Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([O:5][CH2:6][C:7]#[CH:8])(C)C.C([Mg]Br)C.[CH2:13]([N:20]1[CH2:25][CH2:24][CH2:23][C:22](=[O:26])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:13]([N:20]1[CH2:25][CH2:24][CH2:23][C:22]([C:8]#[C:7][CH2:6][OH:5])([OH:26])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C#CCO[Si](C)(C)C
Reactant: O=C1CCCN(Cc2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CC[Mg]Br
Agent: [F-]
Solvent: C1CCOC1
Product: OCC#CC1(O)CCCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 94.9 %

Procedure:
O-Trimethylsilylpropargyl alcohol (15.4 ml, 100 mmol) was added slowly at 0 to 5° C. to a cooled (0° C.) solution of ethylmagnesium bromide (1 M in tetrahydrofuran, 100 ml, 100 mmmol) in tetrahydrofuran. The reaction mixture was stirred at 0° C. for 15 minutes and then allowed to warm to room temperature over 30 minutes (exotherm and gas evolution observed), before recooling to 0° C. To this was added a solution of 1-benzyl-3-piperidone (15.16 g, 80.1 mmol) in tetrahydrofuran (30 ml), keeping the temperature below 5° C. The reaction mixture was stirred at room temperature overnight, quenched by addition of water/saturated aqueous ammonium chloride (50 ml/50 ml) and extracted with ethyl acatate (2×100 ml). The organic phases were washed with brine (100 ml), combined, dried (MgSO4) and evaporated to an amber oil (25.55 g). This oil was dissolved in tetrahydrofuran (50 ml), the solution cooled to 0° C. and treated with a solution of tetrabutylammonium fluoride (1.1 M in tetrahydrofuran, 100 ml, 110 mmol). After stirring at room temperature for 20 minutes the solution was concentrated in vacuo, diluted with water (250 ml) and extracted with ethyl acatate (2×100 ml). The extracts were washed with brine (100 ml), combined, dried (MgSO4) and evaporated to give the title product as an oil (18.65 g, 95%); m/z (ES+) 246 ([M+H]+).
Reaction SMILES: [NH:1]1[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>C(OCC)C>[C:11]([N:1]1[CH2:3][CH2:2]1)([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C1CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: O=C(OCc1ccccc1)N1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred, distilled aziridine solution (500 m, 0.1 mol) in a round-bottom flask cooling with an ice bath, three equivalents of potassium carbonate was added. After all of the solid dissolved, benzyl chloroformate (1.5 equivalents) in ethyl ether (150 mL) was added over 2 h. The solution was stirred overnight and warmed to room temperature, and the aqueous phase was extracted with methylene chloride (5×30 mL). The organic phases were combined and passed through a flash silica gel pad and concentrated to afford the Cbz-aziridine as colorless thick oil, yield: 7.2 g, 81%.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3[C:8](=[C:9]([Cl:11])[CH:10]=1)[N:7]=[C:6](S)[C:5]=3[CH:13]=[CH:14][CH:15]=2.[N:16]1([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH:20]=[CH:19][N:18]=[CH:17]1>CN(C)C=O>[Cl:1][C:2]1[C:3]2[C:4]3[C:8](=[C:9]([Cl:11])[CH:10]=1)[N:7]=[C:6]([NH:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)[C:5]=3[CH:13]=[CH:14][CH:15]=2
Reactant: NCCCCCn1ccnc1
Reactant: SC1=Nc2c(Cl)cc(Cl)c3cccc1c23
Solvent: CN(C)C=O
Product: Clc1cc(Cl)c2cccc3c2c1N=C3NCCCCCn1ccnc1
Yield: 24.5 %

Procedure:
A mixture of 5.0 g of 6,8-dichloro-benz[cd]indole-2-thiol, 3.1 g of 5-(1H-imidazol-1-yl)pentanamine, 100 ml of dry dimethylformamide and 6.3 g of mercuric acetate was reacted as described in Example 1, giving 1.8 g of the desired product, mp 191°-192.5° C.
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([CH2:7][NH:8][C:9](=[O:27])[CH:10]([O:24][CH2:25][CH3:26])[N:11]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[OH:23])=[N:12]2)=[CH:5][CH:4]=1)#[N:2].I[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[C:14]([CH3:16])=[CH:15][N:11]([CH:10]([C:9](=[O:27])[NH:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:29][CH:28]=2)[O:24][CH2:25][CH3:26])[N:12]=1)[CH3:36]
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)n1cc(C)c(-c2ccccc2O)n1
Reactant: CCOC(=O)CI
Product: CCOC(=O)COc1ccccc1-c1nn(C(OCC)C(=O)NCc2ccc(C#N)cc2)cc1C

