Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]2[S:21][C:20]([C:22]3([NH2:26])[CH2:25][CH2:24][CH2:23]3)=[N:19][CH:18]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH2:27]([N:29]=[C:30]=[O:31])[CH3:28]>O1CCCC1.O.[Cl-].[Na+].O>[Cl:1][C:2]1[C:3]([C:17]2[S:21][C:20]([C:22]3([NH:26][C:30]([NH:29][CH2:27][CH3:28])=[O:31])[CH2:25][CH2:24][CH2:23]3)=[N:19][CH:18]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cn1cc(-c2cc3c(-c4cnc(C5(N)CCC5)s4)c(Cl)cnc3[nH]2)cn1
Reactant: CCN=C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)NC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5cnn(C)c5)cc34)s2)CCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 1-(5-(5-chloro-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanamine (30 mg, 0.078 mmol) (Example 121B) in anhydrous tetrahydrofuran (1 mL) was treated with ethyl isocyanate (6.79 μL, 0.086 mmol), and the reaction mixture was stirred at ambient temperature for about 4 hours. The reaction was diluted with water and brine, and extracted with dichloromethane. The extracts were combined and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 2% to 8% methanol in dichloromethane, to provide the title compound. MS ESI(+) m/z 456.2 [M+H]+. 1H NMR (500 MHz, DMSO-d6) ppm 12.34 (s, 1H) 8.26 (s, 1H) 8.22 (s, 1H) 8.16 (s, 1H) 8.03 (s, 1H) 7.06 (s, 1H) 6.75 (s, 1H) 5.93 (t, 1H) 3.89 (s, 3H) 3.01 (dd, 2H) 2.70 (m, 2H) 2.40 (m, 2H) 2.05 (m, 2H) 0.99 (t, 3H).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([N:32]1[CH2:31][CH2:30][CH:29]([NH:28][C:26]([C:22]2[C:18]3=[N:19][CH:20]=[CH:21][C:16]([C:8]4[CH:9]=[C:10]([O:14][CH3:15])[C:11]([F:13])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)=[C:17]3[NH:24][C:23]=2[CH3:25])=[O:27])[CH2:34][CH2:33]1)(=[O:37])[CH3:36]
Reactant: COc1cc(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1cc(-c2ccnc3c(C(=O)NC4CCN(C(C)=O)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f21) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([NH2:12])[N:3]=1.C(N(CC)CC)C.[CH:20]1([CH2:26][NH2:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(O)CCC>[NH2:12][C:4]1[N:3]=[C:2]([NH:27][CH2:26][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=1
Reactant: NCC1CCCCC1
Reactant: Nc1nc(Cl)c2c(n1)CCCC2
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: Nc1nc2c(c(NCC3CCCCC3)n1)CCCC2

Procedure:
A mixture of 4-chloro-5,6,7,8-tetrahydroquinazoline-2-ylamine (107 mg, 0.58 mmol), triethylamine (221 mg, 2.18 mmol), cyclohexylmethylamine (132 mg, 1.17 mmol) and n-butanol (3 ml) was reacted for 4 hours at 80-90° C. According to the post-treatment of Example 1, the object compound was obtained (102 mg, 67.9%).
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28]>ClCCl.C(=O)(O)[O-].[Na+]>[C:16]([O:15][C:13]([N:9]1[CH2:10][CH2:11][N:12]([C:27](=[O:29])[CH3:28])[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNC(c2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
To a mixture of tert-butyl 3-phenylpiperazine-1-carboxylate (400 mg, 1.52 mmol) and triethyl amine (309 mg, 3.05 mmol) in dichloromethane (5 mL) was added acetyl chloride (156 mg, 1.98 mmol) at 0° C. After stirring for 3 h at room temperature, the reaction mixture was diluted with saturated sodium bicarbonate solution and dichloromethane. The aqueous part was extracted with dichloromethane and the combined organic part was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (20/1 dichloromethane/methanol) to afford 4-acetyl-3-phenyl-piperazine-1-carboxylic acid tert-butyl ester (250 mg, 54%). [M-BOC]H+=205.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[S:12][C@@H:11]([CH2:13][C:14]#N)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:19]>C(OCC)C.[H-].C([Al+]CC(C)C)C(C)C.CCCCCC>[C:1]([O:5][C:6]([C@@H:8]1[S:12][C@@H:11]([CH2:13][CH:14]=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@H]1CC[C@H](CC#N)S1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)[C@H]1CC[C@H](CC=O)S1
Reaction time: 2 h

