Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([C:19](=[O:28])[CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[CH:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][C:31]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[O:32])[C:6]=2[CH:40]=1.[BH4-].[Na+]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([CH:19]([OH:28])[CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[CH:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][C:31]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[O:32])[C:6]=2[CH:40]=1
Reactant: Cc1ccccc1CC(=O)c1ccc(C(=O)N2CCCC(CC(=O)N3CCN(C)CC3)c3cc(Cl)ccc32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1ccccc1CC(O)c1ccc(C(=O)N2CCCC(CC(=O)N3CCN(C)CC3)c3cc(Cl)ccc32)cc1
Reaction time: 2 h
Yield: 100.6 %

Procedure:
7-Chloro-5-[(4-methyl-1-piperazinyl)carbonylmethyl]-1-{4-[2-(2-methylphenyl)acetyl]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (2.06 g) is dissolved in a mixture of methylene chloride (20 ml) and methanol (20 ml), and thereto ia added with stirring sodium borohydride (0.28 g) under cooling over an ice-bath. The mixture is stirred for two hours over an ice-bath, and the mixture is evaporated to remove almost of the solvent. To the residue is added water, and the mixture is extracted with methylene chloride. The organic layer is washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated. The residue is purified by silica gel column chromatography (solvent; methylene chloride:methanol =20~10:1) to give 7-chloro-5-[(4-methyl-1-piperazinyl)carbonylmethyl]-1-{4-[2-(2-methyl-phenyl)-1-hydroxyethyl]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (2.08 g) as colorless amorphous.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH2:6][N:7]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:10]=3[C:11]=2[N:12]=1.[CH3:25][NH:26][CH3:27]>CN(C)C=O>[Cl:17][C:15]1[CH:14]=[CH:13][C:10]2[C:11]3[N:12]=[C:2]([N:26]([CH3:27])[CH3:25])[N:3]=[CH:4][C:5]=3[CH2:6][N:7]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9]=2[CH:16]=1
Reactant: Fc1ccccc1C1=NCc2cnc(Cl)nc2-c2ccc(Cl)cc21
Reactant: CNC
Solvent: CN(C)C=O
Product: CN(C)c1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of 4.0 g (0.0112 mol) of 2,9-dichloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine in 15 ml of N,N-dimethylformamide was cooled in an ice bath and saturated with dimethylamine. After 18 hr at room temperature, 80 ml of ice water was added and the precipitate was collected by filtration and recrystallized twice from methanol to give the end product as white rods, mp 175°-179°.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[C:8]([NH:11][C:12]1[CH:21]=[CH:20][C:15]([S:16](Cl)(=[O:18])=[O:17])=[CH:14][CH:13]=1)(=[O:10])[CH3:9].O>CC(C)=O>[C:8]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([S:16]([N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])(=[O:18])=[O:17])=[CH:20][CH:21]=1)(=[O:10])[CH3:9]
Reactant: OCCNCCO
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)Nc1ccc(S(=O)(=O)N(CCO)CCO)cc1
Temperature: 5 °C

Procedure:
Step 1) Diethanolamine (105 parts) was added dropwise over 10 minutes to a stirred mixture of N-acetyl sulphanilyl chloride (93.5 parts), water (400 parts) and acetone (200 parts) while maintaining the temperature at approximately 5° C. The mixture was allowed to warm to room temperature and stirred over night. The resultant 4-acetylamino-N,N-bis-(2-hydroxyethyl)benzenesulphonamide (103 parts) was isolated by filtration, washed with water and dried.
Reaction SMILES: [ClH:1].C[C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[C:5]([Br:15])[CH:4]=1.Cl.Br[C:18]1C(C)=CC=CC=1NN>>[ClH:1].[CH3:18][C:4]1[C:5]([Br:15])=[C:6]2[C:13](=[CH:14][CH:3]=1)[C:9]([CH2:10][CH2:11][NH2:12])=[CH:8][NH:7]2
Reactant: Cc1cc(Br)c2[nH]cc(CCN)c2c1
Reactant: Cc1cccc(NN)c1Br
Agent: Cl
Product: Cc1ccc2c(CCN)c[nH]c2c1Br

