Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[N:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:29]=[CH:28][N:27]=[C:26](Cl)[N:25]=3)[CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1>>[O:15]=[S:12]1(=[O:16])[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][N:11]1[CH2:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH:31][CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=3)[N:25]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3ccnc(Cl)n3)c2)S(=O)(=O)CC1
Reactant: NCCc1ccc(O)cc1
Product: O=S1(=O)CCNCCN1Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 144 was coupled with tyramine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 454. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.36 (s, 1H) 8.30 (d, 1H) 8.20 (d, 1H) 7.73 (d, 1H) 7.64 (t 1H) 7.53 (d, 1H) 7.14 (d, 2H) 6.68 (d, 2H) 4.70 (s, 2H) 3.80 (t, 2H) 3.67 (m, 4H) 3.56 (t, 2H) 3.36 (t, 2H) 2.95 (t, 2H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6](I)=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:13][CH2:12]2)=[N:9][CH:10]=1)=[O:4].[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(COC)OC>[CH3:1][NH:2][C:3]([C:5]1[C:6]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[Cl:26])=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:13][CH2:12]2)=[N:9][CH:10]=1)=[O:4]
Reactant: OB(O)c1ccccc1Cl
Reactant: CNC(=O)c1cnc(N2CCC(O[Si](C)(C)C(C)(C)C)CC2)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CNC(=O)c1cnc(N2CCC(O[Si](C)(C)C(C)(C)C)CC2)cc1-c1ccccc1Cl
Temperature: 90 °C
Reaction time: 3 h
Yield: 91.5 %

Procedure:
A mixture of 480 mg (1.01 mmol) 4-(tert-butyl-dimethyl-silanyloxy)-4′-iodo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid methylamide, 174 mg (1.11 mmol) 2-chlorophenylboronic acid, 6 ml dimethoxyethane and 1 ml of a 2 M aqueous solution of sodium carbonate was deoxygenated by three freeze-thaw cycles. After addition of 60 mg (0.052 mmol) tetrakis(triphenylphosphine)palladium(0) the reaction mixture was stirred at 90° C. for 3 h. Cooling to room temperature was followed by dilution with water and extraction with ethyl acetate. The organic extract was washed with saturated aqueous sodium carbonate and sodium chloride solutions, dried with sodium sulfate and concentrated. Column chromatography afforded 425 mg (91.5%) of the title compound as an off-white solid. MS m/e (%):460 (M+H+, 100).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]1[C:11]1[CH:16]=[C:15]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=3)[CH:20]=[C:19]([CH2:31][O:32]C(=O)C)[C:18]=2[CH2:36][O:37]C(=O)C)[CH:14]=[CH:13][N:12]=1.C[O-].[Na+].C(O)(=O)C>CO>[O:1]=[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]1[C:11]1[CH:16]=[C:15]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=3)[CH:20]=[C:19]([CH2:31][OH:32])[C:18]=2[CH2:36][OH:37])[CH:14]=[CH:13][N:12]=1
Reactant: COc1cc2cc(COC(C)=O)c(COC(C)=O)c(-c3ccnc(-n4cc([N+](=O)[O-])ccc4=O)c3)c2cc1OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc2cc(CO)c(CO)c(-c3ccnc(-n4cc([N+](=O)[O-])ccc4=O)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
To a solution of 1-{2-[2-oxo-1,2-dihydro-5-nitropyridin-1-yl]-4-pyridyl }-2,3-bis(acetoxymethyl)-6,7-dimethoxynaphthalene (1.83 g) in methanol (50 ml) is added sodium methoxide (0.72 g) under ice-cooling. The mixture is stirred at room temperature for one hour. To the mixture is added acetic acid (0.8 ml) under ice-cooling, and the mixture is concentrated under reduced pressure to remove the solvent. To the residue are added chloroform and an aqueous sodium hydrogen carbonate solution, and the chloroform layer is separated, washed, dried and concentrated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:acetone=3:1), and crystallized from ethyl acetate to give 1-{2-[2-oxo-1,2-dihydro-5-nitropyridin-1-yl]-4-pyridyl}-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene (0.81 g) which is listed in Table 1.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9](OC(C)(C)C)=O.Cl[C:17]1[C:22]([C:23]2[N:28]=[CH:27][N:26]=[C:25]([O:29][C:30]3[C:35]4[N:36]=[C:37]([NH2:39])[S:38][C:34]=4[CH:33]=[CH:32][CH:31]=3)[CH:24]=2)=[CH:21][CH:20]=[C:19]([C:40]([F:43])([F:42])[F:41])[N:18]=1>>[CH2:9]([N:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C@H:3]1[CH2:2][NH:1][C:17]1[C:22]([C:23]2[N:28]=[CH:27][N:26]=[C:25]([O:29][C:30]3[C:35]4[N:36]=[C:37]([NH:39][C:25](=[O:29])[CH3:24])[S:38][C:34]=4[CH:33]=[CH:32][CH:31]=3)[CH:24]=2)=[CH:21][CH:20]=[C:19]([C:40]([F:43])([F:42])[F:41])[N:18]=1)[CH:19]([CH3:40])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CN
Reactant: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)nc4Cl)ncn3)cccc2s1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)nc4NC[C@@H]4CCCCN4CC(C)C)ncn3)cccc2s1

