Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C)C=O.[Cl:15][C:16]1[C:17]([CH3:38])=[C:18]([CH:27]2[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]2)[C:19]([O:25][CH3:26])=[C:20]([CH:22](O)[CH3:23])[CH:21]=1.O>C(Cl)Cl>[Cl:15][C:16]1[C:17]([CH3:38])=[C:18]([CH:27]2[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]2)[C:19]([O:25][CH3:26])=[C:20]([CH:22]([Cl:3])[CH3:23])[CH:21]=1
Reactant: COc1c(C(C)O)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(C(C)Cl)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
Cyanuric chloride (from Aldrich, 1.22 g, 6.62 mmol) was weighed into a flask and N,N-dimethylformamide (0.512 mL, 6.62 mmol) was added. After stirring for a few minutes a solution of tert-butyl 3-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]azetidine-1-carboxylate (1.5 g, 4.2 mmol) in methylene chloride (30 mL) was added. The resulting mixture was stirred at room temperature overnight. Water was added, and then diluted with dichloromethane. The layers were separated and the organics were washed with sat. NaHCO3 solution, water, brine, dried over MgSO4, and concentrated. The resulting residue was purified on silica gel, eluting with 0-35% EtOAc in hexanes to give the desired product (1.36 g, 86%). LCMS calculated for C13H17ClNO (M—Cl—Boc+H)+: m/z=238.1; Found: 238.1. 1H NMR (400 MHz, CDCl3): δ 7.46 (s, 1H), 5.44, (q, 1H), 4.32 (m, 2H), 4.18-4.10 (m, 3H), 3.67 (s, 3H), 2.27 (s, 3H), 1.79 (d, 3H), 1.44 (s, 9H) ppm.
Reaction SMILES: C1COCC1.[C:6]([C:10]1[CH:20]=[CH:19][C:13]([O:14][CH2:15][C:16]([OH:18])=O)=[CH:12][C:11]=1[Cl:21])([CH3:9])([CH3:8])[CH3:7].C1N=CN(C(N2C=NC=C2)=O)C=1.C(C1C=CC(OCC([NH:46][CH2:47][C:48]2[CH:57]=[CH:56][C:51]3[NH:52][C:53](=[O:55])[NH:54][C:50]=3[CH:49]=2)=O)=CC=1)(C)(C)C>C(N(CC)CC)C>[C:6]([C:10]1[CH:20]=[CH:19][C:13]([O:14][CH2:15][C:16]([NH:46][CH2:47][C:48]2[CH:57]=[CH:56][C:51]3[NH:52][C:53](=[O:55])[NH:54][C:50]=3[CH:49]=2)=[O:18])=[CH:12][C:11]=1[Cl:21])([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1Cl
Reactant: CC(C)(C)c1ccc(OCC(=O)NCc2ccc3[nH]c(=O)[nH]c3c2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(OCC(=O)NCc2ccc3[nH]c(=O)[nH]c3c2)cc1Cl
Reaction time: 2 h
Yield: 10.9 %

Procedure:
To a THF (3.0 ml) solution of the compound of 4A (109 mg, 0.45 mmol) was added CDI (73 mg, 0.45 mmol) at room temperature and the mixture was stirred for 2 hours followed by the additional stirring for 10 hours after the injection of triethylamine (0.3 ml) and the amine compound of Example 1 (156 mg, 0.5 mmol). The resulting precipitate was removed by filtration, followed by evaporation under reduced pressure to give the crude residue which was purified through silica gel column chromatography eluting with DCM/MeOH (9:1) to furnish the title compound as a white solid (19 mg, 11%). 1H NMR (CDCl3): δ 1.40 (9H, s), 4.29 (2H, d, J=5.9 Hz), 4.53 (2H, s), 6.78-6.92 (4H, m), 7.01 (1H, d, J=2.6 Hz), 7.37 (1H, d, J=8.5 Hz), 8.61 (1H, bt, J=6.6 Hz), 10.55, 1H, bs), 10.57 (1H, bs). MS (ESI) m/z 388 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:14]([O-])=O)[C:11]=1[NH:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6]>C(O)(=O)C.C(O)C.[Fe]>[NH2:14][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([Br:1])[C:11]=1[NH:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CNc1c(Br)cc(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: CNc1c(N)cc(C(=O)OC)cc1Br

