Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:22][C:21]([S:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][C@@H:27]3[C:32]([NH:34][O:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)=[O:33])(=[O:25])=[O:24])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[S:22][C:21]([S:23]([N:26]3[CH2:31][CH2:30][N:29]([C:2]([O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[O:3])[CH2:28][C@@H:27]3[C:32]([NH:34][O:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)=[O:33])(=[O:24])=[O:25])=[CH:20][CH:19]=2)=[CH:16][CH:17]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: O=C(NOC1CCCCO1)[C@H]1CNCCN1S(=O)(=O)c1ccc(-c2ccc(F)cc2)s1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(NOC1CCCCO1)[C@H]1CN(C(=O)Oc2ccccc2)CCN1S(=O)(=O)c1ccc(-c2ccc(F)cc2)s1
Yield: 107.2 %

Procedure:
Phenyl chloroformate (60 mg) in CHCl3 (1 ml) was added to (2R)-1-[5-(4-Fluorophenyl)thiophene-2-sulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (150 mg) in pyridine (0.5 ml) and CHCl3 (0.5 ml) dropwise with cooling on an ice bath. The reaction mixture was stirred at said temperature for 2 hours. The mixture was concentrated in vacuo, and the residue was partitioned between AcOEt and 5% aqueous citric acid. The organic layer was washed with 5% aqueous citric acid, saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution, dried over MgSO4, and concentrated in vacuo to give 202 mg of (2R)-1-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-4-phenoxycarbonyl-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][C:11]([C:17]4[N:18]=[C:19]([CH2:27][CH:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[N:20]5[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[C:21]=45)=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[Cl:43][CH2:44][C:45](Cl)=[O:46]>C(Cl)Cl>[NH2:26][C:22]1[C:21]2[N:20]([C:19]([CH2:27][CH:28]3[CH2:33][CH2:32][N:31]([C:45](=[O:46])[CH2:44][Cl:43])[CH2:30][CH2:29]3)=[N:18][C:17]=2[C:11]2[CH:10]=[C:9]3[C:14]([CH:15]=[CH:16][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:8]3)=[CH:13][CH:12]=2)[CH:25]=[CH:24][N:23]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1nccn2c(CC3CCNCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1nccn2c(CC3CCN(C(=O)CCl)CC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Reaction time: 0.17 h

Procedure:
1-(2-phenylquinolin-7-yl)-3-(piperidin-4-ylmethyl)-imidazo-[1,5-a]-pyrazin-8-amine (110.00 mg, 0.25 mmol) in a dried 15 mL round bottom flask was dissolved in 2.00 mL of methylene chloride and was charged with PS-DIEA (150 mg, 0.46 mmol). Chloroacetyl chloride (10 μL, 0.42 equiv) was added in one portion. After 10 min., another 5 μL of chloroacetyl chloride (0.21 equiv) was added. After another 10 min., another 2.5 μL of methoxylacetyl (0.11 equiv) was added. The reaction was filtered through a flitted funnel, and the resins were rinsed multiple times with methylene chloride. The crude product was purified by a 5 g Jones silica gel (dry loaded with silica, wetted with 100% ethyl acetate and eluted with 5% NH3 in MeOH/Ethyl Acetate) and afforded the desired product; 1H NMR (400 MHz, CHLOROFORM-d) δ 8.74 (1 H, s), 8.30 (1 H, d, J=8.68), 8.21 (2 H, d, J=7.01), 7.98 (2 H, m), 7.86 (1 H, dd, J=1.70, J=1.70), 7.53 (3 H, m), 7.24 (1 H, d, J=5.34), 7.08 (1 H, d, J=5.31), 4.63 (1 H, d, J=13.24), 3.90 (1 H, d, J=13.2), 3.15 (1 H, t), 2.97 (2 H, d, J=5.64), 2.70 (1 H, t), 2.34 (1 H, m), 2.05 (2 H, s), 1.92 (2 H, t), 1.42 (2 H, m); MS (ES+): m/z 511.06/513.02 (50/25) [MH+]; HPLC: tR=2.20 min (OpenLynx, polar—5 min).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([OH:15])=O)=[CH:12][C:7]=2[N:6]=[C:5]1[NH:16][C:17]1[S:18][C:19]2[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:20]=2[N:21]=1.[CH2:31]([O:33][CH2:34][CH2:35][NH2:36])[CH3:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:31]([O:33][CH2:34][CH2:35][NH:36][C:13]([C:11]1[CH:10]=[CH:9][C:8]2[N:4]([CH2:3][CH2:2][F:1])[C:5]([NH:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([O:26][C:27]([F:30])([F:28])[F:29])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[N:6][C:7]=2[CH:12]=1)=[O:15])[CH3:32]
Reactant: O=C(O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2CCF
Reactant: CCOCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2CCF
Yield: 43 %

