Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[CH2:15][CH2:16][CH2:17][C:18]1([CH3:23])[O:22][CH2:21][CH2:20][O:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([NH-])(C)C.C[Si]([NH-])(C)C.[Li+].[Li+].Br[CH2:38][C:39]([CH3:41])=[CH2:40]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[C@@H:15]([CH2:16][CH2:17][C:18]1([CH3:23])[O:19][CH2:20][CH2:21][O:22]1)[CH2:40][C:39]([CH3:41])=[CH2:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)CBr
Reactant: CC1(CCCC(=O)N2C(=O)OC[C@H]2Cc2ccccc2)OCCO1
Agent: C[Si](C)(C)[NH-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(C)C[C@H](CCC1(C)OCCO1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 2-2 (18 g, 54 mmol) in tetrahydrofuran (400 mL) at −78° C. under argon was added a solution of lithium bis(trimethylsilylamide) (70.2 mL of a 1.0 M solution in tetrahydrofuran) over 20 min. After an additional 20 min., 3-bromo-2-methylpropene (14.6 g, 108 mmol) was added in one portion. After 20 min., the reaction mixture was allowed to warm to 0° C. After 3.5 h, the reaction mixture was diluted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate, saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The reaction mixture was filtered and concentrated at reduced pressure. The resulting oil (3-1) was used without further purification.
Reaction SMILES: C([O-])(O)=O.[Na+].OC(C(F)(F)F)=O.[CH2:13]([O:20][N:21]1[C:27](=[O:28])[N:26]2[CH2:29][C@H:22]1[CH2:23][CH2:24][C@H:25]2[C:30]([NH:32][NH2:33])=[O:31])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[N:34]#[C:35]Br>O1CCOCC1>[NH2:34][C:35]1[O:31][C:30]([C@@H:25]2[CH2:24][CH2:23][C@@H:22]3[CH2:29][N:26]2[C:27](=[O:28])[N:21]3[O:20][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:32][N:33]=1
Reactant: N#CBr
Reactant: NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: Nc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)o1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 31.8 %

Procedure:
Saturated NaHCO3 (7.0 mL, 6.26 mmol) was added to a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide TFA salt (2.3 g, 5.69 mmol) in dioxane (11.4 mL) and the reaction mixture was stirred at rt for 5 minutes. Cyanic bromide (3 M solution, 2.3 mL, 6.90 mmol) was added and the reaction mixture was stirred at rt for 30 minutes. The reaction mixture was then loaded on a silica gel cartridge and purified by silica gel column chromatography (gradient elution 0-10% MeOH/DCM) to give (2S,5R)-2-(5-amino-1,3,4-oxadiazol-2-yl)-6-(benzyloxy)-1,6-diazabicyclo[3.2.1]octan-7-one (0.57 g, 32%). ESI-MS (EI+, m/z): 316.4 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)=[CH:17][N:16]=2)=[CH:10][CH:9]=1)C.C(N(CC)CC)C.[C:40](Cl)(=[O:42])[CH3:41].[OH-].[Na+].Cl>ClCCl.O>[C:40]([N:6]([CH2:5][C:4]([OH:3])=[O:32])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)=[CH:17][N:16]=2)=[CH:12][CH:13]=1)(=[O:42])[CH3:41]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)CNCc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(CC(=O)O)Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)cc1
Reaction time: 1 h

Procedure:
To a solution of ethyl{4-[5-(3,4-dichloro-benzoylamino)pyridin-2-yloxy]benzylamino}acetate (0.811 g, 1.59 mmol) in dichloromethane (5 mL) were added triethylamine (0.332 mL, 2.39 mmol) and acetyl chloride (0.136 mL, 1.91 mmol) at room temperature. The resulting solution was stirred for 1 hour at the same temperature. To the reaction solution was added water, and extracted with dichloromethane. The dichloromethane layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated, to thereby yield 0.785 g of residue. This residue was dissolved in ethanol (5 mL). To the resulting solution was added 5 M aqueous sodium hydroxide (0.350 mL, 1.75 mmol) at room temperature and stirred at the same temperature for 14 hours. To the resulting reaction solution were added 5 M hydrochloric acid (0.400 mL) and water, and extracted with dichloromethane. The dichloromethane layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated, to thereby yield 0.776 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:24]([N:27](CC3C=CC(OC)=CC=3)[C:28]3[S:29][CH:30]=[CH:31][N:32]=3)(=[O:26])=[O:25])=[CH:20][C:21]=2[CH3:23])[N:16]=[CH:15][CH:14]=1>CO.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:24]([NH:27][C:28]3[S:29][CH:30]=[CH:31][N:32]=3)(=[O:25])=[O:26])=[CH:20][C:21]=2[CH3:23])[N:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2cc(C)c3c(-c4ccc(C(F)(F)F)cc4OC)ccnc3c2)cc1
Solvent: CO
Solvent: O
Product: COc1cc(C(F)(F)F)ccc1-c1ccnc2cc(S(=O)(=O)Nc3nccs3)cc(C)c12
Reaction time: 1 h
Yield: 32 %