Procedure:
6-Methyl-7-bromotryptamine hydrochloride was prepared (2.42 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 4, except using 2-bromo-3-methylphenylhydrazine hydrochloride as starting material. ##STR52##
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:7])[O:5][CH3:6].[H-].[Na+].[CH3:10][C:11]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13]Br.O>CN(C)C=O>[CH3:1][O:2][N:3]([CH2:13][C:12]1[CH:15]=[CH:16][CH:17]=[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:11]=1[CH3:10])[C:4](=[O:7])[O:5][CH3:6]
Reactant: Cc1c(CBr)cccc1-c1ccccc1
Reactant: CONC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)N(Cc1cccc(-c2ccccc2)c1C)OC
Reaction time: 3 h
Yield: 50.6 %

Procedure:
0.40 g of methyl N-methoxycarbamate in N,N-dimethylformamide (20 ml) was stirred together with 0.18 g of 60% sodium hydride at room temperature for 30 minutes. 1.00 g of 2-methyl-3-phenylbenzyl bromide was added dropwise at room temperature, and the resulting solution was stirred for 3 hours. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate, and the organic layer was separated, dried over anhydrous magnesium sulfate and evaporated under reduced pressure for removal of the solvent. The residue was purified by silica gel column chromatography to give 0.55 g of methyl N-methoxy-N-(2-methyl-3-phenylbenzyl)carbamate as a transparent viscous liquid.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[NH:8].O.[OH-].[Na+].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[N:20]=[C:21]=[O:22]>C1C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[NH:20][C:21]([N:8]=[C:4]1[CH2:5][CH2:6][CH2:7][N:3]1[CH3:2])=[O:22]
Reactant: CN1CCCC1=N
Reactant: O=C=Nc1cc(Cl)ccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CN1CCCC1=NC(=O)Nc1cc(Cl)ccc1Cl

