Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[N:15][C:14]([N:17]([CH2:19][CH2:20][O:21][CH3:22])[CH3:18])=[CH:13][N:12]=1)C1C=CC=CC=1>CO.C1COCC1.[Pd]>[CH3:22][O:21][CH2:20][CH2:19][N:17]([CH3:18])[C:14]1[CH:13]=[N:12][C:11]([NH2:10])=[CH:16][N:15]=1
Reactant: COCCN(C)c1cnc(NC(=O)OCc2ccccc2)cn1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COCCN(C)c1cnc(N)cn1
Reaction time: 1 h
Yield: 98.8 %

Procedure:
The above carbamic acid benzyl ester (316 mg, 1.0 mmol) was suspended in a mixture of methanol (25 mL) and THF (5 mL) containing 5% palladium on carbon (60 mg). The solution was placed under an atmosphere of hydrogen (hydrogen balloon) for one hour. The mixture was filtered through a thin layer of Celite and the solution was evaporated to give a green oil as N-(2-methoxyethyl)-N-methylpyrazine-2,5-diamine (180 mg, 100%). LCMS calcd for C8H14N4O (m/e) 182, obsd 183.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1.C(Cl)CCl>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:15][CH:12]2[CH2:14][CH2:13]2)=[O:8])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: NC1CC1
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1cc(Br)ccc1C(=O)NC1CC1
Reaction time: 8 h
Yield: 73.1 %

Procedure:
To a stirred solution of 4-bromo-2-methylbenzoic acid (300 g, 1.4 mol) in DCM (8.4 L) at rt was added cyclopropanamine (79.64 g, 1.4 mol) and EDC (320.9 g, 1.67 mol) in one portion. After stirring overnight, the solution was washed with water and the aqueous phase was reextracted with DCM. The combined organic phases were dried over sodium sulfate, filtered and evaporated. The remaining solid was triturated with diisopropyl ether, filtered, washed and dried in vaccuo to yield 260 g (73.4%) 4-bromo-N-cyclopropyl-2-methylbenzamide.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[F:17]>CS(C)=O.CCOC(C)=O>[F:17][C:9]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CCNCC2)c(F)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
To a warm solution of piperazine (7.78 g, 90 mmol) in DMSO (40 mL) was added dropwise 1,2-difluoro-4-nitrobenzene (2.0 mL, 18.07 mmol). The solution was stirred at 70° C. for 2 h, cooled to room temperature, diluted with EtOAc, washed with H2O, brine, dried (Na2SO4), filtered and solvent removed in vacuo to give the title compound (4.05 g, 17.98 mmol, 100%). 1H NMR (400 MHz, CDCl3) δ ppm 3.03-3.09 (m, 4H) 3.26-3.29 (m, 4H) 6.91 (t, J=8.8 Hz, 1H) 7.91 (dd, J=13.1, 2.6 Hz, 1H) 7.96-8.01 (m, 1H). MS (ESI) m/z 226 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[N+:14]([O-])=O)[C:9]#[N:10].CO.[H][H]>[Pd].O1CCOCC1>[NH2:14][C:13]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[NH:5][CH2:4][C:3]1[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=1[Cl:1]
Reactant: [H][H]
Reactant: N#Cc1ccc([N+](=O)[O-])c(NCc2ccccc2Cl)c1
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: N#Cc1ccc(N)c(NCc2ccccc2Cl)c1
Yield: 83.8 %

Procedure:
Fifty milligrams of 10% palladium on carbon were added to a mixed solution of 261 mg of 3-[N-(2-chlorobenzyl)amino]-4-nitrobenznitrile, 15 ml of methanol and 3 ml of 1,4-dioxane to conduct the catalytic reduction in a hydrogen atmosphere at 3 atm. After the completion of the reaction, the reaction solution was filtered through celite, and the filtrate was distilled off under reduced pressure. The resulting solid material was washed with ether, and was collected through filtration to give 196 mg of 4-amino-3-[N-(2-chlorobenzyl)amino]benznitrile.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:3]=1.C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CCOCC>[CH2:24]([O:23][C:21]([O:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:10])[Cl:11])[N:3]=1)=[O:22])[CH3:25]
Reactant: Cc1cc(O)nc(C(Cl)(Cl)Cl)n1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)Oc1cc(C)nc(C(Cl)(Cl)Cl)n1
Yield: 67 %