Procedure:
Using an analogous procedure as described in example 11.2 (RS)-N-(4-cyano-benzyl)-2-ethoxy-2-[3-(2-hydroxy-phenyl)-4-methyl-pyrazol-1-yl]-acetamide was reacted with ethyl iodoacetate to give (RS)-(2-{1-[(4-cyano-benzylcarbamoyl)-ethoxy-methyl]-4-methyl-1H-pyrazol-3-yl}-phenoxy)-acetic acid ethyl ester. White amorphous solid. MS 477.5 ([M+H]+)
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[CH2:6]([OH:11])[CH2:7][CH2:8][CH2:9][OH:10]>>[P:1]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][O:11][P:1]([Cl:5])([Cl:3])=[O:2])([Cl:5])([Cl:3])=[O:2]
Reactant: OCCCCO
Reactant: O=P(Cl)(Cl)Cl
Product: O=P(Cl)(Cl)OCCCCOP(=O)(Cl)Cl
Reaction time: 2 h

Procedure:
A 500 ml four-necked flask with stirrer, thermometer, dropping funnel with pressure compensation and reflux condenser was charged with 300.0 g of phosphoryl chloride at 20° C. Then a vacuum of 200 mbar was applied and 45.0 g of 1,4-butanediol were added dropwise over the course of 45 minutes. Cooling in an ice-water bath kept the temperature at 20° C. A clear, colourless reaction mixture was formed. After the end of the metered addition, the pressure was lowered to about 100 mbar, and stirring was continued for 2 hours. A distillation bridge was then mounted on, and the excess of phosphoryl chloride was removed by distillation. This left 144.9 g (91%) of 1,4-butanediol bis(dichlorophosphate).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[N:17]([Sn](C)(C)C)[N:16]=[N:15][N:14]=3)[CH:10]=[CH:9][C:8]=2[NH2:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[K+].[C:24]([C:26]1[N:27]=[C:28]([C:39]([O-])=[O:40])[N:29]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:30]=1)#[N:25].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[NH:17][N:16]=[N:15][N:14]=3)[CH:10]=[CH:9][C:8]=2[NH:22][C:39]([C:28]2[N:29]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:30]=[C:26]([C:24]#[N:25])[N:27]=2)=[O:40])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: C[Sn](C)(C)n1nnnc1-c1ccc(N)c(C2=CCCCC2)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(-c2nnn[nH]2)cc1C1=CCCCC1

Procedure:
The title compound was prepared from 2-cyclohex-1-enyl-4-(1-trimethylstannanyl-1H-tetrazol-5-yl)-phenylamine (as prepared in the previous step), potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 11, step (d)), PyBroP and DIEA according to the procedure in Example 11, step (f). Mass spectrum (ESI, m/z): Calcd. for C24H30N8O2Si, 491.2, found 491.1.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][N:6]([C:8]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)=[O:9])[CH:5]([CH3:16])[CH2:4][N:3]1[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=1.C(=O)(O)[O-:30].[Na+].ClC1C=CC=C(C(OO)=O)C=1.C(Cl)(Cl)Cl>ClCCl>[CH3:1][C@H:2]1[CH2:7][N:6]([C:8]([N:10]2[CH2:11][CH2:12][S:13](=[O:30])[CH2:14][CH2:15]2)=[O:9])[C@H:5]([CH3:16])[CH2:4][N:3]1[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:27])([F:28])[F:26])[CH:18]=1
Reactant: O=C([O-])O
Reactant: CC1CN(c2ccc(C#N)c(C(F)(F)F)c2)C(C)CN1C(=O)N1CCSCC1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc(C#N)c(C(F)(F)F)c2)[C@@H](C)CN1C(=O)N1CCS(=O)CC1
Reaction time: 6 h