Procedure:
1-(2-Fluoro-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylic acid (2-ethoxy-ethyl)-amide (50.0 mg) was prepared by following General Procedure F starting from 1-(2-fluoro-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100.0 mg), 2-ethoxy-ethylamine (31.0 mg), HBTU (130.0 mg) and DIEA (0.1 mL) in DMF (1.0 mL). LCMS: m/z 513.
Reaction SMILES: C1(S(O)(=O)=O)C=CC=CC=1.[NH2:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1/[C:17](=[CH:19]/[CH:20]([CH3:22])[CH3:21])/[CH3:18].NC1C=CSC=1/C(=C\C(C)C)/C>>[NH2:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17]([CH2:19][CH:20]([CH3:22])[CH3:21])=[CH2:18]
Reactant: C/C(=C\C(C)C)c1sccc1N
Agent: C/C(=C/C(C)C)c1sccc1N
Agent: O=S(=O)(O)c1ccccc1
Product: C=C(CC(C)C)c1sccc1N
Temperature: 25 °C
Reaction time: 30 h
Yield: 80 %

Procedure:
Into a solution obtained by dissolving 3-aminothiophene (1.4 g, 14.5 mmol) in 4-methyl-2-pentanone (30.0 g), which was obtained in the same manner as in Example 14 using methyl 3-aminothiophene-2-carboxylate as a starting material was added anhydrous benzenesulfonic acid (4.7 g, 29.7 mmol) at room temperature, and the resulting solution was stirred under nitrogen atmosphere at 60 degree centigrade for 30 hours. The reaction solution was cooled to room temperature, and then washed with a 10% aqueous sodium hydroxide solution, and separated. As a result of the analysis by the HPLC internal standard method of the obtained organic layer, 2.1 g was produced as a mixture of three compounds including 3-amino-2-{(E)-(4-methyl-2-penten-2-yl)}thiophene, 3-amino-2-{(Z)-(4-methyl-2-penten-2-yl)}thiophene and 3-amino-2-(4-methyl-1-penten-2-yl)thiophene (yield: 80%).
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH2:11]O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].O=S(Cl)[Cl:15]>C(Cl)Cl>[Cl:15][CH2:11][CH2:10][N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: CCN(CCO)c1ccccc1
Solvent: ClCCl
Product: CCN(CCCl)c1ccccc1
Yield: 50 %