Procedure:
To a solution of 3.0 g (0.013 mole) 4-hydroxy-6-methyl-2-trichloromethylpyrimidine, 1.4 g (0.013 mole) triethylamine, and 75 ml ether was added 1.4 g (0.013 mole) ethyl chloroformate. The reaction mixture was refluxed for 2 hours, filtered, and rotary evaporated under aspiration to give a dark oil. This was triturated with petroleum ether and the solution decanted from tars. The solvent was stripped in vacuo and the product distilled to give 2.7 g (67% yield; bp0.5 mm 125° C.). The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([C:11]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=3[OH:18])=[N:8][C:7](=O)[C:6]=2[CH:20]=1.Cl.[CH3:22][N:23]([CH3:33])[C:24]1[CH:32]=[CH:31][C:27]([CH2:28][NH:29][NH2:30])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=3[OH:18])[N:29]([CH2:28][C:27]3[CH:31]=[CH:32][C:24]([N:23]([CH3:33])[CH3:22])=[CH:25][CH:26]=3)[N:30]=2)[CH:20]=1
Reactant: CN(C)c1ccc(CNN)cc1
Reactant: O=c1nc(-c2cc(Cl)ccc2O)oc2ccc(Cl)cc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)c1ccc(Cn2nc(-c3cc(Cl)ccc3O)nc2-c2cc(Cl)ccc2O)cc1

Procedure:
3.0 g of 6-chloro-2-(5-chloro-2-hydroxyphenyl)benz[e][1,3]oxazin-4-one are boiled under reflux for 4 h with 2.2 g of 4-dimethylaminobenzylhydrazine hydrochloride and 3 ml of triethylamine in 50 ml of ethanol. The crystals precipitating on cooling are washed with ethanol. After drying, 3,5-bis(5-chloro-2-hydroxyphenyl)-1-(4-dimethylaminobenzyl)-1H-[1,2,4]triazole remains as colorless crystals of m.p. 205-207 C.
Reaction SMILES: Cl[C:2]1[C:7]2=[CH:8][CH:9]=[CH:10][N:6]2[NH:5][C:4]([N:12]([CH3:14])[CH3:13])(N)[N:3]=1.[NH2:15][C:16]1[CH:21]=[C:20]([OH:22])[C:19]([CH3:23])=[CH:18][CH:17]=1>C(O)C>[CH3:14][N:12]([CH3:13])[C:4]1[N:3]=[C:2]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:23])=[C:20]([OH:22])[CH:21]=2)[C:7]2=[CH:8][CH:9]=[CH:10][N:6]2[N:5]=1
Reactant: Cc1ccc(N)cc1O
Reactant: CN(C)C1(N)N=C(Cl)c2cccn2N1
Solvent: CCO
Product: Cc1ccc(Nc2nc(N(C)C)nn3cccc23)cc1O
Temperature: 75 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
To a solution of 4-chloro-2-dimethylaminopyrrolo[2,1-f][1,2,4]triazin-2-amine (50 mg, 0.26 mmol) (Tetrahedron, 3037, 52, 1996, José Ma. Quintela, María J. Moreira and Carlos Peinador) in ethanol (2.5 mL) under argon was added 5-amino-o-cresol (35 mg, 0.28 mmol). The reaction mixture was stirred overnight at 75° C. Upon cooling, a solid precipitated which was recrystallized from warm ethanol to provide 52 mg (72%) of the title compound as white solid. MS: [M+H]+=284.2, ESI [M−H]−=282.1; 1H NMR (CDCl3): δ 7.52 (s, 1H), 7.13–6.98 (m, 4H), 6.58 (s, 1H), 3.15 (s, 6H), 2.19 (s, 3H).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[C:5]1([C:11]2([C:18]3[CH:27]=[C:26]([O:28][CH2:29][C:30]4[CH:39]=[CH:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:31]=4)[CH:25]=[CH:24][C:19]=3[C:20]([NH:22][NH2:23])=[O:21])[CH2:16][CH:15]3[CH2:17][CH:12]2[CH2:13][CH2:14]3)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[C:5]1([C:11]2([C:18]3[CH:27]=[C:26]([O:28][CH2:29][C:30]4[CH:39]=[CH:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:31]=4)[CH:25]=[CH:24][C:19]=3[C:20]3[O:21][C:1](=[S:2])[NH:23][N:22]=3)[CH2:16][CH:15]3[CH2:17][CH:12]2[CH2:13][CH2:14]3)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: S=C(Cl)Cl
Reactant: NNC(=O)c1ccc(OCc2ccc3ccccc3n2)cc1C1(c2ccccc2)CC2CCC1C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: S=c1[nH]nc(-c2ccc(OCc3ccc4ccccc4n3)cc2C2(c3ccccc3)CC3CCC2C3)o1
Reaction time: 0.75 h