Procedure:
To a stirred solution of trans-5-tert-butoxycarbonyl-2-cyanomethyltetrahydrothiophene (2.3 g) in diethylether (100 ml), 1M diisobutyl-aluminiumhydride dissolved in hexane (12.1 ml) is added at -30° C. and the mixture is stirred for 2 hours at -20°--10° C. 10% aqueous citric acid solution is added to the mixture and extracted with ethyl acetate - benzene (1:1). The organic layer is washed with 10% aqueous citric acid solution, water and saturated sodium chloride solution. The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give trans-5-tert-butoxycarbonyl-2-formylmethyltetrahydrothiophene.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[F:24][CH2:25][CH:26]([CH2:43][F:44])[O:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[N:30][CH:29]=[C:28]([O:27][CH:26]([CH2:25][F:24])[CH2:43][F:44])[CH:33]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CC1(C)OB(c2cncc(OC(CF)CF)c2)OC1(C)C
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncc(OC(CF)CF)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-(2-fluoro-1-fluoromethyl-ethoxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 182.1.1) to give the title compound as a white solid. (HPLC: tR 2.31 min (Method A); M+H=465 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.40-8.37 (m, 1H), 8.36-8.33 (m, 1H), 8.16-8.10 (m, 2H), 8.02-7.97 (m, 1H), 7.59-7.54 (m, 2H), 5.24-5.08 (m, 1H), 4.91-4.65 (m, 4H), 3.90 (s, 3H), 3.58 (s, 3H), 1.96 (s, 3H))
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([O:11][CH:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[C:5]([F:19])=[CH:4][N:3]=1.[H][H]>CO.[Zn+2].[Br-].[Br-].[Pd]>[F:19][C:5]1[C:6]([O:11][CH:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[C:7]([NH2:8])[CH:2]=[N:3][CH:4]=1
Reactant: [H][H]
Reactant: CN1CCC(Oc2c(F)cnc(Br)c2[N+](=O)[O-])CC1
Agent: [Pd]
Agent: [Br-]
Agent: [Zn+2]
Solvent: CO
Product: CN1CCC(Oc2c(N)cncc2F)CC1
Reaction time: 8 h

Procedure:
A solution of 2-bromo-5-fluoro-4-[(1-methyl-4-piperidyl)oxy]-3-nitro-pyridine (96 mg, 0.2873 mmol), ZnBr2 (12.94 mg, 3.080 μL, 0.05746 mmol) and Pd on C, wet, Degussa (31 mg) in methanol (5 mL) was flushed with hydrogen and evacuated (3×) and then stirred under a hydrogen atmosphere overnight. The catalyst was filtered off through a celite pad and washed with methanol and ethyl acetate mixtures and the filtrate was concentrated in vacuo to leave a pale yellow oil that was used in next step without further purification. MS (ES+) 226.1.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[CH:24]=2)[N:19](C2CCCCO2)[N:18]=1>C(Cl)Cl>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=3)[CH:24]=2)[NH:19][N:18]=1
Reactant: FC(F)(F)c1cccc(-c2ccc3c(c2)c(-c2nc4ccccc4[nH]2)nn3C2CCCCO2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1cccc(-c2ccc3[nH]nc(-c4nc5ccccc5[nH]4)c3c2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
TFA (0.5 mL, 6.490 mmol) was added to a solution 3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-5-(3-(trifluoromethyl)phenyl)-1H-indazole (8 mg, 0.017 mmol) in CH2Cl2 (4 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound as an off-white solid in a 50% yield. ESI-MS [M+H]+: 379.2.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][CH3:14])[C:10](=[O:15])[C:9]([F:17])([F:16])[CH2:8][N:7]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:6]=2[N:23]=1.[NH2:24][C:25]1[CH:40]=[CH:39][C:28]([C:29]([NH:31][CH:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=[O:30])=[CH:27][CH:26]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH:18]1([N:7]2[CH2:8][C:9]([F:17])([F:16])[C:10](=[O:15])[N:11]([CH2:12][CH2:13][CH3:14])[C:5]3[CH:4]=[N:3][C:2]([NH:24][C:25]4[CH:26]=[CH:27][C:28]([C:29]([NH:31][CH:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)=[O:30])=[CH:39][CH:40]=4)=[N:23][C:6]2=3)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CN1CCC(NC(=O)c2ccc(N)cc2)CC1
Reactant: CCCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: CCCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3)ncc21
Yield: 62.8 %