Procedure:
A 270 mg portion of 4-[2,5-dimethyl-4-(thiomorpholine-4-carbonyl)piperazin-1-yl]-2-trifluoromethylbenzonitrile synthesized in Example 7-6 was dissolved in 7 ml of dichloromethane, and the solution was mixed with 110 mg of sodium bicarbonate and 155 mg of m-chloroperbenzoic acid (MCPBA) at −78° C. and stirred at the same temperature for 6 hours. The reaction solution was mixed with chloroform, washed with 1 N aqueous sodium hydroxide and saturated brine and then dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by a silica gel column chromatography to obtain 232 mg of the title compound from methanol-chloroform (1:50, v/v) eluate.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>>[C:12]([O:11][C:9]([N:16]1[CH2:21][CH2:20][CH:19]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:18][CH2:17]1)=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: Nc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Br)cc2)CC1
Yield: 256.6 %

Procedure:
Using general procedure A, 4-bromoaniline (1.23 g, 7.13 mmol) and 1-Boc-4-piperidone (1.42 g, 7.13 mmol) afforded 4-(4-bromo-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (6.5 g, 53%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]([F:10])[CH:4]=1)#[N:2].CC(N=NC(C#N)(C)C)(C#N)C.[Br:23]N1C(=O)CCC1=O>ClCCCl>[Br:23][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[F:10]
Reactant: Cc1ccc(C#N)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: N#Cc1ccc(CBr)c(F)c1
Temperature: 72 °C

Procedure:
1,2-Dichloroethane (151 kg) was charged to a suitable vessel along with 4-cyano-2-fluorotoluene (24 kg) and AIBN (2 kg). The mixture was heated to 70˜74° C. Once the batch temperature reached 70° C., N-bromosuccinimide (47.4 kg) was added in portions at the rate of 12 kg/h, maintaining the temperature at 70˜74° C. (it is important to control addition rate to avoid exothermic reaction). The mixture was sampled via GC detection after 24 kg of N-bromosuccinimide was added, and the reaction was heated at 70-74° C. until complete reaction was observed. The mixture was cooled to 0-5° C. and allowed to stand for 2 additional hours. The mixture was filtered, and the cake was washed with MTBE (24 kg). The filtrate was washed with water (3×65 kg). The organic layer was dried with sodium sulfate (10.3 kg) for 6 hours, filtered and the cake was washed with MTBE (24 kg). The solution was evaporated under reduced pressure, ethanol (12 kg) was added and the mixture was heated to 40-45° C., then cooled slowly to 0-5° C. while stirring to crystallize. The mixture was filtered and the cake was washed with cold ethanol (5 kg). The crude solid was recrystallized from petroleum ether, filtered and washed with petroleum ether (10 kg), giving the title compound 4-(bromomethyl)-3-fluorobenzonitrile as an off white solid (21 kg, 55% yield). 1H NMR (300 MHz, CDCl3) δ ppm 4.46-4.50 (m, 2 H) 7.36 (dd, J=8.85, 1.32 Hz, 1H) 7.44 (dd, J=7.91, 1.32 Hz, 1 H) 7.52 (dd, J=7.91, 7.16 Hz, 1 H). 13C NMR (75 MHz, CDCl3) δ ppm 23.65 (d, J=4.60 Hz, 1 C) 113.76 (d, J=9.77 Hz, 1 C) 117.09 (d, J=2.87 Hz, 1 C) 119.44 (d, J=24.71 Hz, 1 C) 128.44 (d, J=4.02 Hz, 1 C) 130.66-130.81 (s, 1 C) 130.81-131.06 (s, 1 C) 132.18 (d, J=3.45 Hz, 1 C) 159.86 (d, J=254.03 Hz, 1C). IR: (KBr) 3088, 3077, 3040, 2982, 2250, 1571, 1508, 1439, 1248 cm−1.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[C:30]1([CH:36]2[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1>[C:30]1([CH:36]2[CH2:41][CH2:40][C:39](=[CH:2][O:3][CH3:4])[CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=C1CCC(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.5 %

