Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.[Br:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([CH:14]=1)C=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:14]=1[CH:1]=[CH2:2]
Reactant: O=Cc1cncc(Br)c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1ccncc1Br
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyltriphenylphosphonium bromide (2.97 g, 8.33 mmol) in THF (45 ml) at −78° C. was added n-butyllithium (2.5 M in hexanes, 2.7 mL, 6.75 mmol). The resulting yellow reaction mixture was stirred for 30 min at −78° C. In a separate flask THF (9 mL) was added to 5-bromonicotinaldehyde (CAS#113118-81-3, 837 mg, 4.5 mmol). The resulting 5-bromonicotinaldehyde solution was the transferred, via cannula, to the phosphonium ylide mixture followed by a 2 mL THF wash. The reaction was allowed to warm to room temperature over 120 minutes and then permitted to stir for an additional 30 minutes. The reaction was then quenched with saturated aqueous sodium bicarbonate and diluted with ethyl acetate. The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate. The organic layer was concentrated to near dryness and the resulting residue was then diluted with ethyl acetate and 1M sodium bisulfate and the layers were separated. The organic layer was extracted two additional times with 1M sodium bisulfate. The aqueous layers were combined, diluted with dichloromethane, and neutralized via the careful addition of saturated aqueous sodium bicarbonate and solid sodium carbonate. The layers were separated and the now basic aqueous layer was extracted three additional times with dichloromethane. The dichloromethane layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 0 to 16%) to furnish 3-bromo-4-vinyl-pyridine; MS: (ES+) m/z 183.9 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[CH2:10](O)[CH2:11][CH2:12][CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][CH2:12][CH3:13])=[C:4]([F:9])[CH:3]=1
Reactant: CCCCO
Reactant: Oc1ccc(Br)cc1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCOc1ccc(Br)cc1F
Reaction time: 8 h
Yield: 95.6 %

Procedure:
0.315 mol of each of 4-bromo-2-fluorophenol (1), 1-butanol and triphenylphosphine were dissolved in 1000 ml of tetrahydrofuran, and 0.315 mol of diisopropyl azodicarboxylate was added dropwise at about 20° C. After the mixture had been stirred overnight, the solvent was removed by distillation in a rotary evaporator, and the residue was subjected to conventional work-up, giving the compound (2) in a yield of 95.6% of theory.
Reaction SMILES: N1C=CC=CC=1.[C:7]([N:14]1[CH2:21][C@H:20]([OH:22])[CH2:19][C@@H:15]1[C:16]([OH:18])=[O:17])([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>ClCCl.[O-2].[Cr+6].[O-2].[O-2]>[C:7]([N:14]1[CH2:21][C:20](=[O:22])[CH2:19][C@@H:15]1[C:16]([OH:18])=[O:17])([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1C(=O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(=O)C[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6.1 12.2 g (122 mmol) of chromium(VI) oxide are added to a mixture, held at 0° C., of 22 ml of pyridine and 50 ml of dichloromethane, and the mixture is stirred at the same temperature for 30 minutes. The solution is allowed to warm to room temperature, and a solution of 5.00 g of cis-Boc-4-hydroxy-D-proline in 80 ml of dichloromethane is added dropwise over the course of 5 minutes. After stirring at room temperature for 1 hour, the solution is filtered, and the filtrate is evaporated. The residue is partitioned between 1N HCl and tert-butyl methyl ether. The organic phase is dried over sodium sulfate, evaporated and recrystallised from diethyl ether/petroleum ether, giving Boc-4-keto-D-proline as a colourless solid; ESI 130.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][CH3:10])[CH:5]=[N:6][CH:7]=1.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]([CH3:10])[C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CNCc1cncc(Br)c1
Reactant: O=C(Cl)c1ccccc1
Product: CN(Cc1cncc(Br)c1)C(=O)c1ccccc1
Yield: 87.4 %

