Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[F:21])[NH:17][C:16]([C:22]1[CH:23]=[CH:24][C:25]([O:29][CH3:30])=[C:26]([NH2:28])[CH:27]=1)=[CH:15]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[F:21])[NH:17][C:16]([C:22]1[CH:23]=[CH:24][C:25]([O:29][CH3:30])=[C:26]([NH:28][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:27]=1)=[CH:15]2
Reactant: N#Cc1ccc(C=O)cc1
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
4-Cyanobenzaldehyde (0.262 g, 2.0 mmol) was added to a stirred mixture of 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (0.548 g, 2.0 mmol) in methylene chloride (125 mL), followed by acetic acid (0.2 g). The resulting mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.46 g, 2.2 mmol) was added in one portion, and the resulting homogeneous solution stirred at room temperature for 4 days. Saturated aqueous sodium bicarbonate solution (100 mL) was added and the mixture stirred for 2 hours. The mixture was shaken, the organic layer separated and dried over Na2SO4. The solvent was evaporated to give a colorless gum. Recrystallization from methanol gave the product (300 mg), mp 158-159° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:29])[C:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[CH:20][OH:21])=[CH:11][C:10]=1[O:30][CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl[CH:35]([F:37])[F:36].Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.COCCOC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:29])[C:19]([C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)=[CH:20][O:21][CH:35]([F:37])[F:36])=[CH:11][C:10]=1[O:30][CH3:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(CCNC(=O)C(=CO)c2ccc(C)cc2)ccc1OCc1ccccc1
Reactant: FC(F)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: COCCOC
Product: COc1cc(CCNC(=O)C(=COC(F)F)c2ccc(C)cc2)ccc1OCc1ccccc1

Procedure:
4.17 g (10.00 mmol) of N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-3-hydroxy-2-(4-methylphenyl)acrylamide, 22.4 g (40.0 mmol) of 10% aqueous potassium hydroxide solution, 1.62 g (5.00 mmol) of tetrabutylammonium bromide and 50 ml of ethylene glycol dimethyl ether were mixed and chlorodifluoromethane gas was blown thereto at room temperature. After a sample was taken out from the reaction mixture and the disappearance of the starting material was confirmed by thin layer chromatography, 5% hydrochloric acid was added to the reaction mixture, which was followed by extracted with ethyl acetate, washed with 5% hydrochrolic acid, saturated aqueous sodium bicarbonate solution and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was washed with diethyl ether to give 3.46 g of N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-3-difluoromethoxy-2-(4-methylphenyl)acrylamide (the present compound 1451).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([CH:10]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:11][O:12][C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)[CH2:7][CH2:8][CH3:9].[OH-].[Na+].CN([CH:29]=[O:30])C>>[CH:29]([C:14]1[S:15][CH:16]=[CH:17][C:13]=1[O:12][CH2:11][CH:10]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:30]
Reactant: CCCCCCC(CCCC)COc1ccsc1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCC(CCCC)COc1ccsc1C=O
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
Under a nitrogen atmosphere, phosphorous oxychloride (3.5 ml, 40 mmol) was slowly dropped into DMF (70 ml) at 0° C. and stirred for 10 minutes. Then, a DMF (15 ml) solution of 3-(2-butyloctoxy)thiophene (9 g, 30.4 mmol) was slowly dropped into the reaction solution. The reaction solution was then heated for two hours at 70° C. Then, the reaction solution was cooled to room temperature. While cooling the reaction solution in a water bath, a 10% aqueous sodium hydroxide solution was slowly added and stirred for 30 minutes. Then, the reaction solution was extracted with chloroform, and an organic layer was washed with a saturated saline solution and water. The organic layer was dried with anhydrous magnesium sulfate, and, after filtration, the solution was distilled off under reduced pressure. By separating and purifying the obtained reaction mixture by silica gel column chromatography in which a mixed solvent of hexane and ethyl acetate was used as a mobile phase, a target substance was obtained as clear oil (80% yield). 1H-NMR (400 MHZ, CDCl3, TMS) δ 10.00 (s, 1 H), 7.67 (d, J=4.8 Hz, 1 H), 6.84 (d, J=4.8 Hz, 1 H), 4.03 (d, J=4.8 Hz, 2 H), 1.25 (m, 17 H), 0.88 (m, 6 H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:21][CH2:22][S:23][CH3:24])[NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([SH:13])=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[S:26]1[CH:30]=[CH:29][N:28]=[C:27]1[N:31]=[C:32]=[O:33]>C1COCC1>[CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:21][CH2:22][S:23][CH3:24])[NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([S:13][C:32]([NH:31][C:27]2[S:26][CH:30]=[CH:29][N:28]=2)=[O:33])=[CH:9][C:8]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C=Nc1nccs1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(S)cc1-c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(SC(=O)Nc2nccs2)cc1-c1ccccc1