Procedure:
A mixture of 0.05 g (0.15 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-propyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-144), 0.05 g (0.17 mmole) of 4-amino-N-(1-methyl-piperidin-4-yl)-benzamide, 0.04 g (0.22 mmole) of p-toluenesulfonic acid monohydrate and 4.0 mL of 2-propanol was heated at 160 degrees for 2 hours in a microwave reactor. The cooled mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phases were extracted with dichloromethane, and the combined organic layers washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with methanol-dichloromethane (gradient, 0:100-25:75), to give 0.051 g of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-5-propyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methyl-piperidin-4-yl)-benzamide (I-147).
Reaction SMILES: N([C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[C:5]([C:10]([F:13])([F:12])[F:11])[N:4]=1)N.[OH-].[Na+].Cl[O-].[Na+]>ClCCl>[Cl:9][C:8]1[CH:3]=[N:4][C:5]([C:10]([F:12])([F:11])[F:13])=[CH:6][CH:7]=1
Reactant: NNc1nc(C(F)(F)F)ccc1Cl
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: ClCCl
Product: FC(F)(F)c1ccc(Cl)cn1
Reaction time: 3 h
Yield: 110.9 %

Procedure:
The remaining 2-hydrazino-3-chloro-6-trifluoromethyl pyridine (63.36 g, 0.299 mol) was dissolved in dichloromethane (600 g) and charged to a 2 L, three-neck flask with a mechanical stirrer. Sodium hydroxide (300 g, 1N solution) was added, and sodium hypochlorite (NaCl) (448 g, 0.301 mol, 5% solution) was added in one portion. The solution was stirred for three hours after addition of the sodium hypochlorite, at which point sampling indicated the reaction was complete. The layers were separated, and the aqueous layer was extracted twice with dichloromethane (150 mL). The organic layers were combined, washed with water, dried with magnesium sulfate, filtered, and concentrated on the rotovap to give 60.2 g of 3-chloro-6-trifluoromethyl pyridine.
Reaction SMILES: Br[CH:2]=[C:3]([C:5]1[CH:6]=[C:7]([F:14])[C:8]([O:12]C)=[C:9]([F:11])[CH:10]=1)[CH3:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.[CH3:31][N:32]1[CH2:45][CH2:44][C:35]2[NH:36][C:37]3[CH:38]=[CH:39][C:40]([CH3:43])=[CH:41][C:42]=3[C:34]=2[CH2:33]1>CN(C=O)C.[Cu]I>[CH3:31][N:32]1[CH2:45][CH2:44][C:35]2[N:36](/[CH:2]=[C:3](/[C:5]3[CH:6]=[C:7]([F:14])[C:8]([OH:12])=[C:9]([F:11])[CH:10]=3)\[CH3:4])[C:37]3[CH:38]=[CH:39][C:40]([CH3:43])=[CH:41][C:42]=3[C:34]=2[CH2:33]1
Reactant: COc1c(F)cc(C(C)=CBr)cc1F
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(C)CC2)c1cc(F)c(O)c(F)c1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