Procedure:
In a manner similar to that of Example 2(f), starting with 0.5 g (3 mmol) of (5-bromopyrid-3-ylmethyl)methylamine and 0.4 ml (3.6 mmol) of benzoyl chloride, 0.8 g (90%) of N-(5-bromopyrid-3-ylmethyl) -N-methylbenzamide is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]1[O:15][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C[O-].[Na+].O>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:15])[CH2:14][O:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C1CO1
Reactant: COc1ccc(O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(OCC(O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Yield: 51.8 %

Procedure:
(S)-1-(tert-Butoxycarbonyl)-2-(1,2-epoxyethyl)pyrrolidine (10.0 g) was added to a mixed solution of p-methoxyphenol (11.64 g) and a solution of sodium methoxide in methanol (1M, 47 ml), and the mixture was stirred at 75° C. for 14 hours under heating. The reaction mixture was poured into water and extracted with toluene. The extract was washed with 10% sodium hydroxide and water in order, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to give the title compound (8.20 g).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[C:19]2[C:14](=[CH:15][C:16]([S:20]([N:23](CC3C=CC(OC)=CC=3OC)[C:24]3[S:28][N:27]=[CH:26][N:25]=3)(=[O:22])=[O:21])=[CH:17][CH:18]=2)[N:13]([CH3:40])[CH:12]=1>>[CH3:40][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[C:16]([S:20]([NH:23][C:24]3[S:28][N:27]=[CH:26][N:25]=3)(=[O:21])=[O:22])[CH:15]=2)[C:11]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:12]1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cn(C)c3c2)c(OC)c1
Reactant: OB(O)c1ccccc1
Product: Cn1cc(-c2ccccc2)c2ccc(S(=O)(=O)Nc3ncns3)cc21

Procedure:
The title compound was prepared in an analogous manner to that described in Example 28 using phenylboronic acid and 3-bromo-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, and the desired product, 1-methyl-3-phenyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, was isolated as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.88 (s, 3 H) 7.15-7.30 (m, 1 H) 7.43 (t, J=7.73 Hz, 2 H) 7.48-7.55 (m, 1 H) 7.61-7.68 (m, 2 H) 7.81 (d, J=4.47 Hz, 2 H) 7.85-7.89 (m, 2 H). m/z (ESI) 370.1 (M+H)+.
Reaction SMILES: [Sb](Cl)(Cl)(Cl)(Cl)Cl.[F:7][C:8]([F:22])([C:18]([F:21])([F:20])[F:19])[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([F:11])[F:10].[Br:23]Br.ClCl.S(=O)(O)[O-].[Na+]>O>[Br:23][C:14]1[CH:13]=[C:12]([C:9]([F:11])([F:10])[C:8]([F:22])([F:7])[C:18]([F:19])([F:20])[F:21])[CH:17]=[CH:16][CH:15]=1
Reactant: FC(F)(F)C(F)(F)C(F)(F)c1ccccc1
Reactant: BrBr
Agent: ClCl
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Agent: O=S([O-])O
Solvent: O
Product: FC(F)(F)C(F)(F)C(F)(F)c1cccc(Br)c1
Temperature: 26 °C

Procedure:
First meta-bromo(heptafluoropropyl)benzene is prepared as follows. 12 g (0.04 mole) of antimony pentachloride are added to 389 g (1.58 mole) of heptafluoropropylbenzene and then, with intensive stirring, 41 ml (0.79 mole) of bromine are added in drops within an hour with simultaneously cooling the reaction mixture on a water bath. The temperature of the reaction mixture is maintained at 26° C maximum. After adding all the bromine, the reaction mixture is given another stirring for 15 minutes. In the course of the entire bromination reaction, dry chlorine is passed into the reaction mixture at a rate of 3 liters per hour. On completion of the reaction, for binding the unreacted bromine, the reaction mixture is poured into 500 ml of water containing 25 ml of saturated solution of sodium bisulphite. The reaction product is distilled with steam, neutralized with a 5 percent solution of sodium hydroxide dried over calcined calcium chloride, and rectified. The yield of meta-bromo(heptafluoropropyl)benzene is 447.2 g (87 percent of theory).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]3[CH:25]=C[C:23](F)=[CH:22][CH:21]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC([N:34]1CCN(C2N=CC(Br)=CN=2)CC1)=O)(C)(C)C.B1(C2C=CC=NC=2)OCCCO1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[CH:16][C:17]([C:20]3[CH:25]=[N:34][CH:23]=[CH:22][CH:21]=3)=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Agent: c1cncc(B2OCCCO2)c1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3cccnc3)cn2)CC1
Yield: 99 %

