Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19](O)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:22])[N:10]1[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[NH:29][S:30]([CH3:33])(=[O:32])=[O:31].[C:34]1([CH2:40][S:41]([NH2:44])(=[O:43])=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCN=C=NCCCN(C)C.Cl.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH2:40]([S:41]([NH:44][C:19]([CH:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:22])[N:10]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]2[NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[CH:9]1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])=[O:20])(=[O:43])=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NS(=O)(=O)Cc1ccccc1
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)O)C1c1ccc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NS(=O)(=O)Cc2ccccc2)C1c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.6 %

Procedure:
To a solution of 700 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid, 351 mg of 1-phenylmethanesulfonamide, and 334 mg of DMAP in 10.5 ml of DMF was added 525 mg of WSC/hydrochloride, followed by stirring at room temperature overnight. 0.1 M hydrochloric acid was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol), and ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution were then added thereto for liquid separation. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Ethyl acetate and diisopropyl ether were added thereto, and the precipitated solid was collected by filtration to obtain 33 mg of (3RS,4RS)—N-(benzylsulfonyl)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH:16](Br)[CH3:17]>CC(C)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:4]1([C:5](=[O:6])[CH3:7])[CH2:17][CH2:16]1)=[O:8]
Reactant: COC(=O)CC(C)=O
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COC(=O)C1(C(C)=O)CC1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
56 g of acetoacetic acid methyl ester 3 is dissolved in 500 ml of acetone, and 276.2 g of potassium carbonate as well as 86 ml of dibromoethane are added while being cooled with ice. It is heated under nitrogen to 50° C. and stirred for 72 hours at this temperature. After cooling, the mixture is diluted with ethyl acetate, washed with water and saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation. The residue is distilled in a vacuum, whereby 66 g of the title compound is obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][C:5]2=[C:7]([C:11](O)=[O:12])[CH:8]=[CH:9][CH:10]=[C:4]2[O:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH3:1][C:2]1([CH3:14])[CH2:6][C:5]2=[C:7]([CH2:11][OH:12])[CH:8]=[CH:9][CH:10]=[C:4]2[O:3]1
Reactant: CC1(C)Cc2c(cccc2C(=O)O)O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC1(C)Cc2c(CO)cccc2O1
Yield: 91.6 %

Procedure:
2,2-Dimethyl-2,3-dihydro-benzofuran-4-carboxylic acid (8.6 g, 45 mmol) was reduced with LAH (3.41 g, 89 mmol) similar to the above procedures to give the product as a clear oil (7.35 g, 93%).
Reaction SMILES: [Br:1][CH2:2]/[CH:3]=[CH:4]/[C:5](Cl)=[O:6].[OH:8][CH2:9][CH2:10][NH:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(OCC)C>[CH:12]1([N:11]([CH2:10][CH2:9][OH:8])[C:5](=[O:6])/[CH:4]=[CH:3]/[CH2:2][Br:1])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(Cl)/C=C/CBr
Reactant: OCCNC1CCCCC1
Solvent: CCOCC
Product: O=C(/C=C/CBr)N(CCO)C1CCCCC1

Procedure:
Into 100 ml of diethylether was added 19 g of γ-bromocrotonylchloride, while the mixture was stirred at 0°-10° C., 25 g of N-(2-hydroxyethyl)cyclohexylamine was added dropwise. After the addition then the reaction mixture was stirred at the same temperature for 3 hours. The reaction mixture was extracted with ether and the ether extract was washed with 2 N-HCl, a diluted NaHCO3 aqueous solution saturated with NaCl, and water in this order. The organic layer was dried with anhydrous Na2SO4 and the solvent was removed by distillation. 17.5 Grams of N-cyclohexyl-N-(2-hydroxyethyl)-γ-bromocrotonamide was obtained as an oil substance. The chemical stracture of this substance was identified by the NMR spectrum and the data of elementary analysis.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=2)[CH:3]=1.[CH:26]12[O:33][CH:30]([CH2:31][CH2:32]1)[CH2:29][C:28](=[O:34])[CH2:27]2>>[CH3:24][C:21]1([CH3:25])[CH2:22][CH2:23][C:18]([C:4]2[CH:3]=[C:2]([C:28]3([OH:34])[CH2:27][CH:26]4[O:33][CH:30]([CH2:31][CH2:32]4)[CH2:29]3)[CH:7]=[CH:6][C:5]=2[NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[CH:19][CH2:20]1
Reactant: O=C1CC2CCC(C1)O2
Reactant: CC1(C)CC=C(c2cc(Br)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Product: CC1(C)CC=C(c2cc(C3(O)CC4CCC(C3)O4)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1