Procedure:
A solution of 2-phenyl-4-mercaptobenzoyl-methionine methyl ester from example 12E or 12F (1.0 mmol) and the isocyanate prepared in example 29A (1.0 mmol) in THF is refluxed until TLC shows no thiol left. The solvent is then evaporated in vacuo, and the residue is purified by column chromatography on silica gel to give the title compound.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1CCCCC1.O>C1C=CC=CC=1.C(O)(=O)C1C=CC=CC=1>[CH:12](=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=Cc1ccccc1
Agent: O=C(O)c1ccccc1
Solvent: O
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CCOC(=O)C(=Cc1ccccc1)C(=O)OCC
Yield: 87.7 %

Procedure:
A mixture containing 3.0 mL (19.8 mmoles) of diethyl malonate, 2.0 mL (19.6 mmoles) of benzaldehyde, 0.10 mL of piperidine, and 65 mg of benzoic acid in 35 mL of benzene was heated at reflux for 6 hours with continuous azeotropic removal of water by means of a Dean-Stark trap. Isolation of the product in the manner described in the procedure of Example I, followed by fractional distillation, afforded 4.27 g (88% yield) of diester 8: bp 105°-140° C. (bath temperature, 0.10 mm). Subsequent treatment of diester 8 with 2-nitropropane and sodium ethoxide in ethanol at reflux, as described for the corresponding cyanoester 1 in Example VIII, failed to yield a cyclopropanoid product.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)=[CH:8]2)(=[O:4])=[O:3].[H-].[Na+].[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1.O>CN(C)C=O>[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:10]2[C:11]3[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:13][CH:12]=3)[CH:8]=[C:9]2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:25][CH:24]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CS(=O)(=O)c1ccc2[nH]c(-c3ccncc3)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc2c(c1)cc(-c1ccncc1)n2Cc1ccc(F)cc1
Reaction time: 0.33 h

Procedure:
To a solution of the compound obtained in Example 31 (1) (0.4 g) in N,N-dimethylformamide (160 ml), 60% sodium hydride (0.065 g) was added at 0° C. under nitrogen atmosphere and the mixture was stirred for 20 minutes, followed by addition of 4-fluorobenzyl bromide (0.2 ml), and the mixture was stirred at 15 to 30° C. for 15 hours. The reaction solution was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (hexane:ethyl acetate=1:3) to obtain 0.3882 g of the desired product.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH2:12])=[O:11])=[O:6].Cl.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:26])=[CH:21][CH:20]=1.C(N(CC)CC)C>C(#N)C>[NH2:12][C:10]([C:9]1[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=1[NH:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:30]1[CH2:31][CH2:32][CH:27]([C:25](=[O:26])[C:22]2[CH:21]=[CH:20][C:19]([F:18])=[CH:24][CH:23]=2)[CH2:28][CH2:29]1)=[O:11]
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: NC(=O)c1ccccc1NC(=O)CCCCl
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NC(=O)c1ccccc1NC(=O)CCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Yield: 81 %

Procedure:
A mixture of 7.2 parts of 2-[(4-chloro-1-oxobutyl)amino]benzamide, 7.3 parts of (4-fluorophenyl) (4-piperidinyl)methanone hydrochloride, 10.1 parts of N,N-diethylethanamine and 120 parts of acetonitrile is stirred and refluxed for 24 hours. The reaction mixture is evaporated and water is added to the residue. The oily product is extracted with trichloromethane. The extract is dried, filtered and evaporated, yielding 10 parts (81%) of N-[2-(aminocarbonyl)phenyl]-4-(4-fluorobenzoyl)-1-piperidinebutanamide as a residue.
Reaction SMILES: [NH2:1][CH:2]([CH3:12])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(OCC)(=O)C>[OH:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][CH:2]([NH:1][C:20](=[O:22])[CH3:21])[CH3:12])=[CH:10][CH:9]=1
Reactant: CC(N)CCc1ccc(O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)NC(C)CCc1ccc(O)cc1