Procedure:
Prepared according to the method for the preparation of 4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-carboxylic acid tert-butyl ester, from 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (0.403 g) and pyridine-3-boronic acid 1,3-propanediol cyclic ester (0.211 g), to yield the title compound as an orange solid (0.399 g, 99%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[C:11]([N+:18]([O-:20])=[O:19])[CH:10]=2)[CH2:4][CH2:3]1.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[C:47]1([C:53]2[CH2:54][CH2:55][N:56]([CH2:59][CH2:60][CH2:61][CH2:62][NH2:63])[CH2:57][CH:58]=2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.Cl>O.C(N(CC)CC)C.CN(C)C=O>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH:63][CH2:62][CH2:61][CH2:60][CH2:59][N:56]3[CH2:55][CH:54]=[C:53]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[CH2:58][CH2:57]3)=[O:15])=[C:11]([N+:18]([O-:20])=[O:19])[CH:10]=2)[CH2:6][CH2:7]1
Reactant: NCCCCN1CC=C(c2ccccc2)CC1
Reactant: CN1CCN(Cc2ccc(C(=O)O)c([N+](=O)[O-])c2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCN(Cc2ccc(C(=O)NCCCCN3CC=C(c4ccccc4)CC3)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 4-(4-methylpiperazin-1-ylmethyl)-2-nitrobenzoic acid (0.28 g), hydroxybenzotriazole (0.14 g) and dry dimethylformamide (5 ml) was added dicyclohexylcarbodiimide (0.21 g), and the mixture was stirred for 1 hour at room temperature. Then 4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butylamine hydrochloride (0.27 g) and triethylamine (0.20 g) were added and the stirring was continued for additional 1 hour. 1N Hydrochloric acid (2 ml) and water (20 ml) were added and the mixture was washed with ethyl acetate, adjusted to pH 8 with aqueous sodium bicarbonate solution and extracted with ethyl acetate (x2). The combined organic extracts were dried over magnesium sulfate and solvent was evaporated to give 4-(4-methylpiprazin-1-ylmethyl)-2-nitro-N-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]benzamide (0.21).
Reaction SMILES: NC1C=C(OC)C(F)=CC=1C(C1C=CC=CC=1Cl)=O.NC1C(C)=NN(CC=C)C=1Cl.[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]1[C:44]2[CH:45]=[C:46]([F:51])[C:47]([O:49][CH3:50])=[CH:48][C:43]=2[N:42]=[C:41]2[N:52](CC=C)[NH:53][C:54]([CH3:55])=[C:40]2[N:39]=1.[H-].C([Al+]CC(C)C)C(C)C>>[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]1[C:44]2[CH:45]=[C:46]([F:51])[C:47]([O:49][CH3:50])=[CH:48][C:43]=2[N:42]=[C:41]2[NH:52][NH:53][C:54]([CH3:55])=[C:40]2[N:39]=1
Reactant: C=CCN1NC(C)=C2N=C(c3ccccc3Cl)c3cc(F)c(OC)cc3N=C21
Agent: C=CCn1nc(C)c(N)c1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: COc1cc(N)c(C(=O)c2ccccc2Cl)cc1F
Product: COc1cc2c(cc1F)C(c1ccccc1Cl)=NC1=C(C)NNC1=N2