Procedure:
The title compound was prepared as described in Example 1, step (h) using 4-cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in Example 1, step (g)) and 8-oxa-bicyclo[3.2.1]octan-3-one (Liebigs Annalen der Chemie, (1), 1-5 (1987)). 1H-NMR (CDCl3; 400 MHz): δ 11.69 (br s, 1H), 9.56 (s, 1H), 8.36 (d, 1H, J=8.4 Hz), 7.70 (s, 1H), 7.48 (dd, 1H, J=8.4, 2.0 Hz), 7.30 (d, 1H, J=2.0 Hz), 5.79-5.74 (m, 1H), 4.58-4.50 (m, 2H), 2.48-2.41 (m, 2H), 2.40-2.37 (m, 2H), 2.32-2.25 (m, 2H), 2.12-2.07 (m, 2H), 2.05-1.96 (m, 2H), 1.83-1.76 (m, 2H), 1.57-1.53 (m, 2H), 1.10 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C26H30N4O3, 447.2 (M+H). found 447.1.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]([S:16][CH2:17][CH2:18][CH3:19])[C:13]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[CH:8][CH:7]=[N:6]3)[N:3]=1.[O:20]1CCOCC1>O>[CH2:17]([S:16][C:14]1[C:13]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[CH:8][CH:7]=[N:6]3)[N:3]=[C:2]([CH:1]=[O:20])[CH:15]=1)[CH2:18][CH3:19]
Reactant: CCCSc1cc(C)nc2c1ccc1cccnc12
Reactant: C1COCCO1
Solvent: O
Product: CCCSc1cc(C=O)nc2c1ccc1cccnc12
Yield: 27 %

Procedure:
A solution of SeO2 (0.98 g, 8.8 mmol) in a mixture of dioxane (50 mL) and water (2 mL) was heated to reflux in a two-neck 250 mL round-bottomed flask. A solution of 2-methyl-4-propylsulfanyl-[1,10]phenanthroline (0.95 g, 3.5 mmol) in hot dioxane (50 mL) was added through an addition funnel over a period of 30 minutes and the reaction mixture was refluxed for additional 1 hour. The reaction mixture was filtered while hot and the residue rinsed with more hot dioxane (20 mL) and filtered. The filtrates were combined and evaporated in vacuo and the residue was treated with methylene chloride (100 mL) and a 10% K2CO3 aqueous solution (100 mL). The aqueous layer was extracted several times with methylene chloride (3×100 mL) and the combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (neutral Al2O3, MeOH/DCM, 1:50 to 1:15) to afford the pure product as a brown solid (0.27 g, 27%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](F)[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:21][CH:22]([OH:24])[CH3:23]>>[Cl:1][C:2]1[CH:10]=[C:9]([O:24][CH:22]([CH3:23])[CH3:21])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: CC(C)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)Oc1cc(Cl)c(C(=O)O)cc1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
A mixture of 2-chloro-4-fluoro-5-nitro-benzoic acid (5.0 g, 22.8 mmol) and cesium carbonate (29.7 g, 91.1 mmol) in 2-propanol (100 mL) is heated at 50° C. overnight. The solvent is removed in vacuo and 100 mL of water is added. Concentrated aqueous HCl is added dropwise to this solution at 0° C. until pH=2. The product precipitate which forms is isolated by filtration, washed by water and dried under vacuum to give 2-chloro-4-isopropoxy-5-nitro-benzoic acid.
Reaction SMILES: O[C@@H:2]1[CH2:5][C@H:4]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:3]1.C(N(C(C)C)CC)(C)C.CS(Cl)(=O)=O.[NH2:31][NH2:32]>ClCCl>[NH:31]([C@H:2]1[CH2:5][C@H:4]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:3]1)[NH2:32]
Reactant: NN
Reactant: O=C(N[C@H]1C[C@@H](O)C1)OCc1ccccc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NN[C@H]1C[C@H](NC(=O)OCc2ccccc2)C1
Temperature: 80 °C