Procedure:
4-(3-Aminobutyl)phenol (510 mg, 3.087 mmol) and triethylamine (1.3 ml, 9.26 mmol) were dissolved in 30 ml of ethyl acetate. At 0° C., acetic anhydride (029 ml, 3.087 mmol) was added. The cooling bath was removed after 1 h. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 472 mg (74%) of N-[3-(4-hydroxyphenyl)-1-methylpropyl]acetamide, M+H+: 208.14 and 54 mg (7%) of 4-(3-acetylaminobutyl)phenyl acetate, M+H+: 250.13.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([C:18](=[O:22])[C:19](Cl)=[O:20])=[CH:12][NH:13]2.[C:23]1([C:29]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[C:30]([C:33]#[N:34])[C:31]#[N:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[F:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([C:18](=[O:22])[C:19]([N:38]1[CH2:37][CH2:36][N:35]([C:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:30]([C:33]#[N:34])[C:31]#[N:32])[CH2:40][CH2:39]1)=[O:20])=[CH:12][NH:13]2
Reactant: N#CC(C#N)=C(c1ccccc1)N1CCNCC1
Reactant: O=C(Cl)C(=O)c1c[nH]c2cccc(F)c12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#CC(C#N)=C(c1ccccc1)N1CCN(C(=O)C(=O)c2c[nH]c3cccc(F)c23)CC1
Reaction time: 16 h

Procedure:
Triethyl amine (2 ml) was added into a solution of 2-(4-fluoro-1H-indol-3-yl)-2-oxoacetyl chloride (284 mg) and 2-(phenyl(piperazin-1-yl)methylene)malononitrile (300 mg) in dry THF (20 ml). After 16 hours, the reaction mixture was partitioned between saturated NaHCO3 (20 ml) and EtOAc (20 ml), and the aqueous phase was extracted with EtOAc (3×20 ml). Then the combined organic layer was dried over MgSO4 and concentrated to offer a residue which was purified using Shimadzu automated preparative HPLC System to afford 2-((4-(2-(4-fluoro-1H-indol-3-yl)-2-oxoacetyl)piperazin-1-yl)(phenyl)methylene)malononitrile.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][NH2:16])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(CCN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CCN)CC1

Procedure:
Batch size: 42.2 g (120 mmol) 2-{2-[4-(tert-butoxycarbonyl)-piperazin-1-yl]-ethyl}-isoindolin-1,3-dione and 11.6 ml (240 mmol) hydrazine-hydrate in 450 ml ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH:5]=[CH:4][C:3]=1[C:18]([C:20]1[CH:25]=[C:24]([OH:26])[CH:23]=[CH:22][C:21]=1[F:27])=[O:19].Cl.Cl[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH:5]=[CH:4][C:3]=1[C:18]([C:20]1[CH:25]=[C:24]([O:26][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:23]=[CH:22][C:21]=1[F:27])=[O:19]
Reactant: ClCCN1CCOCC1
Reactant: O=C(c1cc(O)ccc1F)c1ccc(Nc2ccccc2[N+](=O)[O-])cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(c1cc(OCCN2CCOCC2)ccc1F)c1ccc(Nc2ccccc2[N+](=O)[O-])cc1Cl
Temperature: 130 °C
Reaction time: 1.75 h

Procedure:
Compound 517 (30 mg, 0.08 mmol) was dissolved in acetonitrile (2 mL) in a reaction vial. 4-(2-Chloro-ethyl)-morpholine hydrochloride (44 mg, 0.24 mmol) and K2CO3 (33 mg, 0.24 mmol) were added. The reaction vial was flushed with argon, closed and then stirred at 130° C. for a total of 105 min. in a microwave oven. The reaction mixture was poured into a mixture of EtOAc:H2O (1:1, 10 mL). The layers were separated and the aqueous phase was extracted with EtOAc (2×10 mL). The combined organic layers were dried (MgSO4), filtered, concentrated in vacuo and purified by continuously gradient flash chromatography using EtOAc/petroleum ether (40-60)(v:v=1:9 to 3:2) as the eluent, affording the title compound as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:23])[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH:21][CH3:22])=[CH:16][CH:15]=3)[S:11][C:7]=2[C:6]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:5][CH:4]=1.[CH:30]1([C:33](Cl)=[O:34])[CH2:32][CH2:31]1>>[CH:30]1([C:33]([N:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:13]([NH:12][C:10]3[S:11][C:7]4[C:6]([N:24]5[CH2:25][CH2:26][O:27][CH2:28][CH2:29]5)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=4[N:9]=3)=[O:23])=[CH:19][CH:18]=2)[CH3:22])=[O:34])[CH2:32][CH2:31]1
Reactant: CNCc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1
Reactant: O=C(Cl)C1CC1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CN(C)C(=O)C4CC4)cc3)nc12