5-(1-Bromoprop-1-en-2-yl)-1,3-difluoro-2-methoxybenzene (223 mg, 1.2 mmol) was dissolved in DMF (5 mL) and potassium phosphate (424 mg, 2 mmol) was added followed by copper (I) iodide (19 mg, 0.1 mmol) and L-proline (23 mg, 0.2 mmol). 2,3,4,5-Tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (200 mg, 1 mmol) was added and the mixture purged with nitrogen for 2 min. The reaction mixture was stirred at 85° C. overnight. Water was added and the solid mass was filtered under vacuum. The crude product was purified on silica gel (100-200 mesh) using 0-10% MeOH:DCM as eluent. Yield: 52 mg. 1H NMR (CD3OD, HCl salt) δ (ppm): 7.30 (s, 1H), 7.24 (d, 2H), 7.10 (m, 2H), 7.0 (s, 1H), 4.70 (m, 1H), 4.40 (m, 1H), 3.82 (m, 1H), 3.60 (m, 1H), 3.18 (s, 3H), 3.14 (m, 2H), 2.42 (s, 3H), 1.90 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.I[Si](C)(C)C.C(OC([N:20]1[CH2:25][C:24](=[O:26])[N:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH2:34][O:35][CH3:36])[CH2:22][C:21]1([CH3:38])[CH3:37])=O)(C)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:36][O:35][CH2:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[N:23]1[CH2:22][C:21]([CH3:37])([CH3:38])[NH:20][CH2:25][C:24]1=[O:26]
Reactant: COCOc1ccccc1N1CC(C)(C)N(C(=O)OC(C)(C)C)CC1=O
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCOc1ccccc1N1CC(C)(C)NCC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
0.58 ml of triethylamine (4.10 mmol) and 0.3 ml of iodotrimethylsilane (2.05 mmol) were added to a solution of 497 mg of 4-(2-methoxymethoxyphenyl)-2,2-dimethyl-5-oxopiperazine-1-carboxylic acid t-butyl ester obtained in the above reaction (1.36 mmol) in methylene chloride (14 ml), and the mixture was stirred at 0° C. for 30 minutes. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by basic silica gel (NH type) column chromatography (elution solvent: methylene chloride/methanol=20/1) to obtain 310 mg of the title compound (yield: 86%).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:10])([CH3:9])[CH2:4][S:5]([NH2:8])(=[O:7])=[O:6].[H-].[Na+].Cl[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[CH:21][N:22]=2)[N:19]=1>CN(C=O)C>[CH3:9][C:3]([CH3:10])([CH2:4][S:5](=[O:7])(=[O:6])[NH2:8])[CH2:2][O:1][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[CH:21][N:22]=2)[N:19]=1
Reactant: CC(C)(CO)CS(N)(=O)=O
Reactant: Clc1ccc2nccn2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(COc1ccc2nccn2n1)CS(N)(=O)=O
Temperature: 70 °C
Yield: 88 %

Procedure:
To a solution of 3.5 g of 3-hydroxy-2,2-dimethyl-1-propanesulfonamide in 30 ml of DMF was added by portions 0.85 g of sodium hydride (60%, in oil)with stirring. To the mixture were added 3.18 g of 6-chloroimidazo[1,2-b]pyridazine and then 0.85 g of sodium hydride. The reaction solution was heated at 70° C. for 1.5 hours and then at 100° C. for an hour with stirring, and concentrated under reduced pressure. The residue was added into 100 ml of ice-water, extracted with ethyl acetate and tetrahydrofuran (1:1) (100 ml×4), dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was recrystallized from ethanol to obtain 5.18 g of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:34])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26]C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:35]>>[ClH:35].[ClH:35].[NH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:34]
Reactant: CC(C)(C)OC(=O)NCCCCCCCCCCCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Product: NCCCCCCCCCCCC(=O)N1CCNCC1

