Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.ClCCl.[CH2:10]([CH:12]([C:14]1[N:18]([CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH2:21][CH2:20]2)[CH:17]=[N:16][CH:15]=1)[OH:13])[CH3:11]>[O-2].[Cr+6].[O-2].[O-2].O>[CH:19]1([N:18]2[C:14]([C:12](=[O:13])[CH2:10][CH3:11])=[CH:15][N:16]=[CH:17]2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: CCC(O)c1cncn1C1CCCc2ccccc21
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CCC(=O)c1cncn1C1CCCc2ccccc21
Reaction time: 4 h
Yield: 12.3 %

Procedure:
A solution of 42 parts of chromium(VI) oxide and 66 parts of pyridine in 665 parts of dichloromethane was stirred for 20 minutes at room temperature. A solution of 19 parts of α-ethyl-1-(1,2,3,4-tetrahydro-1-naphthalenyl)-1H-imidazole-5-methanol in 13.3 parts of dichloromethane was added dropwise to the thus obtained mixture. Upon complete addition, stirring was continued for 4 hours at room temperature. The reaction mixture was poured into water and the layers were separated. The organic layer was washed twice with water and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was dried for a long time in vacuo at 100° C., yielding 2.2 parts (12.3%) of 1-[1-(1,2,3,4-tetrahydro-1-naphthalenyl)-1H-imidazol-5-yl]-1-propanone as an oily residue (compound 2.53).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[C:7]([O:10][C:11]1[C:16]([O:17][C:18](=[O:20])[CH3:19])=[CH:15][N:14]=[C:13]([C:21]([OH:23])=O)[CH:12]=1)(=[O:9])[CH3:8].C(OC(C)C)(C)C>C(Cl)Cl>[ClH:2].[C:7]([O:10][C:11]1[C:16]([O:17][C:18](=[O:20])[CH3:19])=[CH:15][N:14]=[C:13]([C:21]([Cl:2])=[O:23])[CH:12]=1)(=[O:9])[CH3:8]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(=O)Oc1cnc(C(=O)O)cc1OC(C)=O
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: CC(=O)Oc1cnc(C(=O)Cl)cc1OC(C)=O
Product: Cl
Yield: 158.5 %

Procedure:
To a suspension of phosphorus pentachloride (4.6 g) in methylene chloride (40 ml) was added 4,5-diacetoxy-2-pyridinecarboxylic acid (4.5 g) at -20° C. with stirring. The stirring was continued for an hour at -18°~12° C. To the reaction mixture was added diisopropyl ether (80 ml) below 0° C. The resulting precipitates were collected by filtration, washed with diisopropyl ether and dried over phosphorus pentoxide to give 4,5-diacetoxy-2-pyridinecarbonyl chloride hydrochloride (5.15 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:20])[N:3]=1.B([C:24]1[CH:35]=[CH:34][C:27]([CH2:28][C@@H:29]([C:31]([OH:33])=[O:32])[NH2:30])=[CH:26][CH:25]=1)(O)O.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[NH2:30][CH:29]([CH2:28][C:27]1[CH:34]=[CH:35][C:24]([C:2]2[N:3]=[C:4]([NH2:20])[N:5]=[C:6]([O:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([F:13])([F:12])[F:11])[N:7]=2)=[CH:25][CH:26]=1)[C:31]([OH:33])=[O:32]
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Reactant: Nc1nc(Cl)nc(OC(c2ccccc2)C(F)(F)F)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Nc1nc(OC(c2ccccc2)C(F)(F)F)nc(-c2ccc(CC(N)C(=O)O)cc2)n1
Temperature: 150 °C
Yield: 7.4 %