Procedure:
Prepared analogously to example 91a from methyl 3-bromo-4-(methylamino)-5-nitrobenzoate using iron powder in acetic acid and ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[N+:18]([C:21]1[CH:30]=[C:29]([C:31]([NH:33][NH2:34])=[O:32])[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24])([O-:20])=[O:19]>>[N+:18]([C:21]1[CH:30]=[C:29]([C:31]([NH:33][N:34]=[C:15]([C:12]2[C:13]([OH:14])=[C:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[S:10][CH:11]=2)[CH3:17])=[O:32])[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24])([O-:20])=[O:19]
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: COC(=O)c1ccc(C(=O)NN)cc1[N+](=O)[O-]
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2csc(-c3ccc(Cl)c(Cl)c3)c2O)cc1[N+](=O)[O-]

Procedure:
Using 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (100 mg, 0.35 mmol) and methyl 2-nitro-4-hydrazinocarbonylbenzoate (93 mg, 0.39 mmol) as the starting materials, the desired product was obtained in the same manner as in Synthetic Example 65 as a yellow solid (147 mg, yield 83%)
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:6]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)=[N:7]2.[NH:26]1[CH:30]=[N:29][C:28]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[N:27]1.C(N(CC)CC)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:6]([C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:34]3[CH2:33][CH2:32][CH:31]([C:28]4[NH:29][CH:30]=[N:26][N:27]=4)[CH2:36][CH2:35]3)=[CH:14][CH:13]=1)=[N:7]2
Reactant: c1nc(C2CCNCC2)n[nH]1
Reactant: O=Cc1ccc(-c2nc3ccnc(Cl)c3cc2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Clc1nccc2nc(-c3ccc(CN4CCC(c5nnc[nH]5)CC4)cc3)c(-c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 9-1 (0.25 g, 0.73 mMol) and 21-1 (0.13 g, 0.87 mMol) in NMP (5 mL) was added triethylamine (0.3 mL, 2.2 mMol) followed by acetic acid (0.082 mL, 1.5 mMol). After stirring at ambient temperature overnight, sodium triacetoxyborohydride (0.18 g, 0.87 mMol) was added. Upon completion, the reaction was diluted with ethyl acetate and washed with saturated NaHCO3, followed by water, then brine. The organic layer was dried with Na2SO4 and MgSO4, filtered and concentrated in vacuo to yield 21-2. LC/MS (M+1) calculated: 482.0; observed: 482.2
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[CH3:15]O>>[CH3:1][CH:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:15])=[O:7]
Reactant: CO
Reactant: CC(C)CCCC(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)CCCC(C)C

Procedure:
The 5-methyl-caproic acid (30 g) was treated with methanol (600 ml) and sulfuric acid (3 ml), and thus methyl 5-methylcaproate was obtained. Yield: 27 g (81%).
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:41]O)[CH:19]=[C:20]([Cl:40])[C:21]=1[C:22]1[NH:23][C:24]2[C:30]3[CH:31]=[CH:32][N:33]=[CH:34][C:29]=3[NH:28][C:27]3[N:35]=[CH:36][CH:37]=[CH:38][C:26]=3[C:25]=2[N:39]=1.C(N(CC)CC)C.S(Cl)([Cl:52])=O>C1(C)C=CC=CC=1.CO>[Cl:15][C:16]1[CH:17]=[C:18]([CH2:41][Cl:52])[CH:19]=[C:20]([Cl:40])[C:21]=1[C:22]1[NH:23][C:24]2[C:30]3[CH:31]=[CH:32][N:33]=[CH:34][C:29]=3[NH:28][C:27]3[N:35]=[CH:36][CH:37]=[CH:38][C:26]=3[C:25]=2[N:39]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(Cl)c(-c2nc3c([nH]2)-c2ccncc2Nc2ncccc2-3)c(Cl)c1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: ClCc1cc(Cl)c(-c2nc3c([nH]2)-c2ccncc2Nc2ncccc2-3)c(Cl)c1
Reaction time: 0.08 h
Yield: 67.6 %