Procedure:
To a microwave vial charged with (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (3.16 mg, 0.014 mmol), 4-chloro-N-(4-methoxybenzyl)-5-methyl-N-(thiazol-2-yl)quinoline-7-sulfonamide (6 mg, 0.013 mmol), potassium phosphate tribasic (3.24 μl, 0.039 mmol) and 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(ii) chloride (0.924 mg, 1.304 μmol) was added dioxane (52.3 μl) and water (17.44 μl). The mixture was irradiated at 100° C. for 30 min affording conversion to desired product according to LC-MS, 4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-5-methyl-N-(thiazol-2-yl)quinoline-7-sulfonamide. m/z (ESI) 600.2 (M+H)+. The mixture was dried under reduced pressure. To the crude oil was added DCM (0.9 ml) and TFA (0.3 ml) was added at room temperature. After 1 hr of stirring, LC/MS indicated complete PMB cleavage. The mixture was dried under reduced pressure and purified with a 25 g (15 μm spherical silica) column ramping EtOAc in heptane (0 to 100%, 10% DCM throughout) providing product, obtained as a film. The material was lyophilized from MeOH/H2O providing 4-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methyl-N-(thiazol-2-yl)quinoline-7-sulfonamide (2 mg, 4.17 μmol, 32.0% yield) as a yellow film. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.75 (s, 3H) 6.86 (d, J=4.59 Hz, 1H) 7.28 (d, J=4.59 Hz, 1H) 7.38 (d, J=4.27 Hz, 1H) 7.41-7.48 (m, 2H) 7.49 (s, 1H) 7.63 (s, 1H) 8.32-8.39 (m, 1H) 8.99 (d, J=4.27 Hz, 1H). m/z (ESI) 480.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=1>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][O:27][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: OCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(Cn2c(NC3CCN(CCOc4ccc5ccccc5n4)CC3)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
5.5 Parts of 4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidineethanol and 135 parts of N,N-dimethylformamide were stirred at room temperature and 0.75 parts of a sodium hydride dispersion 50% were added. After stirring for one hour at room temperature, 2.5 parts of 2-chloroquinoline were added and the whole was stirred overnight at room temperature. The reaction mixture was poured onto water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was crystallized from acetonitrile, yielding 4.3 parts (58%) of 1-[(4-fluorophenyl)methyl]-N-[1-[2-(2-quinolinyloxy)ethyl]-4-piperidinyl]1H-benzimidazol-2-amine; mp. 149.9° C. (compound 77)
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:22][CH3:23])=[C:5]([CH:19]=[CH:20][CH:21]=1)[O:6][C:7]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10])=O.CN.[C:26]([BH3-])#[N:27].[Na+].[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34]>C(OCC)(=O)C.C(O)(=O)C.CO>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34].[CH3:23][O:22][C:4]1[C:3]([CH2:1][NH:27][CH3:26])=[CH:21][CH:20]=[CH:19][C:5]=1[O:6][C:7]1[CH:14]=[C:13]([C:15]([F:17])([F:16])[F:18])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10]
Reactant: [BH3-]C#N
Reactant: COc1c(C=O)cccc1Oc1cc(C(F)(F)F)ccc1C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CNCc1cccc(Oc2cc(C(F)(F)F)ccc2C#N)c1OC
Yield: 30.4 %

Procedure:
2-(3-Formyl-2-methoxy-phenoxy)-4-trifluoromethyl-benzonitrile (0.46 g, 1.43 mmol), methylamine (2M in methanol, 22.2 mL, 4.4 mmol) and sodium cyanoborohydride (0.13 g, 2.1 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (70 mL) for 20 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. Fumaric acid (0.15 g, 1.3 mmol) was added to the separated ethyl acetate layer and the solvent removed in vacuo. The residue was triturated with diethyl ether overnight, filtered and dried to give 2-(2-methoxy-3-methylaminomethyl-phenoxy)-4-trifluoromethyl-benzonitrile fumarate (179 mg, 28%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][C:16]([C:22]([NH2:24])=[O:23])=[C:15]2Cl.C(O)(=O)C.C(O)C>C(O)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:15]2[C:14]3[C:19](=[CH:20][CH:21]=[C:12]([O:11][CH3:10])[CH:13]=3)[N:18]=[CH:17][C:16]=2[C:22]([NH2:24])=[O:23])=[C:4]([CH3:9])[CH:3]=1
Reactant: COc1ccc2ncc(C(N)=O)c(Cl)c2c1
Reactant: Cc1cc(F)ccc1N
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc2ncc(C(N)=O)c(Nc3ccc(F)cc3C)c2c1
Temperature: 25 °C