Procedure:
The title compound was prepared from (S)-2-aminomethyl-N-Boc-piperidine (AstaTech) and 4-(6-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yloxy)-benzo[d]thiazol-2-amine, Example 1(b), analogous to the procedures described for Example 3(a-d). MS (ESI, pos. ion.) m/z: 600 (M+1).
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:12]([C:13](=O)[CH:14]=1)=[CH:11][CH:10]=[C:9]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([OH:32])[C:24]=1[CH2:33][CH2:34][CH3:35])[C:8]=2[CH2:36][CH2:37][CH3:38])([O:3][CH3:4])=[O:2].[H][H]>C(O)(=O)C.[Pd]>[C:1]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH2:36][CH2:37][CH3:38])[C:9]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([OH:32])[C:24]=3[CH2:33][CH2:34][CH3:35])=[CH:10][CH:11]=2)[O:6]1)([O:3][CH3:4])=[O:2]
Reactant: CCCc1c(OCCCCCOc2ccc3c(=O)cc(C(=O)OC)oc3c2CCC)ccc(C(C)=O)c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCc1c(OCCCCCOc2ccc3c(c2CCC)OC(C(=O)OC)CC3)ccc(C(C)=O)c1O
Yield: 89.5 %

Procedure:
7.65 g (14.6 mmole) of the compound from Example 5 was hydrogenated in 80 ml of acetic acid at 70° C. and 50 psi pressure in a 250 ml Parr shaker using 5% palladium on carbon as the catalyst. Theoretical hydrogen uptake occurred at 40 minutes. The shaker was cooled and vented, and its contents filtered. The filtrate was placed in a rotary evaporator and the acetic acid was removed by azeotropation three times with toluene and then once with methyl alcohol. Recrystallization from ethyl acetatehexane yielded 6.7 g (89%) of the title compound, mp 57°-58°, Calc: C, 70.29; H, 7.86; Found C, 70.09; H, 7.76.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH2:13][CH2:12][C:11](=O)[CH:10]=2)=[CH:5][CH:4]=1.Cl.[NH2:25][OH:26]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH2:13][CH2:12][C:11](=[N:25][OH:26])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2=CC(=O)CCC2c2ccc(OC)cc2)cc1
Reactant: NO
Agent: Cl
Solvent: CO
Product: COc1ccc(C2=CC(=NO)CCC2c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 188.6 g. of 3,4-bis(4-methoxyphenyl)-2-cyclohexen-1-one and 84.8 g. of hydroxylamine hydrochloride in 1.5 liters of methanol was heated to reflux for three hours. The reaction was then stirred overnight at room temperature and evaporated in vacuo. To the residue were added one liter of ethyl acetate and 600 ml. of water. The layers were separated and the organic layer was washed three times each with 500 ml. of water. The organic layer was dried over sodium sulfate, filtered, and evaporated in vacuo to provide 192.59 g. of the title oxime intermediate.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=1.[NH2:18][C:19]1[C:24]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[CH:23][C:22]([Cl:32])=[CH:21][N:20]=1.O>CS(C)=O>[Cl:32][C:22]1[CH:23]=[C:24]([C:25]2[CH:26]=[CH:27][C:28]([O:31][C:8]3[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=3)=[CH:29][CH:30]=2)[C:19]([NH2:18])=[N:20][CH:21]=1
Reactant: Fc1ncccc1C(F)(F)F
Reactant: Nc1ncc(Cl)cc1-c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ncc(Cl)cc1-c1ccc(Oc2ncccc2C(F)(F)F)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
A mixture of potassium carbonate (376 mg), 2-fluoro-3-(trifluoromethyl)pyridine (269 mg) and 4-(2-amino-5-chloropyridin-3-yl)phenol (300 mg) in DMSO (10 mL) was stirred at 120° C. for 3 hr. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with 1N NaOH aq. and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with EtOAc in hexane) to give the title compound (470 mg) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:18][CH2:19][C@@H:20]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)(=O)=O>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:18][CH2:19][C@@H:20]([NH:29][C:30](=[O:31])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CCOS(C)(=O)=O)Cc1ccc(Cl)cc1
Reactant: Brc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CCn1cc(Br)cn1)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.3 %