Procedure:
A microwave vial was charged with 4-chloro-6-[2,2,2-trifluoro-1-phenyl-ethoxy]-[1,3,5]triazine-2-ylamine (33 mg, 0.1 mmol), 4-borono-L-phenylalanine (31 mg, 0.15 mmol), 1 ml of actonitrile, and 0.7 ml of water. Aqueous sodium carbonate (0.3 ml, 1M) was added to above solution followed by 5 mol percent dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes by microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, was then purified with Prep-LC to give 3.2 mg 2-amino-3-{4-[4-amino-6-(1-phenyl-2,2,2-trifluoro-ethoxy]-[1,3,5]triazin-2-yl]-phenyl)-propionic acid. 1H NMR (300 MHz, CD3OD) δ 8.22 (d, J=8.20 Hz, 2H), 7.52 (m, 2H), 7.33 (m, 5H) 6.62 (m, 1H), 4.19 (t, 1H), 3.1-3.33 (m, 2H).
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:17][S:18]C(=O)C)[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C.Cl>O.N>[SH:4][CH2:5][CH:6]([CH2:17][SH:18])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8]
Reactant: CC(=O)SCC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Agent: N
Solvent: O
Product: O=C(O)[C@@H]1CCCN1C(=O)C(CS)CS

Procedure:
N-[(2-Acetylthiomethyl-3-(acetylthio)propanoyl]-L-proline (1.2 g.) is dissolved in a mixture of water (12 ml.) and concentrated ammonia (12 ml.) under an atmosphere of argon. After twenty minutes, the mixture is acidified with concentrated hydrochloric acid. The crystalline precipitate N-(2-mercaptomethyl-3-mercaptopropanoyl)-L-proline is filtered and dried, yield 0.63 g., m.p. 138°-140°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][NH:12][CH2:13][CH2:14][C:15]([NH:17][CH3:18])=[O:16])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(N(CC)CC)C.[Br:26][C:27]1[C:28](Cl)=[N:29][C:30]([Cl:33])=[N:31][CH:32]=1>C(Cl)Cl>[Br:26][C:27]1[C:28]([N:12]([CH2:11][C:5]2[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:13][CH2:14][C:15]([NH:17][CH3:18])=[O:16])=[N:29][C:30]([Cl:33])=[N:31][CH:32]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CNC(=O)CCNCc1cc(OC)cc(OC)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)CCN(Cc1cc(OC)cc(OC)c1)c1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 26.2 %

Procedure:
3-[(3,5-dimethoxyphenyl)methylamino]-N-methyl-propanamide (Intermediate 98; 1 g, 3.96 mmol) was dissolved in DCM (10 mL) and triethylamine (0.68 mL, 4.36 mmol). 5-bromo-2,4-dichloropyrimidine (Aldrich; 993 mg, 4.36 mmol) was added and the mixture stirred at room temperature for 18 hours. The mixture was diluted with DCM and washed with water, brine, dried (MgSO4), filtered and evaporated to give a yellow gum which was purified on a 40 g ISCO companion eluting with 50-70% ethyl acetate in iso-hexane to give the title compound as a white solid (461 mg, 26%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][P:5]([CH2:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:8])[O:6][CH3:7].[CH2:17]1[C@@H]2OC(C[C@@H]2[C@@H](CO)[C@@H]1O)=O.C(O)(=O)C>C1COCC1>[CH3:3][O:4][P:5]([CH2:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:17])[CH3:15])(=[O:8])[O:6][CH3:7]
Reactant: CCCCCC(=O)CP(=O)(OC)OC
Reactant: O=C1C[C@@H]2[C@@H](CO)[C@H](O)C[C@@H]2O1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)CCCC(C)C)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the suspension of sodium hydride (NaH) (60%, 250 mg) in THF (40 ml) was added dropwise dimethyl(2-oxoheptyl)phosphonate, and the reaction solution was stirred for 30 min. A THF solution (40 ml) of the aldehyde (2) previously prepared by Collins oxidization of (−)-Corey lactone (1) (2 g) was added. Reaction was maintained at room temperature overnight, and then acetic acid was added. After the usual work-up, an α,β-unsaturated ketone (3) was obtained. Yield: 1.95 g (50%).
Reaction SMILES: [P:1]([O-:35])([O:31][CH2:32][CH2:33]Br)([O:3][CH2:4][CH:5]([O:29][CH3:30])[CH2:6][O:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:2].[S:36]1[CH:40]=[CH:39][N:38]=[CH:37]1>>[P:1]([O-:35])([O:31][CH2:32][CH2:33][C:37]1[S:36][CH:40]=[CH:39][NH+:38]=1)([O:3][CH2:4][CH:5]([O:29][CH3:30])[CH2:6][O:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(COP(=O)([O-])OCCBr)OC
Reactant: c1cscn1
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(COP(=O)([O-])OCCc1[nH+]ccs1)OC
Temperature: 60 °C

