Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].ClC(Cl)(O[C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH3:37][C:38]1[CH:50]=[CH:49][CH:48]=[CH:47][C:39]=1[CH2:40][N:41]1[CH2:45][CH2:44][CH:43]([NH2:46])[CH2:42]1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29]([NH:46][CH:43]2[CH2:44][CH2:45][N:41]([CH2:40][C:39]3[CH:47]=[CH:48][CH:49]=[CH:50][C:38]=3[CH3:37])[CH2:42]2)=[O:35])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: Cc1ccccc1CN1CCC(N)C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CCN(Cc5ccccc5C)C4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
Chloroform (10 ml) and triethylamine (2 ml) were added to 4-[(6,7-dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (100 mg) to prepare a solution. Triphosgene (101 mg) was added to the solution, and the mixture was stirred at room temperature for 30 min. 1-(2-Methylbenzyl)-3-pyrrolidinamine (88 mg) was then added thereto, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/acetone for development. Diethyl ether was added to the purification product, and the precipitated crystal was collected by filtration and was washed to give the title compound (68 mg, yield 41%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[N:7]3[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.CCN(CC)CC.[S:26](Cl)([CH3:29])(=[O:28])=[O:27]>C(Cl)Cl.O>[CH3:29][S:26]([O:17][CH:14]1[CH2:15][CH2:16][N:7]2[C:8](=[N:9][C:10]3[C:5]([C:6]2=[O:18])=[CH:4][CH:3]=[C:2]([Br:1])[CH:11]=3)[CH2:12][CH2:13]1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: O=c1c2ccc(Br)cc2nc2n1CCC(O)CC2
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCc2nc3cc(Br)ccc3c(=O)n2CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 3-bromo-8-hydroxy-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one (290 mg, 0.938 mmol) and excess Et3N in DCM (10 mL) was added Ms-Cl (0.76 mL). The mixture was stirred for 1.5 h at room temperature. Then the reaction mixture was diluted with water and extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the crude product was directly used for the next step. MS (ESI): 387, 389 (MH+).
Reaction SMILES: ClC([O:4][CH3:5])Cl.[CH3:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[CH3:13]>>[CH3:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][C:12]=1[CH3:13])[CH:5]=[O:4]
Reactant: COC(Cl)Cl
Reactant: Cc1ccccc1C
Product: Cc1ccc(C=O)cc1C

Procedure:
The above reaction of Example 68(A) is repeated except that o-xylene and dichloromethyl methylether are the starting materials. Using the same reaction conditions and techniques, there is obtained 3,4-dimethylbenzaldehyde.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:11])/[CH:6]=[CH:7]/[CH2:8][CH2:9][CH3:10])[CH2:3][CH2:2]1.OO.NC(N)=[O:16].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([NH:4][C:5]([CH:6]2[CH:7]([CH2:8][CH2:9][CH3:10])[O:16]2)=[O:11])[CH2:3][CH2:2]1
Reactant: NC(N)=O
Reactant: CCC/C=C/C(=O)NC1CC1
Agent: OO
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCCC1OC1C(=O)NC1CC1
Temperature: 35 °C
Reaction time: 2 h