Procedure:
To a solution of [3,5-dichloro-4-(3,8-dihydroimidazo[4,5-d]dipyrido[2,3-b:4′,3′-f]azepin-2-yl)phenyl]methanol bis(trifluoroacetate) (20.0 g, 0.03 mmol) in toluene (1.0 mL) was added triethylamine (11 μL, 0.08 mmol) and stirred for 5 minutes, followed by the addition of thionyl chloride (5.0 μL, 0.06 mmol) at room temperature for 16 hours. The reaction mixture was diluted with methanol and purified by preparative LCMS at pH 10 to give the desired product (8.7 mg, 65%). LC/MS: 428 (M+H)+.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:12]=[N:11][S:10][N:9]=1)[C:5]([OH:7])=O.[NH2:13][CH:14]1[C:31](=[O:32])[N:16]2[C:17]([C:28]([OH:30])=[O:29])=[C:18]([CH2:21][S:22][C:23]3[S:24][CH:25]=[N:26][N:27]=3)[CH2:19][S:20][C@H:15]12>>[CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:12]=[N:11][S:10][N:9]=1)[C:5]([NH:13][CH:14]1[C:31](=[O:32])[N:16]2[C:17]([C:28]([OH:30])=[O:29])=[C:18]([CH2:21][S:22][C:23]3[S:24][CH:25]=[N:26][N:27]=3)[CH2:19][S:20][C@H:15]12)=[O:7]
Reactant: CON=C(C(=O)O)c1cnsn1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1cnsn1
Yield: 68.7 %