Procedure:
To a mixture of 4-bromopyrazole (1.26 g, 8.57 mmol) and cesium carbonate (4.66 g, 14.3 mmol) in DMF (20 mL) was added (3S)-3-((tert-butoxycarbonyl)amino)-4-(4-chlorophenyl)butyl methanesulfonate (2.70 g, 7.15 mmol). The mixture was stirred for 16 hours at room temperature. The mixture was diluted with DCM and washed with H2O (2×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (EtOAc/Hexanes, 0-25%) to give the product as an off-white solid (2.86 g, 93%). LCMS (API-ES) m/z: 428, 430 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:24][CH2:25][CH2:26][O:27][C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: COC(=O)c1ccc(OCCN)cc1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OCCNC(=O)c2ccc(Br)cc2)cc1
Yield: 56.7 %

Procedure:
p-Bromobenzoic acid (6 g) and 3.35 g of triethylamine were dissolved in 80 ml of chloroform, the mixture was cooled at 0°-5° C. with stirring, and 3.26 g of ethyl chlorocarbonate was dropped thereinto. The mixture was stirred at the same temperature for 30 minutes, 5.86 g of methyl 4-(2-aminoethoxy)benzoate was added, and the mixture was stirred for 7 hours more. The reaction solution was washed with 10% hydrochloric acid, saturated potassium carbonate solution, and with water, dried with anhydrous magnesium sulphate, concentrated in vacuo, the residue was crystallised with n-hexane, and 8.5 g of crystals obtained were recrystallised from ethyl acetate to give 6.4 g of the product, m.p. 134°-136° C.
Reaction SMILES: [N:1]1([C:6]2[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][NH2:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:16]1[C:21]([CH:22]=O)=[CH:20][C:19]2[O:24][CH2:25][O:26][C:18]=2[CH:17]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[N:1]1([C:6]2[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][NH:13][CH2:22][C:21]3[CH:16]=[CH:17][C:18]4[O:26][CH2:25][O:24][C:19]=4[CH:20]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: NCCOc1ccc(-n2ccnc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: c1cn(-c2ccc(OCCNCc3ccc4c(c3)OCO4)cc2)cn1
Reaction time: 1 h
Yield: 51.9 %