Procedure:
Thiophosgene (10.0 μL, 0.13 mmol) was added to a stirred solution of 4d (0.11 mmol) in THF (900 μL) at −78° C. After approximately 45 min, the reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted three times with methylene chloride. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by preparative reversed phase HPLC on YMC Pack Pro C18 stationary phase (gradient elution; 0-75% acetonitrile/water as eluent, 0.1% TPA as modifier). Lyophilization of the purified fractions afforded the title compound 5a, m/z (ES) 506 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH2:15]([S:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O)[CH3:16].S(=O)(O)[O-].[Na+].C(=O)(O)[O-].[Na+]>O.CC(N(C)C)=O>[CH2:15]([S:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]1[NH:6][C:4](=[O:5])[C:3]2[C:2](=[CH:10][C:9]([C:11]([F:12])([F:13])[F:14])=[CH:8][CH:7]=2)[N:1]=1)[CH3:16]
Reactant: CCSc1ccccc1C=O
Reactant: NC(=O)c1ccc(C(F)(F)F)cc1N
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCSc1ccccc1-c1nc2cc(C(F)(F)F)ccc2c(=O)[nH]1
Temperature: 150 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A mixture of 1.0 g of 2-amino-4-trifluromethylbenzamide, 813 mg of 2-ethylsulfanylbenzaldehyde, 764 mg of sodium bisulfite and 4 ml of DMA was stirred at 150° C. for 8 hours. A saturated aqueous sodium bicarbonate solution and water were added to the cooled reaction mixture, and the precipitated solid was filtered. The resulting solid was washed with water and n-hexane and then dried to obtain 1.49 g of 2-(2-ethylsulfanylphenyl)-7-trifluoromethyl-3H-quinazolin-4-one.
Reaction SMILES: [N:1]1([C:6]2[O:10][C:9]3[C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:8]=3[C:7]=2[C:18](=[O:31])[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH:5]=NC=N1.N1C=[CH:35][CH:34]=[CH:33]1>>[N:1]1([C:6]2[O:10][C:9]3[C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:8]=3[C:7]=2[C:18](=[O:31])[C:19]2[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=2)[CH:35]=[CH:34][CH:33]=[CH:5]1
Reactant: c1cc[nH]c1
Reactant: COc1cc(C(=O)c2c(-n3cncn3)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Product: COc1cc(C(=O)c2c(-n3cccc3)oc3c(O)c(OC)ccc23)cc(OC)c1OC