Procedure:
2-(N-ethyl-N-phenylamino)ethanol (10 g, 60 mmol) in CH2Cl2 (150 mL) was reacted with SOCl2 (8.8 mL, 121 mmol). The mixture was heated to reflux for one hour and quenched. The solvent was evaporated and the residue was purified by silica gel column chromatography to provide intermediate 15a (5.54 g, 30 mmol, 50%) as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 7.28 (m, 2H), 6.74 (m, 3H), 3.65 (m, 4H), 3.46 (q, J=7.2 Hz, 2H), 1.22 (t, J=7.2 Hz, 3H); HRMS (ESI, positive) m/z calcd. for C10H15ClN [M+H]+: 184.0893, found: 184.0836.
Reaction SMILES: CNC.C1COCC1.[CH3:9][N:10]([CH:12]=O)[CH3:11].ClC[C:16](=[NH:49])[NH:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=[O:48])[C:28](=[C:39]2[NH:43][C:42]3[CH:44]=[CH:45][CH:46]=[CH:47][C:41]=3[NH:40]2)[C:29]([C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=2)=[O:30])[CH:22]=1)(=[O:20])=[O:19]>O>[F:37][C:35]1[CH:36]=[C:31]([C:29](=[O:30])[C:28](=[C:39]2[NH:40][C:41]3[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=3[NH:43]2)[C:27]([C:23]2[CH:22]=[C:21]([S:18]([NH:17][C:16](=[NH:49])[CH2:12][N:10]([CH3:9])[CH3:11])(=[O:19])=[O:20])[CH:26]=[CH:25][CH:24]=2)=[O:48])[CH:32]=[C:33]([F:38])[CH:34]=1
Reactant: CN(C)C=O
Reactant: N=C(CCl)NS(=O)(=O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1
Agent: CNC
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CC(=N)NS(=O)(=O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2 M dimethylamine/THF solution (0.85 mL) was added to a DMF (5 mL) solution of 2-chloro-N-({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)ethanimidamide (181 mg), followed by stirring at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=50/1), and recrystallized from ethyl acetate/n-hexane to obtain N-({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)-2-(dimethylamino)ethanimidamide (76 mg).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:21][N:5]2[C:6](=[O:20])[N:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)[CH2:8][C@@H:4]2[CH2:3]1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.CCN(CC)CC>C(Cl)Cl>[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:1][C@@H:2]2[CH2:21][N:5]3[C:6](=[O:20])[N:7]([C:9]4[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:17])[F:18])=[CH:11][CH:10]=4)[CH2:8][C@@H:4]3[CH2:3]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: N[C@H]1C[C@H]2CN(c3ccc(OC(F)(F)F)cc3)C(=O)N2C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N[C@H]2C[C@H]3CN(c4ccc(OC(F)(F)F)cc4)C(=O)N3C2)cc1
Temperature: 10 °C
Reaction time: 8 h

Procedure:
A mixture of (6S,7aS)-6-Amino-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[1,2-c]imidazol-3-one (example 20, step d) (80 mg, 0.266 mmol), 4-Methyl-benzenesulfonyl chloride (101 mg, 0.53 mmol) and NEt3 (100 mg, 0.99 mmol) in DCM (10 mL) was stirred at 10° C. overnight. The mixture was washed with water (5 mL×3), dried with anhydrous sodium sulfate and then purified with silica gel column chromatography (eluting with DCM/MeOH=150:1) to 58 mg (46%) of the title compound as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.72 (d, 2H, J=9 Hz), 7.31 (d, 2H, J=9 Hz), 7.24 (d, 2H, J=6 Hz), 7.04 (d, 2H, J=9 Hz), 6.00 (d, 1H, J=9 Hz), 4.07-4.00 (m, 1H) 3.76-3.74 (m, 2H), 3.49-3.36 (m, 2H), 3.22-3.19 (m, 1H), 2.47 (s, 3H), 2.23-2.15 (m, 1H), 1.55-1.44 (m, 1H); LC-MS: 456.1 [M+1]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([F:34])=[CH:31][CH:32]=4)[NH:27][N:26]=3)=[CH:23][N:24]=[C:19]2[N:18]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:17]=1)=[O:15])([CH3:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[CH2:55][CH2:56][C:57](=[O:59])[CH3:58].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Si:1]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([F:34])=[CH:31][CH:32]=4)[N:27]([CH2:55][CH2:56][C:57](=[O:59])[CH3:58])[N:26]=3)=[CH:23][N:24]=[C:19]2[N:18]([C:35]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:17]=1)=[O:15])([CH3:11])[CH3:12])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(=O)CCCl
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3n[nH]c4cc(F)ccc34)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)CCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(F)cc21
Temperature: 65 °C
Yield: 60.6 %

Procedure:
To a solution of N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-fluoro-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (60 mg, 0.083 mmol) in DMF (4 mL) was added 4-chlorobutan-2-one (11 mg, 0.1 mmol) followed by K2CO3 (34 mg, 0.25 mmol). The mixture was heated at 65° C. for 1.5 hours. After cooling to room temperature, the mixture was poured into water and filtered to give N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-fluoro-1-(3-oxobutyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (40 mg, 61%). After drying, the crude was used into the next step without further purification. LCMS: (M+H)+=795.
Reaction SMILES: S(Cl)(Cl)=O.O[CH:6]([NH:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])[C:7]([Cl:10])([Cl:9])[Cl:8].C(Cl)(Cl)(Cl)[Cl:22]>CN(C)C=O>[Cl:22][CH:6]([NH:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])[C:7]([Cl:10])([Cl:9])[Cl:8]
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=C(NC(O)C(Cl)(Cl)Cl)c1ccccc1O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(NC(Cl)C(Cl)(Cl)Cl)c1ccccc1O