Procedure:
2-Methoxyimino-2-(1,2,5-thiadiazol-3-yl)acetic acid (syn isomer) (0.6 g.) and 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (1.16 g.) were reacted according to similar manners to those of Examples 12 and 15 to give 7-[2-methoxyimino-2-(1,2,5-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.10 g.), mp 111° to 120° C.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:19]2[CH2:21][CH:20]2[C:22](OCC)=[O:23])(=[O:11])=[O:10])=[CH:5][CH:4]=1>C1COCC1>[F:27][C:2]([F:1])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:19]2[CH2:21][CH:20]2[CH2:22][OH:23])(=[O:10])=[O:11])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1CC1c1ccccc1OS(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Product: O=S(=O)(Oc1ccccc1C1CC1CO)c1ccc(C(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
A solution of ethyl 2-[2-({[4-(trifluoromethyl)phenyl]sulfonyl}oxy)phenyl]-cyclopropanecarboxylate (0.84 g, 2.0 mmol) in THF (2 mL) is treated under an inert atmosphere with a 2 M solution of borane-methyl sulfide complex in THF (1 mL). The reaction is heated to 70° C. for 1 h, and stirred at room temperature overnight. The reaction is worked up by partitioning between ethyl acetate and 1 N HCl. The organic layer is dried and evaporated. The product, 2-[2-(hydroxymethyl)cyclopropyl]phenyl 4-(trifluoromethyl)benzenesulfonate, is obtained as a mixture of isomers. A yield of 93% is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][CH2:12][CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[H-].[Na+].CC([O:31][C@H:32]1[CH:36]=[CH:35][C@@H:34](O)[CH2:33]1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:35]2[CH2:36][C@H:32]([OH:31])[CH:33]=[CH:34]2)=[C:4]([NH:11][CH2:12][CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1
Reactant: Clc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Reactant: CC(=O)O[C@H]1C=C[C@@H](O)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Product: O[C@@H]1C=C[C@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2-Chloro-9H-purin-6-yl)-(2,2-diphenyl-ethyl)-amine (12.92 g, 36.97 mmol) is placed in an oven-dried flask under an atmosphere of argon. Dry deoxygenated THF (100 ml) and dry DMSO (2 ml) are added and the suspension is cooled on an ice-bath. Sodium hydride 95% (0.89 g, 36.97 mmol) is then slowly added and the solution is stirred at room temperature for 30 minutes. (1S,4R)-cis 4-Acetoxy-2-cyclopenten-1-ol (5.00 g. 35.20 mmol) and triphenylphosphine (1.38 g, 5.28 mmol) are placed in an oven-dried flask under an atmosphere of argon. Dry deoxygenated THF (50 ml) is added. This solution is added to the anion solution. Tetrakis(triphenylphosphine)palladium(0) (2.03 g, 1.76 mmol) is added and the reaction mixture is stirred at 50° C. The reaction is shown to be complete by LCMS after 3 hours. The reaction mixture is allowed to cool and the solvent is removed in vacuo. The residue is taken up in dichloromethane (50 ml) and poured into vigorously stirring diethyl ether (300 ml). The precipitate is filtered off, the filtrate is taken and the solvent is removed in vacuo to give the title compound. 1H nmr (CDCl3, 400 MHz); 7.65(m, 1H), 7.35-7.15(m, 10H), 6.35(m, 1H), 5.90(m, 1H), 5.80(m, 1H), 5.50(m, 1H), 5.25(d, 1H), 4.85(t, 1H), 4.35(t, 1H), 4.25(m, 2H), 2.95(m, 1H), 2.15(d, 1H), MS (ES+) m/e 432 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:20][C:21]([O:23][CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:22])[CH:18]=3)[N:13]([CH:29]([F:31])[F:30])[CH:12]=2)=[C:6]([O:32][CH3:33])[CH:5]=1.O1CCCC1.CO.O.[OH-].[Li+].Cl>O>[F:31][CH:29]([F:30])[N:13]1[C:14]2[C:19](=[CH:18][C:17]([NH:20][C:21]([O:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:22])=[CH:16][CH:15]=2)[C:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:34])=[O:2])=[CH:5][C:6]=2[O:32][CH3:33])=[CH:12]1
Reactant: COC(=O)c1ccc(Cc2cn(C(F)F)c3ccc(NC(=O)OC4CCCC4)cc23)c(OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Cc1cn(C(F)F)c2ccc(NC(=O)OC3CCCC3)cc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-[1-difluoromethyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid methylester (0.40 grams, 0.84 mmol) in a 5:5:2 ratio of methanol tetrahydrofuran:water (24 mL) was added lithium hydroxide monohydrate (0.18 grams, 4.18 mmol). The resulting solution was stirred for 24 hours at room temperature. The reaction mixture was then acidified with 1 M hydrochloric acid (aq) and extracted with ethyl acetate. The combined organics were washed with water and brine, then dried over sodium sulfate. Concentration in vacuo gave 4-[1-difluoromethyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid as a white solid (0.40 grams, 1005 yield). An analytical sample was attained by recrystallization from ethyl acetate/hexanes.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([C:8]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([S:24][CH3:25])[N:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].F[B-](F)(F)F.[C:37](P(C(C)(C)C)C(C)(C)C)(C)(C)[CH3:38].C(B1OC(C)(C)C(C)(C)O1)=C>O.O1CCOCC1>[CH2:37]([C:2]1[N:3]=[CH:4][C:5]2[N:6]([C:8]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([S:24][CH3:25])[N:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1)[CH3:38]
Reactant: CSc1nccc(-c2c(-c3ccc(F)cc3)nc3cnc(Cl)cn23)n1
Reactant: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: C=CB1OC(C)(C)C(C)(C)O1
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCc1cn2c(-c3ccnc(SC)n3)c(-c3ccc(F)cc3)nc2cn1
Temperature: 95 °C
Reaction time: 4 h
Yield: 625.5 %