Procedure:
This material was prepared in a similar manner as 2-(1,2,4-triazol-1-yl)-7-hydroxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzo[b]furan (entry 43, Table 1), above, using pyrrole in place of 1,2,4-triazole as the nucleophile. 1H NMR (300 MHz, CDCl3) δ 8.47 (d, 1H, J=1.21 Hz), 7.75 (d, 1H, J=1.20 Hz), 7.27 (d, 1H, J=8.60 Hz), 7.18 (d, 1H, J=8.66 Hz), 7.05 (s, 2H, benzoyl Hs), 3.94 (s, 3H, OMe), 3.74 (s, 6H, 2×OMe), 3.73 (s, 3H, OMe).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[CH:13][C:12]=1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:30]>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:26])[N:10]([C:11]1[CH:16]=[CH:15][C:14]([O:17][Si:18]([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:19])[CH3:20])=[CH:13][C:12]=1[CH3:25])[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: Cc1cc(O[Si](C)(C)C(C)(C)C)ccc1NC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(O[Si](C)(C)C(C)(C)C)ccc1N(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
To a 0° C. solution of [4-(tert-butyl-dimethyl-silanyloxy)-2-methyl-phenyl]-carbamic acid benzyl ester (18 g, 48.5 mmol) in DMF (100 mL) is added sodium hydride (60% dispersion in oil, 2.3 g, 58 mmol) portionwise. The reaction mixture is stirred at room temperature for 30 minutes, followed by the addition of iodomethane (8.2 g, 58 mmol). The mixture is stirred at room temperature overnight. The solvent is removed under reduced pressure to give a residue, which is partitioned between EtOAc (100 mL) and water (100 mL). The organic phase is washed with brine (100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography to give [4-(tert-Butyl-dimethyl-silanyloxy)-2-methyl-phenyl]-methyl-carbamic acid benzyl ester as oil (14.0 g, 75%). LC-ES/MS: 386.0 (M+1).
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][N:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:12][CH2:13][C:14](=O)[CH2:15]Cl>COCCOC.CCO>[Cl:12][CH2:13][C:14]1[N:11]=[C:6]2[N:7]([CH:15]=1)[CH:8]=[CH:9][C:10]1[N:1]=[CH:2][CH:3]=[CH:4][C:5]2=1
Reactant: Nc1nccc2ncccc12
Reactant: O=C(CCl)CCl
Solvent: CCO
Solvent: COCCOC
Product: ClCc1cn2ccc3ncccc3c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
To a solution of 1,6-naphthyridin-5-amine (145 mg, 1 mmol) in 1,2-dimethoxyethane (5 mL) was added 1,3-dichloropropan-2-one (140 mg, 1.1 mmol). The solid dissolved immediately and a white precipitate was observed. The mixture was stirred at room temperature for 1 h, and then was cooled to 0° C. for 20 min. The resulting mixture was filtered to give a white solid. The precipitate was suspended in EtOH (40 mL) and heated at reflux. After refluxing for 2 h, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in water and saturated aqueous NaHCO3 solution was added to adjust the pH value to 7. A white suspension formed during the course of addition. The resulting mixture was stirred for 20 min and then filtered to give 2-(chloromethyl)imidazo[2,1-f][1,6]naphthyridine as a white solid (130 mg). MS (ESI): m/z 218 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][NH:13][C:14]([CH:16]1[CH2:20][CH2:19][O:18][CH2:17]1)=O.O=S(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:6])[N:13]([CH3:12])[C:14]([CH:16]3[CH2:20][CH2:19][O:18][CH2:17]3)=[N:1]2)=[CH:7][CH:8]=1
Reactant: Nc1cc(Br)ccc1C(=O)O
Reactant: CNC(=O)C1CCOC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cn1c(C2CCOC2)nc2cc(Br)ccc2c1=O
Temperature: 80 °C
Reaction time: 5 h