Procedure:
To 2-[4-(imidazol-1-yl)phenoxy]ethylamine (4.0 g, 20 mmol) dissolved in MeOH (150 mL) was added piperonal (3.0 g, 20 mmol) and acetic acid (1.5 mL). After stirring for 1 h, NaBH3CN (2.6 g, 40 mmol) was added. After stirring for 18 hour, the solvent was removed in vacuo and the residue was chromatographed on silical gel with 2% methanol in methylene chloride to give 3.5 g of N-[2-(4-(imidazol-1-yl)phenoxy)ethyl]-N-[(1,3-benzodioxol-5-yl)methyl]amine, 1H NMR (DMSO-d6) 8.12 (s, 1), 7.62 (s, 1), 7.54 (d, 2), 7.08-7.02 (m, 3), 6.90 (s, 1), 6.82-6.75 (m, 2), 5.94 (s, 2), 4.03 (t, 2), 3.62 (s, 2), 3.32 (s, 1), 2.80 (t, 2) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([NH2:20])[CH2:13][S:14]([N:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH:21]1[CH:26]=[C:25]([CH:27]=[O:28])[C:24]([CH:29]=O)=[CH:23][CH:22]=1>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:20]2[CH2:29][C:24]3[C:25](=[CH:26][CH:21]=[CH:22][CH:23]=3)[C:27]2=[O:28])[CH2:13][S:14]([N:17]([CH3:18])[CH3:19])(=[O:15])=[O:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(N)CS(=O)(=O)N(C)C)ccc1OC
Reactant: O=Cc1ccccc1C=O
Solvent: CC(=O)O
Product: CCOc1cc(C(CS(=O)(=O)N(C)C)N2Cc3ccccc3C2=O)ccc1OC

Procedure:
2-[1-(3-Ethoxy-4-methoxyphenyl)-2-(N,N-dimethylaminosulfonyl)ethyl]isoindolin-1-one was prepared by the procedure of Example 3 from 1-(3-ethoxy-4-methoxyphenyl)-2-(N,N-dimethylaminosulfonyl)ethylamine (150 mg, 0.49 mmol) and 1,2-phthalic dicarboxaldehyde (67 mg, 0.49 mmol) in acetic acid (2 mL). The product was obtained as a solid (142 mg, 69% yield): mp, 165.0-167.0° C.; 1H NMR (CDCl3) δ 1.45 (t, J=7 Hz, 3H, CH3), 2.86 (s, 6H, N(CH3)2), 3.58 (dd, J=4.7, 14.4 Hz, 1H, CHH), 3.86 (s, 3H CH3), 4.08 (q, J=7 Hz, 2H, CH2), 4.30 (d, J=16.5 Hz, 1H, NCHH), 4.33 (dd, J=9, 14.4 Hz, 1H, CHH), 4.49 (d, J=16.5 Hz, 1H, NCHH), 5.60 (dd, J=4.7, 9.5 Hz, 1H, NCH), 6.83 (d, J=8.3 Hz, 1H, Ar), 6.98 (dd, J=2, 8.3 Hz, 1H, Ar), 7.06 (d, J=2 Hz, 1H, Ar), 7.37-7.56 (m, 3H, Ar), 7.84 (d, J=7 Hz, 1H, Ar), 13C NMR (CDCl3) δ 14.69, 37.31, 48.64, 49.73, 52.91, 52.95, 64.54, 111.31, 112.46, 119.29, 122.76, 123.72, 128.03, 130.67, 131.55, 132.75, 141.26, 148.73, 149.39, 168.63; Anal Calcd for C21H26NO5S: C, 60.27; H, 6.26; N, 6.69. Found: C, 60.04; H, 6,10: N, 6.62.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[C:28]([F:31])([F:30])[F:29])[N:15]=[CH:14]3)/[S:6][C:5]1=[O:32].[F:33][C:34]([F:46])([F:45])[C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:16]2[C:17]3[C:13](=[CH:12][C:11](/[CH:10]=[C:7]4/[C:8](=[O:9])[N:4]([CH2:3][CH2:2][NH:1][S:41]([C:38]5[CH:37]=[CH:36][C:35]([C:34]([F:33])([F:45])[F:46])=[CH:40][CH:39]=5)(=[O:43])=[O:42])[C:5](=[O:32])[S:6]/4)=[CH:19][CH:18]=3)[CH:14]=[N:15]2)=[C:22]([C:28]([F:30])([F:29])[F:31])[CH:23]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: NCCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CCNS(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
N-{2-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]ethyl}-4-(trifluoromethyl)benzenesulfonamide was prepared from 3-(2-aminoethyl)-(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione (from Example 49) and p-trifluoromethyl-benzenesulfonyl chloride following General Procedure U.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][NH:11]2)=[CH:2]1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>C(Cl)Cl.CN(C=O)C>[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([N:11]2[CH2:12][CH2:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]2[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[O:29])=[CH:23][CH:22]=1
Reactant: c1ccc2c(c1)CCNC2c1c[nH]c2ccccc12
Reactant: O=C=Nc1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)N1CCc2ccccc2C1c1c[nH]c2ccccc12
Reaction time: 48 h