Procedure:
To 6.73 g. (0.05 mole) of 1-methyl-2-iminopyrrolidine HCl is added 1 ml. of water and 50 ml. of benzene. After solution is complete (magnetic stirring), 10 ml. of aqueous sodium hydroxide (50%) is added in one portion. After stirring for about 1 min., the benzene layer is decanted onto anhydrous potassium carbonate. The extraction is repeated twice. After drying (occasional swirling) the combined benzene extracts are filtered (dicalite) from drying agent and 9.4 g. (0.05 mole) of 2,5-dichlorophenylisocyanate is added to the filtrate in one portion with swirling. After stirring for 3 hours, the solvent is removed in vacuo affording a colorless solid, 1-(2,5-dichlorophenyl)-3-(1-methyl-2-pyrrolidylidene)urea. Recrystallization from acetone (twice) yields the pure product, m.p. = 148.5°-150.5° C.
Reaction SMILES: C([O:8][C:9](=[O:53])[CH2:10][CH2:11][N:12]([CH2:43][C:44]1[O:45][C:46]2[CH:52]=[CH:51][CH:50]=[CH:49][C:47]=2[CH:48]=1)[S:13]([C:16]1[CH:21]=[CH:20][C:19]([C@H:22]([C:29](=[O:42])[NH:30][C:31]2[S:32][C:33]3[C:38]([N:39]=2)=[CH:37][CH:36]=[C:35]([O:40][CH3:41])[N:34]=3)[CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:18][CH:17]=1)(=[O:15])=[O:14])C1C=CC=CC=1.[OH-].[Na+].Cl>C1COCC1.O>[O:45]1[C:46]2[CH:52]=[CH:51][CH:50]=[CH:49][C:47]=2[CH:48]=[C:44]1[CH2:43][N:12]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([C@H:22]([C:29](=[O:42])[NH:30][C:31]2[S:32][C:33]3[C:38]([N:39]=2)=[CH:37][CH:36]=[C:35]([O:40][CH3:41])[N:34]=3)[CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:18][CH:17]=1)(=[O:14])=[O:15])[CH2:11][CH2:10][C:9]([OH:53])=[O:8]
Reactant: COc1ccc2nc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(=O)(=O)N(CCC(=O)OCc4ccccc4)Cc4cc5ccccc5o4)cc3)sc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2nc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(=O)(=O)N(CCC(=O)O)Cc4cc5ccccc5o4)cc3)sc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title I compound, 3-(benzofuran-2-ylmethyl-{4-[(R)-2-cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-amino)-propionic acid benzyl ester (280 mg, 0.372 mmol) is dissolved in THF. To this is added a solution of sodium hydroxide (22 mg, 0.558 mmol) in water. The reaction is stirred at RT overnight. LC/MS indicates ˜80% reaction completion and, therefore, more sodium hydroxide (10 mg, 0.250 mmol) is added. After 2 h of stirring at RT, the reaction is acidified to pH 1 with concentrated hydrochloric acid, then concentrated to remove solvent. The residue is diluted with ethyl acetate and water. The organic layer is separated, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude product as a yellow foam. Purification by preparative HPLC affords 3-(benzofuran-2-ylmethyl-{4-[(R)-2-cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-amino)-propionic acid as a white solid: 1H NMR (400 MHz, DMSO-D6) δ 1.4 (m, 2 H) 1.6 (m, 3 H) 1.7 (m, 3 H) 2.1 (m, 1H) 3.35 (m, 1 H) 3.9 (s, 3 H) 4.0 (m, 1 H) 4.6 (s, 2 H) 6.7 (s, 1 H) 6.9 (d, J=8.8 Hz, 1 H) 7.1 (m, 2 H) 7.3 (m, 2 H) 7.5 (dt, J=4.3, 2.1 Hz, 1 H) 7.6 (d, J=8.3 Hz, 2 H) 7.8 (d, J=8.6 Hz, 2 H) 8.0 (d, J=8.8 Hz, 1 H) 12.7 (s, 1 H); LC/MS 663.5 (M+1), 661.5 (M−1). EC50 in primary enzyme assay 0.22 μM.
Reaction SMILES: CO[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[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[N:17]=1.[Br-].[CH2:21]1[CH2:25]OC[CH2:22]1>>[CH:21]([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[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[N:17]=1)([CH3:25])[CH3:22]
Reactant: COc1cc(C(F)(F)F)ccc1C1=NC(C)(C)CO1
Reactant: C1CCOC1
Agent: [Br-]
Product: CC(C)c1cc(C(F)(F)F)ccc1C1=NC(C)(C)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a cooled (0° C.) solution of 2-(2-methoxy-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole (intermediate AG) (1.0 g, 3.66 mmol) in 6.0 ml THF, was added dropwise a 1M ispropylmagnesium bromide solution in THF (11.0 ml, 10.98 mmol) maintaining the temperature below 5° C. The mixture was allowed to warm to room temperature and stirred for 1 hour. The mixture was cooled in an ice bath and quenched dropwise with 25 ml saturated NH4Cl solution. Ethyl acetate was added. The organic layer was separated and the aqueous layer was reextracted once with ethyl acetate. The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude oil was purified on silica gel (eluent: heptane/ethyl acetate 0 to 20%) to provide 0.95 g (91%) of the title compound as a light yellow oil. MS (m/e): 286.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=1[F:15])=[O:5].[O:21]1CCOC[CH2:22]1>>[Br:20][C:18]1[CH:19]=[C:2]2[C:3]([C:4](=[O:5])[N:6]([CH2:7][C:8]3[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=3[F:15])[C:22](=[O:21])[NH:1]2)=[CH:16][CH:17]=1
Reactant: Nc1cc(Br)ccc1C(=O)NCc1ccc(Br)cc1F
Reactant: C1COCCO1
Product: O=c1[nH]c2cc(Br)ccc2c(=O)n1Cc1ccc(Br)cc1F
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
2-Amino-4-bromo-N-(4-bromo-2-fluorobenzyl)benzamide (2.90 g) and N,N'-carbonyldiimidazole (4.68 g) were dissolved in dioxane (50 ml). The solution was evaporated to give a residue, which was stirred at 150° C. for 30 minutes. After cooling, the precipitates were collected by filtration and washed with ethanol to give 7-bromo-3-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (2.92 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[C:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])=[CH:12][CH:11]=2)O)[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([CH:7]=1)[CH2:8][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[C:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:23])[CH3:24])[CH:19]([CH3:20])[CH3:21])=[CH:12][CH:11]=1
Reactant: CC(C)[Si](C#Cc1ccc(C(O)c2cc(Br)ccc2F)cc1)(C(C)C)C(C)C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[Si](C#Cc1ccc(Cc2cc(Br)ccc2F)cc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 5.6 g (5-bromo-2-fluoro-phenyl)-{4-[(triisopropylsily)-ethynyl]-phenyl}-methanol and 4.1 ml triethylsilane in 50 ml dichloromethane is cooled in an ice bath. Then 4.7 ml trifluoroacetic acid are slowly added dropwise, and the solution is stirred for 4 h at ambient temperature. The solution is diluted with dichloromethane and washed with aqueous sodium hydrogen carbonate solution. After drying over sodium sulphate the solvent is removed and the residue is purified using silica gel (cyclohexane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][N:9]=[C:8]([CH3:11])[C:7]=2[CH:12]=1.I[CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.[Li+].CC([N-]C(C)C)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][N:9]=[C:8]([CH2:11][CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17][CH2:16]3)[C:7]=2[CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CI)CC1
Reactant: COc1ccc2onc(C)c2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2onc(CCC3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Yield: 87.8 %