Procedure:
A mixture of 2.0 g of the phosphate ester obtained in Example 10 and 4.5 g of thiazole is stirred and warmed at 60° C. for 5 days. The thiazole is distilled off under reduced pressure, and 50 ml of methanol and 2 g of silver carbonate are added to the residue. The mixture is heated under reflux for 2 hours. After filtration, the filtrate is evaporated to dryness, and the residue is separated and purified by silica gel chromatography [eluent: chloroform-methanol-water (65:25:4)] and crystallized from chloroform-acetone to obtain the contemplated product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])[N:9]=2)[CH:3]=1.[CH3:29][N:30](C)C=O>COC(C)(C)C.[C-]#N.[C-]#N.[Zn+2].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>[C:17]([N:14]1[CH2:15][CH2:16][C:11]2[N:10]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([CH:7]=[CH:6][N:5]=3)[C:29]#[N:30])[C:12]=2[CH2:13]1)(=[O:19])[CH3:18]
Reactant: CN(C)C=O
Reactant: CC(=O)N1CCc2c(c(-c3cc(Br)ccn3)nn2Cc2ccc(F)cc2F)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: COC(C)(C)C
Product: CC(=O)N1CCc2c(c(-c3cc(C#N)ccn3)nn2Cc2ccc(F)cc2F)C1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
To a solution of Zn(CN)2 (39 mg, 0.335 mmol) and tetrakis(triphenylphosphine)palladium(0) (19 mg, 0.016 mmol) in dry N,N-dimethylformamide (0.6 ml) at 150° C. was slowly added a solution of 1-[3-(4-Bromo-pyridin-2-yl)-1-(2,4-difluoro-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (6j) (0.15 g, 0.335 mmol) in dry N,N-dimethylformamide (1 ml). The mixture was stirred at 150° C. for 3 h and then at 25° C. for 16 h. The mixture was diluted with methyl-tert-butylether, filtrated over Celite, washed with water, dried over Na2SO4, filtrated and evaporated to dryness. The residue was suspended in methanol, and the solid was filtrated off to give 67 mg of 2-[5-Acetyl-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-isonicotinonitrile (13a).
Reaction SMILES: [NH2:1][NH2:2].Cl[C:4]([O:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])[CH3:9])=[O:5]>C(Cl)Cl>[N+:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH:8]([CH3:9])[CH2:7][O:6][C:4]([NH:1][NH:2][C:4]([O:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])[CH3:9])=[O:5])=[O:5])([O-:18])=[O:17]
Reactant: NN
Reactant: CC(COC(=O)Cl)c1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Product: CC(COC(=O)NNC(=O)OCC(C)c1ccccc1[N+](=O)[O-])c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.6 %

