Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([NH:15][C@H:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:17][CH3:18])=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2.[CH3:31][S-:32].[Na+]>C1COCC1.CCOC(C)=O>[CH3:31][S:32][CH2:2][C:3]1[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([NH:15][C@H:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:17][CH3:18])=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: C[S-]
Reactant: CC[C@H](NC(=O)c1c(CBr)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC[C@H](NC(=O)c1c(CSC)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Reaction time: 1.5 h
Yield: 92.7 %

Procedure:
To a stirring solution of 3-(bromomethyl)-2-phenyl-N-[(1S)-1-phenylpropyl]quinoline-4-carboxamide (8) (2.9 g, 6.32 mmol) in anhydrous THF (35 mL) under N2 was added sodium thiomethoxide (NaSMe, 880 mg, 12.64 mmol) and reaction stirred 1.5 h. It was then diluted with EtOAc; washed with aqueous 0.3 N NaOH, then H2O, then brine; dried over Na2SO4; filtered; and concentrated under reduced pressure. The residue was purified by silica gel chromatography (5-15% EtOAc/CH2Cl2) to give the desired product (2.5 g, 90% yield) as a solid. 1H NMR (300 MHz, CDCl3, 52° C.) δ 8.10 (d, J=8.4 Hz, 1H), 7.78 (d, J=8.1 Hz, 1H), 7.72-7.60 (m, 3H), 7.53-7.25 (m, 9H), 6.68 (d, J=7.8 Hz, 1H), 5.29 (q, J=7.6 Hz, 1H), 3.79 (q, J=13.7 Hz, 2H), 2.19-1.90 (m, 2H), 1.77 (s, 3H), 1.03 (t, J=7.4 Hz, 3H); LCMS: m/z 427 (MH+).
Reaction SMILES: Cl[S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH2:10]/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][C:16]2[O:19][CH2:20][O:21][C:15]=2[CH:14]=1)(=[O:4])=[O:3].[NH2:22][C:23]1[O:27][N:26]=[C:25]([CH3:28])[C:24]=1[Br:29]>>[Br:29][C:24]1[C:25]([CH3:28])=[N:26][O:27][C:23]=1[NH:22][S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH2:10]/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][C:16]2[O:19][CH2:20][O:21][C:15]=2[CH:14]=1)(=[O:4])=[O:3]
Reactant: O=S(=O)(Cl)c1ccsc1C/C=C/c1ccc2c(c1)OCO2
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2ccsc2C/C=C/c2ccc3c(c2)OCO3)c1Br
Yield: 33 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-[trans-3,4-(methylenedioxy)cinnamyl]thiophene-3-sulfonamide was prepared in the same manner as described in Example 1 by reaction of 3-chlorosulfonyl-2-[trans-3,4-(methylenedioxy)cinnamyl]thiophene with 5-amino-4-bromo-3-methylisoxazole. The crude product was purified by HPLC resulting in a 33% yield, m.p. 147°-149° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:23][CH2:24][CH:25]2[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]2)[C:5]2[C:10]([C:11]#[N:12])=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:38][C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH2:50][CH2:49][N:48]([C:51](=[O:53])[CH3:52])[CH2:47][CH2:46]2)=[CH:41][CH:40]=1.C[Si](Cl)(C)C>C(O)CCC>[C:51]([N:48]1[CH2:47][CH2:46][N:45]([C:42]2[CH:43]=[CH:44][C:39]([NH:38][C:2]3[N:3]=[C:4]([NH:23][CH2:24][CH:25]4[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]4)[C:5]4[C:10]([C:11]#[N:12])=[CH:9][NH:8][C:6]=4[N:7]=3)=[CH:40][CH:41]=2)[CH2:50][CH2:49]1)(=[O:53])[CH3:52]
Reactant: Cc1ccc(S(=O)(=O)n2cc(C#N)c3c(NCC4CCN(C(=O)OC(C)(C)C)CC4)nc(Cl)nc32)cc1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(NCC4CCNCC4)c4c(C#N)c[nH]c4n3)cc2)CC1
Temperature: 135 °C
Reaction time: 68 h
Yield: 22.7 %