Procedure:
The procedure described in Example 1d was followed using 5-methoxy-3-methyl-1,2-benzisoxazole (0.32 g, 1.96 mmol), 4-iodomethyl-1-piperidinecarboxylic acid, 1-(1,1-dimethylethyl) ester (0.70 g, 2.15 mmol), and 1M LDA (2.0 mL, 2.0 mmol) in dry THF (2 mL). After purification, the title compound (0.62 g, 87%) was obtained as a clear oil.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[F:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][CH:11]=1.O>CS(C)=O>[F:9][C:10]1[CH:11]=[CH:12][C:13]([C@@H:16]2[CH2:2][C@H:17]2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:15]=1
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)/C=C/c1ccc(F)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.7 %

Procedure:
Trimethylsulfoxonium iodide (7.92 g, 36.0 mmol) in dimethyl sulfoxide (40 mL) was mixed with sodium hydride (55 wt % dispersion in mineral oil, 1.57 g, 36.0 mmol) under cooling with ice, stirred at room temperature for 1 hour and then stirred with (E)-ethyl 3-(4-fluorophenyl)acrylate (5.83 g, 30.0 mmol) for 18 hours. After addition of water, the reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1) to give the title compound as a colorless oil (793 mg, yield 13%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:45])[N:15]([CH3:44])[C@@H:16]([C:28](=[O:43])[N:29]([C@@H:31]([C:39](=[O:42])[NH:40][CH3:41])[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH3:30])[CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:44][N:15]([C@@H:16]([C:28](=[O:43])[N:29]([CH3:30])[C@@H:31]([C:39](=[O:42])[NH:40][CH3:41])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)[C:14]([CH:11]1[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]1)=[O:45]
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)C1CCC(NC(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)C1CCC(N)CC1
Reaction time: 0.08 h
Yield: 49.3 %