Procedure:
6-Chloro-2-(4-fluorophenyl)-3-(2-methylsulfanylpyrimidin-4-yl)-imidazo[1,2-a]pyrazine, (Example #F.1.34, 0.25 g, 0.27 mmol), tris(dibenylideneacetone)dipalladium(0) (0.0306 g, 0.034 mmol), sodium carbonate (0.213 g, 2.0 mmol), and tri-t-butylphosphine tetrafluoroborate (Strem, 0.0194 g, 0.07 mmol) were combined in water (0.645 mL) and dioxane (3.35 mL). The reaction was degassed with nitrogen and vinylboronic acid pinacol ester (0.227 mL, 1.34 mmol) was added and the reaction heated at about 95° C. overnight. The reaction was poured onto a pad of silica gel and eluted with EtOAc. The EtOAc solution was washed with brine, dried over sodium sulfate, and concentrated. Ethanol (7.5 mL), EtOAc (7.5 mL), and 10% palladium on carbon (0.050 g) were added. The reaction was purged with hydrogen and stirred under a balloon of hydrogen for about 4 h. The reaction was filtered and concentrated. The residue was purified by FCC using 1:1 EtOAc/heptane and then triturated with heptane to provide the title compound (0.16 g, 65%) on drying: LC/MS (Table 1, Method b) Rt=2.52 min; MS m/z: 366.3 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[N:10]=[C:9]2[NH:11][CH:12]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]2=[C:7]([C:20]([F:23])([F:22])[F:21])[CH:6]=1.[CH3:24]I.[NH4+].[Cl-]>CN(C=O)C>[CH3:3][O:4][C:5]1[N:10]=[C:9]2[N:11]([CH3:24])[CH:12]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]2=[C:7]([C:20]([F:23])([F:21])[F:22])[CH:6]=1
Reactant: CI
Reactant: COc1cc(C(F)(F)F)c2c(-c3ccccc3)c[nH]c2n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1cc(C(F)(F)F)c2c(-c3ccccc3)cn(C)c2n1
Reaction time: 0.5 h
Yield: 94 %

Procedure:
NaH (15 mg, 0.38 mmol) was added to a stirred solution of 6-methoxy-3-phenyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (73 mg, 0.25 mmol) in DMF (3 ml) and the resulting mixture was stirred for 30 min. Then methyl iodide (0.06 ml, 0.99 mmol) was added and the mixture was stirred for additional 1 h. To the mixture saturated aqueous NH4Cl solution was added and the solution was extracted with EtOAc. The organic layer was washed with water and brine, filtered and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure. The crude product was purified by flash column chromatography (2% EtOAc in hexane) to yield the title compound (72 mg, 94%). [LCMS RtC=0.93 min; [M+H]+=307.0]
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:16]1[NH:17][C:18]2[CH:24]=[C:23]([C:25]([OH:27])=O)[CH:22]=[CH:21][C:19]=2[N:20]=1.[NH4+].[Cl-].C[N:31](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:16]1[NH:17][C:18]2[CH:24]=[C:23]([C:25]([NH2:31])=[O:27])[CH:22]=[CH:21][C:19]=2[N:20]=1
Reactant: COc1ncccc1-c1ccc(O)c(-c2nc3ccc(C(=O)O)cc3[nH]2)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncccc1-c1ccc(O)c(-c2nc3ccc(C(N)=O)cc3[nH]2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.4 %

Procedure:
To a mixture of 2-[2-hydroxy-5-(2-methoxy-pyridin-3-yl)-phenyl]-3H-benzoimidazole-5-carboxylic acid (containing 1 equivalent of DMA, 145 mg, 0.33 mmol), NH4Cl (160 mg, 3.0 mmol) and HATU (141 mg, 0.37 mmol) in DMF (2 mL) was added DIEA (0.52 mL, 388 mg, 3.0 mmol). The reaction mixture was stirred at room temperature for 3 h and heated at 60° C. for 15 h, and then evaporated under reduced pressure. The residue was purified by chromatography (333:10:1 CH2Cl2/MeOH/28% aqueous NH4OH) to afford the title compound (29 mg, 24%). 1H NMR (DMSO-d6) δ 3.94 (s, 3H), 7.11-7.17 (2H), 7.36 (br s, 1H), 7.64 (d, J=9 Hz, 1H), 7.67 (d, J=9 Hz, 1H), 7.83-7.88 (2H), 8.05 (br s, 1H), 8.19-8.21 (2H), 8.30 (s, 1H). ESI-MS m/z 361.3 (MH+).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8]C)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].B(Br)(Br)Br>ClCCl>[F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CCc1cccc(OC)c1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)CCc1cccc(O)c1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.8 %

