Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:34]([F:35])=[CH:33][C:32]([F:36])=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:37])=[CH:20][N:19]=1>>[Cl:37][C:21]1[C:22]([NH:24][C:25]2[C:34]([F:35])=[CH:33][C:32]([F:36])=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: CNC(=O)c1cc(F)cc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: CNC(=O)c1cc(F)cc(F)c1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamino]-pyrimidin-4-ylamino}-3,5-difluoro-N-methyl-benzamide was prepared from 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3,5-difluoro-N-methyl-benzamide in an analogous manner to Example 1221d. Title compound was isolated as a white solid (91 mg, 58%). HPLC purity 99%, LCMS 517.14 (M+H), 1H-NMR (DMSO-D6, 400 MHZ) Δ 9.66 (s, 1H), 9.33 (s, 1H), 9.01 (s, 1H), 8.48 (d, J=4.9 Hz, 1H), 8.16 (s, 1H), 7.60-7.58 (m, 1H), 7.39 (d, J=8.6 Hz, 1H), 7.29 (s, 1H), 7.22 (d, J=8.8 Hz, 1H), 6.95 (8.1 Hz, 1H), 3.69-3.67 (m, 2H), 3.57-3.54 (m, 2H), 3.44-3.42 (m, 2H), 3.408 (s, 3H), 3.20-3.17 (m, 2H), 3.10-3.02 (m, 2H), 2.80 (s, 3H), 2.79-2.70 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:18][OH:19])=[C:8]2[C:13](Cl)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2].[O:20]([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:18][OH:19])=[C:8]2[C:13]([NH:31][C:30]3[CH:29]=[CH:28][C:27]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:33][CH:32]=3)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1CO
Reactant: Nc1ccc(Oc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1CO
Temperature: 25 °C
Yield: 91.8 %

Procedure:
A solution of compound 16B (84 mg, 0.30 mmol), 4-phenoxyaniline (72 mg, 0.39 mmol) and triethylamine (0.083 mL, 0.60 mmol) in THF (2.5 mL) was heated at 70° C. for 30 min. After cooled to room temperature, the reaction was concentrated to about 0.5 mL, diluted with MeOH (2 mL) and filtered. The solid was washed with MeOH and dried to give compound 16C as yellow solid (118 mg, 92%). HPLC: 92% at 2.12 min (retention time) (Prime Sphere 5u C18-HC column. 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm). MS (ES): m/z 429.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.[Li]CCCC.CCCCCC.CN([CH:30]=[O:31])C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[C:3]=1[CH:30]=[O:31]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)ccn1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nccc(Cl)c1C=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Dissolve tert-butyl 4-chloropyridin-2-ylcarbamate (1.95 g, 0.00855 moles) in dry THF (50 mL) and cool to −78° C. under nitrogen atmosphere. Add dropwise 1.6 M n-BuLi/hexane (12.8 mL, 0.02053 moles) over a period of 15 minutes while maintaining the reaction temperature below −70° C. Stir the resulting red orange solution at −78° C. for 2 hours. Add DMF (3.3 mL, 0.04275 moles) dropwise to the reaction mixture while maintaining the reaction temperature below −70° C. Stir further at −78° C. for 2 hours and then quench the reaction mixture with saturated ammonium chloride (50 mL). Warm the reaction mixture to room temperature, extract with EtOAc (3×50 mL) and dry with MgSO4. Filter and concentrate under reduced pressure to afford a yellow viscous oil. Purify the crude product by flash column chromatography using 15-20% EtOAc/hexane to afford the title product as a white solid.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:23])[CH:15]=[CH:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CC(C)=O>[CH2:30]([N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:23])[CH:15]=[CH:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:5][CH2:4]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: O=C(C=Cc1cccnc1)NCCCCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(C=Cc1cccnc1)NCCCCC1CCN(Cc2ccccc2)CC1
Reaction time: 8 h

Procedure:
6.5 g (180 mmol) N-[4-(piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide dihydrochloride (substance 22) are suspended in 80 ml acetone added to 9.9 g (72.0 mmol) potassium carbonate. A solution of 3.4 g (19.8 mmol) benzyl bromide in 10 ml acetone is added dropwise to this mixture at RT and stirred overnight. Subsequently, the suspension is filtered and the filtrate is concentrated under vacuum. The residue is taken up in 100 ml CHCl3 and washed with 30 ml water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3/CH3OH (95/5 to 90/10) and crystallized from 15 ml acetonitrile after drawing off the solvent. Beige colored crystals with a MP of 88-90° C. were recovered; yield: 1.1 g (16%).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[CH:11](=O)[CH3:12].[ClH:14]>[Cl-].[Zn+2].[Cl-]>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([Cl:14])[CH3:12])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: Cl
Reactant: CC=O
Reactant: CC(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(C)Cc1ccc(C(C)Cl)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Isobutylbenzene (402 g, 3 mol) and zinc chloride (136 g, 1 mol) are fed into a one liter flask equipped with termometer, stirrer, and gas inlet tube. The reaction is maintained below 10° C. by external cooling. A mixture of acetaldehyde (44 g, 1 mol) and isobutylbenzene (67 g, 0.5 mol) are added to the flask dropwise for 2 hours while maintaining the temperature of the flask below 10° C. The reaction is heated to room temperature and HCl is passed through the reaction medium in the flask for about 2 hours. The reaction is stirred for 6 hours. The solution is quenched with water and the organic layer is separated from the aqueous layer. The organic layer is washed with sodium bicarbonate and water, and then dried. It is then stripped of isobutylbenzene and vacuum distilled to give 1-(4′-isobutylphenyl)ethyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[N:16]=[CH:17][C:18]([C:19]([N:56]4[CH2:61][CH2:60][O:59][CH2:58][CH2:57]4)=[O:21])=[CH:22][CH:23]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.6 %

Procedure:
To a solution of 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (60 mg, 0.2 mmol) in DMF (300 μL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (71 mg, 0.22 mmol), N,N-diisopropyl ethyl amine (171 μL, 1.0 mmol) and morpholine (0.22 mmol). The resulting reaction mixture was stirred for 1 h at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (10 mg, 13%) which was obtained as a white solid. MS: m/e=398.3 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[CH3:17]I>C1COCC1>[CH3:17][N:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[C:2]1=[O:1]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCCNC1=O
Solvent: C1CCOC1
Product: CN1CCCC[C@@H](NC(=O)OC(C)(C)C)C1=O
Reaction time: 0.5 h

Procedure:
To a stirred solution of [(3R)-hexahydro-2-oxo-1H-azepin-3-yl]-carbamic acid, 1,1-dimethylethyl ester (500 mg) in THF (5 mL) at rt, KHDMS (5.26 mL, 1.0 M in THF) was added. After 30 min, CH3I (0.26 mL) was introduced. The reaction was kept at rt overnight, and then quenched with brine. The reaction mixture was extracted with EtOAc, washed with brine, and dried over Na2SO4. Concentration in vacuo afforded the crude product which was used directly for the next step reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[N:3]=1.[Cl:19]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.C(OCC)(=O)C.O>[Cl:19][C:8]1[N:7]2[C:2]([Cl:1])=[N:3][C:4]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])=[CH:5][C:6]2=[N:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Clc1ccc(-c2cc3nccn3c(Cl)n2)c(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: Clc1ccc(-c2cc3ncc(Cl)n3c(Cl)n2)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