Procedure:
To a solution of (4-[N-Methyl-N-{(1R)-1-(N-methyl-[(1R)-1-(methylcarbamoyl)-2-phenylethyl]carbamoyl)-2-(2-naphthyl)-ethyl}carbamoyl]cyclohexyl)carbamic acid tert-butyl ester (240 mg, 0.38 mmol) in 1 ml dichloromethane was added 0.5 ml trifluoroacetic acid and the mixture was stirred for 5 min. Sodium bicarbonate was added until gas evolution has ceased, and the mixture was extracted with dichloromethane (3×15 ml). The combined organic phases were washed with brine (5 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed on silica (16 g) with dichloromethane/methanol (4:1). The obtained product was dissolved in 3 ml of methanol and added 40 ml of water and 0.5 ml of acetic acid and lyophilized to give 99 mg of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([I:15])[N:12]=[C:11]1[CH3:16])(C)(C)C.[ClH:18].O1CCOCC1>C(Cl)Cl>[I:15][C:13]1[N:12]=[C:11]([CH3:16])[N:10]([CH2:9][CH2:8][NH2:7])[CH:14]=1.[ClH:18]
Reactant: Cc1nc(I)cn1CCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1nc(I)cn1CCN
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of [2-(4-iodo-2-methyl-imidazol-1-yl)-ethyl]-carbamic acid tert-butyl ester (2.800 g; 7.973 mmol) in DCM (45 ml) was added slowly 4N HCl in dioxane (28.25 ml; 113.000 mmol). The resulting suspension was stirred at 0° C. for 15 min., then at rt for 1 h. The volatiles were removed under reduced pressure, then under HV. The product 2-(4-iodo-2-methyl-imidazol-1-yl)-ethylamine was obtained as a pale beige solid (2.880 g; 100%; presence of 3 eq. of HCl). LC-MS: tR=0.14 min.; [M+H]+=251.92 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][N:4]=1.C1C(=O)N([Br:25])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:25][CH2:9][C:7]1[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(-c2cnc(OC)cc2C)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(-c2cnc(OC)cc2CBr)cc1
Reaction time: 48 h
Yield: 103.2 %

Procedure:
According to Scheme 31 Step 2: To a solution of 2-methoxy-5-(4-methoxyphenyl)-4-methylpyridine (2.20 mmol, 0.50 g, Example 48 Step 1) in CCl4 (10 mL) was added NBS (2 eq, 4.40 mmol, 0.78 g). The reaction was then heated to reflux and subjected to UV light for 48 hours. The reaction was allowed to cool, filtered and concentrated under reduced pressure to afford crude 4-(bromomethyl)-2-methoxy-5-(4-methoxyphenyl)pyridine (0.70 g) as a yellow oil which was used without any purification in the next step.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[C:16]([C:19]#N)[CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][C:10]3[CH:21]=[CH:22][CH:23]=[CH:24][C:9]2=3)[CH2:4][CH2:3]1.C(O)=[O:26]>[Al].[Ni]>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[C:16]([CH:19]=[O:26])[CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][C:10]3[CH:21]=[CH:22][CH:23]=[CH:24][C:9]2=3)[CH2:4][CH2:3]1
Reactant: CN1CCC(=C2c3ccccc3C=Cc3ccc(C#N)cc32)CC1
Reactant: O=CO
Agent: [Ni]
Agent: [Al]
Product: CN1CCC(=C2c3ccccc3C=Cc3ccc(C=O)cc32)CC1

Procedure:
A mixture of 1.70 g of 1-methyl-4-(3-cyano-5H-dibenzo[a,d]cycloheptene-5-ylidene)piperidine (prepared as described in U.S. Pat. No. 3,988,342 (1976)), 1.70 g of Raney nickel-aluminum alloy, and 25 ml of 75% aqueous formic acid was stirred under reflux for 1.5 hours. The cooled mixture was filtered and the filtrate was made basic by the additional of solid sodium bicarbonate. Extraction of the neutralized mixture with chloroform and evaporation of the solvent gave 1.30 g of 1-methyl-4-(3-formyl-5H-dibenzo[a,d]cycloheptene-5-ylidene)piperidine.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.[OH:17][C:18]1[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=1.Cl>CN(C=O)C>[CH3:23][C:21]1[NH:20][N:19]=[C:18]([O:17][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH:22]=1
Reactant: Cc1cc(O)n[nH]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc([N+](=O)[O-])cc2)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 182.5 %

