride (0.035 mL, 0.447 mmol), and pyridine (0.073 mL, 0.893 mmol) in acetone (1.5 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give the desired product (0.049 g, 89%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([NH2:15])[CH2:13][NH2:14])=[CH:3][CH:2]=1.Cl.[CH2:17](OC=N)C.N>ClCCl>[NH:14]1[CH2:13][CH:12]([CH2:11][C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=2)[N:15]=[CH:17]1
Reactant: NCC(N)Cc1ccnc2ccccc12
Reactant: CCOC=N
Agent: Cl
Agent: N
Solvent: ClCCl
Product: C1=NC(Cc2ccnc3ccccc23)CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
To 3-Quinolin-4-yl-propane-1,2-diamine (0.080 g, 3.98 mmol) in 5 ml of dry dichloromethane, formimidic acid ethyl ester hydrochloride (0.174 g, 7.36 mmol) (Ohme, R. et al. Angew.Chem.Int.Engl.Ed. 1967, 6, 90.) was added. The reaction mixture was stirred overnight at room temperature. Aqueous ammonia (2 ml) was added to he reaction mixture and was partitioned between EtOAc (2×5 ml) and water. The organic layer was dried, filtered and concentrated to give 0.084 g (110%) of the product as a syrup.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:16][CH:17]=[CH:18][C:19]=3[NH:20][S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[CH:11][CH:10]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][OH:43])=[CH:37][CH:36]=1>COCCOC.CCO>[OH:43][CH2:42][CH2:41][C:38]1[CH:39]=[CH:40][C:35]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[S:16][CH:17]=[CH:18][C:19]=3[NH:20][S:21]([CH:24]([CH3:25])[CH3:26])(=[O:22])=[O:23])=[CH:13][CH:14]=2)=[CH:36][CH:37]=1
Reactant: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: OCCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(-c2ccc(CCO)cc2)cc1
Temperature: 92.5 °C
Reaction time: 1.5 h

Procedure:
Mix propane-2-sulfonic acid{2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-thiophen-3-yl}-amide (0.10 g), 0.1 equiv of tetrakis triphenylphosphine palladium (0), 2 equiv of 2M sodium carbonate aqueous solution in DME (2 mL) and EtOH(1 mL) and warm to 90-95° C. After warming two min, add 2-(4-bromo-phenyl)-ethanol (1.3 equiv) and stir at that temperature for 1.5 h. Evaporate solvents over Celite® and purify by silica gel Strata® cartridges eluting with hexanes-EtOAc gradient to give 0.041 g of the title compound. MS (ES+) (m/z): 402 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][O:8][C:9]2[C:10]([C:21]([O:23][CH3:24])=[O:22])=[N:11][C:12]([CH:19]=[CH2:20])=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)=[CH:5][CH:4]=1.[CH2:27]=O.[C:29]([NH:32][NH:33][CH3:34])(=[O:31])[CH3:30]>C1(C)C=CC=CC=1>[C:29]([N:32]1[CH:19]([C:12]2[N:11]=[C:10]([C:21]([O:23][CH3:24])=[O:22])[C:9]([O:8][CH2:7][C:6]3[CH:25]=[CH:26][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[C:18]3[C:13]=2[CH:14]=[CH:15][CH:16]=[N:17]3)[CH2:20][CH2:34][N:33]1[CH3:27])(=[O:31])[CH3:30]
Reactant: CNNC(C)=O
Reactant: C=O
Reactant: C=Cc1nc(C(=O)OC)c(OCc2ccc(OC)cc2)c2ncccc12
Solvent: Cc1ccccc1
Product: COC(=O)c1nc(C2CCN(C)N2C(C)=O)c2cccnc2c1OCc1ccc(OC)cc1
Temperature: 120 °C

Procedure:
A mixture of methyl 8-[(4-methoxybenzyl)oxy]-5-vinyl-[1,6]-naphthyridine-7-carboxylate (0.26 g, 0.73 mmol), paraformaldehyde (96 mg), and 1-acetyl-2-methylhydrazine (0.22 g, 2.45 mmol; J. Org. Chem. 1972, 37, 3608) in toluene (15 mL) was heated in an oil bath at 120° C. for 1.5 hour. The resulting mixture was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting first with a gradient of 0-5% methanol in ethyl acetate. Collection and concentration of appropriate fractions provided the title acetylpyrazolidine.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[CH:30]=O>>[CH3:20][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[CH2:30][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: Cn1c(C=O)cc2ccccc21
Product: Cn1c(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc2ccccc21