Procedure:
A solution of hydrazine (0.32 mL, 10.25 mmol) in DCM (20 mL) was added dropwise to a solution of 2-(2-nitrophenyl)propyl chloroformate (5.0 g, 20 mmol) in methylene chloride (25 mL) over a period of 30 min. The reaction mixture was stirred at room temperature for an additional 15 min. The solvent was evaporated and the residue was purified on a silica gel column. Elution of the column with 20% ethyl acetate in hexanes gave 1.46 g (3.26 mmol, 32% yield) of di-(2-(2-nitrophenyl)propoxycarbonyl) hydrazine. 1H-NMR (300 MHz, DMSO-d6): δ 9.06-8.73 (d, 1 H, CONH), 7.84 (d, J=7.8 Hz, 1 H, Ar—H), 7.63 (m, 2 H, Ar—H), 7.48 (m, 1 H, Ar—H), 4.20 (m, 2 H, CH2), 3.39 (m, 1 H, CH), 1.26 (d, J=6.9 Hz, 3 H, CH3). 13C-NMR (75 MHz, DMSO-d6): δ 156.19 (OCOR), 149.85 (C ipso to NO2), 136.53 (C ipso to CH(CH3)CH2OCOR), 132.91 (C para to NO2), 128.52 (C para to CH(CH3)CH2OCOR), 127.76 (C ortho to CH(CH3)CH2OCOR), 123.77 (C ortho to NO2), 67.86 (CH2OCOR), 33.30 (CH), 17.99 (CH3). Mass analysis (MALDI-TOF): calculated for C20H22N4O8 446.42, found 446.24 (C20H22N4O8Na 469.38 is the major peak). TLC: 5% methanol in chloroform, Rf=0.7.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]5)=[CH:18][CH:17]=4)[CH:14]=3)[N:9](S(C3C=CC(C)=CC=3)(=O)=O)[CH:8]=2)=[C:5]([CH3:45])[N:4]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([CH3:53])[CH:48]=2)[N:3]=1.[OH-].[Li+]>C1COCC1.CO.O>[CH3:1][C:2]1[C:6]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:16]4[CH:17]=[CH:18][C:19]([N:22]5[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]5)=[CH:20][CH:21]=4)[CH:14]=3)[NH:9][CH:8]=2)=[C:5]([CH3:45])[N:4]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([CH3:53])[CH:48]=2)[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(C)c4)c3C)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(Cn2nc(C)c(-c3c[nH]c4ncc(-c5ccc(N6CCN(C(=O)OC(C)(C)C)CC6)cc5)cc34)c2C)c1
Yield: 34.7 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl 4-(4-(3-(3,5-dimethyl-1-(3-methylbenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (90 mg, 0.1 mmol) was hydrolyzed by lithium hydroxide (9 mg, 0.3 mmol), THF/Methanol/water (1/1/0.5 ml) to afford 20 mg (29% yield) of the titled compound. MS: m/z=577.2 (M+1).
Reaction SMILES: N1C=CN=C1.[S:6]1[CH:10]=[CH:9][N:8]=[C:7]1[NH2:11].[S:12](Cl)(Cl)(=[O:14])=[O:13].Cl.[Br:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][NH:23][CH2:24]2.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[Br:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][N:23]([S:12]([NH:11][C:7]1[S:6][CH:10]=[CH:9][N:8]=1)(=[O:14])=[O:13])[CH2:24]2
Reactant: O=S(=O)(Cl)Cl
Reactant: Brc1cccc2c1CCNC2
Reactant: Nc1nccs1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1nccs1)N1CCc2c(Br)cccc2C1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 52 %

Procedure:
A solution of imidazole (1.530 g, 22.47 mmol) and thiazol-2-amine (0.750 g, 7.49 mmol) in 8 mL DCM was cooled to −78° C. and was treated with sulfuryl chloride (0.609 ml, 7.49 mmol). After stirring for 20 minutes, the cooling bath was removed and the reaction mixture was allowed to stir for an additional 30 minutes. 5-Bromo-1,2,3,4-tetrahydroisoquinoline hydrochloride (ASW Medchem, Brunswick, N.J., 1.396 g, 5.62 mmol) was added, followed by triethylamine (7.31 ml, 52.4 mmol). The reaction mixture was then heated to 80° C. for 30 minutes. The mixture was cooled to rt and poured into 1N citric acid solution before being extracted into EtOAc. The organics were dried over MgSO4 and concentrated. Purification of the residue by silica gel column chromatography (0 to 100% EtOAc/heptane) gave 5-bromo-N-(thiazol-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (1.092 g, 2.92 mmol). [M+H]+=375.6.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]#[CH:20])[C:5]([N:7]1[CH:13]2[CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12]2)=[O:6].[Cl-:21].[NH4+]>[Cl-].[Zn+2].[Cl-].C(Cl)(Cl)Cl>[Cl:21][CH:13]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[NH:7][C:5](=[O:6])[C:4]1[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]#[CH:20])=[C:2]([F:1])[CH:3]=1
Reactant: C#CCOc1ccc(C(=O)N2C3CCCCC32)cc1F
Reactant: [Cl-]
Agent: [NH4+]
Agent: [Zn+2]
Solvent: ClC(Cl)Cl
Product: C#CCOc1ccc(C(=O)NC2CCCCC2Cl)cc1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 2 ml of chloroform and 229 mg of zinc (II) chloride was stirred at room temperature for 5 minutes. Then, a mixture of 230 mg of 7-[3-fluoro-4-(2-propynyloxy)benzoyl]-7-azabicyclo[4.1.0]heptane and 2 ml of chloroform was added dropwise thereto at room temperature, and the resulting mixture was stirred at room temperature for 5 hours. Then, an aqueous saturated ammonium chloride solution was added to the reaction mixture, and this was extracted with chloroform. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with hexane to obtain 0.20 g of N-(2-chlorocyclohexyl)-3-fluoro-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 110 of the present invention) represented by the formula:
Reaction SMILES: Br[C:2]1[C:3]([F:27])=[CH:4][C:5]([F:26])=[C:6]([C:8]23[CH2:17][CH2:16][O:15][CH2:14][CH:13]2[CH2:12][S:11][C:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:9]3)[CH:7]=1.[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.C(O)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>[F:26][C:5]1[CH:4]=[C:3]([F:27])[C:2]([C:32]2[CH:33]=[N:28][CH:29]=[N:30][CH:31]=2)=[CH:7][C:6]=1[C@:8]12[CH2:17][CH2:16][O:15][CH2:14][CH:13]1[CH2:12][S:11][C:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:9]2
Reactant: CC(C)(C)OC(=O)NC1=NC2(c3cc(Br)c(F)cc3F)CCOCC2CS1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(-c4cncnc4)c(F)cc3F)CCOCC2CS1
Temperature: 97 °C
Yield: 86.2 %