Procedure:
4-(12-tert-Butoxycarbonylaminododecanoyl)piperazine-1-carboxylic acid tert-butyl ester (10) (464 mg, 0.96 mmol) was treated with HCl (4 M in dioxane, 8 mL, 32 mmol) at room temperature for 14 hours. The reaction mixture was concentrated in vacuo and further dried under high vacuum. The white solid (342 mg, 99%) was used directly without further purification: m/z ESI 284 [C16H33N3O+H]+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:40])[CH2:10][CH2:11][CH2:12][N:13]1[C:17]2[CH:18]=[CH:19][C:20]([NH2:22])=[CH:21][C:16]=2[N:15]=[C:14]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].[C:41](Cl)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C(Cl)(Cl)Cl>[CH3:40][N:9]([CH3:8])[CH2:10][CH2:11][CH2:12][N:13]1[C:17]2[CH:18]=[CH:19][C:20]([NH:22][C:41](=[O:48])[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:21][C:16]=2[N:15]=[C:14]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCCc1nc2cc(N)ccc2n1CCCN(C)C
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCc1nc2cc(NC(=O)c3ccccc3)ccc2n1CCCN(C)C
Temperature: 25 °C

Procedure:
Triethylamine is added to a solution containing Compound 27 in chloroform, and then benzoyl chloride is added thereto while being cooled with ice. The mixture is stirred at room temperature to give the entitled compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[NH:9][CH:10]=1)=[O:5])[CH3:2].[H-].[Na+].Cl[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([S:30][CH3:31])[N:25]=1>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[CH:12]=2)[N:9]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([S:30][CH3:31])[N:25]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CSc1nccc(Cl)n1
Reactant: CCOC(=O)c1c[nH]c(-c2cccc(C(F)(F)F)c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2ccnc(SC)n2)c(-c2cccc(C(F)(F)F)c2)n1
Temperature: 140 °C
Yield: 74.6 %

Procedure:
To a solution of 2-(3-trifluoromethylphenyl)-1H-imidazole4-carboxylic acid ethyl ester (6.0 g, 0.0211 mol) in dimethyl formamide (60 mL) was added a 60% dispersion of sodium hydride in mineral oil (1.01 g, 0.0253 mol) and stirring was continued until noticeable H2 evolution stopped. 4-Chloro-2-methylthiopyrimidine (3.73 g, 0.0232 mol) was added dropwise and the reaction heated to 120° C. for 2 h and 140° C. overnight. The reaction was cooled and partitioned between H2O (300 mL) and ethyl acetate (300 mL). A small (30 mL) portion of 10% citric acid solution was added before the layers were shaken and separated. The ethyl acetate layer was dried over anhydrous magnesium sulfate and then concentrated to an oil which was chromatographed on silica using 15-35% ethyl acetate in hexanes to yield 6.43 g (75%) of the title compound as an oil.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][C:7]#[N:8])[CH3:3].[Cl:9][CH2:10][CH2:11][CH2:12]I>>[CH3:1][N:2]([CH2:4][CH2:5][CH:6]([CH2:12][CH2:11][CH2:10][Cl:9])[C:7]#[N:8])[CH3:3]
Reactant: ClCCCI
Reactant: CN(C)CCCC#N
Product: CN(C)CCC(C#N)CCCCl