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1-methylindole-2-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(1-methylindol-2-yl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [N:1]1([C:7]2[O:12][C:11]([C:13]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:14]=3[S:15][C:16]3[CH:17]=[CH:18][C:19]([CH:27]=[O:28])=[CH:20][C:21]=3[CH2:22]4)=[CH:10][C:9](=[O:29])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([BH3-])#N.[Na+].C(O)(=O)C>C(O)C>[OH:28][CH2:27][C:19]1[CH:20]=[C:21]2[C:16]([S:15][C:14]3[C:13]([C:11]4[O:12][C:7]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)=[CH:8][C:9](=[O:29])[CH:10]=4)=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:17][CH:18]=1
Reactant: O=Cc1ccc2c(c1)Cc1cccc(-c3cc(=O)cc(N4CCOCC4)o3)c1S2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: O=c1cc(-c2cccc3c2Sc2ccc(CO)cc2C3)oc(N2CCOCC2)c1
Reaction time: 5 h
Yield: 84 %

Procedure:
To a suspension of 5-(6-Morpholin-4-yl-4-oxo-4H-pyran-2-yl)-9H-thioxanthene-2-carbaldehyde (2)(0.392 g, 0.97 mmol) in ethanol (7 mL) at room temperature was added sodium cyanoborohydride (121 mg, 1.93 mmol), followed by the addition of acetic acid (1 mL). After 5 hours, a second addition of acetic acid (1 mL) was made. After a further 12 hours, the excess borohydride was quenched with acetone. After evaporation in vacuo, saturated NaHCO3 was added, followed by extraction into dichloromethane. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The brown coloured solid was dried under vacuum at 50° C. to give the crude title compound (0.332 g, 84%) which was used without any further purification. m/z (LC-MS, ESP), RT=3.09 min, (M++1)=408.3
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[C@H:10]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:11]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[NH2:11][C@H:10]([C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:29])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1.[F:38][C:37]([C:35]([OH:41])=[O:36])([F:40])[F:39]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-Boc-L-tryptophan benzyl ester (0.5 g, 1.27 mmol) was dissolved in a solution of 20% TFA in CH2Cl2. The reaction mixture was stirred under nitrogen at room temperature for 30 min and evaporated to dryness. Trituration of the resulting oil with Et2O provided 7 as a white solid (quantitative yield). mp=143-145° C.; 1H NMR (CD3CN) 9.42 (br s, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.43 (d, J=8.2 Hz, 1H), 7.35 (m, 3H), 7.26 (m, 2H), 7.16 (m, 2H), 7.04 (t, J=7.9 Hz, 1H), 5.15 (d, J=12.3 Hz, 1H), 5.09 (d, J=12.3 Hz, 1H), 4.36 (t, J=6.2 Hz, 1H), 3.44 (d, J=6.2 Hz, 2H) ppm; 13C NMR (CDCl3) 170.1, 137.6, 136.0, 129.5, 129.4, 129.3, 128.1, 126.2, 122.9, 120.3, 119.1, 112.6, 107.5, 68.8, 54.4, 26.9 ppm; IR (KBr) 3412, 2840, 1742, 1673, 1498, 1205, 1137, 735 cm−1; HRMS calcd for C18H19N2O2 294.1368 found 294.1362.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:31]=[CH:30][C:8]2[N:9]=[C:10]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]45[CH2:29][CH:24]6[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]6)[CH2:21]4)[CH2:27]5)=[CH:16][CH:15]=3)[O:11][C:7]=2[CH:6]=1)=[O:4].[Br-].[Al+3].[Br-].[Br-].O.Cl>CSC.ClCCl>[C:20]12([C:17]3[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:10]4[O:11][C:7]5[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:31]=[CH:30][C:8]=5[N:9]=4)=[CH:15][CH:16]=3)[CH2:27][CH:26]3[CH2:28][CH:22]([CH2:23][CH:24]([CH2:25]3)[CH2:29]1)[CH2:21]2
Reactant: COC(=O)c1ccc2nc(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)oc2c1
Agent: Cl
Agent: [Al+3]
Agent: [Br-]
Solvent: ClCCl
Solvent: CSC
Solvent: O
Product: O=C(O)c1ccc2nc(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)oc2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 77.8 %

