Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S([O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH3:13])=[CH:8][CH:7]=1)(O)(=O)=O.[C:14](=O)([O-])[O-].[K+].[K+].IC.CN(C)C=O>O1CCCC1>[CH3:14][N:12]([CH3:13])[C:9]1[CH:10]=[CH:11][C:6]([OH:5])=[CH:7][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: CNc1ccc(OS(=O)(=O)O)cc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C)c1ccc(O)cc1
Reaction time: 18 h
Yield: 38.5 %

Procedure:
A mixture of 4-methylaminophenol sulfate (1.00 g) and potassium carbonate (0.88 g) in dry tetrahydrofuran (29 mL) was stirred for 45 minutes at room temperature before iodomethane (0.36 mL) was added. After the reaction was stirred for 18 h, TLC showed incomplete reaction. Dimethylformamide (5 mL) was added to make the reaction mixture homogeneous and stirring was continued. After a total of 42 h, the reaction was evaporated and the residue was suspended in ethyl acetate (75 mL). The suspension was washed (saturated sodium bicarbonate, brine), dried, evaporated and dried under vacuum to give the crude product as an oil. The oil was preadsorbed onto silica gel; and chromatography, eluting with hexane:ethyl acetate (2:1), gave 4-dimethylaminophenol as a white solid (0.26 g); TLC: Rf =0.35, hexane:ethyl acetate (2:1); MS: m/z=138(M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:9]([NH2:11])=[O:10])[CH:5]=[CH:6][CH:7]=1>C(O)(=O)C.[Pt]>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]2)[C:9]([NH2:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)C(c1cccc(Cl)c1)c1ccccn1
Agent: [Pt]
Solvent: CC(=O)O
Product: Cl
Product: NC(=O)C(c1cccc(Cl)c1)C1CCCCN1

Procedure:
Yet another process, published in Journal of Medicinal Chemistry 1996, Vol. (39), (6), 1201-1209, teaches catalytic hydrogenation of a solution of 0.43 gm (1.7 mmole) of 3-chlorophenyl pyridyl acetamide in 15 ml of acetic acid and 0.14 gm of 5% Platinum on carbon at 30-40° C. for 10 hrs. The catalyst was removed by filtration and the solvent acetic acid was evaporated to dryness, excess concentrated hydrochloric acid was added, further evaporated to dryness to give hydrochloride of 3-chlorophenyl-2-piperidyl acetamide hydrochloride.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:19](O)=[O:20])[N:10]([CH3:18])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl.O>[N:23]1([NH:22][C:19]([C:9]2[N:10]([CH3:18])[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)=[O:20])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[N:29]1([C:19]([C:9]2[N:10]([CH3:18])[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)=[O:20])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: Cn1c(C(=O)O)nc(-c2ccccc2)c1-c1ccccc1
Reactant: NN1CCCCC1
Reactant: C1CCNCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1c(C(=O)N2CCCCC2)nc(-c2ccccc2)c1-c1ccccc1
Product: Cn1c(C(=O)NN2CCCCC2)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 4,5-diphenyl-I-methylimidazole-2-carboxylic acid (50 mg, 0.18 mmol) from Step A, 1-aminopiperidine (0.052 mL, 0.36 mmol) (containing a small percent of piperidine as an impurity), PyBOP (NovaChem) (140 mg, 0.2 mmol) and N,N-diisopropyl-N-ethylamine (DIPEA) (0.065 mL, 0.2 mmol) in methylene chloride (2 mL) was stirred at rt for 20 hr. The reaction was diluted with water and extracted twice with methylene chloride. The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified twice by prep TLC (1 mm, silica gel) eluting with 5% methylene chloride, 35% ethyl acetate in hexanes to afford the primary product N-(piperidin-1-yl)-4,5-diphenyl-1-methylimidazole-2-carboxamide and 2-(piperidin-1-ylcarbonyl)-4,5-diphenyl-1-methylimidazole as a byproduct. HPLC/MS: 361 (M+1); Rt=2.64 min; 1HNMR (CDCl3): 1.4–1.7 (m, 2H), 1.92 (m, 4H), 2.96 (br s, 4H), 3.90 (s, 3H), 7.24 (m, 3H), 7.34 (m, 2H), 7.50 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[N:10]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][S:25][CH2:26][CH2:27][CH2:28][C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])[C:9]2=[O:36])=[CH:4][C:3]=1[CH3:37].CCN(CC)CC.Cl[S:46]([N:49]=[C:50]=[O:51])(=[O:48])=[O:47].[CH3:52][C:53]([OH:56])([CH3:55])[CH3:54]>C(Cl)Cl>[CH3:14][C:11]1([CH3:15])[C:12](=[O:13])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:46]([NH:49][C:50](=[O:51])[O:56][C:53]([CH3:55])([CH3:54])[CH3:52])(=[O:48])=[O:47])=[C:3]([CH3:37])[CH:4]=2)[C:9](=[O:36])[N:10]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][S:25][CH2:26][CH2:27][CH2:28][C:29]([F:35])([F:34])[C:30]([F:33])([F:31])[F:32]
Reactant: Cc1cc(N2C(=O)N(CCCCCCCCCSCCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)ccc1N
Reactant: CC(C)(C)O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(N2C(=O)N(CCCCCCCCCSCCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)ccc1NS(=O)(=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A solution of the compound of Example 25 (612 mg, 1.1 mmole) and Et3N (0.19 ml, 1.33 mmole) in anhydrous CH2Cl2 (30 ml) is stirred at 0° C. Then a solution of chlorosulphonyl isocyanate (0.11 ml, 1.22 mmole) in anhydrous CH2Cl2 (10 ml), cooled down to 0° C., is completed with t-BuOH (0.12 ml, 1.22 mmole) before being added rapidly to the solution of the compound of Example 25. The mixture is stirred for 30 min at 0° C. followed by 1 hour and a half at 23° C. The reaction medium is then washed successively with water (2×100 ml), a saturated aqueous solution of NaHCO3 (50 ml) and salt water (50 ml). The organic solution is dried over Na2SO4, filtered and concentrated to dryness. The evaporation residue is purified on a silica column (eluent: Heptane/AcOEt: 1/0 to 6/4). The expected compound is obtained in the form of a white solid with a yield of 85%. Melting point 122-124° C.
Reaction SMILES: [O:1]([C:8]1[C:9]([C:18]#[N:19])=[N:10][CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:21].[OH-].[NH4+]>>[O:1]([C:8]1[C:9]([C:18]([NH2:19])=[O:21])=[N:10][CH:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ncc(C(F)(F)F)cc1Oc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Product: NC(=O)c1ncc(C(F)(F)F)cc1Oc1ccccc1
Reaction time: 3 h
Yield: 84.3 %