Procedure:
A mixture of 4-fluoro-2-methylaniline (0.025 mmol), 6-methoxy-4-chloro-3-quinolinecarboxamide (0.025 mmol), 50 μl 20% Acetic acid/Ethanol and 250 μl ethanol was refluxed for four hours. After cooling to room temperature the solvent was removed in vacuu.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([C:11]#[N:12])=[CH:7][NH:8][C:9]=1[CH3:10])[CH2:2][CH2:3][CH3:4].[CH2:13]([O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=1)[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:13]([O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20]([N:8]2[CH:7]=[C:6]([C:11]#[N:12])[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[C:9]2[CH3:10])=[CH:19][CH:18]=1)[CH3:14]
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: CCCCc1c(C#N)c[nH]c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1c(C#N)cn(-c2ccc(C(=O)OCC)cc2)c1C
Temperature: 70 °C
Reaction time: 8 h
Yield: 20.6 %

Procedure:
A suspension of 4-butyl-5-methyl-1H-pyrrole-3-carbonitrile (0.081 g), 4-fluoro-benzoic acid ethyl ester (0.10 g) and cesium carbonate (0.21 g) in N,N-dimethylformamide (3 mL) was stirred at 70° C. overnight. This reaction mixture was poured into water, and this mixture was extracted with ethyl acetate. This organic layer was washed with brine, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=1/6) to give the title compound (0.032 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([N:41]([CH2:48][CH3:49])[CH2:42][CH2:43][O:44][CH2:45][CH2:46][CH3:47])=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[CH2:48]([N:41]([C:38]1[CH:37]=[CH:36][C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:12])(=[O:13])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:40][CH:39]=1)[CH2:42][CH2:43][O:44][CH2:45][CH2:46][CH3:47])[CH3:49]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCCOCCN(CC)c1ccc(OB([O-])[O-])cc1
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: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCOCCN(CC)c1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.8 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (200 mg), 4-[N-ethyl-N-(2-propoxyethyl)amino]phenyl borate (290 mg) and potassium carbonate (266 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (40 mg), and the mixture was refluxed for 8 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and was concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethanol/ethyl acetate=1:3) to give crystals, which were recrystallized from ethanol to give pale yellow crystals of 7-[4-[N-ethyl-N-(2-propoxyethyl)amino]phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 71) (89 mg).
Reaction SMILES: [CH2:1]([C@H:8]1[C:12](=[O:13])[NH:11][CH:10]([CH2:14][CH2:15][C:16]([O:18]CC(C)C)=O)[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[CH2:1]([C@@H:8]1[N:9]2[C:16](=[O:18])[CH2:15][CH2:14][CH:10]2[NH:11][C:12]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)COC(=O)CCC1NC(=O)[C@H](Cc2ccccc2)N1
Solvent: Cc1ccccc1
Product: O=C1NC2CCC(=O)N2[C@H]1Cc1ccccc1
Yield: 50.4 %