Procedure:
5 g of thionyl chloride was added dropwise to the mixture of 10 g of N-(1-hydroxy-2,2,2-trichloroethyl)-2-hydroxybenzamide, 50 ml of carbon tetrachloride and 0.1 g of N,N-dimethylformamide under stirring. After effecting the reaction under reflux for one hour, the solvent was distilled off under reduced pressure to obtain N-(1,2,2,2-tetrachloroethyl)-2-hydroxybenzamide (m.p.: 113°-113.5° C.). Without taking out the compound thus resulted, thereto were added 50 ml of acetone and also 7.2 g of octyl thioglycolate (n), and the mixture was stirred at room temperature for one hour. The solvent was distilled off and the rest was purified by silica gel column chromatography to obtain 3.0 g of N-(1-n-octyloxycarbonylmethylthio-2,2,2-trichloroethyl)-2-hydroxybenzamide as a light yellow oily substance. nD25 1.5031
Reaction SMILES: [OH:1][CH:2]([C:6]([O:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=1)([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=1)[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].CN(C=O)C.[H-].[Na+].[CH3:43][O:44][C:45]1[CH:50]=[C:49]([CH3:51])[N:48]=[C:47](S(C)(=O)=O)[N:46]=1>O>[CH3:43][O:44][C:45]1[CH:50]=[C:49]([CH3:51])[N:48]=[C:47]([O:1][CH:2]([C:6]([O:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][CH:8]=2)[C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=2)[C:3]([OH:5])=[O:4])[N:46]=1
Reactant: COc1cc(C)nc(S(C)(=O)=O)n1
Reactant: CCc1ccc(C(OCCc2ccc(OC)c(OC)c2)(c2ccc(CC)cc2)C(O)C(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(C(OCCc2ccc(OC)c(OC)c2)(c2ccc(CC)cc2)C(Oc2nc(C)cc(OC)n2)C(=O)O)cc1
Reaction time: 0.25 h
Yield: 23.7 %

Procedure:
1.8 g (3.8 mmol) of 2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-di(4-ethylphenyl)propionic acid were introduced into 20 ml of DMF, and 554 mg of NaH (50% suspension) were added. After the mixture had stirred for 15 minutes, 855 mg (4.2 mmol) of 4-methoxy-6-methyl-2-methylsulfonylpyrimidine were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the mixture, which was then extracted with ether. The aqueous phase was acidified with 1 N aqueous HCl, extracted with ether and dried over magnesium sulfate. The solvent was distilled off and 540 mg (23%) of colorless powder were isolated after recrystallization from ether/n-hexane.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[C:22]2[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:21]=2[C:20]2[C:19]3[CH:18]=[C:17]([OH:28])[CH:16]=[CH:15][C:14]=3[N:13]([CH2:29][CH2:30][C:31]([NH:33][CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])=[O:32])[C:12]=2[CH:11]=1>C(OCC)(=O)C.CO.[Pd]>[CH3:38][N:36]([CH3:37])[CH2:35][CH2:34][NH:33][C:31](=[O:32])[CH2:30][CH2:29][N:13]1[C:12]2[CH:11]=[C:10]([C:3]3[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=3[O:8][CH3:9])[C:22]3[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:21]=3[C:20]=2[C:19]2[CH:18]=[C:17]([OH:28])[CH:16]=[CH:15][C:14]1=2
Reactant: COc1cccc(Cl)c1-c1cc2c(c3c1C(=O)NC3=O)c1cc(O)ccc1n2CCC(=O)NCCN(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccccc1-c1cc2c(c3c1C(=O)NC3=O)c1cc(O)ccc1n2CCC(=O)NCCN(C)C
Yield: 17.1 %