Procedure:
Potassium carbonate (0.5 g, 3.6 mmol) and 4-fluoronitrobenzene (1.6 g, 1.0 mmol) were added to a solution of 3-hydroxy-5-methylpyrazole (0.33 g, 3.4 mmol) in DMF (50 ml) at room temperature, and further, the mixture was stirred at room temperature for 8 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid (100 ml) and extracted with ethyl acetate (30 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/7→1/3), to give a white solid of 5-methyl-3-(4-nitrophenyloxy)pyrazole (0.4 g, yield: 63.3%) mp: 124-125° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.33 (s, 3H), 5.75 (s, 1H), 7.20 (dd, J=2.2 and 7.1 Hz, 2H), 8.22 (dd, J=2.2 and 7.1 Hz, 2H), 9.30-9.90 (br s, 1H).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]([CH:20]4[C:29](=O)[C:28]5[C:27]([C:31]([O:33]C)=O)=[CH:26][CH:25]=[CH:24][C:23]=5[NH:22][CH:21]4[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.O.[NH2:42][NH2:43]>CO>[CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]([CH:20]4[C:29]5=[N:42][NH:43][C:31](=[O:33])[C:27]6[CH:26]=[CH:25][CH:24]=[C:23]([C:28]=65)[NH:22][CH:21]4[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:2][CH2:3]1
Reactant: NN
Reactant: COC(=O)c1cccc2c1C(=O)C(c1cccc(C(=O)N3CCN(C(=O)C4CC4)CC3)c1)C(c1ccccc1)N2
Solvent: O
Solvent: CO
Product: O=C(c1cccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccccc2)c1)N1CCN(C(=O)C2CC2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 13 %

Procedure:
A mixture of methyl 3-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (64 mg, 0.12 mmol) in 85% hydrazine monohydrate (5 mL) and methanol (2 mL) was stirred at 25° C. for 4 hr. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by prep-HPLC to give 9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (8 mg, yield 13%) as a light yellow solid. 1H-NMR (400 MHz, CD3OD) δ (ppm): 0.73-0.81 (m, 4H), 1.18-1.19 (m, 1H), 3.20-3.71 (m, 8H), 4.23-4.25 (d, J=10.0 Hz, 1H), 4.59-4.61 (d, J=8.4 Hz, 1H), 7.08-7.26 (m, 10H), 7.45-7.54 (m, 2H); LC-MS (ESI) m/z: 520(M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22]O.C(Br)(Br)(Br)[Br:25].C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:25][CH2:22][CH2:21][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)/[C:7](=[CH:11]\[C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)/[C:6]=1[CH3:20]
Reactant: BrC(Br)(Br)Br
Reactant: CSc1ccc(/C=C2/C(C)=C(CCO)c3cc(F)ccc32)cc1
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CSc1ccc(/C=C2/C(C)=C(CCBr)c3cc(F)ccc32)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the alcohol from Step 1 (4.8 g, 14.7 mmol) and carbon tetrabromide (6.34 g, 19.1 mmol) in methylene chloride (100 mL) at 0° C. there was added, in portions, 1,2-bis(diphenylphosphino)ethane (6.34 g, 17.3 mmol). The mixture was stirred at 0° C. for 1 hour, and the solvent was evaporated. The residue was stirred in a mixture of ethyl acetate and water (150 mL each) for 30 minutes. After filtration, the organic portion of the filtrate was evaporated down and the crude product purified by column chromatography on silica gel using 10% ethyl acetate in hexane as eluent to afford pure title compound as a yellow oil which solidified on standing.