Procedure:
5-(2-chlorophenyl)-1,2-dihydro-7-fluoro-8-methoxy-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine (IVa) was prepared by reacting 0.0014 moles of (2-amino-5-fluoro-4-methoxyphenyl)(2-chlorophenyl)-methanone (Xa) with 4-amino-5-chloro-3-methyl-1-(2-propenyl)-1H-pyrazole (XIII), and subsequent dealkylation of the intermediate, 5-(2-chlorophenyl)-1,2-dihydro-7-fluoro-8-methoxy-3-methyl-1-(2-propenyl)-pyrazolo[3 ,4-b][1,4]benzodiazepine (XIVa) with diisobutylaluminum hydride in a manner analogous to Example 72. MH+/Z=357.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:12]1[CH:13]=[CH:14][C:15](=[O:21])[N:16]([CH:18]([CH3:20])[CH3:19])[N:17]=1)[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O=C1CCC(=O)N1[O:29][C:30](=O)[CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH:18]([N:16]1[C:15](=[O:21])[CH:14]=[CH:13][C:12]([CH:3]([NH:2][C:30](=[O:29])[CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])[C:4](=[O:11])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[N:17]1)([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Reactant: CC(C)n1nc(C(N)C(=O)c2ccccc2)ccc1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)n1nc(C(NC(=O)CNC(=O)OC(C)(C)C)C(=O)c2ccccc2)ccc1=O
Temperature: 22.5 °C
Reaction time: 18 h
Yield: 81.2 %

Procedure:
Under ice-cooling, to a suspension of 6-(1-amino-2-oxo-2-phenylethyl)-2-isopropyl-3(2H)-pyridazinone hydrochloride (1.00 g) and tert-butyl {2-[(2,5-dioxo-1-pyrrolidinyl)oxy]-2-oxoethyl}carbamate (973 mg) in CH2Cl2 (10 ml) was added ethyl(diisopropyl)amine (0.651 ml) and stirred at the same temperature for 2 hours and at 20-25° C. for 18 hours. The mixture was washed with water, dried over MgSO4 and concentrated under reduced pressure to give syrup. The syrup was purified by column chromatography on silica gel (EtOAc only) to give tert-butyl (2-{[1-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-oxo-2-phenylethyl]amino}-2-oxoethyl)carbamate as an amorphous solid (1.13 g).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C@@H:4]([C:12]([OH:14])=O)[NH:3]1.ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.Cl.Cl.[NH2:40][C@H:41]([C:48]([N:50]1[C@H:54]([C:55]([NH2:57])=[O:56])[CH2:53][S:52][CH2:51]1)=[O:49])[CH2:42][C:43]1[N:47]=[CH:46][NH:45][CH:44]=1.C(N(CC)CC)C>CN(C=O)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C@@H:4]([C:12]([NH:40][C@H:41]([C:48]([N:50]2[C@H:54]([C:55]([NH2:57])=[O:56])[CH2:53][S:52][CH2:51]2)=[O:49])[CH2:42][C:43]2[N:47]=[CH:46][NH:45][CH:44]=2)=[O:14])[NH:3]1
Reactant: O=C1N[C@H](C(=O)O)Cc2ccccc21
Reactant: NC(=O)[C@@H]1CSCN1C(=O)[C@@H](N)Cc1c[nH]cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)[C@@H]1CSCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1Cc2ccccc2C(=O)N1
Reaction time: 1.5 h
Yield: 43.9 %