Procedure:
To a solution of amide (260) (40 mg, 0.07 mmol)) prepared as described in example 219 in ethyl acetate/methanol (1:1, 80 mL) was added 5% Pd-C (catalytic). The resulting suspension was hydrogenated at 60 psi with stirring for 4 days, with additional portions of Pd-C being added every 24 hours. The reaction mixture was then filtered through celite and concentrated under reduced pressure before being chromatographed on silica eluting with methanol/ethyl acetate/triethylamine (1:4:trace), to give amide (330) (6 mg, 16%) as a yellow powder, mp 232–238° C. 1H NMR δ [(CD3)2SO] 10.95 (br s, 1H), 9.33 (br s, 1H), 8.37 (d, J=2.4 Hz, 1H), 8.01 (br s, 1H), 7.69 (s, 1H), 7.54 (d, J=8.9 Hz, 1H), 7.43 (m, 1H), 7.34 (dd, J=7.5, 1.8 Hz, 1H), 7.13–7.05 (m, 3H), 4.67 (t, J=6.2 Hz, 2H), 3.69 (s, 3H), −3.2 (obscured m, 2H), 2.60 (t, J=6.2 Hz, 2H), 2.54–2.49 (obscured m, 8H). FABMS found [M+H]+: 501.2142. C28H28N4O5 requires 501.2138.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[NH2:11].Cl[CH2:13][CH2:14][N:15]=[C:16]=[S:17]>C(OCC)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[NH:11][C:16]1[S:17][CH2:13][CH2:14][N:15]=1
Reactant: NC1CCc2c(Cl)cccc21
Reactant: S=C=NCCCl
Solvent: CCOCC
Product: Clc1cccc2c1CCC2NC1=NCCS1
Reaction time: 2 h
Yield: 40.8 %

Procedure:
To a solution of 4-chloro-indan-1-ylamine (390 mg) in diethyl ether (20 ml) was added 1-chloro-2-isothiocyanatoethane (283 mg) at 0° C. and the solution stirred for 2 h at the same temperature. The reaction mixture was quenched with diluted sodium hydroxide solution and extracted with diethyl ether. The residue was purified on silica gel to yield 240 mg of the product (41%).
Reaction SMILES: [C:1](=[O:3])=[O:2].[OH-:4].[CH3:5][N+:6]1([CH3:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>C1(C)C=CC=CC=1>[C:1](=[O:4])([OH:3])[O-:2].[CH3:5][N+:6]1([CH3:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C=O
Reactant: [OH-]
Agent: C[N+]1(C)CCCCC1
Solvent: Cc1ccccc1
Product: O=C([O-])O

Procedure:
Carbon dioxide was passed for 1 hour into 553 g of a 15.56% strength aqueous N,N-dimethylpiperidinium hydroxide solution. The solution heated up from 20° C. to 38° C. within 20 minutes, and then cooled down again. 300 ml of toluene was added to 100 ml of the solution. The resultant mixture was refluxed and the water was distilled off azeotropically over a period of 11 hours.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[N+:6]([C:9]1[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7]>N1C=CC=CC=1.C(Cl)Cl>[CH2:1]([N:3]([CH2:4][CH3:5])[S:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([N+:6]([O-:8])=[O:7])[CH:10]=1)(=[O:16])=[O:17])[CH3:2]
Reactant: CCNCC
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN(CC)S(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 51.2 %