Procedure:
(Methoxymethyl)triphenylphosphonium chloride (5.14g) was suspended in anhydrous tetrahydrofuran (THF) (15ml) and stirred under argon at 0° C. A solution of potassium t-butoxide (1.68g) in THF (15ml) was added dropwise and stirring continued at the same temperature for 0.5h. To the resulting dark red near- solution was added a solution of 4-phenylcyclohexanone (2.61g) in THF (4ml), then the mixture was allowed to regain ambient temperature and stirring continued for 16h. Workup and chromatography as described in Example 5(a) gave 4-phenyl-1-(methoxymethylene)cyclohexane (1.59g) contaminated with a little triphenylphosphine; δ(CDCl3,60MHz), inter alia, 3.55 (3H,s), 5.90 (1H,br s), and 7.35 (6H,m). This material in THF (8ml) and water (2ml) was stirred at 20° C. with toluene sulphonic acid hydrate (2.50g) for 8h. Workup as described in Example 5(b) followed by chromatography on silica gel, eluting with ethyl acetate in hexane mixtures, gave the aldehyde (1.29g) as an approximately 2:3 cis:trans mixture; υMax (CHCl3) 1725, 1605, 1495, and 1450cm-1 ; δ(CDCl3,250MHz), 1.3-2.60 (10H,m), 7.15-7.35 (5H,m), 9.68, and 9.79 (1H,d,J=1.5Hz and s). [M. Carissimi et al., Farmaco (Pavia) Ed.Sci., 1965, 20. 106 (Chem.Abs., 1965, 62, 14560)].
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8](SC)=[CH:9][N+:10]([O-:12])=[O:11])[CH2:2]1.[CH3:15][NH2:16]>CO.[OH-].[Na+].C(O)C>[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8]([NH:16][CH3:15])=[CH:9][N+:10]([O-:12])=[O:11])[CH2:2]1
Reactant: CSC(=C[N+](=O)[O-])NCC1CCOC1
Reactant: CN
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CNC(=C[N+](=O)[O-])NCC1CCOC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture comprising 7.0 g of (tetrahydro-3-furanyl)methylamine, 12.5 g of 1,1-bis(methylthio)-2-nitroethylene and 100 ml of acetonitrile was refluxed for 5 hours. The reaction mixture was concentrated under a reduced pressure, and purified by silica gel column chromatography (eluent:ethyl acetate/hexane=1/1) to give 6.6 g of 1-[{tetrahydro-3-furanyl)methyl}amino]-1-methylthio-2-nitroethylene. Then, a mixture comprising 4.0 g of the 1-[{(tetrahydro-3-furanyl)methyl}amino]-1-methylthio-2-nitroethylene obtained above, 6.0 ml of 40% methylamine in methanol solution, 20 ml of 1N aqueous sodium hydroxide solution and 20 ml of ethanol was stirred at room temperature for 5 hours. The resulting reaction mixture was concentrated under a reduced pressure, and purified by silica gel column chromatography (eluent:ethyl acetate/methanol=9/1) to obtain 3.2 g of 1-[{(tetrahydro-3-furanyl)methyl}amino]-1-methylamino-2-nitroethylene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24](OC)=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10].[CH:30]([NH2:33])([CH3:32])[CH3:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24]([NH:33][CH:30]([CH3:32])[CH3:31])=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10]
Reactant: COC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Reactant: CC(C)N
Product: CC(C)NC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2

Procedure:
Following Example 47 and General Procedure C, methyl 2-((2-chlorophenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylate 138 and isopropylamine gave 205. MS: (ESI+) 455.0
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:10][OH:11])[C:5]([F:16])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:11][CH2:10][C@@H:9]([NH:8][C:6]1[C:5]([F:16])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)[C:12]([CH3:13])([CH3:15])[CH3:14])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[C@@H](CO)Nc1nc(Cl)ncc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[C@@H](COS(C)(=O)=O)Nc1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of (S)-2-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3,3-dimethylbutan-1-ol, 14a, (1.95 g, 7.87 mmol) and triethylamine (1.37 mL, 9.84 mmol) in dichloromethane (25 mL) was added methanesulfonyl chloride (0.76 mL, 9.84 mmol). The solution was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and water (100 mL) and EtOAc (50 mL) were added. The organic phase was separated, dried (MgSO4) and concentrated under reduced pressure to afford 2.55 g of the desired product as a pale yellow foamy solid: LC/MS (10-90% ACN/water 5 min with 0.9% FA, C4) m/z 326.99 (M+H) RT=2.96 minutes.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH:18]3[CH2:20][CH2:19]3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1Br.[C:22]([C:25]1[CH:26]=[CH:27][C:28](B(O)O)=[N:29][CH:30]=1)(=[O:24])[NH2:23]>>[NH2:1][C:2]1[C:3]([C:28]2[CH:27]=[CH:26][C:25]([C:22]([NH2:23])=[O:24])=[CH:30][N:29]=2)=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14](=[O:16])(=[O:15])[NH:17][CH:18]3[CH2:20][CH2:19]3)=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: Nc1ncc(-c2ccc(S(=O)(=O)NC3CC3)cc2)cc1Br
Reactant: NC(=O)c1ccc(B(O)O)nc1
Product: NC(=O)c1ccc(-c2cc(-c3ccc(S(=O)(=O)NC4CC4)cc3)cnc2N)nc1
Yield: 28.1 %