Procedure:
To a three-neck 250 mL round bottom flask equipped with mechanical stirrer and containing compound 37 (10.0 g, 65.3 mmol) and urea hydrogen peroxide (UHP) (25.0 g, 4.0 eq.) in CH2Cl2 (100 mL, 10 vol) at 0° C., was added trifluoroacetic anhydride (41.1 g, 27.2 mL, 3.0 eq.). The reaction mixture was heated to 35±5° C. and stirred for 2 hours. After cooling the reaction mixture down to room temperature, another aliquot of trifluoroacetic anhydride (13.7 g, 9.0 mL, 1.0 eq.) was added. The reaction mixture was heated again to 35±5° C. and stirred for another 3 hours. The reaction mixture was then again cooled to 0° C. and quenched by adding saturated NaHCO3 (5 vol.) slowly and stirring for 30 minutes. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (50 mL, 5 vol). The combined organic layer was dried and evaporated to afford the crude product, N-cyclopropyl-3-propyloxirane-2-carboxamide (38), as a pale yellow oil. The crude product was used for the next step without further purification.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH2:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:14]=3[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].CCOC(C)=O.Cl>O1CCOCC1.O>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=2)[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:14]=3[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(CN(c2nc3cc(O)ccc3n2C)C2CCC(C(C)(C)C)CC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1c(N(Cc2ccc(C(=O)O)cc2)C2CCC(C(C)(C)C)CC2)nc2cc(O)ccc21
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution of the title compound of Example 15 Step A (0.09 mmol, 40 mg) in 1 mL of dioxane was added LiOH (1 mmol, 24 mg) in 0.5 mL of H2O. The reaction mixture was stirred at 40° C. for 1 h. The reaction mixture was taken up in dilute pH 7 buffer and EtOAc, and acidified with 2 N HCl until two clear layers formed after agitation. The organic layer was collected and the aqueous layer was washed 2× with EtOAc. The combined organic layers were dried with Na2SO4 and concentrated under reduced pressure to afford the acid as a beige solid. HPLC A: 2.01 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14])[C:5]([N:7]=[C:8]=[O:9])=O.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:20][C:19]=1[NH:32][NH:33]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:20][C:19]=1[N:32]1[C:8](=[O:9])[NH:7][C:5]([C:4]2[CH:10]=[CH:11][C:12]([C:13]([F:16])([F:15])[F:14])=[C:2]([F:1])[CH:3]=2)=[N:33]1
Reactant: CC(C)(C)OC(=O)NNc1cc(CNC(=O)C(C)(C)C)ccc1Cl
Reactant: O=C=NC(=O)c1ccc(C(F)(F)F)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(C(F)(F)F)c(F)c3)[nH]c2=O)c1
Yield: 68 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 3-fluoro-4-(trifluoromethyl)benzoyl isocyanate (Intermediate-99, 2.0 g), tert-butyl 2-(2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}phenyl)hydrazinecarboxylate (Intermediate-94, 1.0 g), DCM (15 mL), and trifluoro acetic acid (3.0 mL) to afford 0.900 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.12 (s, 9H), 4.29 (d, J=5.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 1H), 7.44 (s, 1H), 7.62 (d, J=8.7 Hz, 1H), 7.86-8.10 (m, 3H), 8.19 (m, 1H), 12.86 (s, 1H); MS (m/z): 471.35 (M+H)+.
Reaction SMILES: C([O:8][C:9](=[O:29])[CH2:10][N:11]1[C:16]([CH3:17])=[C:15]([Cl:18])[N:14]=[C:13]([NH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:12]1=[O:28])C1C=CC=CC=1.C1COCC1.CO.O[Li].O>O>[Cl:18][C:15]1[N:14]=[C:13]([NH:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:12](=[O:28])[N:11]([CH2:10][C:9]([OH:29])=[O:8])[C:16]=1[CH3:17]
Reactant: Cc1c(Cl)nc(NCCc2ccccc2)c(=O)n1CC(=O)OCc1ccccc1
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Cl)nc(NCCc2ccccc2)c(=O)n1CC(=O)O
Reaction time: 2 h

Procedure:
Water (1 ml) was added to a stirred solution of (5-chloro-6-methyl-2-oxo-3-phenethylamino-2H-pyrazin-1-yl)acetic acid benzyl ester (436 mg) in 1:1 THF/MeOH (6 ml) and LiOH.H2O was added to the resulting mixture. After 2 h, the reaction mixture was diluted with water and washed with EtOAc. The aqueous layer was acidified with 10% KHSO4 solution to give a cloudy mixture that was extracted with methylene chloride. The organic layer was dried (Na2SO4) and evaporated in vacuo to give 1-4 as a crystalline solid. 1H NMR (DMSO-d6) δ2.19 (s, 3 H, Me), 2.84 (t, J=7.0 Hz, 2 H, PhCH2), 3.45 (q, J=7.0 Hz, 2 H, CH2NH), 4.70 (s, 2 H, CH2CO2), 7.18-7.31 (m, 5 H, Ph), 7.46 (br s, 1H, NH).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][NH:7][C:6](=[O:10])[C:5]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:2].[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)[C:6](=[O:10])[C:5]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)c1c(OCC)cc[nH]c1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1c(OCC)ccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
A mixture of ethyl 4-ethoxy-2-oxo-1,2-dihydropyridine-3-carboxylate (60 g, 0.284 mol), 4-fluoro phenylboronic acid (120 g, 0.853 mol), Cu(AcO)2 (113 g, 0.568 mol) and pyridine (88 g, 1.137 mol) in CH2Cl2 (500 mL) was stirred at ambient temp (˜25° C.) for 4 h open to air. The reaction mixture was filtered and the solids were washed with water. The filtrate was extracted with CH2Cl2 (2×250 mL). The combined organic layers were dried over Na2SO4 and concentrated to afford ethyl 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate. The product was carried forward without further purification. (77 g, 95% yield).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]([CH3:27])([CH3:26])[C:22]([O:24][CH3:25])=[O:23])[CH:19]=2)[NH:14][C:13]=1I)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][C:31]=1B(O)O.[C:40]([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CO.C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][C@H:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]([CH3:27])([CH3:26])[C:22]([O:24][CH3:25])=[O:23])[CH:19]=2)[NH:14][C:13]=1[C:35]1[CH:30]=[C:31]([CH3:40])[CH:32]=[C:33]([CH3:36])[CH:34]=1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C)c(B(O)O)c1
Reactant: COC(=O)C(C)(C)c1cnc2[nH]c(I)c([C@H](C)COCc3ccccc3)c2c1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C(C)(C)c1cnc2[nH]c(-c3cc(C)cc(C)c3)c([C@H](C)COCc3ccccc3)c2c1
Temperature: 80 °C
Yield: 100 %