Procedure:
Separately, (3S)-1-oxo-1,2,3,4-tetrahyroisoquinoline-3-carboxylic acid (70 mg, 0.36 mmole) and N-hydroxysuccinimide (41 mg, 0.36 mmole) are dissolved in DMF (5 ml) and thereto is added DCC (74 mg, 0.36 mmole) under ice-cooling. The mixture is stirred for 1.5 hours. To the solution of the activated ester thus prepared are added the (4R)-3-(L-histidyl)-thiazolidine-4-carboxamide dihydrochloride (150 mg, 0.4 mmole) prepared above and triethylamine (0.21 ml, 0.8 mmole) under ice-cooling. The mixture is stirred at 8° C. for 24 hours. The precipitated DCU is filtered off, and the filtrate is concentrated under reduced pressure. The residue is dissolved in water, and the solution is adjusted to pH 8 with sodium bicarbonate and is passed through a column (2.3×26 cm) packed with CHP-20P resin. The column is washed with water (500 ml) and further with 30% methanol (one liter), and then the product is eluted with 50% methanol. The fractions being positive to Pauly reagent are collected, distilled to remove methanol, and then lyophilized to give (4R)-3-{Nα -[(3S)-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carbonyl]-L-histidyl}-thiazolidine-4-carboxamide (70 mg, yield: 41.8%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[C:7]#[N:8].O.[BH4-].[Na+].Cl>C1COCC1.O.O.O.O.O.O.[Co](Cl)Cl>[Br:1][C:2]1[CH:9]=[C:6]([CH2:7][NH2:8])[CH:5]=[N:4][CH:3]=1
Reactant: N#Cc1cncc(Br)c1
Agent: Cl[Co]Cl
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: O
Product: NCc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
To the cobalt chloride hexahydrate (71 mg, 0.55 mmol) and 5-bromonicotinonitrile (Aldrich, 1 g, 5.5 mmol) in THF:water (19.5:9.25 ml) at 0° C., Sodium borohydride (416 mg, 11.0 mmol) was added in portions with intermittent cooling of the reaction mixture. Once all the sodium borohydride was added, the reaction mixture was stirred for RT for 2 h. Then the reaction mixture was acidified with 3N HCl and stirred at RT for 3.5 h. Then THF was removed under vacuum and the aqueous layer was extracted with ether and ethereal layer was discarded. Then aqueous layer was basified with aqueous NH4OH solution and extracted repeatedly with CHCl3 (3×100 ml). Organic layer was dried on anhydrous sodium sulfate and volatiles were removed under vacuum. Column chromatography (MeOH/CHCl3: 3/97) of the crude residue resulted in (5-bromopyridin-3-yl)methanamine in 25% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](Cl)(=[O:12])=[O:11])=[O:4].[NH2:14][C:15]1[O:19][N:18]=[C:17]([CH3:20])[C:16]=1[CH3:21]>N1C=CC=CC=1>[CH3:20][C:17]1[C:16]([CH3:21])=[C:15]([NH:14][S:10]([C:9]2[CH:8]=[CH:7][S:6][C:5]=2[C:3]([O:2][CH3:1])=[O:4])(=[O:12])=[O:11])[O:19][N:18]=1
Reactant: Cc1noc(N)c1C
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.5 %

Procedure:
2-Methoxycarbonylthiophene-3-sulfonyl chloride (2.50 g, 10.05 mmol) was added to a solution of 5-amino-3,4-dimethylisoxazole(0.98 g, 8.75 mmol) in dry pyridine (5.0 ml). The reaction mixture was stirred at room temperature for 16 h. Pyridine was removed under reduced pressure and the residue was partitioned between water and dichloromethane. The organic layer was washed with 1 N HCl (2×50 ml) and dried over anhydrous magnesium sulfate. Evaporation of the solvents left an oily residue, which, after purification by column chromatography over silica gel (1:1 hexanes/ethyl acetate as eluent), yielded 2.20 g (65%) of a brown solid. Further purification was achieved by recrystallization from ethyl acetate/hexanes, giving the pure product as a white solid, m.p. 113-116° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[N:10][N:11]([CH2:17][C:18]([O-:20])=O)[C:12]=2[C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:33]1C=CN=C1)=O.[OH-].[NH4+]>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:21]3[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=3)=[N:10][N:11]([CH2:17][C:18]([NH2:33])=[O:20])[C:12]=2[C:13]([F:14])([F:16])[F:15])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2nn(CC(=O)[O-])c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2nn(CC(N)=O)c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.9 %