Procedure:
A solution of isobutyl (4S)-4-benzyl-5-oxo-2-imidazolidinepropanoate (2.3 g, 7.33 mmol) in toluene (100 ml) was refluxed for 8 days. After evaporation of the solvent, the residue was chromatographed over silica gel (dichlorometane-methanol 9:1). The appropriate fractions were collected and evaporated; the residue was triturated with diethyl ether to afford 850 mg (50%) of the title compound, m.p. 141°-145° C. NMR (CDCl3): deltaH =7.25 (s, 5H, PhH); 7.02 (b.s., 1H, NH); 4.52 (t, J=4.5 Hz, 1H, PhCH2CH); 4.37 (t, J=5 Hz, 1H, NCHNH); 3.13 (d, J=4.5 Hz, 2H, PhCH2); 2.80-1.6 (c.a., 4H, CH2CH2). MS (E.I., 70 eV, 1.5 mA) m/Z=230 (M+), 139 (M-C7H7)+, 91 (C7H7)+, 84 (C4H6NO)+.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[Cl:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]([N:18]2[CH2:23][CH2:22][N:21]([S:24]([CH2:27][CH:28]([NH:37][OH:38])[C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=3)(=[O:26])=[O:25])[CH2:20][CH2:19]2)[CH:13]=1>O1CCCC1>[Cl:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]([N:18]2[CH2:23][CH2:22][N:21]([S:24]([CH2:27][CH:28]([N:37]([OH:38])[CH:5]=[O:7])[C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=3)(=[O:25])=[O:26])[CH2:20][CH2:19]2)[CH:13]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=S(=O)(CC(NO)c1ccc(Cl)c(Cl)c1)N1CCN(c2cc(Cl)ncn2)CC1
Solvent: O=CO
Solvent: C1CCOC1
Product: O=CN(O)C(CS(=O)(=O)N1CCN(c2cc(Cl)ncn2)CC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (0.23 ml) was added directly to formic acid (0.9 ml). The solution was stirred at room temperature for 30 minutes and then added a solution of N-[2-{[4-(6-chloropyrimidin-4-yl)tetrahydropyrazin-1-yl]sulfonyl}-1-(3,4-dichlorophenyl)ethyl]hydroxylamine (0.227 g) in tetrahydrofuran (5 ml). The solution was stirred at room temperature for 18 hours. The solution was evaporated (water-bath temperature 30° C.) and the residual gum was purified by chromatography using a 10 g silica isolute eluting with CH2Cl2-3% Methanol/CH2Cl2 to give N-[2-{[4-(6-chloropyrimidin-4-yl)piperazino]sulfonyl}-1-(3,4-dichlorophenyl)ethyl]-N-hydroxyformamide (0.178 g), 98-101° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:20])=[C:6]([CH:19]=1)[CH2:7][N:8]([CH:16]1[CH2:18][CH2:17]1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[F-].[Cs+].[CH2:23]([Sn](CCCC)(CCCC)CCCC)[CH:24]=[CH2:25]>C1COCC1>[CH2:25]([C:2]1[CH:3]=[CH:4][C:5]([Cl:20])=[C:6]([CH:19]=1)[CH2:7][N:8]([CH:16]1[CH2:18][CH2:17]1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:24]=[CH2:23]
Reactant: CC(C)(C)OC(=O)N(Cc1cc(Br)ccc1Cl)C1CC1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCc1ccc(Cl)c(CN(C(=O)OC(C)(C)C)C2CC2)c1

Procedure:
A THF solution (0.13 M) of tert-butyl (5-bromo-2-chlorobenzyl)cyclopropylcarbamate from the previous step (1 eq.), Pd(PCy3)2 (0.05 eq.) and cesium fluoride (2.0 eq.) was added allyl tributylstannane (1.2 eq.). The resulting brown solution was heated at reflux for 8 h and then filtered through a pad of SiO2. The insolubles were rinsed further with ether and the filtrate was concentrated in vacuo to afford a brown semisolid. Purification of the crude product thus obtained by way of column chromatography (SiO2, Hex→90:10 (v/v) Hex:Et2O) afforded the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH:4]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)[CH2:5][NH:6][C:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)=O.[ClH:31].[CH2:32]([O:34][C:35]([CH:37]1[C:46]2[C:41](=[CH:42][C:43]([O:49][CH3:50])=[C:44]([O:47][CH3:48])[CH:45]=2)[C:40]([CH2:51][C:52]2[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[C:54]([O:60][CH3:61])[CH:53]=2)=[N:39][CH2:38]1)=[O:36])C>>[CH3:1][O:2][C:3]([CH:4]1[C:20]2[C:25](=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)=[N:6][CH2:5]1)=[O:30].[ClH:31].[CH3:32][O:34][C:35]([CH:37]1[C:46]2[C:41](=[CH:42][C:43]([O:49][CH3:50])=[C:44]([O:47][CH3:48])[CH:45]=2)[C:40]([CH2:51][C:52]2[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[C:54]([O:60][CH3:61])[CH:53]=2)=[N:39][CH2:38]1)=[O:36]
Reactant: CCOC(=O)C1CN=C(Cc2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc21
Reactant: COC(=O)C(CNC(=O)Cc1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Agent: Cl
Product: COC(=O)C1CN=C(Cc2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc21