Procedure:
A mixture of tert-butyl 8a-(5-bromo-2,4-difluorophenyl)-4,4a,5,7,8,8a-hexahydropyrano[4,3-d][1,3]thiazin-2-ylcarbamate (0.300 g, 0.647 mmol) in 1,2-dimethoxyethane (10 mL), ethanol (4 mL) and water (5 mL) is purged with nitrogen and heated to 97° C. Pyrimidine-5-boronic acid (0.655 g, 5.18 mmol), cesium carbonate (1.90 g, 5.83 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.091 g, 0.129 mmol) is added in a single portion and the reaction is heated at 97° C. for 20 minutes. The reaction is cooled, diluted with water, and extracted with EtOAc. The organic layer is dried over Na2SO4 and the crude product is purified by silica gel chromatography eluting with a linear gradient of 5% to 100% EtOAc in hexanes to give the title compound (0.258 g, 86%). ES/MS (m/e): 463 (M+1).
Reaction SMILES: [N:1]1([C:7]2C3C(=CC=CC=3)N(C3C=CC(C(F)(F)F)=CC=3)[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N+](NC(N)=O)([O-])=[O:27].CN(C)C=O>O>[N:1]1([C:7]([NH2:8])=[O:27])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)c1ccc(-n2nc(N3CCNCC3)c3ccccc32)cc1
Reactant: NC(=O)N[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)N1CCNCC1

Procedure:
A mixture of 5.5 g of 3-(1-piperazinyl)-1-[4-(trifluoromethyl)phenyl]-1H-indazole, 4.8 g of nitrourea, and 80 ml of dimethylformamide was heated on a steam bath for 15 minutes. The reaction mixture was then poured into water and the resulting precipitate was collected, washed with water, and dried. The precipitate was purified on a Water's Model 500 Preparative High Pressure Liquid Chromatograph (2×) utilizing two silica gel columns and chloroform/methanol (5%) as the eluent. Concentration of the appropriate fractions yielded a solid which was recrystallized from acetonitrile to afford 2.3 g (37%) of 4-[1-(4-trifluoromethyl)phenyl)-1H-indazol-3-yl]-1-piperazine carboxamide, m.p. 138°-140°.
Reaction SMILES: C1([CH:7](C)[C:8]([OH:10])=O)C=CC=CC=1.S(Cl)([Cl:14])=O.[C:16]1([CH3:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[C:16]1([CH2:22][CH2:7][C:8]([Cl:14])=[O:10])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccccc1
Reactant: O=S(Cl)Cl
Reactant: CC(C(=O)O)c1ccccc1
Solvent: c1ccncc1
Product: O=C(Cl)CCc1ccccc1
Reaction time: 1 h