Procedure:
The amine of formula III, when n is equal to 3, p equal to 2 and q equal to zero, is prepared from 4-(N,N-dimethylamino)butyronitrile. This compound is condensed with 3-chloro-l-iodopropane to form 2-[2-(N,N-dimethylamino) ethyl]-5-chloropentanenitrile which, after cyclization, gives 4-cyano-l-methylperhydroazepine. From this compound and using conventional methods, the expected amine is obtained.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[N:13]=[C:12]([S:14][C@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[N:11]=[C:10]([OH:23])[CH:9]=1.[C:24]([S-:26])#[N:25].[K+].BrBr>CN(C=O)C.O>[NH2:25][C:24]1[S:26][C:9]2[C:10]([OH:23])=[N:11][C:12]([S:14][C@H:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH3:16])=[N:13][C:8]=2[N:7]=1
Reactant: N#C[S-]
Reactant: C[C@H](Sc1nc(N)cc(O)n1)c1ccccc1
Agent: BrBr
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](Sc1nc(O)c2sc(N)nc2n1)c1ccccc1
Temperature: 0 °C
Reaction time: 30 h
Yield: 65.7 %

Procedure:
Pyridine (0.6 g, 7.6 mmol) was added to 6-amino-2-{[(1S)-1-phenylethyl]thio}pyrimidin-4-ol (1 g, 4 mmol) and KSCN (1.7 g, 16 mmol) in DMF (20 mL). The reaction mixture was cooled to 0° C. and bromine (0.65 g, 4.0 mmol) was then added in one portion. The reaction mixture was poured into water after 2 h and the orange precipitate was filtered off and washed with water. The solid was suspended in a mixture of DMF (6 mL) and water (2 mL) and heated to 110° C. After 30 h, the reaction mixture was poured into water, the yellowish precipitate was filtered off and washed with water and ether. The solid was dried in vacuum at 40° C. to give the title compound (0.8 g, 65% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:21])=[C:4]([C:9]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][CH:15]=[N:14]3)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1.[CH2:22]([S:25](Cl)(=[O:27])=[O:26])[CH2:23][CH3:24]>C(Cl)Cl>[F:21][C:3]1[C:4]([C:9]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][CH:15]=[N:14]3)=[O:10])=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[N:1]([S:25]([CH2:22][CH2:23][CH3:24])(=[O:27])=[O:26])[S:25]([CH2:22][CH2:23][CH3:24])(=[O:27])=[O:26]
Reactant: CCCS(=O)(=O)Cl
Reactant: Nc1ccc(F)c(C(=O)c2ccc3nccnc3c2)c1F
Solvent: ClCCl
Product: CCCS(=O)(=O)N(c1ccc(F)c(C(=O)c2ccc3nccnc3c2)c1F)S(=O)(=O)CCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.3 %

Procedure:
To a solution of (3-amino-2,6-difluorophenyl)(quinoxalin-6-yl) methanone (50 mg, 0.176 mmol, 1 eq.) in DCM (5 mL) were added TEA (89 mg, 0.88 mmol, 5 eq.) and propane-1-sulfonyl chloride (55 mg, 0.387 mmol, 2.2 eq.). The resulting mixture was stirred at rt for 1 h, then washed with water and extracted with DCM (20 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified via flash column chromatography (PE/EA=2/1, v/v) to afford N-(2,4-difluoro-3-(quinoxaline-6-carbonyl)phenyl)-N-(propylsulfonyl)propane-1-sulfonamide (30 mg, 34.5%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][CH2:6][CH2:5]2.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[N:7]([S:22]([C:19]1[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:21][CH:20]=1)(=[O:24])=[O:23])[CH2:6][CH2:5]2
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1cc(Br)cc2c1NCC2
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)N2CCc3cc(Br)cc([N+](=O)[O-])c32)cc1
Yield: 85 %

Procedure:
A solution of 5-bromo-7-nitroindoline (5 g, 0.021 mol), 4-methoxyphenylsulfonyl chloride (6.36 g, 0.030 mol) in pyridine (10 ml) was stirred at 120° C. for 16 h. The reaction was quenched with water and extracted with CH2Cl2. The combined organic layer was dried over anhydrous MgSO4 and evaporated to give a residue that was chromatographed over silica gel (EtOAc:n-hexane=1:2) to afford compound 17, yield 85%.