Procedure:
A mixture of tert-butyl 4-((2-chloro-5-cyano-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)methyl)piperidine-1-carboxylate (127 mg, 0.233 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (100 mg, 0.456 mmol) and TMSCl (0.200 mL, 1.58 mmol) in nBuOH (5 mL) was stirred at 135° C. for 68 h. It was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (25 mg). MS 475 (M+H); UV 204.9, 265.1, 297.2 nm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]([NH2:13])([CH3:12])([CH3:11])[CH3:10]>CS(C)=O.O>[Br:8][C:4]1[N:3]=[C:2]([NH:13][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)N
Reactant: Brc1cccc(Br)n1
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)Nc1cccc(Br)n1
Temperature: 25 °C
Yield: 10.6 %

Procedure:
A stirred solution of 2,6-dibromopyridine (4.0 g, 16.5 mmol) and tert-butylamine (1.8 ml, 17.2 mmol) in dimethylsulfoxide (10 ml) was heated at 100° C. in a sealed tube for 20 h. After cooling to ambient temperature the reaction was diluted with water and extracted into dichloromethane. Combined organic extracts were washed with water and saturated brine then dried over magnesium sulfate, filtered and evaporated in vacuo to give a solid. Purification by chromatography on silica gel eluting with 20% diethyl ether in isohexane gave 6-bromo-N-(tert-butyl)pyridin-2-ylamine (0.4 g) as a solid: δH (360 MHz, CDCl3) 1.40 (9H, s), 6.34 (1H, d, J 8), 6.66 (1H, d, J 8), 7.18 (1H, dd, J 8 and 8); m/z (ES+) 229/231 (M++H).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[C:15]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=4)=[N:16][C:17]4[C:22]([C:23]=3[C:24](O)=[O:25])=[CH:21][CH:20]=[C:19]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:18]=4)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:41]1([C@@H:47]([NH2:49])[CH3:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.ClCCCl>[N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[C:15]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:38])[F:39])[CH:32]=4)=[N:16][C:17]4[C:22]([C:23]=3[C:24]([NH:49][C@H:47]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH3:48])=[O:25])=[CH:21][CH:20]=[C:19]([S:27]([CH3:30])(=[O:28])=[O:29])[CH:18]=4)[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[C@H](N)c1ccccc1
Reactant: CS(=O)(=O)c1ccc2c(C(=O)O)c(CN3CCC(N4CCCCC4)CC3)c(-c3cccc(C(F)(F)F)c3)nc2c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1c(CN2CCC(N3CCCCC3)CC2)c(-c2cccc(C(F)(F)F)c2)nc2cc(S(C)(=O)=O)ccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
A mixture of 3-(1,4′-bipiperidin-1′-ylmethyl)-7-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.100 g, 0.174 mmol), (1S)-1-phenylethanamine (0.032 g, 0.261 mmol), EDC (0.167 g, 0.869 mmol), HOBT (0.027 g, 0.174 mmol), and N,N-diisopropylethylamine (0.303 mL, 1.74 mmol) in N,N-dimethylformamide (2 mL) and 1,2-dichloroethane (2 mL) was stirred at room temperature overnight before it was heated to 50° C. for 4 h. The solvent was removed under reduced pressure. The residue was dissolved in DMSO and purified via HPLC (Waters, 30-80% MeCN/H2O with 0.1% TFA). The fractions containing the product were neutralized with saturated aqueous NaHCO3, acetonitrile was removed under reduced pressure, and the residue was diluted with water. The solid material was collected by filtration, washed with water, and air dried to afford 3-(1,4′-bipiperidin-1′-ylmethyl)-7-(methylsulfonyl)-N-[(1S)-1-phenylethyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxamide (0.086 g, 73% yield). MS (m/z) 679.3 (M+H+).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:14]2[N:13]([CH2:15][C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[C:12](=[O:22])[N:11](C(OC(C)(C)C)=O)[C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].Cl>C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[CH2:1]([CH:3]([C:6]1[C:14]2[N:13]([CH2:15][C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[C:12](=[O:22])[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cccc2c1n(CC(=O)OC(C)C)c(=O)n2C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCC(CC)c1cccc2[nH]c(=O)n(CC(=O)OC(C)C)c12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 77 %