Procedure:
To a stirred suspension of phenylpropionic acid (120 g) in toluene (120 ml) and pyridine (6 ml) was added thionyl chloride (115 ml), vigorous gassing ensued and the temperature fell rapidly to 5° C. Reaction was complete in 1 h and the solvent was evaporated in vacuo. The residue was redissolved in toluene (120 ml), the solution was filtered to remove pyridine hydrochloride and the filtrate was evaporated in vacuo to give 166 g of phenylpropionyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[N:13]3[CH2:14][CH:15](C(O)(C)C)[CH2:16][C@@H:17]([O:18][C:19]4[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=4)[C:12]3=[N:11][N:10]=2)[CH:6]=[CH:5][C:4]=1[N:32]1[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]1.[C:38]([OH:48])(=[O:47])[CH:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[OH:40].[CH3:49][CH2:50][CH2:51]CCC>C(O)C>[C:38]([O:48][C:50]([C@@:17]1([O:18][C:19]2[CH:20]=[C:21]([F:27])[C:22]([F:26])=[C:23]([F:25])[CH:24]=2)[CH2:16][CH2:15][CH2:14][N:13]2[C:9]([C:7]3[CH:6]=[CH:5][C:4]([N:32]4[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]4)=[C:3]([O:2][CH3:1])[N:8]=3)=[N:10][N:11]=[C:12]12)([CH3:51])[CH3:49])(=[O:47])[C@H:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[OH:40]
Reactant: CCCCCC
Reactant: COc1nc(-c2nnc3n2CC(C(C)(C)O)C[C@H]3Oc2cc(F)c(F)c(F)c2)ccc1-n1cnc(C)c1
Reactant: O=C(O)C(O)c1ccccc1
Solvent: CCO
Product: COc1nc(-c2nnc3n2CCC[C@]3(Oc2cc(F)c(F)c(F)c2)C(C)(C)OC(=O)[C@@H](O)c2ccccc2)ccc1-n1cnc(C)c1
Reaction time: 3 h

Procedure:
To a mixture of 2-{(8R)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-8-(3,4,5-trifluorophenoxy)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}propan-2-ol (0.50 g) in ethanol (2 mL) was added a mixture of (+)-mandelic acid (148 mg) in ethanol (1 mL) at room temperature. To the reaction mixture was added hexane/IPE at room temperature, and the mixture was stirred for 3 hr. The crystals were collected by filtration and dried to give the title compound (0.55 g).
Reaction SMILES: Cl[C:2]1[N:21]=[C:5]2[C:6]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:20][S:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:35][C:32]3[CH:31]=[CH:30][C:29]([N:26]4[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]4)=[CH:34][CH:33]=3)[N:21]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:19])=[O:18]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CS(=O)(=O)c1ccccc1Nc1cccn2nc(Cl)nc12
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(Nc5ccccc5S(C)(=O)=O)cccn4n3)cc2)CC1

Procedure:
N(8)-(2-Methanesulfonyl-phenyl)-N(2)-[4-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonyl-phenyl)-amine (57.0 mg, 0.176 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (37.0 mg, 0.193 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (20.0 mg, 0.0366 mmol) as the ligand in a manner analogous to Step 2d and was isolated as a tan foam (0.037 g, 44%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.46 (s, 1H), 8.11 (d, J=6.1 Hz, 1H), 7.98 (d, J=7.7 Hz, 1H), 7.57-7.45 (m, 4H), 7.11 (t, J=7.3 Hz, 1H), 6.96 (d, J=7.7 Hz, 2H), 6.78 (t, J=7.0 Hz, 1H), 6.67 (s, 1H), 3.18-3.12 (m, 7H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=478 (MH)+.
Reaction SMILES: F[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:15][CH3:16])[CH:3]=1.CCN(C(C)C)C(C)C.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][NH2:35])=[CH:30][CH:29]=1>CN(C)C=O.O>[CH3:16][O:15][C:4]1[CH:3]=[C:2]([NH:35][CH2:34][C:31]2[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COc1ccc(CN)cc1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(F)cc1OC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])c(NCc2ccc(OC)cc2)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a solution of methyl 4-fluoro-2-methoxy-5-nitrobenzoate (40 g, 174.55 mmol) in N,N-dimethylformamide (1000 mL) was added DIEA (45.2 g, 349.74 mmol). Then (4-methoxyphenyl)methanamine (31.1 g, 226.71 mmol) was added dropwise with stirring for 1 hour at 25° C. The reaction mixture was diluted with water (2 L). The solids were collected by filtration to afford methyl 2-methoxy-4-(4-methoxybenzylamino)-5-nitrobenzoate as a yellow solid (44 g, 75%).