Procedure:
The mixture of 2-amino-4-bromobenzoic acid (349 mg, 1.62 mmol), N-methyltetrahydrofuran-3-carboxamide (190 mg, 1.47 mmol), SOCl2 (0.13 mL, 1.76 mmol) and toluene (10 mL) was stirred at 80° C. for 5 h, and Na2CO3 aqueous solution was added after the mixture was cooled to room temperature. The water layer was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over Na2SO4, filtered, and evaporated to give the desired product, which was directly used for the next step. MS (ESI): 309, 311 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11](C(OC(C)(C)C)=O)[CH:12]=2)=[CH:4][CH:3]=1.Cl[C:21]1[CH:26]=[C:25]([C:27]2[CH:28]=[CH:29][C:30]([O:35][CH:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[C:31]([CH:34]=2)[C:32]#[N:33])[CH:24]=[CH:23][N:22]=1>>[NH:11]1[CH:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:23]3[CH:24]=[C:25]([C:27]4[CH:28]=[CH:29][C:30]([O:35][CH:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[C:31]([CH:34]=4)[C:32]#[N:33])[CH:26]=[CH:21][N:22]=3)=[N:7][CH:6]=2)[CH:9]=[N:10]1
Reactant: N#Cc1cc(-c2ccnc(Cl)c2)ccc1OC1CCOCC1
Reactant: CC(C)(C)OC(=O)n1cc(-c2ccc(N)nc2)cn1
Product: N#Cc1cc(-c2ccnc(Nc3ccc(-c4cn[nH]c4)cn3)c2)ccc1OC1CCOCC1
Yield: 16 %

Procedure:
85 mg of tert-butyl 4-(6-aminopyridin-3-yl)pyrazole-1-carboxylate are reacted with 100 mg of 5-(2-chloropyridin-4-yl)-2-(tetrahydropyran-4-yloxy)benzonitrile in accordance with the above-mentioned general procedure for the Buchwald-Hartwig reaction, giving the desired product in 16% yield;
Reaction SMILES: [NH2:1][CH:2]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([C:12]2[N:17]=[C:16]([C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[CH:15]=[CH:14][CH:13]=2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)[CH3:3].Cl[C:26]1[N:34]=[CH:33][N:32]=[C:31]2[C:27]=1[N:28]=[CH:29][N:30]2[CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1.COCCO.CCN(C(C)C)C(C)C>>[Cl:10][C:8]1[C:7]([CH3:11])=[C:6]([C:12]2[N:17]=[C:16]([C:18]([N:20]([CH3:21])[CH3:22])=[O:19])[CH:15]=[CH:14][CH:13]=2)[C:5]([O:23][CH3:24])=[C:4]([CH:2]([NH:1][C:26]2[N:34]=[CH:33][N:32]=[C:31]3[C:27]=2[N:28]=[CH:29][N:30]3[CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH3:3])[CH:9]=1
Reactant: COc1c(C(C)N)cc(Cl)c(C)c1-c1cccc(C(=O)N(C)C)n1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: COCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(C)c1-c1cccc(C(=O)N(C)C)n1
Temperature: 105 °C

Procedure:
The 6-{3-[1-aminoethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide (0.025 g, 0.072 mmol) was combined with 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.022 g, 0.14 mmol, from Example 176, Step 4) in 2-methoxyethanol (1.0 mL, 13 mmol) and DIPEA (0.037 g, 0.29 mmol) in a sealed tube. The reaction was heated to 105° C. in an oil bath for 18 hours. Without workup, the reaction was carried into the next step.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][O:18][CH3:19])[CH:11]=1.[I:20]I>C1COCC1>[I:20][C:11]1[C:12]([O:16][CH2:17][O:18][CH3:19])=[CH:13][CH:14]=[CH:15][C:10]=1[O:9][CH2:8][O:7][CH3:6]
Reactant: COCOc1cccc(OCOC)c1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1cccc(OCOC)c1I
Reaction time: 0.08 h
Yield: 79.6 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 0.22 mL, 0.56 mmol) was added to a solution of 12 (100 mg, 0.50 mmol) in anhydrous THF (790 μL) at 0° C. After 5 minutes, iodine (141 mg, 0.56 mmol) in anhydrous THF (320 μL) was added. After 2 hours at room temperature, the reaction was quenched via dropwise addition of MeOH and the solvent was concentrated. Water (5 mL) was added and the solution was extracted with EtOAc (3×10 mL). Combined organics were washed with saturated aqueous Na2S2O3, saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated to afford 15 as a brown oil (129 mg, 79%): 1H NMR (CDCl3, 100 MHz) 7.25-7.18 (m, 1H), 6.79-6.71 (m, 2H), 5.27 (s, 2H), 5.18 (s, 2H), 3.54 (s, 3H), 3.50 (s, 3H); IR (film) νmax 2953, 2924, 2853, 1458, 1377 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([S:18]([NH2:21])(=[O:20])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].N1C=CC=CC=1.Cl[C:43]([O:45][CH3:46])=[O:44].Cl>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([S:18]([NH:21][C:43](=[O:44])[O:45][CH3:46])(=[O:19])=[O:20])=[C:13]2[N:12]=[CH:11][C:10]=1[C:22]([N:24]1[CH2:25][CH2:26][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][CH2:29]1)=[O:23]
Reactant: COC(=O)Cl
Reactant: NS(=O)(=O)c1cnn2c(Nc3ccccc3Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)NS(=O)(=O)c1cnn2c(Nc3ccccc3Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Temperature: 0 °C
Reaction time: 48 h
Yield: 39.8 %