Procedure:
A vigorously stirred suspension of methyl (S)-2-[3-(2-benzyloxy-1-methylethyl)-2-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-methylpropanoate (4.00 g, 8.12 mmol), 2,5-dimethylphenylboronic acid (1.83 g, 12.2 mmol) and Pd(dppf)Cl2 ·CH2Cl2 (0.33 g, 0.406 mmol) in toluene/MeOH (5:2; 140 mL) was degassed via three vacuum/nitrogen ingress cycles and the resulting mixture was heated to approximately 80° C. 1M Na2CO3 (20.3 mL, 20.3 mmol) was added dropwise via syringe and the resulting mixture maintained at reflux overnight. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and filtered through celite® washing copiously with ethyl acetate. The filtrate was poured into water and extracted with ethyl acetate (×3). The combined organic extract was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (25% ethyl acetate/hexanes as eluent) to afford the title compound as a colourless foam (3.82 g).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:16]=1[CH:17]=O>>[Cl:14][C:15]1[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][C:16]=1[CH2:17][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1cc(C(F)(F)F)ccc1Cl
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: O=c1cc(N2CCN(Cc3cc(C(F)(F)F)ccc3Cl)CC2)nc[nH]1

Procedure:
6-[4-(2-Chloro-5-trifluoromethyl-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 2-chloro-5-(trifluoromethyl)benzaldehyde. Mass spectrum (ES) MH+=373.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>CCN(CC)CC.C1C=CC=CC=1.[Cu]I.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>[CH3:14][O:13][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6]
Reactant: C#C[Si](C)(C)C
Reactant: COc1cc(C(=O)O)cc(I)c1OC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1cc(C(=O)O)cc(C#C[Si](C)(C)C)c1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 100.6 %

Procedure:
To a stirred solution of 3-iodo-4,5-dimethoxybenzoic acid (6.16 g, 20.0 mmol) in a mixture of Et3N (40 mL) and benzene (40 mL) at room temperature, was added CuI (380 mg, 2 mmol), Pd(PPh3)4 (462 mg, 0.4 mmol) and (trimethylsilyl)acetylene (3.4 mL, 24 mmol). After stirring for 3 days at room temperature, the solvent was removed in vacuo, the residue was diluted with 1 N HCl aqueous solution (300 mL) and then extracted with EtOAc (3×100 mL). The combined organic layer was washed with brine (300 mL), dried over Na2SO4 and concentrated in vacuo to give 3,4-dimethoxy-5-(trimethylsilanylethynyl)benzoic acid (5.6 g). The product was used without further purification.
Reaction SMILES: C(N(CC)[C:4](=[O:32])[CH:5]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)[C:6]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])=[O:7])C.[CH:35]([NH2:48])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[C:36]1([CH:35]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[NH:48][C:4](=[O:32])[CH:5]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)[C:6]([NH:8][S:9]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)(=[O:11])=[O:10])=[O:7])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCN(CC)C(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Reactant: NC(c1ccccc1)c1ccccc1
Product: O=C(NC(c1ccccc1)c1ccccc1)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Yield: 31.6 %