Procedure:
To a solution of tert-butyl 4-(1-ethylpropyl)-3-(2-isopropoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate (obtained above) in ethyl acetate (20 mL) was added a 4N solution of hydrogen chloride in ethyl acetate (40 mL) at 0° C., and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate (100 ml) and ethyl acetate (40 mL). The organic layer was separated, washed with water (70 mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residual solid was suspended in n-hexane (40 mL), and the suspension was stirred at 60° C. for 30 min and then at room temperature for 1 hr. The resulting solid was collected by filtration and washed with n-hexane to give the title compound (17.9 g, 58.8 mmol, 77%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[C:10]([C:15](=[CH:21]OCC)[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:14])[CH2:11][CH2:12][CH3:13]>>[C:10]([C:15](=[CH:21][NH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:14])[CH2:11][CH2:12][CH3:13]
Reactant: Nc1ccc(CO)cc1
Reactant: CCCC(=O)C(=COCC)C(=O)OCC
Product: CCCC(=O)C(=CNc1ccc(CO)cc1)C(=O)OCC

Procedure:
4-Aminobenzylalcohol (25 g) and ethyl 2-butyryl-3-ethoxyacrylate (61 g) were heated together on a rotary evaporator (bath temp 100°) for 30 minutes. Ethyl 2-butyryl-3-(4-(hydroxymethyl)phenylamino)acrylate (49.5 g, 84%) crystallized on standing, was filtered off, washed with a little petroleum ether and vacuum dried, m.p. 44°-6°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[NH:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])([O-])=O>[Pd].O1CCCC1>[NH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([NH2:1])[C:5]=1[NH:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23]
Reactant: CC(C)(C)OC(=O)NCCCNc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCNc1c(N)cccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
Under hydrogen gas atmosphere, a mixture of tert-butyl {3-[(2,6-dinitrophenyl)amino]propyl}carbamate (6.79 g, 20.0 mmol) and 10% palladium on carbon (50% wet, 1.4 g) in tetrahydrofuran (200 mL) was stirred at room temperature for 2 h. The reaction mixture was filtered and concentrated in vacuo to give the title compound as an orange oil (5.47 g, 19.5 mmol, 98%).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9](=[O:17])[C:10]([CH3:16])([CH3:15])[CH2:11][C:12]([OH:14])=[O:13])=[C:4]([CH3:18])[CH:3]=1.C(N1C=CN=C1)(N1[CH:25]=[CH:24]N=C1)=O.C(O)C>O1CCCC1>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9](=[O:17])[C:10]([CH3:15])([CH3:16])[CH2:11][C:12]([O:14][CH2:24][CH3:25])=[O:13])=[C:4]([CH3:18])[CH:3]=1
Reactant: Cc1cc(C(=O)C(C)(C)CC(=O)O)c(C)cc1Br
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CC(C)(C)C(=O)c1cc(C)c(Br)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3.2 g (10 mmol) of 4-(4-bromo-2,5-dimethyl-phenyl)-3,3-dimethyl4-oxo-butanoic acid in tetrahydrofuran is combined with 3.60 g (11 mmol) of carbonyldiimidazole and stirred for 1 hour at ambient temperature. The solvent is replaced by 20 ml of ethanol and the mixture is heated to boiling for 2 hours. Then the solvent is distilled off, the crude product is taken up in methylene chloride, washed with water, dried with sodium sulphate, concentrated and purified by flash chromatography (silica gel; ethyl acetate/petroleum ether=3:97).
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:6][CH:5]=1)=[O:3].[F:16][C:17]([F:22])([F:21])[C:18]([NH2:20])=[O:19]>C(Cl)Cl>[CH3:1][S:2]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:9]=1)(=[N:20][C:18](=[O:19])[C:17]([F:22])([F:21])[F:16])=[O:3]
Reactant: COC(=O)CCc1ccc(S(C)=O)cc1
Reactant: NC(=O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CCc1ccc(S(C)(=O)=NC(=O)C(F)(F)F)cc1
Reaction time: 8 h
Yield: 49.2 %