Procedure:
General method B was applied to 4-(6-amino-5-bromopyridin-3-yl)-N-cyclopropylbenzenesulfonamide (112 mg, 0.304 mmol) and 5-carbamoylpyridin-2-ylboronic acid (75 mg, 0.453 mmol) to provide 2′-amino-5′-(4-(N-cyclopropylsulfamoyl)phenyl)-[2,3′-bipyridine]-5-carboxamide as a white solid (35 mg, 28% yield) after purification by reverse phase preparatory HPLC. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.07-9.16 (m, 1H), 8.53 (d, J=2.3 Hz, 1H), 8.47 (d, J=2.3 Hz, 1H), 8.32 (dd, J=14.1, 10.8 Hz, 2H), 8.21 (br. s., 1H), 8.01 (d, J=8.5 Hz, 2H), 7.91 (d, J=2.5 Hz, 1H), 7.85 (d, J=8.3 Hz, 2H), 7.79 (br. s., 2H), 7.61 (br. s., 1H), 2.06-2.18 (m, 1H), 0.34-0.55 (m, 4H); MS (EI) m/z: 410 [M+H]+.
Reaction SMILES: [C:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[N:13]=2)[C:8](=[O:20])[C:7]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].[Br:26]N1C(C)(C)C(=O)N(Br)C1=O.S(=O)(O)[O-].[Na+]>ClCCl>[Br:26][C:11]1[CH:10]=[C:9]2[C:14](=[N:13][C:12]=1[N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=[C:7]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:8]2=[O:20]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc(N3CCCC3)ccc2c1=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1cn(C(C)(C)C)c2nc(N3CCCC3)c(Br)cc2c1=O

Procedure:
A solution of Example 74A (343.42 mg) and 1,3-dibromo-5,5-dimethylhydantoin (171.5 mg) in dichloromethane (15 mL) was stirred for 15 minutes, treated with 10% sodium bisulfite, and extracted with dichloromethane (50 mL). The extract was washed with water and brine, dried (MgSO4), filtered, and concentrated; and the concentrate was crystallized from dichloromethane/diethyl ether.
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]([C:15]([CH3:29])=[C:16]([C:18]3[CH:19]=[CH:20][C:21]4[O:25][C:24](=[O:26])[N:23]([CH3:27])[C:22]=4[CH:28]=3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>C(O)C.O1CCCC1.[Pd]>[OH:8][C:9]1[C:10]2[N:11]([C:15]([CH3:29])=[C:16]([C:18]3[CH:19]=[CH:20][C:21]4[O:25][C:24](=[O:26])[N:23]([CH3:27])[C:22]=4[CH:28]=3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: Cc1c(-c2ccc3oc(=O)n(C)c3c2)nc2c(OCc3ccccc3)cccn12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(-c2ccc3oc(=O)n(C)c3c2)nc2c(O)cccn12
Yield: 63.6 %

Procedure:
A solution of 5-(8-benzyloxy-3-methylimidazo[1,2-a]pyridin-2-yl)-3-methyl-2-benzoxazolinone (1.6 g) in a mixture of ethanol (200 ml) and tetrahydrofuran (100 ml) was hydrogenated over 10% palladium on carbon (wet, 0.5 g) under an atmospheric pressure of hydrogen at ambient temperature for an hour. The catalyst and an insoluble material were filtered off and the filtrate was evaporated in vacuo. The residue was recrystallized from a mixture of tetrahydrofuran and ethanol to give 5-(8-hydroxy-3-methylimidazo[1,2-a]pyridin-2-yl)-3-methyl-2-benzoxazolinone (0.78 g). mp. >280° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].I[C:15]1[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH2:20]([N:18]1[CH:19]=[C:15]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)[CH:16]=[N:17]1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CCCCCCCn1cc(I)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCCCCn1cc(-c2ccc(C(=O)OC)cc2)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 22.2 %