Procedure:
3-Phenoxy-5-(trifluoromethyl)picolinonitrile (0.190 g, 0.719 mmol) was combined with 2 ml of sulfuric acid and agitated for 3 hours. Ice was added to the mixture, and the solution was basified with ammonium hydroxide solution. The resulting slurry was filtered and solids washed with water and dried in the air to afford 3-phenoxy-5-(trifluoromethyl)picolinamide (0.171 g, 84.3% yield) as a white solid.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C(N(CC)CC)C.[CH3:12][O:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18](=[O:23])[CH2:19][CH2:20]2)=[CH:16][C:15]=1[C:24]([OH:26])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:2][N:3]([CH3:4])[C:24]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][C:14]=1[O:13][CH3:12])[CH2:20][CH2:19][C:18]2=[O:23])=[O:26]
Reactant: CNC
Reactant: COc1cc2c(cc1C(=O)O)C(=O)CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1C(=O)N(C)C)C(=O)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
To a solution of Dimethylamine hydrochloride (2.22 g, 27.24 mmol) and triethylamine (7 ml, 54.48 mmol) in CH2Cl2 (30 ml) was added 6-Methoxy-3-oxo-indan-5-carboxylic acid (2 g, 9.08 mmol), HOBt (2.45 g, 18.18 mmol), EDCI (3.48 g, 18.18 mmol) at 0° C. in order. The mixture was stirred at room temperature for 3 hrs and washed with 8% NaOH, water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to give the product (1.69 g, 80% yield). LC-MS: m/e 234 (MH+)
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH:15]1[N:19]=[CH:18][N:17]2[CH2:20][CH2:21][C:22](=[O:23])[C:16]=12.Cl.ClCCl>O1CCCC1>[OH:23][C:22]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[C:16]2[N:17]([CH:18]=[N:19][CH:15]=2)[CH2:20][CH2:21]1
Reactant: N#Cc1ccc(I)cc1
Reactant: O=C1CCn2cncc21
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: N#Cc1ccc(C2(O)CCn3cncc32)cc1
Reaction time: 0.25 h