300 mg (1.0 mmol) of 5-chloro-7-(2,4-dichlorophenyl)imidazo[1,2-c]pyrimidine (Example 6A) are suspended in chloroform (15 ml), 240 mg (1.8 mmol) of N-chlorosuccinimide are added, and the reaction mixture is stirred at RT for 12 h. The reaction mixture is diluted with ethyl acetate (100 ml) and water (75 ml), and the organic phase is separated off, dried over magnesium sulphate and concentrated in a rotary evaporator. The residue is stirred with diethyl ether (20 ml), and the solid is filtered off with suction and dried. 63 mg (18% of theory) of the product are isolated.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([C@H:5]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH3:21])[N:16]=[CH:15]2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]#[N:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:31][CH2:32][CH3:33])C.[F:34][C:35]([F:42])([F:41])CS(Cl)(=O)=O>C1COCC1>[CH3:1][C:2]([CH3:22])([C@H:5]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH3:21])[N:16]=[CH:15]2)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH2:3][NH:4][C:32](=[O:31])[CH2:33][C:35]([F:42])([F:41])[F:34]
Reactant: Cn1ncc2cc([C@H](c3ccccc3)C(C)(C)C#N)ccc21
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: CCOCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1ncc2cc([C@H](c3ccccc3)C(C)(C)CNC(=O)CC(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(a)(b) To a stirred solution of (S)-2,2-dimethyl-3-(1-methyl-1H-indazol-5-yl)-3-phenylpropanenitrile (24 mg, 0.078 mmol) in anhydrous THF (10 mL) was added 1.0M lithium aluminum hydride in diethyl ether (0.5 mL, 0.5 mmol) portionwise at RT under nitrogen. After stirring at RT for 3 hr, the mixture was carefully quenched with MeOH, poured into brine, extracted with ethyl acetate (2×100 mL), dried (MgSO4) and concentrated. The crude product was coupled with 2,2,2-trifluoroethanesulfonyl chloride (14 mg, 0.073 mmol) using General Coupling Method B to give (S)—N-(2,2-dimethyl-3-(1-methyl-1H-indazol-5-yl)-3-phenylpropyl)-3,3,3-trifluoropropanamide. MS found: (M+H)+=468.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:3][C@H:4]([OH:23])[C@@H:5]([NH:13][C:14]([O:16][CH2:17][C:18]1[O:22][CH:21]=[N:20][CH:19]=1)=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:31][N:32]([C:42]([NH:44][C@H:45]([C:49](O)=[O:50])[CH:46]([CH3:48])[CH3:47])=[O:43])[CH2:33][C:34]1[N:35]=[C:36]([CH:39]([CH3:41])[CH3:40])[O:37][CH:38]=1.CO>ClCCl>[CH3:31][N:32]([C:42]([NH:44][C@H:45]([C:49]([NH:1][C@@H:2]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:3][C@H:4]([OH:23])[C@@H:5]([NH:13][C:14]([O:16][CH2:17][C:18]1[O:22][CH:21]=[N:20][CH:19]=1)=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:50])[CH:46]([CH3:48])[CH3:47])=[O:43])[CH2:33][C:34]1[N:35]=[C:36]([CH:39]([CH3:41])[CH3:40])[O:37][CH:38]=1
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cnco1
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)co1
Solvent: CO
Solvent: ClCCl
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cnco2)C(C)C)co1
Yield: 80 %

Procedure:
Using the procedure of Example 1U but replacing (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)-methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane with (2S,3S,5S)-5-amino-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane and replacing N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine with N-((N-methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)-L-valine provided, after silica gel chromatography using a gradient of 1%-4% methanol in dichloromethane, 145 mg (80%) of the desired compound. 1H NMR (CDCl3) δ 0.74 (d, J=6.9 Hz, 6H), 1.23 (d, J=6.9 Hz, 6H), 1.39-1.50 (m, 2H), 1.80-1.94 (m, 1H), 2.56-2.74 (m, 4H), 2.83 (s, 3H), 2.94-3.09 (m, 1H), 3.52-3.62 (m, 1H), 3.72-3.84 (m, 1H), 3.88-3.92 (m, 1H), 4.08-4.35 (m, 3H), 4.62 (d, J=6Hz, 1H), 4.94 (s, 2H), 5.91 (d, J=8.4 Hz, 1H), 6.89 (d, J=9 Hz, 1H), 7.06-7.26 (m, 11H), 7.69 (d, J=9 Hz, 1H), 7.77 (s, 1H), 8.35 (s, 1H). Mass spectrum: (M+NH4)+ =706; (M+H)+ =689. Anal. Calcd for C37H48N6O7.0.5 H2O: C, 63.68; H, 7.08; N, 12.04. Found: C, 63.50; H, 7.13; N, 11.60.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:12]=2)=[C:5]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:4]=1.CS(O)(=O)=O.S(Cl)(Cl)=O.[CH3:36][N:37]([CH3:43])[CH2:38][CH2:39][CH2:40][CH2:41]O.CN(C)C>C(#N)C.C(OCC)(=O)C>[NH2:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][C:18]([O:20][CH2:41][CH2:40][CH2:39][CH2:38][N:37]([CH3:43])[CH3:36])=[O:19])=[CH:15][CH:16]=2)=[C:5]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:4]=1