Procedure:
To a solution of ethyl 3-(2-fluoro-3-methoxyphenyl)propanoate (2.50 g) in dichloromethane (50 mL) was added a 3.0 M solution of boron tribromide in dichloromethane (11 mL) at 0° C., and the mixture was stirred at room temperature for 15 hr. Ice water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (2.20 g) as a solid. This compound was used for the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[NH:8][C:9]1[C:14]([C:15](O)=[O:16])=[CH:13][N:12]=[C:11]([S:18][CH3:19])[N:10]=1.C[N:21](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].CCN(C(C)C)C(C)C>CN(C=O)C.O>[OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[NH:8][C:9]1[C:14]([C:15]([NH2:21])=[O:16])=[CH:13][N:12]=[C:11]([S:18][CH3:19])[N:10]=1
Reactant: CSc1ncc(C(=O)O)c(N[C@@H]2CCC[C@@H]2CO)n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(C(N)=O)c(N[C@@H]2CCC[C@@H]2CO)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.7 %

Procedure:
A white suspension of the 4-(cis-2-(hydroxymethyl)-cyclopentylamino)-2-(methylthio)pyrimidine-5-carboxylic acid (5.6 g, 19.76 mmol) and HATU (11.27 g, 29.60 mmol) were dissolved in DMF (79 mL) and stirred for 5 min at room temperature before adding ammonium chloride (5.29 g, 99 mmol) and DIEA (17.26 mL, 99 mmol). The reaction mixture was stirred at room temperature for 1 h and then diluted with water (200 mL) and extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated. The residual DMF was removed by suspending the white suspension in 200 mL water and 200 mL hexanes. The biphasic mixture was stirred vigorously for 30 min, filtered and washed with hexanes to afford 4-(cis-2-(hydroxyl-methyl)cyclopentylamino)-2-(methylthio)pyrimidine-5-carboxamide (4.50 g, 81% yield) as a white solid. MS (ESI) m/z 283.4 [M+1]+.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.[CH2:18]([O:20][C:21](=[O:28])[C@:22]([F:27])([CH3:26])[C:23](O)=[O:24])[CH3:19]>>[CH2:18]([O:20][C:21](=[O:28])[C@:22]([F:27])([CH3:26])[C:23]([NH:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2)=[O:24])[CH3:19]
Reactant: N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reactant: CCOC(=O)[C@@](C)(F)C(=O)O
Product: CCOC(=O)[C@@](C)(F)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21

Procedure:
In an analogous manner to that described in Example 1 a), the condensation of (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one and (2S)-2-fluoro-2-methyl-malonic acid mono ethyl ester (96.9% e.e.) yielded the title compound as a white solid; MS: m/e=371 (M+H)+. The (2S)-2-fluoro-2-methyl-malonic acid mono ethyl ester was obtained by stereoselective hydrolysis of the corresponding diester by Candida cylindracea hydrolase following the procedure described in J. Org. Chem. 1986, 51, 1003-6.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[N:12]1[CH:17]=CC=C[CH:13]=1.CNC>>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:12]([CH3:17])[CH3:13])=[O:8])=[CH:5][CH:4]=1
Reactant: c1ccncc1
Reactant: O=C(Cl)c1ccc(CBr)cc1
Agent: CNC
Product: CN(C)C(=O)c1ccc(CBr)cc1
Temperature: 23 °C
Reaction time: 15 h
Yield: 99.7 %

Procedure:
A mixture of 4-bromomethyl-benzoyl chloride (7.0 g, 30.24 mmol), polyvinyl pyridine (9.6 g, 90.7 mmol) and dimethyl amine (15.9 ml, 31.8 mmol, 2.0 M in THF) was stirred at 23° C. for 15 h. The solution was filtered and the solvent removed to give 7.3 g (99% yield) of 4-bromomethyl-N,N-dimethyl-benzamide as a yellow solid.