Procedure:
To a solution of 1-(1H-indol-3-yl)-1,2,3,4-tetrahydroisoquinoline (16.3 mg, 66 μmol) in CH2Cl2 (0.5 mL) at RT was added 1-fluoro-4-isocyanatobenzene (10 μL, 66 μmol). The reaction was stirred 48 h, the suspension dissolved in DMF and purified by HPLC to give N-(4-fluorophenyl)-1-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide as a white solid. MS (ESI pos. ion) m/z: 386 (M+1).
Reaction SMILES: ON=[CH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([CH3:15])[CH:8]=1)=[O:5].CS(O)(=O)=[O:18]>>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[CH3:15])[NH:6][C:4](=[O:5])[C:3]2=[O:18]
Reactant: CS(=O)(=O)O
Reactant: COc1ccc(NC(=O)C=NO)cc1C
Product: COc1cc2c(cc1C)NC(=O)C2=O
Reaction time: 0.17 h
Yield: 77 %

Procedure:
2-Hydroxyimino-N-(4-methoxy-3-methylphenyl)acetamide (0.5 g, 2.4 mmol) was added portionwise to concentrated methanesulfonic acid (1.5 mL). The 2-hydroxyimino-N-(4-methoxy-3-methylphenyl)acetamide was added over a period of 45 min in order to keep the reaction temperature between 65 to 70° C. After addition, the mixture was stirred for 10 min and then poured onto ice (10 g). The resulting aqueous solution was extracted with ethyl acetate (3×50 mL). Combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel with petroleum ether:ethyl acetate (20:1, v/v) as eluent to afford 5-methoxy-6-methyl-1H-indole-2,3-dione (350 mg, 1.8 mmol, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([O:12][C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[N:8]=[CH:9]2)=[CH:4][CH:3]=1.Br[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+].ClCCl>C(C(C)=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([O:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:18]=3)[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Oc2cc3ccc(Cl)cc3cn2)cc1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)Oc1ccc(Oc2cc3ccc(Cl)cc3cn2)cc1
Yield: 86.3 %

Procedure:
4-[(7-chloroisoquinolin-3-yl)oxy]phenol (2.82 g) and ethyl 2-bromopropionate (2.07 g) in the presence of anhydrous potassium carbonate (1.58 g) were refluxed in methyl ethyl ketone (50 ml) for 4 hrs. The mixture was cooled, poured into dichloromethane, washed with water, dried (MgSO4) and evaporated. Purification by column chromatography over silica gel (eluant dichloromethane) gave ethyl 2-{4-[(7-chloroisoquinolin-3-yl)oxy]phenoxy}propionate (3.33 g) as a brown oil.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=3[CH2:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:17]1[C:11]2[CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=3[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:5][CH2:6]3)=[N:13][C:12]=2[CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)CBr
Reactant: c1ccc2c(c1)Cc1ccccc1C(N1CCNCC1)=N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCN(C2=Nc3ccccc3Cc3ccccc32)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 80.2 %

Procedure:
A mixture of 2.77 g of 6-(1-piperazinyl)-11H-dibenz[b,e]azepine, 2.00 g of ethyl bromoacetate and 1.38 g of potassium carbonate in 14 ml of N,N-dimethylformamide was stirred at 70° C. for 3 hrs. After cooling, water was added to the reaction mixture and extracted with ether. The etheral layer was washed with water, dried and concentrated. The residue was chromatographed on silica gel using a mixture of n-hexane and ethyl acetate (2:1 and 1:1) as eluents to give 2.91 g of colorless crystals, which were recrystallized from isopropyl ether to give colorless prisms, mp 107°-108° C.
Reaction SMILES: [CH2:1]([C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].S(Cl)([Cl:17])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:17])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCc1ccc(C(=O)Cl)cc1