Procedure:
In a 100 mL round bottom flask, methyl 3-(4-(methylsulfinyl)phenyl)propanoate (0.4 g, 1.77 mmol) was added to CH2Cl2 (18 mL). Subsequently the reaction was treated with MgO (0.285 g, 7.08 mmol), trifluoroacetamide (0.400 g, 3.54 mmol), PhI(OAc)4 (0.884 g, 2.66 mmol), and Rh2(OAc)4 (19.55 mg, 0.0443 mmol). The suspension was stirred overnight then filtered through celite. The filtrate was the concentrated. The resulting residue was purified via column chromatography (silica gel, gradient eluant mixture: 20% EtOAc in hexanes to 100% EtOAc) to give the title compound (0.294 g, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH:24]1([N:30]=[C:31]=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.CCN(CC)CC>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[C:31]([NH:30][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:32])=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C=NC1CCCCC1
Reactant: Clc1ccc(-n2nc3ccccc3c2Nc2cccnc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(NC1CCCCC1)N(c1cccnc1)c1c2ccccc2nn1-c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-pyridin-3-yl-amine was reacted with cyclohexylisocyanate ([3173-53-3]) in 1,2-dichloroethane in the presence of Et3N (3 eq.) for 3 days under reflux conditions to give the title compound as colorless oil. MS: m/e=446.0 [M+H+].
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@H:12]([B:29]1[O:37][CH:36]2[C:31]([CH3:41])([CH:32]3[CH2:38][CH:34]([CH2:35]2)[C:33]3([CH3:40])[CH3:39])[O:30]1)[CH2:13][C:14]1[C:15]([O:27][CH3:28])=[C:16]([CH:24]=[CH:25][CH:26]=1)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[NH2:42][CH2:43][CH2:44][NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49]>CO>[C:48]([O:47][C:46]([NH:45][CH2:44][CH2:43][NH:42][C:2]([C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:4]([NH:3][C@H:12]([B:29]1[O:37][CH:36]2[C:31]([CH3:41])([CH:32]3[CH2:38][CH:34]([CH2:35]2)[C:33]3([CH3:39])[CH3:40])[O:30]1)[CH2:13][C:14]1[C:15]([O:27][CH3:28])=[C:16]([CH:24]=[CH:25][CH:26]=1)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:11])=[O:1])=[O:52])([CH3:51])([CH3:50])[CH3:49]
Reactant: COc1c(C[C@@H](B2OC3CC4CC(C4(C)C)C3(C)O2)N2C(=O)c3ccccc3C2=O)cccc1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CO
Product: COc1c(C[C@H](NC(=O)c2ccccc2C(=O)NCCNC(=O)OC(C)(C)C)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C

Procedure:
To tert-butyl 3-((2R)-2-(1,3-dioxoisoindolin-2-yl)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)ethyl)-2-methoxybenzoate (100 mg from Step 1, Example 53) in 2 mL methanol was added tert-butyl 2-aminoethylcarbamate (1.1 eq). The resulting reaction mixture was stirred at reflux for 2 hr. Methanol was then removed under reduced pressure. The crude product was used in the next step without further purification.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:38][N:39]1[CH2:46][CH2:45][CH2:44][C@H:40]1[C:41](O)=[O:42]>>[CH3:1][N:2]([C:41](=[O:42])[C@@H:40]1[CH2:44][CH2:45][CH2:46][N:39]1[CH3:38])[CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CN1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CN(C(=O)[C@@H]1CCCN1C)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
By allowing tert-butyl 4-(methylamino)piperidine-1-carboxylate to react with EDCI hydrochloride, HOBt and 1-methyl-L-proline, tert-butyl 4-[methyl(1-methyl-L-prolyl)amino]piperidine-1-carboxylate was obtained. Then, trifluoroacetic acid was added thereto to obtain N,1-dimethyl-N-piperidin-4-yl-L-prolinamide.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([CH2:17][CH:18]=[O:19])[C:11]=2[NH:10][C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([CH2:17][CH2:18][OH:19])[C:11]=2[NH:10][C:9]1=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CCc1cccc2c1[nH]c(=O)n2Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: O=c1[nH]c2c(CCO)cccc2n1Cc1ccccc1
Reaction time: 2 h
Yield: 102.8 %