Procedure:
Using N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-methylaminomethyl-benzamide and cyclopropanecarbonyl chloride, the title compound was prepared as light yellow crystals (82% yield). MS: m/e=481(M+H+).
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][N:11]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[NH2:9][C:10]1[N:11]=[CH:12][C:13]([NH:16][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:14][CH:15]=1
Reactant: Nc1ccc(N)nc1
Reactant: CCCCCC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCC(=O)Nc1ccc(N)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
Hexanoyl chloride (1.1 equiv., 10.08 mmol, 1.36 g) was added dropwise to a cooled (0° C.) suspension of 2,5-diaminopyridine (I13) (1.0 equiv., 9.16 mmol, 1.00 g) and triethylamine (1.1 equiv., 10.08 mmol, 1.02 g) in chloroform (100 ml). The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure, and the residue was brought on a filter and successively washed with saturated NaHCO3 solution, water and isopropyl ether. The crude product was further purified by column chromatography (dichloromethane/methanol 95:5; Rf=0.3) to give N-[6-amino-pyridin-3-yl]-hexanamide (I14) (1.24 g, yield=65%). 1H NMR (6, DMSO-D6): 0.87 (3H, t, J=6.9), 1.23-1.33 (4H, m), 1.53-1.60 (2H, m), 2.22 (2H, t, J=7.5 Hz), 5.67 (2H, s), 6.39 (1H, d, J=8.8 Hz), 7.54 (1H, dd, J=8.8, 2.6 Hz), 8.05 (1H, d, J=2.5 Hz), 9.53 (1H, s)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:19]=1)[C:7]([N:9]=[S@@:10]([CH3:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[F:28])#[CH:21].C(N(CC)CC)C>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:20]#[C:21][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:19]=1)[C:7]([N:9]=[S@@:10]([CH3:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Reactant: C#Cc1ccccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2ccccc2F)c1)c1ccccc1
Temperature: 25 °C
Yield: 93.8 %

Procedure:
A mixture of (S)-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (105 mg, 0.31mmol) and 1-ethynyl-2-fluorobenzene (75 mg, 0.62 mmol) in 2.0 mL EtOAc was degassed with argon at 70° C. Upon cooling to room temperature the reaction mixture was treated with triethylamine (0.16 mL, 1.1 mmol), dichlorobis(triphenylphosphine)palladium(II) (22 mg, 0.031 mmol) and copper(I) iodide (2 mg, 0.012 mmol). The reaction was heated at 70° C. for 20 hours then partitioned between EtOAc and H2O. The EtOAc layer was washed with acetic acid solution, saturated NaHCO3, brine, dried with anhydrous Na2SO4 and concentrated. The dark film obtained was purified by chromatography (silica gel, hexane/EtOAc) to give the title compound as a tan foam (110 mg, 94%).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:14][C:15]2[CH:25]=[CH:24][C:18]([C:19]([N:21]([CH3:23])[CH3:22])=[O:20])=[CH:17][CH:16]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)#[N:2].[OH-].[Na+].CC[OH:30].OO>CS(C)=O.O>[CH3:22][N:21]([CH3:23])[C:19]([C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:4]2[C:3]([C:1]([NH2:2])=[O:30])=[CH:7][N:6]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:5]=2)=[CH:25][CH:24]=1)=[O:20]
Reactant: CN(C)C(=O)c1ccc(Nc2nn(-c3ccccc3)cc2C#N)cc1
Reactant: CCO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CN(C)C(=O)c1ccc(Nc2nn(-c3ccccc3)cc2C(N)=O)cc1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
4-[(4-cyano-1-phenyl-1H-pyrazol-3-yl)amino]-N,N-dimethylbenzamide (83 mg, 0.250 mmol) and 5 N sodium hydroxide (0.351 mL, 1.753 mmol) were taken up in DMSO (1 mL)/EtOH (1 mL) and warmed to 60° C. Hydrogen peroxide (0.329 mL, 3.76 mmol) was added dropwise and stirring continued at 60° C. for 15 minutes. Room temperature was attained, water was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine (×2), dried over MgSO4 and concentrated in vacuo. Purification of the residue by MPLC (25-100% EtOAc-hexanes followed by 0-10% MeOH-EtOAc followed by 15% MeOH—CHCl3) gave 3-({4-[(dimethylamino)carbonyl]phenyl}amino)-1-phenyl-1H-pyrazole-4-carboxamide as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:24]3[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=3)([C:14]3[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([C:30]([F:33])([F:32])[F:31])[C:3]=1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[CH3:81][N:82](C)C(=O)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[C-]#N.[Zn+2].[C-]#N.[Zn]>[OH:13][C:12]([C:24]1[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=1)([C:14]1[CH:15]=[N:16][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:18][CH:19]=1)[C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:30]([F:31])([F:32])[F:33])[C:3]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[C:2]2[C:81]#[N:82].[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]
Reactant: CC(=O)N(C)C
Reactant: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(C(F)(F)F)c(-c3ccccc3)c(Cl)c2c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(C(F)(F)F)c(-c3ccccc3)c(C#N)c2c1
Temperature: 120 °C