Procedure:
To a suspension of 4-Methoxycarbonylphenyl boronic acid (648 mg) and 4-iodo-1-heptylpyrazole (876 mg) and Pd(PPh3)4 (173 mg) in 1,2-dimethoxyethane (10 ml) was added 2M Na2CO3 aq. (3.6 ml). The reaction mixture was stirred at 80° C. for 2 hours under N2 atmosphere, and poured into ice-water and extracted with ethyl acetate. The organic layer was washed with brine, and dried over MgSO4. The solvent was removed under pressure. The residue was subjected to column-chromatography on silica gel 60 (Merk) and eluted with n-hexane/ethyl acetate (80:20). The fractions containing the object compound were combined and evaporated under reduced pressure to give 1-heptyl-4-(4-methoxycarbonylphenyl)pyrazole (0.20 g).
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]([OH:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1)[NH2:2].[N:13]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[C:14]=[S:15]>C(#N)C.CCOCC>[OH:12][C:9]([C:6]1[CH:5]=[CH:4][C:3]([NH:1][NH:2][C:14](=[S:15])[NH:13][C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[N:8][CH:7]=1)([CH3:10])[CH3:11]
Reactant: O=[N+]([O-])c1ccc(N=C=S)cc1
Reactant: CC(C)(O)c1ccc(NN)nc1
Solvent: CC#N
Solvent: CCOCC
Product: CC(C)(O)c1ccc(NNC(=S)Nc2ccc([N+](=O)[O-])cc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.7 %

Procedure:
A mixture of 2-(6-hydrazinylpyridin-3-yl)propan-2-ol (250 mg, 1.495 mmol) and 1-isothiocyanato-4-nitrobenzene (269 mg, 1.495 mmol) in ACN (Volume: 2.0 mL) was stirred at room temperature for 1 hr. The reaction was diluted with Et2O (Volume: 5.0 mL), and the resulting solid was filtered. Minimal product was present in the solid. On standing for 1 hr, the filtrate had formed a precipitate. This was filtered to provide 2-(5-(2-hydroxypropan-2-yl)pyridin-2-yl)-N-(4-nitrophenyl)hydrazinecarbothioamide (175 mg, 0.504 mmol, 33.7% yield) as an orange solid. A solution of 2-(5-(2-hydroxypropan-2-yl)pyridin-2-yl)-N-(4-nitrophenyl)hydrazinecarbothioamide (275 mg, 0.792 mmol) in DME (Volume: 2.0 mL) was heated in a microwave on high absorbance for 3 hr at 110° C. The reaction was stripped to dryness onto silica gel via rotary evaporation and purified compound by MPLC with DCM:MeOH (98:2) to provide 2-(3-mercapto-[1,2,4]triazolo[4,3-a]pyridin-6-yl)propan-2-ol.
Reaction SMILES: Cl.[CH2:2]([NH:5][O:6][CH2:7][CH2:8][CH3:9])[CH2:3][CH3:4].N1C=CC=CC=1.[Br:16][CH2:17][C:18](Br)=[O:19]>C(#N)C>[CH2:2]([N:5]([O:6][CH2:7][CH2:8][CH3:9])[C:18](=[O:19])[CH2:17][Br:16])[CH2:3][CH3:4]
Reactant: CCCNOCCC
Reactant: O=C(Br)CBr
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCON(CCC)C(=O)CBr
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 197.8 %

Procedure:
N-Propyl-N-propoxyamine hydrochloride (0.30 g) was dissolved in acetonitrile and cooled to −20° C. Pyridine (0.2 mL) was added. Bromoacetyl bromide (0.15 g) was added dropwise over 5 min. The solution was stirred at −20° C. for 30 min. The bath was removed and the solution was stirred for 6 hours at room temperature. The solvent was removed in vacuo and the residue taken up in EtOAc (50 mL) and washed with water (1×25 mL), 1N phosphoric acid (3×25 mL), and brine (1×25 mL). The organic layer was dried with sodium sulfate and evaporated to give a dark orange oil (0.35 g). The product is a mixture of chloro- and bromoacetamides in a ratio of ˜3:1.