Procedure:
Benzyl (cis-3-hydroxycyclobutyl)carbamate (intermediate 47, 3.26 g, 14.73 mmol) was suspended in a mixture of diisopropylethylamine (4 ml, 23.00 mmol) and dichloromethane (100 mL) and cooled in an acetone/ice bath under nitrogen. Methanesulfonyl chloride (1.3 ml, 16.80 mmol) was added slowly and the solution stirred for minutes. The reaction was partitioned between water (200 mL), saturated ammonium chloride (50 mL) and dichloromethane (100 mL). The aqueous was extracted with additional dichloromethane (100 mL) and the organic layers combined. They were dried with magnesium sulfate and evaporated to dryness under reduced pressure using a 40° C. water bath. The crude solid mesylate was suspended in ethanol (10 mL) and treated with hydrazine (anhydrous, 4 ml, 127 mmol). The slurry was heated at 80° C. As the mixture warmed it became homogeneous. After 2 hours additional hydrazine (2 mL) was added and the flask was fitted with a reflux condenser. The bath temperature was raised to 95° C. After an additional 3 hours the solution was evaporated to dryness under reduced pressure to give benzyl (trans-3-hydrazinylcyclobutyl)carbamate as a thick white oil. It was further dried under high vacuum at 50° C. for 20 minutes then used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].CCCCCC>O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:9][CH2:10][C:11](=[O:13])[CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)CCC(=O)c1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Product: O=C1C=C(c2cccc(F)c2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 42568.4 %

Procedure:
1-(3-Fluorophenyl)-1,4-pentandione (23 g, 0.12 mmol) was dissolved in water (550 ml) containing 11 g of sodium hydroxide and the solution was stirred at 100° C. for 3 hours. After cooling to 0° C. the resultant brown crystals were collected by filtration and washed with water. The title compound (9 g, 45% yield) was obtained by recrystallization from hexane as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:32]=[CH:31][C:30](Br)=[CH:29][N:28]=2)=[CH:23][CH:22]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35].C(=O)(O)[O-].[Na+].N#N>C(#N)C.C1COCC1.O.CC(=O)OCC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:32]=[CH:31][C:30]([C:41]3[CH:42]=[CH:43][C:38]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:39][CH:40]=3)=[CH:29][N:28]=2)=[CH:23][CH:22]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(-c2ncc(Br)cn2)cc1)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(-c2ncc(-c3ccc(C(C)(C)C)cc3)cn2)cc1)NC(=O)OCc1ccccc1
Temperature: 110 °C
Yield: 70 %

Procedure:
Prepared using General Procedure 10: A stirred solution of (S)-tert-butyl 2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoate INT-7 (0.96 g, 1.86 mmol), (4-(tert-butyl)phenyl)boronic acid (0.43 g, 2.42 mmol) and sodium bicarbonate (0.39 g, 4.66 mmol) in acetonitrile (5 ml), THF (5 ml) and water (5 ml) was degassed with N2 for 5 min. Pd(dppf)Cl2 (0.136 g, 0.186 mmol) was added and the reaction was heated to 110° C. in the microwave for 45 min. The reaction was diluted with EA (50 mL) and filtered over celite. The organic phase was washed with water (100 mL) and concentrated. The crude product was purified by chromatography on silica gel (EA/isohexanes) to afford 757 mg (70%) of (S)-tert-butyl 2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(tert-butyl)phenyl)pyrimidin-2-yl)phenyl)propanoate INT-10 as a white powder. LCMS-ESI (m/z) calculated for C35H39N3O4: 565.3; no m/z observed, tR=3.39 min (Method 8).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].C(N(CC)CC)C.[C:19](Cl)(=[O:23])[C:20]([CH3:22])=[CH2:21]>ClCCl.C(C1C(C)=CC=C(O)C=1C(C)(C)C)(C)(C)C>[C:19]([NH:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:6][CH3:7])[O:8][CH3:9])(=[O:23])[C:20]([CH3:22])=[CH2:21]
Reactant: CO[Si](CCCN)(OC)OC
Reactant: C=C(C)C(=O)Cl
Agent: Cc1ccc(O)c(C(C)(C)C)c1C(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)NCCC[Si](OC)(OC)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
77.4 g 3-(amino)propyltrimethoxysilane, 43.7 g triethylamine and 25 mg di-tert.-butyl-p-cresol were dissolved under argon in 500 ml dichloromethane. 45.1 g methacryloyl chloride was slowly added dropwise at −5° C. within 1 h, and the whole was then stirred for 1 h at 0° C. The precipitated hydrochloride was filtered off and washed with dichloromethane. The volatile constituents were removed at 40° C. under reduced pressure using the rotary evaporator. A yellow liquid with precipitated solid (hydrochloride) remained. The precipitation of the hydrochloride was completed by adding 150 ml diethyl ether, the precipitate was filtered off and the filtrate concentrated at 40° C. using a rotary evaporator with introduction of dry air. The brownish liquid was freed of residual volatile constituents at 4×10−2 mbar, and the raw product (104.2 g) was distilled at a pressure of 6×10−4 mbar. The product had a boiling point of 123-125° C. 76.4 g of product was obtained as yellowish, clear liquid.
Reaction SMILES: S.[C:2]([C:4]1[CH:26]=[CH:25][C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:24]=[CH:23][C:16]([O:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=2)=[O:9])=[CH:6][CH:5]=1)#[N:3].[N:27]1C=CC=CC=1.C(N(CC)CC)C>>[C:2]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:24]=[CH:23][C:16]([O:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=2)=[O:9])=[CH:25][CH:26]=1)(=[NH:27])[NH2:3]
Reactant: COC(=O)COc1ccc(CCNC(=O)c2ccc(C#N)cc2)cc1
Reactant: c1ccncc1
Agent: S
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(CCNC(=O)c2ccc(C(=N)N)cc2)cc1