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1
Reactant: CN(C)CCCCO
Agent: CN(C)C
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)OCCCCN(C)C)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
The solution of the product from step (vi) (2.00 g, 5.28 mmol) and methanesulfonic acid (1.52 g, 15.8 mmol) in acetonitrile (16.0 g) was cooled to 20° C. and thionyl chloride (0.94 g, 7.92 mmol) was slowly added to the solution. After the mixture was stirred at 20° C. for 30 minutes, 4-dimethylamino-1-butanol (1.11 g, 9.50 mmol) was slowly added to the mixture. The mixture was heated to 40° C. and stirred at the temperature for 5 hours. After the reaction mixture was cooled to 20° C., ethyl acetate (18.0 g) and 25% aq. trimethylamine (18.0 g) was slowly added to the mixture. The organic layer was separated and washed respectively with 5% aq. NH4Cl (20.0 g), 1% aq. NaCl (20.0 g) and water (20.0 g). The solution of the subtitle compound was used in the next step without concentration.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[C:4]([CH3:11])=[N:3]1.[Li]CCCC.[I:17]I>O1CCCC1.CCCCC>[I:17][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([CH3:11])[C:5]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: II
Reactant: COC(=O)c1cn(C)nc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: COC(=O)c1c(C)nn(C)c1I
Temperature: -45 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To a solution of methyl 1,3-dimethyl-1H-pyrazole-4-carboxylate (154 mg, 1 mmol) in dry tetrahydrofuran (10 mL) at −78° C., 2 M solution of BuLi (0.550 mL, 1.100 mmol) in pentane was added dropwise. The reaction mixture was then warmed to −45° C. and stirred for 1 h. It was then cooled to −78° C. and a solution of IODINE (279 mg, 1.100 mmol) in THF (2 mL) was added. The reaction mixture was warmed to RT and stirred for 1 h. It was then quenched with saturated NH4Cl solution and extracted with ethyl acetate (2×25 mL). The organic layers were combined, washed with brine, dried over MgSO4, and then concentrated in vacuo. The crude product was obtained as a brown thick oil. This material was then purified by preparative HPLC using CH3CN/H2O/TFA as solvent system. Homogeneous fractions were combined and concentrated in vacuo. The concentrate was then extracted with ethyl acetate and the extracts combined and dried over MgSO4. The suspension was then filtered and the filtrand evaporated under reduced pressure to give the title compound as a white solid, (137 mg, 0.460 mmol, 46.0% yield). MS m/z 281 (MH+), Retention time: 1.107 min. (basic). 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 2.45 (s, 3 H) 3.84 (s, 3H) 3.91 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9]([CH3:13])([CH3:12])[CH:8]=[CH:7]2.CO.C(=O)([O-])[O-:23].[K+].[K+]>[Pd](Cl)Cl.C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9]([CH3:12])([CH3:13])[CH2:8][C:7]2=[O:23]
Reactant: COC(=O)C(C)c1cc(Cl)c2c(c1)C=CC(C)(C)N2
Reactant: O=C([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [K+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)C(C)c1cc(Cl)c2c(c1)C(=O)CC(C)(C)N2
Reaction time: 6 h
Yield: 28.4 %

Procedure:
1.0 g of methyl 2-(8-chloro-1,2-dihydro-2,2-dimethylquinolin-6-yl)propionate was added to 20 ml of methanol. 2.0 g of palladium chloride was further added to the solution, and the mixture was stirred at 55°-60° C. for 6 hours. After cooling, 2 g of potassium carbonate and benzene were added to the mixture, then the mixture was further stirred. The precipitates were filtered off and washed with benzene. The filtrate and the wash were combined and concentrated, followed by addition of dilute aqueous solution of sodium hydrogencarbonate, and extraction with ether. The ethereal solution was washed with water, saturated aqueous solution of sodium sulfate and then the solvent was distilled off. The residue was purified by column chromatography on silica gel (benzene:ether=9:1) to give 0.3 g of methyl 2-(8-chloro-1,2,3,4-tetrahydro-2,2-dimethyl-4-oxoquinolin-6-yl)propionate (Compound 31).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[OH:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
2-Chloromethylquinoline hydrochloride (6.42 g, 30 mmol), 4-hydroxybenzaldehyde (3.66 g, 30 mmol) and potassium carbonate (9.12 g, 66 mmol) were combined, to which 50 ml of DMF were added. The resulting mixture was stirred overnight at 90° C. The solvent was driven off under reduced pressure, the residue was extracted with ethyl acetate. The organic layer was washed with 1 N aqueous solution of sodium hydroxide and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, whereby 7.19 g of the title compound were obtained (yield: 91%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[N:14][C:15]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:16][CH:17]=2)=O)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>C1COCC1>[NH3:4].[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[N:14][C:15]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:16][CH:17]=2)=[S:34])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)N1CCN(C(=O)c2ccc(CN3CCCCC3)nc2)CC1
Solvent: C1CCOC1
Product: CC(C)N1CCN(C(=S)c2ccc(CN3CCCCC3)nc2)CC1
Product: N
Temperature: 25 °C
Yield: 1 %

Procedure:
A solution of (4-isopropyl-piperazin-1-yl)-(6-piperidin-1-ylmethyl-pyridin-3-yl)-methanone (Example 1, 80 mg, 0.24 mmol) and Lawesson's reagent (210 mg, 0.50 mmol) in THF was heated at reflux for 48 h. The reaction was cooled to rt and the solvent was removed in vacuo. Chromatography of the residue (SiO2: 1-6% 2 M NH3 in MeOH/DCM) gave the title compound as an oil. MS (ESI): exact mass calcd. for C19H30N4S, 346.22; m/z found, 347.5 [M+H]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12](Br)[C:13]2[O:17][CH:16]=[CH:15][C:14]=2[CH:18]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([N:30]2[CH2:29][CH2:28][N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[CH2:32][CH2:31]2)[C:13]2[O:17][CH:16]=[CH:15][C:14]=2[CH:18]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(Br)c2occc2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2cc(CO[Si](C)(C)C(C)(C)C)cc3ccoc23)CC1
Yield: 62.7 %

Procedure:
Beginning with 0.51 gm (1.5 mMol) 5-(tert-butyldimethylsilyloxymethyl)-7-bromobenzofuran and 0.30 gm (1.6 mMol) 1-tert-butoxycarbonylpiperazine, 0.42 gm (63%) of the desired compound were prepared essentially as described in GENERAL PROCEDURE II.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:13][O: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][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:4][S:5]([CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])(=[O:7])=[O:6].[CH3:33][I:34]>CCOCC>[I-:34].[CH3:1][O:2][CH:3]([CH2:13][O: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][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:4][S:5]([CH2:8][CH2:9][N+:10]([CH3:33])([CH3:12])[CH3:11])(=[O:6])=[O:7]
Reactant: CI
Reactant: CCCCCCCCCCCCCCCCCCOCC(CS(=O)(=O)CCN(C)C)OC
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCCOCC(CS(=O)(=O)CC[N+](C)(C)C)OC
Product: [I-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
In 5 ml of ether is dissolved 0.24 g of 2-[(2-methoxy-3-octadecyloxypropyl)sulfonyl]ethyldimethylamine to which is added 1 ml of methyl iodide. The solution is then stirred at room temperature for 2 days. The reaction liquid is concentrated under reduced pressure and the residue is treated with methanol to give 275 mg of the captioned compound as powder.