Procedure:
To a solution of 2-(4-adamantan-1-yl-phenoxymethyl)-benzoxazole-6-carboxylic acid methyl ester (110 mg, 0.26 mmol) in dimethyl sulfide (10 ml) and dichloromethane (10 ml) was added aluminum bromide (1.13 g, 4.22 mmol). The reaction mixture was stirred at room temperature for 2.5 h, after which water and 10% HCl were added. After stirring at room temperature for 1 h, the mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (CH2Cl2:MeOH=4:1) to give 2-(4-adamantan-1-yl-phenoxymethyl)-benzoxazole-6-carboxylic acid as a white solid (81.6 mg, 76.8% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[N:11]=[C:10]([NH:22][CH3:23])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[CH3:24][S:25][C:26]1[CH:31]=[CH:30][C:29](OB(O)O)=[CH:28][CH:27]=1>>[CH3:19][O:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][C:14]=1[O:20][CH3:21])[N:11]=[C:10]([NH:22][CH3:23])[N:9]=[C:8]2[C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:29]2[CH:30]=[CH:31][C:26]([S:25][CH3:24])=[CH:27][CH:28]=2)[CH:3]=1
Reactant: CSc1ccc(OB(O)O)cc1
Reactant: CNc1nc(-c2cncc(Br)c2)c2cc(OC)c(OC)cc2n1
Product: CNc1nc(-c2cncc(-c3ccc(SC)cc3)c2)c2cc(OC)c(OC)cc2n1
Yield: 105.2 %

Procedure:
Starting from 375 mg of 4-(5-bromo-3pyridyl)-6,7-dimethoxy-2-methylaminoquinazoline obtained in Example 76 and 225 mg of 4-methylthiophenylboric acid, 440 mg of the title compound was obtained as pale yellow crystals in the same manner as in Example 48.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([CH2:15][O:16][N:17]=[C:18]([C:41]1[N:42]=[C:43]([NH2:46])[S:44][CH:45]=1)[C:19]([NH:21][CH:22]1[C:39](=[O:40])[N:24]2[C:25]([C:36]([OH:38])=[O:37])=[C:26]([CH2:29][S:30][C:31]3[S:32][CH:33]=[N:34][N:35]=3)[CH2:27][S:28][C@H:23]12)=[O:20])=[O:14])(C)(C)C>C1(OC)C=CC=CC=1>[C:13]([CH2:15][O:16][N:17]=[C:18]([C:41]1[N:42]=[C:43]([NH2:46])[S:44][CH:45]=1)[C:19]([NH:21][CH:22]1[C:39](=[O:40])[N:24]2[C:25]([C:36]([OH:38])=[O:37])=[C:26]([CH2:29][S:30][C:31]3[S:32][CH:33]=[N:34][N:35]=3)[CH2:27][S:28][C@H:23]12)=[O:20])([OH:14])=[O:12]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(N)n1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Nc1nc(C(=NOCC(=O)O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)cs1
Yield: 82.5 %

Procedure:
Trifluoroacetic acid (4 ml.) was added under ice-cooling to a stirred suspension of 7-[2-t-butoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.0 g.) in anisole (1 ml.), and the resultant mixture was stirred for 70 minutes at ambient temperature. The reaction mixture was concentrated under reduced pressure and diethyl ether was added thereto. Precipitates were collected by filtration, washed with diethyl ether, dried, suspended in water (10 ml.) and then dissolved in a 10% aqueous solution of sodium hydroxide (pH 7-7.5). The solution was adjusted to pH 3.0 with 10% hydrochloric acid under ice-cooling and stirring and stirred for 30 minutes under ice-cooling. Precipitates were collected by filtration, washed with water and dried to give 7-[2-carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.75 g.).