Procedure:
Diethylamine (2.4 g) was dissolved in pyridine (15 ml) and 3-nitrobenzenesulfonyl chloride (6.7 g) was added, followed by stirring at 50° C. for 2 hours. The residue obtained by an evaporation of pyridine under a reduced pressure was dissolved in methylene chloride (150 ml), washed with water, 1N hydrochloric acid, water, and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. Evaporation of the solvent under a reduced pressure gave N,N-diethyl-3-(nitro)benzenesulfonamide (4.0 g).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1.[I:15][C:16]1[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:17]=1[NH2:18]>N1C=CC=CC=1>[Br:23][C:21]1[CH:20]=[CH:19][C:17]([NH:18][C:8](=[O:9])[C:7]2[CH:11]=[CH:12][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=2)=[C:16]([I:15])[CH:22]=1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: Nc1ccc(Br)cc1I
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Br)cc1I)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled 30 mL vial containing a stirring bar and 4-trifluoromethoxybenzoylchloride (0.70 g, 3.12 mmol), 2-iodo-4-bromoaniline (0.837 g, 2.81 mmol) in 3 mL of anhydrous pyridine was added. The bath was then removed. The reaction solution was stirred at room temperature overnight and 50 mL of EtOAc was added. The resulting solution was poured into 100 mL of 10% aq. HCl. The layers were stirred and then the organic layer was separated and washed with water (2×50 mL), dried with Na2SO4 and concentrated, revealing the desired product. 1H-NMR (400 MHz, CDCl3): δ=7.37 (d, 8.4 Hz, 2HCF3OCCH), 7.53 (m, 1H, ICNCCH), 7.96 (d, 1.6 Hz, 1H, BrCCHCI), 8.8 (d, 8.8 Hz, 2H, CHCHCCOCF3), 8.21 (s, 1H, NH), 8.34 (d, 8.8 Hz, 1H, ICNCCHCH). MS (electrospray) 486 (MH+), 488 (MH++2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:30])=[C:24]([CH2:27][CH:28]=[CH2:29])[CH:25]=2)[NH:20][C:19](=[O:31])[C:18]=1[C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[CH:33]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.[OH-:41].[Na+].OO>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:30])=[C:24]([CH2:27][CH2:28][CH2:29][OH:41])[CH:25]=2)[NH:20][C:19](=[O:31])[C:18]=1[C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[CH:33]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCc1cc2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c(-c3cc(C)cc(C)c3)c(=O)[nH]c2cc1Cl
Reactant: [OH-]
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(CCCO)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-{2-[6-allyl-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (400 mg in 7.0 mL of dry tetrahydrofuran) at 0° C. was added 2.18 mL of a 1M solution of borane in tetrahydrofuran dropwise over 10 minutes. After 3 hours, the reaction was treated sequentially with sodium hydroxide (0.84 mL of a 3M solution) and hydrogen peroxide (0.29 mL of a 30% solution) and the mixture allowed to warm to room temperature. After 2 hours the mixture was extracted with ethyl acetate, washed with brine and dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (hexane:ethyl acetate, 8:2; then 7:3; then 3:2; then 1:1) gave the title compound (253 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:12][C:11]=2[C:10]([CH2:22][NH:23][CH3:24])=[CH:9][CH:8]=1)[CH3:2].C(N(CC)CC)C.[CH2:34]([S:36](Cl)(=[O:38])=[O:37])[CH3:35]>C(Cl)Cl>[CH2:25]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:12][C:11]=2[C:10]([CH2:22][N:23]([CH3:24])[S:36]([CH2:34][CH3:35])(=[O:38])=[O:37])=[CH:9][CH:8]=1)[CH3:26]
Reactant: CCS(=O)(=O)Cl
Reactant: CCN(CC)CCNc1ccc(CNC)c2sc3ccccc3c(=O)c12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)CCNc1ccc(CN(C)S(=O)(=O)CC)c2sc3ccccc3c(=O)c12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95.9 %

Procedure:
A solution of 2.03 g (5.49 mmol) of 1-[[2-(diethylamino)ethyl]amino]-4-[(methylamino)methyl]thioxanthen-9-one (prepared by the method described in Example 5) and triethylamine in 45 mL of methylene chloride was cooled to 0° C. and treated with ethanesulfonyl chloride (0.74 g, 5.76 mmol). After 15 min at 0° C., the reaction mixture was stirred at room temperature for 72 h. The mixture was concentrated in vacuo, the residue dissolved in chloroform and purified by passing through a pad of silica gel (chloroform; then 1% triethylamine/chloroform) affording 2.43 g (96%) of N-[[1-[[2-(diethylamino)ethyl]amino]-9-oxothioxanthen-4-yl]methyl]-N-methylethanesulfonamide. The sulfonamide was recrystallized from ethyl acetate and treated with methanesulfonic acid in isopropanol to afford the product as the methanesulfonate salt, m.p. 159°-161° C.