Procedure:
(1-Benzyl-2-oxo-2,3-dihydro-1H-benzoimidazol-4-yl)-acetaldehyde (90 mg, 0.29 mmol) was dissolved in acetone and p-toluene sulfonic acid (10 mg) added. The mixture was stirred for 2 hours and then partitioned between ethyl acetate and water. After washing with saturated sodium bicarbonate, water, and brine, the organic layer was dried over Na2SO4, filtered, and concentrated to afford 1-benzyl-4-(2-hydroxy-ethyl)-1,3-dihydro-benzoimidazol-2-one (80 mg, quant). 1H NMR (CDCl3) δ 3.84 (d, 2H, J=2.1 Hz), 5.06 (s, 2H), 6.80-7.02 (M, 3H), 7.20-7.33 (m, 5H), 9.78 (t, 1H, J=2.0 Hz), 10.7 (br s, 1H). MS: 265 (M−H)−.
Reaction SMILES: Cl[CH2:2][N:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[N:5][C:4]1=[O:10].[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([SH:18])[CH:13]=1.C(N(CC)CC)C>>[C:12]1([CH3:11])[CH:17]=[CH:16][CH:15]=[C:14]([S:18][CH2:2][N:3]2[CH:8]=[C:7]([Cl:9])[CH:6]=[N:5][C:4]2=[O:10])[CH:13]=1
Reactant: Cc1cccc(S)c1
Reactant: O=c1ncc(Cl)cn1CCl
Solvent: CCN(CC)CC
Product: Cc1cccc(SCn2cc(Cl)cnc2=O)c1
Temperature: 40 °C
Reaction time: 0.33 h

Procedure:
1-Chloromethyl-5-chloropyrimidin-2-one (see Preparation 15) (1.0 mmol) was added to a mixture of m-thiocresol (1.0 mmol) and triethylamine (1.0 mmol). The mixture was stirred at room temperature for 20 mins and at 40° C. for 20 mins before the solvent was distilled off and the residue triturated with water, extracted into chloroform, dried (MgSO4) and evaporated. The residue was washed with cold acetone (1 ml). The insoluble product was identical with an authentic sample prepared as described in Example 14. Yield: 60 mg, 22%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:6]=2[CH:19]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])[C:24]([Cl:39])=[CH:23][N:22]=1>>[Cl:39][C:24]1[C:25]([NH:27][C:28]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])=[N:26][C:21]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH:16]([CH3:17])[CH3:18])[C:6]=3[CH:19]=2)=[N:22][CH:23]=1
Reactant: CC(C)CN1C(=O)CCC(C)(C)c2ccc(N)cc21
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)N(CC(C)C)C(=O)CCC3(C)C)ncc1Cl

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-isobutyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide to yield a yellow solid (21%). mp 289° C.; LCMS: m/z=539.54 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.04 (d, 1H, J=1.0 Hz), 7.60 (s, 1H), 7.47 (s, 2H), 7.43 (d, 1H, J=7.3 Hz), 7.29 (m, 3H), 7.18 (d, 1H, J=8.6 Hz), 3.35 (m, 1H), 2.86 (s, 3H), 2.28 (m, 3H), 1.98 (m, 3H), 1.31 (m, 7H), 0.95 (d, 6H, J=5.8 Hz).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[CH:11]=2)[NH:6][C:5]([CH3:22])([CH3:21])[CH:4]=1.CN(C=O)C.[N-:28]=[N+:29]=[N-:30].[Na+]>CCOC(C)=O.O>[N:28]([CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[CH:11]=2)[NH:6][C:5]([CH3:22])([CH3:21])[CH:4]=1)=[N+:29]=[N-:30]
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1-c1ccc2c(c1)C(CN=[N+]=[N-])=CC(C)(C)N2
Reaction time: 48 h
Yield: 156.9 %