Procedure:
H2S was passed for 45 minutes through a suspension of 2.0 g of methyl 4-[2-(p-cyanobenzamido)ethyl]phenoxyacetate in 24 ml of pyridine/triethylamine (7:1) at 0° C. The solution resulting after 12 hours was concentrated, and a suspension was made of the residue in methanol and filtered. The residue on the filter was immediately suspended in 30 ml of acetone, and 4 ml of methyl iodide were added. After 2.5 hours the precipitate was filtered off, washed with a little acetone and, after drying, dissolved in 20 ml of methanol. 2.0 g of ammonium acetate were added and the mixture was then left to react at room temperature for 2 hours, during which a colorless precipitate formed, and this was filtered off and reprecipitated from methanol. Methyl p-[2-(p-amidinobenzamido)ethyl]phenoxyacetate was obtained as the acetate salt, melting point above 200° C., after drying under high vacuum.
Reaction SMILES: [CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23]C1C=CC(CC(Cl)=O)=CC=1.C1(CC(Cl)=O)C=CC=CC=1>>[CH3:22][O:23][C:5]1[CH:4]=[CH:3][C:2]([CH2:1][CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH2:11][CH2:10][NH:9]2)=[CH:7][CH:6]=1
Reactant: COc1cc2c(cc1OC)C(Cc1ccccc1)NCC2
Reactant: COc1ccc(CC(=O)Cl)cc1
Agent: O=C(Cl)Cc1ccccc1
Product: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1

Procedure:
1,2,3,4-Tetrahydro-1-(4-methoxybenzyl)-6,7-dimethoxyisoquinoline was prepared by a procedure analogous to that described in example 17 for 1,2,3,4-tetrahydro-1-benzyl-6,7-di-methoxyisoquinoline but substituting in the first step (4-methoxyphenyl)acetyl chloride for phenylacetyl chloride.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH3:42][O:43][C:44]1[CH:45]=[C:46]([S:52](Cl)(=[O:54])=[O:53])[CH:47]=[CH:48][C:49]=1[O:50][CH3:51]>C(#N)C>[CH3:42][O:43][C:44]1[CH:45]=[C:46]([S:52]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:53])=[O:54])[CH:47]=[CH:48][C:49]=1[O:50][CH3:51]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)Oc2ccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c2CNC3=O)cc1OC
Yield: 46.1 %

Procedure:
In a similar manner to Step 1 of Example 227, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0315 g, 0.0682 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0570 mL, 0.409 mmol) and 3,4-dimethoxybenzenesulfonyl chloride (0.0480 g, 0.205 mmol) to obtain 4-(3,4-dimethoxybenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0208 g, yield 46%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)=O.C(C1C=C2C(=CC=1)NC=C2)#N.[C:23]([CH2:28][CH:29]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:25][CH2:26][CH3:27])=[O:24]>>[CH3:29][C:28](=[CH:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc2[nH]ccc2c1
Agent: N#Cc1ccc2[nH]ccc2c1
Product: CCOC(=O)C(C)=Cc1ccc2[nH]ccc2c1