Procedure:
7-(2-Chlorophenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.070 g, 0.137 mmol) obtained in Example 6 step 5 was dissolved in dichloromethane (0.7 mL), and the solution was cooled to 0° C. Pyridine (0.325 g, 4.110 mmol) and methyl chloroformate (0.350 g, 3.699 mmol) were added, the mixture was stirred at room temperature for 48 hr, and 1 mol/L hydrochloric acid was added to quench the reaction. The organic layer was separated, and the aqueous layer was extracted twice with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=99/1) to give the title compound (0.031 g, 40%).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)([C:18]#[N:19])[CH:10]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)[NH:9]1)=[O:7])(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[Cl:33][C:29]1[CH:28]=[C:27]([CH:10]2[NH:9][CH:8]([C:6]([OH:7])=[O:5])[CH:12]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]2([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[C:18]#[N:19])[CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)CC1C(C(=O)OC(C)(C)C)NC(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1C(C(=O)O)NC(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 76 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-5-(3-Chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-3-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 32c (1.2 g, 2.5 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-5-(3-Chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-3-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a yellow solid (1.0 g, 76%).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:43]1[N:44]=[C:45]([NH:48]C=O)[S:46][CH:47]=1)[C:5]([NH:7][CH:8]1[C:41](=[O:42])[N:10]2[C:11]([C:25]([O:27][CH:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])=[C:12]([CH2:15][S:16][C:17]3[N:18]=[N:19][N:20]([CH2:22][C:23]#[CH:24])[N:21]=3)[CH2:13][S:14][C@H:9]12)=[O:6].Cl.O1CCCC1>CO>[CH3:1][O:2][N:3]=[C:4]([C:43]1[N:44]=[C:45]([NH2:48])[S:46][CH:47]=1)[C:5]([NH:7][CH:8]1[C:41](=[O:42])[N:10]2[C:11]([C:25]([O:27][CH:28]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:26])=[C:12]([CH2:15][S:16][C:17]3[N:18]=[N:19][N:20]([CH2:22][C:23]#[CH:24])[N:21]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: C#CCn1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)C(=NOC)c4csc(NC=O)n4)[C@H]3SC2)n1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: C#CCn1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)C(=NOC)c4csc(N)n4)[C@H]3SC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a mixture of benzhydryl 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-[2-(2-propynyl)-2H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylate (syn isomer) (2.7 g) in methanol (19.0 ml) were added conc. hydrochloric acid (0.75 g) and tetrahydrofuran (10 ml) and the mixture was stirred for 3 hours at room temperature. After the evaporation of the reaction mixture, to the residue were added water and ethyl acetate and then the resulting mixture was adjusted to pH 7.0 with a saturated aqueous solution of sodium carbonate. After the addition of tetrahydrofuran to the resulting mixture, the organic layer was separated, washed with a saturated aqueous solution of sodium chloride (×2), dried over magnesium sulfate and then evaporated. The residue was pulverized in isopropyl ether, collected by filtration, washed with isopropyl ether and then dried to give benzhydryl 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[2-(2-propynyl)-2H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylate (syn isomer) (2.0 g).