Procedure:
To a solution of [4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (Example 10) (0.24 g, 0.54 mmol) in THF (6 mL) was added 0.10 g of 1,1'-carbonyldiimidazole at 25° C. under nitrogen. After gas evolution had ceased (approx. 30 minutes), 6 mL conc. ammonium hydroxide was added and the mixture stirred at 25° C. for 18 hours. The reaction mixture was diluted with water, extracted with two portions ethyl acetate and the organic layer washed successively with dilute aqueous HCl and brine, dried over MgSO4 and concentrated in vacuo. Recrystallization from chloroform/acetone gave [4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetamide as a white crystalline solid (0.15 g, 34%). Elemental analysis for C19H15N3F4SO3Calc'd: C, 51.70, H, 3.42, N, 9.52. Found: C, 51.46, H, 3.35, N, 9.39.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:18]=1[C:27]1[CH:28]=[CH:29][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:34])=[N:31][CH:32]=1)=O.[Cl:43][C:44]1[CH:49]=[CH:48][C:47]([C:50]2[CH:55]=[CH:54][C:53]([NH2:56])=[CH:52][CH:51]=2)=[CH:46][CH:45]=1.C([O-])([O-])=O.[K+].[K+]>CC(O)=O.C(Cl)Cl>[Cl:43][C:44]1[CH:45]=[CH:46][C:47]([C:50]2[CH:55]=[CH:54][C:53]([NH:56][CH2:15][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:18]=3[C:27]3[CH:28]=[CH:29][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:34])=[N:31][CH:32]=3)=[CH:52][CH:51]=2)=[CH:48][CH:49]=1
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2c(C=O)cccc2C(F)(F)F)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)c1ccc(-c2c(CNc3ccc(-c4ccc(Cl)cc4)cc3)cccc2C(F)(F)F)cn1
Temperature: 40 °C

Procedure:
Solid NaBH(OAc)3 (68 mg, 0.32 mmol) was added to a DCM solution (0.4 mL) of ethyl 3-(5-(2-formyl-6-(trifluoromethyl)phenyl)picolinamido)propanoate (50.8 mg, 0.13 mmol) and 4′-chloro-[1,1′-biphenyl]-4-amine (28.9 mg, 0.14 mmol), and AcOH (0.07 mL) and the resulting mixture was warmed to 40° C. After 45 min 5M aqueous K2CO3 was added and the resulting mixture was extracted with DCM. The combined organics were dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:10]2[C:5](=[CH:6][C:7]([C:11](OC)=[O:12])=[CH:8][CH:9]=2)[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:3]1.[OH-].[Na+].C(Cl)(=O)C(Cl)=O.[NH2:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1>CO.O1CCCC1.CN(C)C=O.N1C=CC=CC=1>[CH3:1][C:2]1([CH3:21])[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:39][CH:40]=3)=[O:12])=[CH:8][CH:9]=2)[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:3]1
Reactant: COC(=O)c1ccc2c(c1)C(c1ccccc1)=CC2(C)C
Reactant: COC(=O)c1ccc(N)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)C(c2ccccc2)=CC3(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
Methyl 1,1-dimethyl-3-phenyl-1H-indene-5-carboxylate (315 mg, 1.13 mmol) was stirred with 10N NaOH (1.1 mL, 11.0 mmol) in 5 mL of methanol and 10 mL of tetrahydrofuran at 60° C. for 1.5 hours. The solution was concentrated under reduced pressure and acidified with 1N HCl (15 mL), extracted with ethyl acetate (15 mL×3). The combined extracts were washed with water (10 mL), dried over magnesium sulfate, and evaporated. The residue was dried in vacuum and dissolved in 2.5 mL of methylene chloride. To the solution was added oxalyl chloride (348 mg, 2.74 mmol) and 2 drops of dimethylformamide at 0° C. The solution was stirred at 0° C. for 30 min and at room temperature for 30 min. The mixture was evaporated and dried in vacuum. The residue was stirred with methyl 4-aminobenzoate (181 mg, 1.32 mmol) in 2 mL of anhydrous pyridine for 18 hours. Excess pyridine was evaporated and the residue was diluted with 20 mL of 2N HCl, extracted with ethyl ether (30 mL×4). The combined extracts were washed with water (10 mL), dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography (EtOAc:hexane=1:20 to 1:5) to give 372 mg (85% yield) of the title compound as a glassy mass; 1H-NMR (CDCl3) δ 1.43 (s, 6H), 3.91 (s, 3H), 6.52 (s, 1H), 7.40-7.50 (m, 4H), 7.59-7.61 (m, 2H), 7.72-7.75 (m, 3H), 7.96 (s, 1H), 8.00 (bs, 1H), 8.05 (d, J=8.7 Hz, 2H); MS m/e 398 (MH+).