Procedure:
To a round bottom flask equipped with a stir bar was added 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline (see Example 1) (0.36 mmol), DMF (3.6 mL), and NaN3 (0.54 mmol, 1.5 equiv). The reaction was stirred 48 hours under argon, then diluted with EtOAc and water, separated, and the aqueous phase was extracted with EtOAc. The combined organics were washed with water. The water was back-extracted with EtOAc and the combined organics were washed with brine and concentrated in vacuo. The residue was diluted with hexanes and a minimal amount of EtOAc and applied to a silica gel column. Flash chromatography, eluting with 0-30% EtOAc/hexanes provided 181 mg of 4-azidomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline as a brown oil.
Reaction SMILES: [C:1]([C:4]1[NH:8][C:7]2[C:9]([Cl:13])=[C:10]([Cl:12])[S:11][C:6]=2[CH:5]=1)([OH:3])=O.[NH2:14][C@H:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C@@H:16]1[NH:24][S:25]([CH3:28])(=[O:27])=[O:26].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:12][C:10]1[S:11][C:6]2[CH:5]=[C:4]([C:1]([NH:14][C@H:15]3[CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C@@H:16]3[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[O:3])[NH:8][C:7]=2[C:9]=1[Cl:13]
Reactant: CS(=O)(=O)N[C@H]1c2ccccc2C[C@@H]1N
Reactant: O=C(O)c1cc2sc(Cl)c(Cl)c2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N[C@H]1c2ccccc2C[C@@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Reaction time: 0.08 h
Yield: 96.8 %

Procedure:
5-Carboxy-2,3-dichloro-4H-thieno[3,2-b]pyrrole (Method 4, 236 mg, 1.0 mmol), N-[(1S,2S)-2-amino-2,3-dihydro-1H-inden-1-yl]methanesulfonamide (226 mg, 1.0 mmol), DIPEA (174 μL, 1.0 mmol) and HOBT (135 mg, 1.0 mmol) were dissolved in DCM (10 mL) and stirred for approximately 5 mins. EDCI (240 mg, 1.25 mmol) was added and the reaction stirred for 20 hours. The volatiles were removed by evaporation, EtOAc (25 mL) added, the mixture washed with water (2×10 mL) and brine (10 mL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure to give the title compound (430 mg, 97%) as a foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](O)=[N:8][C:7]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[CH:6]2.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[C:7]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:8]=1
Reactant: COc1ccc2c(O)nc(N3CCOCC3)cc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)nc(N3CCOCC3)cc2c1
Yield: 95.8 %

Procedure:
A solution of 6-methoxy-3-morpholinoisoquinolin-1-ol (315 mg, 1.210 mmol) in POCl3 (1692 μl, 18.15 mmol) was refluxed for 4 h. The reaction mixture was concentrated. The residue was dissolved in DCM and the pH was adjusted to 7 with 4N NaOH. The organic phase was collected and dried over sodium sulfate, filtered, then concentrated under vacuum. The crude material was purified by silica gel chromatography using 50% DCM in Hexanes as eluent. The product fractions were collected and the solvent removed under vacuum to give 4-(1-chloro-6-methoxyisoquinolin-3-yl)morpholine (323 mg, 95% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.01 (d, J=9.3 Hz, 1H), 6.97 (dd, J=9.3, 2.5 Hz, 1H), 6.86 (d, J=2.5 Hz, 1H), 6.59 (s, 1H), 3.92 (s, 3H), 3.90-3.85 (m, 4H), 3.56-3.50 (m, 4H); MS: MS m/z 279.1 (M++1).