Procedure:
The hydrochloride of 3,4-dihydro-6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methyl]-4-isoquinoline carboxylic acid methyl ester was prepared by treating 2-(3,4-dimethoxyphenyl)-3-{{[(3,4-dimethoxyphenyl)methyl]carbonyl}amino}propanoic acid methyl ester via the method described for the preparation of 3,4-dihydro-6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methyl]-4-isoquinolinecarboxylic acid ethyl ester hydrochloride. Crystallization from methanol provided analytically pure 3,4-dihydro6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methyl]-4-isoquinolinecarboxylic acid methyl ester, hydrochloride, mp 199°-200°.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][CH2:15][S:16]([O-:19])(=[O:18])=[O:17].[Na+]>O>[S:16]([CH2:15][CH2:14][N:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1)([OH:19])(=[O:18])=[O:17]
Reactant: O=S(=O)([O-])CCBr
Reactant: c1ccc(N2CCNCC2)cc1
Agent: [Na+]
Solvent: O
Product: O=S(=O)(O)CCN1CCN(c2ccccc2)CC1
Temperature: 25 °C

Procedure:
A 3.25 g quantity (20 mmols) of 1-phenylpiperazine is dissolved in 10 ml of water, and a solution of 4.3 g (20 mmols) of sodium 2-bromoethanesulfonate in 10 ml of water is added dropwise thereto at room temperature with stirring. The mixture is subjected to reaction at room temperature for 1 hour and then at 70° C. overnight, and cooled. The crystals precipitated are collected by filtration and recrystallized from water-acetone.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][N:6]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][C:21]([C:24]1[S:25][CH:26]([CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH2:27][N:28]=1)=[CH:20]2)[S:7]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)(=[O:9])=[O:8])C.[OH-].[K+].Cl>O1CCCC1.CO.O>[O:33]1[CH2:32][CH2:31][N:30]([CH2:29][CH:26]2[S:25][C:24]([C:21]3[NH:22][C:23]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][C:15]=4[N:6]([S:7]([C:10]3[S:11][CH:12]=[CH:13][CH:14]=3)(=[O:8])=[O:9])[CH2:5][C:4]([OH:36])=[O:3])=[N:28][CH2:27]2)[CH2:35][CH2:34]1
Reactant: CCOC(=O)CN(c1cccc2cc(C3=NCC(CN4CCOCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CN(c1cccc2cc(C3=NCC(CN4CCOCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
To a solution of N-{2-[5-(morpholinomethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-(2-thienylsulfonyl)glycine ethyl ester (120 mg) in tetrahydrofuran (3 mL) and methanol (3 mL) was added, under ice-cooling, a solution prepared by dissolving potassium hydroxide (purity 85%, 30 mg) in water (1 mL), and the mixture was stirred for 30 min, and then at room temperature for 1 hr. 1M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was recrystallized from a mixed solvent of ethyl acetate-hexane to give the title compound (106 mg, yield 93%) as white crystals. MS: 521 (MH+).
Reaction SMILES: [N:1]([O-])=O.[Na+].Cl.[NH:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]([CH3:21])[NH:16][C:17](=[O:20])[NH:18][N:19]=2)=[CH:10][CH:9]=1)[NH2:7].Cl>O>[N:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]([CH3:21])[NH:16][C:17](=[O:20])[NH:18][N:19]=2)=[CH:12][CH:13]=1)=[N+:7]=[N-:1]
Reactant: CC1NC(=O)NN=C1c1ccc(NN)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC1NC(=O)NN=C1c1ccc(N=[N+]=[N-])cc1
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
A solution of sodium nitrite (0.3 g) in water (2 ml) was added dropwise to a solution of 6-(4-hydrazinophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one hydrochloride (0.92 g) in a mixture of 1N-hydrochloric acid (3 ml) and water (20 ml) under ice cooling. After stirring for 30 minutes, the resultant precipitates were collected by filtration and washed successively with water, methanol and diisopropyl ether to give 0.56 g of 6-(4-azidophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5](C=O)=[CH:4][CH:3]=1.[Mg].[B:11]([O:22][CH2:23]CCC)([O:17]CCCC)OCCCC.[O:27]1CCCC1>>[CH:23]([O:22][B:11]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:8][CH:9]=1)[OH:17])=[O:27]
Reactant: O=Cc1ccc(Br)cc1
Reactant: C1CCOC1
Reactant: CCCCOB(OCCCC)OCCCC
Agent: [Mg]
Product: O=COB(O)c1ccccc1
Yield: 70 %

Procedure:
Nöth et al. (Chem. Ber. 1990, 1841-1843) convert p-bromobenzaldehyde into the diethyl acetal, convert this into the corresponding Grignard reagent by means of magnesium turnings in tetrahydrofuran (THF) and, after reaction with tri-n-butyl borate, obtain formylphenylboronic acid in a yield of 70%. A disadvantage of this synthesis is the high price of bromobenzaldehyde compared to chlorobenzaldehyde, the need for ultrasonic activation in the preparation of the Grignard reagent and the use of the expensive tributyl borate; in addition, complicated purification procedures have to be employed (e.g. via the hydrolysis product 1-butanol).