Procedure:
First, 1.2 g (6.1 mmol) of 4-pentyl benzoic acid was mixed with 1.1 g (9.1 mmol) of thionyl chloride, 0.1 ml of pyridine, and 3 ml of toluene, and reacted at 80° C. for 2 hours. Excess amount of thionyl chloride and toluene were distilled off at a reduced pressure to obtain a crude 4-pentylbenzoyl chloride.
Reaction SMILES: I[C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[S:21]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22]1.C(=O)([O-])[O-].[K+].[K+].CC(O)C>[Pd].O>[S:21]1[CH:25]=[CH:24][C:23]([C:2]2[CH:20]=[CH:19][C:5]([O:6][C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[CH:9][CH:8]=3)=[CH:4][CH:3]=2)=[CH:22]1
Reactant: OB(O)c1ccsc1
Reactant: Ic1ccc(Oc2ccc(N3CCOCC3)cc2)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: c1cc(-c2ccc(Oc3ccc(N4CCOCC4)cc3)cc2)cs1
Yield: 35.3 %

Procedure:
The title compound (25 mg, 35%) was prepared by treating 4-[4-(4-Iodo-phenoxy)-phenyl]-morpholine (80 mg, 0.21 mmol) from Example 24 with thiophene-3-boronic acid (35 mg, 0.25 mmol) in the presence of 10% Pd/C (10 mg), potassium carbonate (87 mg, 0.68 mmol), 2-propanol (4 mL) and water (0.4 mL) by using the procedure described in step 2 of Example 16: MS (ESI) m/z 338 (M+H); 1H NMR (400 MHz, CDCl3) δ 3.13 (t, J=4.8 Hz, 4H), 3.87 (t, J=4.8 Hz, 4H), 6.91-7.01 (m, 6H), 7.34-7.38 (m, 3H), 7.51-7.53 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:43])/[N:10]=[C:11](/[NH2:42])\[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20](=[O:41])[CH:21]([O:39][CH3:40])[C:22]2[N:26](COCC[Si](C)(C)C)[C:25]3[CH:35]=[CH:36][CH:37]=[CH:38][C:24]=3[N:23]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl>[CH2:1]([O:8][C:9](=[O:43])/[N:10]=[C:11](/[NH2:42])\[C:12]1[CH:13]=[CH:14][C:15]([CH2:18][NH:19][C:20](=[O:41])[CH:21]([C:22]2[NH:23][C:24]3[CH:38]=[CH:37][CH:36]=[CH:35][C:25]=3[N:26]=2)[O:39][CH3:40])=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(C(=O)NCc1ccc(/C(N)=N\C(=O)OCc2ccccc2)cc1)c1nc2ccccc2n1COCC[Si](C)(C)C
Agent: Cl
Product: COC(C(=O)NCc1ccc(/C(N)=N\C(=O)OCc2ccccc2)cc1)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.9 %

Procedure:
(RS)-[1-Amino-1-[4-({2-methoxy-2-[l -(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-acetylamino }-methyl)-phenyl]-meth-(E)-ylidene]-carbamic acid benzyl ester (0.5 g) was heated in 5 N HCl (20 ml) to 50° C. and stirring at that temperature was continued for 4 h. After cooling to r.t., the mixture was washed with EtOAc and cooled to 0° C. The pH was brought to ˜12 by the dropwise addition of 4 N NaOH. The mixture was then extracted with EtOAc. The combined organics were washed with brine, dried (MgSO4), filtered and concentrated to give (RS)-[1-amino-1-(4-{[2-(1H-benzoimidazol-2-yl)-2-methoxy-acetylamino]-methyl}-phenyl)-meth-(E)-ylidene]-carbamic acid benzyl ester (0.258 g) as light yellow solid. MS472.3 ([M+H]+)