Procedure:
In the same manner as in Example 1 (4), a crude product was obtained using the compound (400 mg) obtained in Example 6 (4) and benzhydrylamine (171 mg). This was purified by silica gel column chromatography to give the title compound (155 mg) as a white powder.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([NH:5][CH2:6][C:7]1([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:4].CCN(CC)CC.[CH:28]1([CH2:31][S:32](Cl)(=[O:34])=[O:33])[CH2:30][CH2:29]1>C(Cl)Cl>[CH:28]1([CH2:31][S:32]([N:16]2[CH2:17][CH2:18][N:13]([C:7]3([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:19])([F:1])[F:20])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]3)[CH2:14][CH2:15]2)(=[O:34])=[O:33])[CH2:30][CH2:29]1
Reactant: O=S(=O)(Cl)CC1CC1
Reactant: O=C(NCC1(N2CCNCC2)CCCCC1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC1(N2CCN(S(=O)(=O)CC3CC3)CC2)CCCCC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirring ice-cold solution of 14 (10.0 g, 34.09 mmol) and Et3N (14.2 mL, 102.27 mmol) in CH2Cl2 (200 mL) was slowly added 1-cyclopropylmethylsulfonyl chloride (5.27 g, 34.09 mmol). The mixture stirred at ambient temperature under an atmosphere of nitrogen for 3 h. The mixture was washed with 2 N NaOH (50 mL), 2 N HCl (50 mL), H2O (50 mL), brine (50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to afford N-((1-(4-(cyclopropylmethylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-2,2,2-trifluoroacetamide (18) as an off-white solid (14.00 g, quantitative): MS (ESI+) m/z 412.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[CH3:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.CC(=O)OCC>>[CH3:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][N:23]([CH2:2][C:3]2[S:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:22][CH2:21]1
Reactant: CSc1ccccc1N1CCNCC1
Reactant: ClCc1nc2cccnc2s1
Solvent: CCOC(C)=O
Product: CSc1ccccc1N1CCN(Cc2nc3cccnc3s2)CC1

Procedure:
The product from Example 38A (150 mg, 0.81 mmol), 1-[2-(methylthio)phenyl]piperazine (160 mg, 0.98 mmol), and D1 EA (280 μL, 1.6 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.37 (s, 3H) 2.75 (m, 4H) 2.97 (m, 4H) 4.06 (s, 2H) 7.13 (m, 3H) 7.56 (dd, J=8.31, 4.58 Hz, 2H) 8.33 (dd, J=8.14, 1.36 Hz, 1H) 8.59 (dd, J=4.58, 1.53 Hz, 1H); (ESI) m/z 357 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:15])[O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.N1C=CC=CC=1.[S:22](Cl)(Cl)=O.[C:26]1([SH:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[CH3:1][N:2]([S:32]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[S:22])[C:3](=[O:15])[O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: CNC(=O)Oc1cccc2ccccc12
Reactant: Sc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CN(C(=O)Oc1cccc2ccccc12)S(=S)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 1-naphthyl methylcarbamate (4.0 g, 0.02 mol) in 20 ml dry tetrahydrofuran was added 1.9 g pyridine (0.024 mol) and 2.5 g thionyl chloride (0.021 mol). The mixture was stirred at room temperature for 6 hours. The reaction mixture was cooled in an ice-water bath and 1.9 g pyridine was added followed by 2.2 g benzenethiol (0.02 mol) added dropwise. Stirring was continued for an additional 1 hour and the mixture was worked up in the usual manner as previously described in Example I. A sample was purified by preparative thin-layer chromatography. Nmr spectrum of the pure product in chloroform-d-TMS showed the following absorptions: δ8.1-6.9 (m, 12H, aromatic protons), 3.2 (s, 3H, NCH3).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:14]4[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=4[S:12][CH:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:44][C:45]1[C:50]([F:51])=[CH:49][CH:48]=[CH:47][C:46]=1[CH2:52][C:53](O)=[O:54].CCN(C(C)C)C(C)C>O.CN(C)C=O>[F:44][C:45]1[C:50]([F:51])=[CH:49][CH:48]=[CH:47][C:46]=1[CH2:52][C:53]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:14]4[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=4[S:12][CH:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)=[O:54]
Reactant: O=C(O)Cc1cccc(F)c1F
Reactant: Nc1nccc2scc(-c3ccc4c(c3)CCN4)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nccc2scc(-c3ccc4c(c3)CCN4C(=O)Cc3cccc(F)c3F)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.4 %