Procedure:
A pressure tube containing (4-chloro-3-phenyl-2-(trifluoromethyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol•TFA (101 mg, 0.128 mmol, Example 172), Pd2 dba3 (12 mg, 0.013 mmol), dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (X-Phos, 6.3 mg, 0.013 mmol), zinc cyanide (10 mg, 0.085 mmol), and zinc nanopowder (2.5 mg, 0.038 mmol) in N,N-dimethylacetamide (1 mL) was purged with nitrogen for 5 min, and then heated at 120° C. for 2.5 hours. The mixture was allowed to cool to room temperature and filtered through a syringe filter. The filtrate was concentrated in vacuo, and EtOAc and NH4OH (aqueous) were added. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by reverse phase HPLC (water/acetonitrile/0.1% TFA) to give the title compound as a white solid. 1H NMR (400 MHz, MeOD-d4) δ 9.06 (s, 1H), 8.87 (d, J=2.02 Hz, 1H), 8.38-8.47 (m, 2H), 8.14 (dd, J=2.27, 8.34 Hz, 1H), 8.05 (dd, J=2.02, 9.09 Hz, 1H), 7.91 (d, J=8.08 Hz, 1H), 7.52-7.62 (m, 3H), 7.47 (d, J=6.06 Hz, 2H), 7.19 (s, 1H), 3.72 (s, 3H); MS m/e 554.1 [M+H]
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([O:11][CH:12]([F:14])[F:13])[CH:8]=[N:7][C:6]=12.[C:15]([O:19][C:20](=[O:49])[NH:21][C@@H:22]1[CH2:27][CH2:26][CH2:25][C:24]([F:29])([F:28])[C@@H:23]1[NH:30][C:31]([C:33]1[S:34][C:35]([CH2:47][CH3:48])=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:37]=1)=[O:32])([CH3:18])([CH3:17])[CH3:16].C([O-])([O-])=O.[Na+].[Na+]>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.CN(C=O)C>[C:15]([O:19][C:20](=[O:49])[NH:21][C@@H:22]1[CH2:27][CH2:26][CH2:25][C:24]([F:29])([F:28])[C@@H:23]1[NH:30][C:31]([C:33]1[S:34][C:35]([CH2:47][CH3:48])=[C:36]([C:2]2[CH:3]=[N:4][N:5]3[CH:10]=[C:9]([O:11][CH:12]([F:14])[F:13])[CH:8]=[N:7][C:6]=23)[CH:37]=1)=[O:32])([CH3:18])([CH3:17])[CH3:16]
Reactant: FC(F)Oc1cnc2c(Br)cnn2c1
Reactant: CCc1sc(C(=O)N[C@@H]2[C@H](NC(=O)OC(C)(C)C)CCCC2(F)F)cc1B1OC(C)(C)C(C)(C)O1
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: CN(C)C=O
Product: CCc1sc(C(=O)N[C@@H]2[C@H](NC(=O)OC(C)(C)C)CCCC2(F)F)cc1-c1cnn2cc(OC(F)F)cnc12
Temperature: 85 °C
Yield: 56.1 %

Procedure:
3-Bromo-6-(difluoromethoxy)pyrazolo[1,5-a]pyrimidine (0.030 g, 0.114 mmol), tert-butyl[(1R,2R)-2-({[5-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl]carbonyl}amino)-3,3-difluorocyclohexyl]carbamate (0.059 g, 0.115 mmol), Pd(PPh3)4 (6.57 mg, 0.007 mmol), and 2 M Na2CO3 (aq) (0.170 mL, 0.341 mmol) were placed in a sealed tube and DMF (1.14 mL) added. The mixture was purged with N2 for 5 min. The reaction was heated to 85° C. for 16 h. The mixture was cooled to room temperature, diluted with dichloromethane, and washed twice with saturated sodium bicarbonate (aq) and once with brine. The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (0-70% EtOAc/Hex) to give the title compound (0.037 g, 0.064 mmol). LRMS (APCI) calc'd for (C25H29F4N5O4S) [M+H]+, 572.2; found 572.1.