Procedure:
Using a similar procedure to that described in Example 12, part c, except starting from 5-formylindole (prepared as described in the literature from 5-cyanoindole: F. Troxler, Helv. Chim. Acta., 51, 1616, (1968)), and using carbethoxyethylidene triphenylphosphorane, ethyl α-methylindol-5-acrylate was obtained (79%) as a low-melting white solid (mp about 50°); partial NMR(250 MHz, DMSO-d6): 1.28(t, 3H, CH2CH3), 2.13(d, J=1.0 Hz, 3H, CCH3), 4.19(q, 2H, CH2CH3), 6.49(m, 1H, H3 -indole), 11.28(br s, 1H, H1 -indole).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:10]=2[C:11]([NH2:13])=[O:12])=O)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]2[N:13]=[C:11]([OH:12])[C:10]3[C:9](=[CH:17][C:16]([O:18][CH3:19])=[C:15]([O:20][CH3:21])[CH:14]=3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(NC(=O)c2ccc(Cl)cc2)c(C(N)=O)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc2nc(-c3ccc(Cl)cc3)nc(O)c2cc1OC
Reaction time: 2 h

Procedure:
21.3 g of 2-(4-chlorobenzoylamino)-4,5-dimethoxybenzamide were heated at 100° C. for 2 h in 250 ml of 10% strength sodium hydroxide solution. The starting compound gradually went into solution in the course of this and a little later a precipitate deposited again. The mixture was diluted with 500 ml of water and adjusted to pH=4 using concentrated hydrochloric acid. After stirring for a further 2 h, the solid was filtered off with suction, washed with plenty of water and dried at 40° C. under reduced pressure. Yield: 19.0 g. M.p.: 329° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([NH2:20])[CH3:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:2].[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[CH:14][C:15]([CH:18]([NH:20][C:23](=[O:24])[N:22]([CH3:26])[CH3:21])[CH3:19])=[CH:16][CH:17]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CN(C)C(=O)Cl
Reactant: CCOc1ccc(C#Cc2ccc(C(C)N)cc2)cc1
Solvent: ClCCl
Product: CCOc1ccc(C#Cc2ccc(C(C)NC(=O)N(C)C)cc2)cc1
Temperature: 25 °C

Procedure:
To 26.5 mg (0.10 mmol) 1-(4-((4-ethoxyphenyl)ethynyl)phenyl)ethanamine (I63) and 27.7 μL (0.20 mmol) TEA in 1.5 mL DCM are added 11.0 μl (0.12 mmol) dimethylcarbamyl chloride at 0° C. The reaction mixture is stirred at r.t. over night and directly purified by HPLC (MeOH/H2O/NH3).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][NH2:15])([O-:3])=[O:2].[CH:16](O)=[O:17]>O>[N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:5]=1[N:14]([CH:16]=[O:17])[NH2:15])([O-:3])=[O:2]
Reactant: O=CO
Reactant: NNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: O
Product: NN(C=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 98 %

Procedure:
64 g of 2-nitro-4-trifluoromethylphenylhydrazine [prepared as described in: J. Org. Chem. 42, 542 (1977)] were heated with 200 ml of 85% formic acid in a water bath for 90 minutes. After cooling down, the yellow solution was poured into 250 ml of water. The crystalline precipitate was filtered by suction, washed with water and dried at 80° C. to yield 72 g (98%) of 2-nitro-4-trifluoromethyl-N-formylphenylhydrazine, m.p.: 152°-153° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[CH:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2.[CH3:18][O:19]C=O>>[CH:18]([NH:1][CH2:2][CH:3]1[C:4]2[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=2[CH:6]=[CH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)=[O:19]
Reactant: NCC1c2ccccc2C=Cc2ccccc21
Reactant: COC=O
Product: O=CNCC1c2ccccc2C=Cc2ccccc21
Temperature: 110 °C

Procedure:
5-Aminomethyl-5H-dibenzo[a,d]cycloheptene (4.82 g., 0.0218 mole) and methylformate, 200 ml. are heated to 110° C. for 161/2 hours in an autoclave. The yellow solution is evaporated to dryness on a film evaporator under reduced pressure. The residue is dissolved in benzene, the solution extracted with dilute hydrochloric acid, then with water and dried over anhydrous sodium sulfate. The benzene is evaporated and the residue dried to constant weight in a film evaporator under reduced pressure. The yellow solid residue weighs 5.49 g. and melts at 115°-117.5° C. to a cloudy melt, clearing at 119° C. Recrystallization from mixtures of benzene and hexane, followed by recrystallization from mixtures of ethanol and water gives a product melting at 120.3°-121° C. (clears 121.8° C.).