Procedure:
To a 4 mL screw cap vial was added 3-(2,3-dihydro-1H-indol-5-yl)thieno[3,2-c]pyridin-4-amine (100 mg, 0.374 mmol) followed by HATU (142 mg, 0.374 mmol), 2,3-difluorophenylacetic acid (56.7 mg, 0.329 mmol) and DIEA (0.261 mL, 1.496 mmol). N,N-Dimethylformamide (DMF) (2 mL) was added and the reaction was sealed and left to stir at room temperature overnight. The reaction mixture was poured into water (4 mL) and extracted with EtOAc (5 mL). The organics were dried over Na2SO4 and concentrated. The residue was taken up in DCM and purified via normal phase chromatography (0-10% MeOH/DCM). Fractions were collected and concentrated to afford 3-{1-[(2,3-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}thieno[3,2-c]pyridin-4-amine (31 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.12 (d, J=8.1 Hz, 1H) 7.85 (d, J=6.1 Hz, 1H) 7.59 (s, 1H) 7.44 (d, J=6.1 Hz, 1H) 7.32-7.41 (m, 2H) 7.26 (d, J=8.3 Hz, 1H) 7.14-7.24 (m, 2H) 6.06 (d, J=8.8 Hz, 2H) 4.33 (t, J=8.5 Hz, 2H) 4.04 (s, 2H) 3.28 (t, 2H).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[CH2:6][NH:7][C:8](=[O:38])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:37])[C:29]2(CCl)[CH:34]=[CH:33][CH:32]=[CH:31][NH:30]2)[CH:10]=1.[NH:44]1[CH2:48][CH2:47][C@H:46]([NH:49][C:50](=[O:52])[CH3:51])[CH2:45]1.[C:53](=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:50]([NH:49][C@H:46]1[CH2:47][CH2:48][N:44]([CH2:53][C:31]2[N:30]=[C:29]([C:28]([NH:27][C:16]3[CH:17]=[CH:18][C:19]([N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:20][C:15]=3[C:11]3[CH:10]=[C:9]([C:8](=[O:38])[NH:7][CH2:6][C:5]4[CH:39]=[CH:40][CH:41]=[C:3]([C:2]([F:43])([F:1])[F:42])[CH:4]=4)[CH:14]=[CH:13][N:12]=3)=[O:37])[CH:34]=[CH:33][CH:32]=2)[CH2:45]1)(=[O:52])[CH3:51]
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)C2(CCl)C=CC=CN2)c1
Reactant: CC(=O)N[C@H]1CCNC1
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N[C@H]1CCN(Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)n2)C1
Temperature: 60 °C
Reaction time: 3 h
Yield: 45.5 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-(2-(chloromethyl)picolinamido)-5-(piperidin-1-yl)phenyl)isonicotinamide (100 mg, 0.15 mmol, 1.00 equiv, 90%) in N,N-dimethylformamide (3 mL), (S)—N-(pyrrolidin-3-yl)acetamide (42 mg, 0.33 mmol, 2.00 equiv), potassium carbonate (45 mg, 0.33 mmol, 2.00 equiv), and potassium iodide (14 mg, 0.08 mmol, 0.50 equiv). The resulting solution was stirred for 3 h at 60° C. in an oil bath. The resulting solution was diluted with 100 mL of ethyl acetate. The resulting mixture was washed with 2×20 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product (100 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 47.8 mg (39%) of a yellow solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.92 (d, J=6 Hz, 1H), 8.42 (s, 1H), 8.19 (m, 1H), 8.15 (m, 1H), 8.10 (m, 1H), 8.04 (m, 1H), 7.83 (d, J=6 Hz, 1H), 7.74 (m, 3H), 7.61 (m, 2H), 7.52 (m, 1H), 4.65 (m, 4H), 4.22 (m, 1H), 3.80 (m, 1H), 3.69-3.54 (m, 5H), 3.44 (m, 1H), 2.49 (m, 1H), 2.05-2.00 (m, 5H), 1.83-1.66 (m, 5H). MS (ES, m/z): 700 [M+H]+.