Procedure:
A solution of 8.18 mmol of 4-iodobenzonitrile [3058-39-7] in 20 ml of tetrahydrofuran at −20° C. is admixed dropwise with 8.18 mmol of isopropylmagnesium chloride (2M in tetrahydrofuran) and the reaction mixture is subsequently stirred for 15 minutes. A mixture of 4.09 mmol of 5,6-dihydropyrrolo[1,2-c]imidazol-7-one [426219-43-4] in 5 ml of tetrahydrofuran is added. After 1 hour the reaction mixture is poured into 1:1 1N HCl/dichloromethane and the phases are separated. The aqueous phase is rendered basic with saturated sodium hydrogen carbonate solution, stirred thoroughly, extracted with tert-butyl methyl ether (in order to separate unreacted ketone) and then extracted with dichloromethane (3×). The combined dichloromethane phases are dried with sodium sulphate and evaporated. From the residue the title compound is obtained by means of flash chromatography (SiO2 60F) as a white foam. Rf=0.20 (dichloromethane/ammonia (2M in EtOH) 95:5), Rt=3.81 (Gradient I).
Reaction SMILES: N1C=CN=C1.CN(C)C=O.[OH:11][CH:12]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[CH2:13][C:14]#[N:15].[C:22]([Si:26]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)Cl)([CH3:25])([CH3:24])[CH3:23]>CCOCC.C(OCC)(=O)C>[O:11]([CH:12]([C:16]1[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=1)[CH2:13][C:14]#[N:15])[Si:26]([C:22]([CH3:25])([CH3:24])[CH3:23])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: N#CCC(O)c1ccncc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](OC(CC#N)c1ccncc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
Next, imidazole (4.60 g, 67.5 mmol) and N,N-dimethylformamide (30 ml) were added to the obtained 3-hydroxy-3-(4-pyridyl)propionitrile (1.00 g, 6.75 mmol), and the mixture was stirred at room temperature. t-Butyldiphenylchlorosilane (2.23 g, 8.10 mmol) was added to the mixture, and the whole was stirred for one day and further stirred at an external temperature of 50° C. for three hours. Ethyl acetate (50 ml) and ether (50 ml) were added to the reaction mixture, the whole was washed with water (20 ml) three times and saturated brine (30 ml) successively, and the organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 2.58 g (98.9%) of 3-(t-butyldiphenylsiloxy)-3-(4-pyridyl)propionitrile as a colorless oily matter.
Reaction SMILES: [NH2:1][C:2]12[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:3]1([OH:22])[O:4][C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=12.C(N([CH2:28][CH3:29])CC)C.[C:30](Cl)(=[O:35])[CH2:31][CH2:32][CH2:33][CH3:34]>ClCCl>[C:30]([O:4][C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[C:2]1([NH:1][C:3](=[O:4])[CH2:2][CH2:6][CH2:28][CH3:29])[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:3]1=[O:22])(=[O:35])[CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCC(=O)Cl
Reactant: CC(C)c1ccc2c(c1)OC1(O)c3ccccc3C(=O)C21N
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)NC1(c2ccc(C(C)C)cc2OC(=O)CCCC)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 129.4 %

Procedure:
A solution of 9b-amino-4b-hydroxy-7-isopropyl-4bH-benzo[d]indeno[1,2-b]furan-10(9bH)-one (0.15 g, 0.50 mmol) in dichloromethane (5 ml) was added triethylamine (0.21 mL, 1.52 mmol) and valeroyl chloride (74 μL, 0.61 mmol) at 0° C. and then stirred for overnight at room temperature. The reaction mixture was extracted with dichloromethane and purified using silica gel column chromatography (30% ethylacetate in hexane) to afford the title compound (150 mg, 68%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)[N:3]=1.[CH3:18][CH2:19][O-:20].[Na+].[Na].C(O)C>CC(C)=O.O1CCOCC1>[CH2:19]([O:20][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)[N:5]=[C:6]([Cl:11])[C:7]=1[N+:8]([O-:10])=[O:9])[CH3:18]
Reactant: O=[N+]([O-])c1c(Cl)nc(N2CCSCC2)nc1Cl
Reactant: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: CCOc1nc(N2CCSCC2)nc(Cl)c1[N+](=O)[O-]
Temperature: -20 °C

Procedure:
14.8 gm (0.05 mol) of 4,6-dichloro-5-nitro-2-thiomorpholino-pyrimidine were dissolved in a mixture of 200 ml each of acetone and dioxane, and the solution was cooled to -20°C. A solution of sodium ethylate, prepared from 1.15 gm (0.05 mol) of sodium and 100 ml of ethanol, was added dropwise while stirring, at -20°C. The mixture was stirred another hour at room temperature, then poured over ice, and the product obtained thereby was recrystallized from isopropanol. Yield: 10.3 gm (67.5% of theory); m.p. 149°-150°C.
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([CH2:15][OH:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([CH:15]=[O:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(Br)c2c1[nH]c1cc(CO)ccc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1ccc(Br)c2c1[nH]c1cc(C=O)ccc12
Reaction time: 0.75 h

Procedure:
Step 1 A partial solution of 4-bromo-7-(hydroxymethyl)-9H-carbazole-1-carboxamide (Example 30-2, 1.00 g, 3.13 mmol) in THF (75 mL) was stirred at rt and treated with 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (Dess-Martin periodinane, 1.993 g, 4.70 mmol). After 45 min, the solution was diluted with EtOAc and washed with 5% aqueous sodium sulfite, NaHCO3 (aq), and brine, then was dried and concentrated. The residue was triturated with methanol, and the precipitate was collected by filtration, washed with methanol and dried to provide 4-bromo-7-formyl-9H-carbazole-1-carboxamide as a tan powder (ca. 85% purity, 948 mg, 81%) used without purification. 1H NMR (400 MHz, DMSO-d6) δ 12.13 (1H, s), 10.14 (1H, s), 8.80 (1H, d, J=8.1 Hz), 8.38 (1H, d, J=0.9 Hz), 8.28 (1H, br. s.), 7.97 (1H, d, J=8.1 Hz), 7.83 (1H, dd, J=8.3, 1.4 Hz), 7.64 (1H, br. s.), 7.54 (1H, d, J=8.1 Hz). Mass spectrum m/z 317, 319 (M+H)+.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH:20]([O:28][C:29](=[O:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:66][CH2:67]I>O1CCOCC1>[C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH:20]([O:28][C:29](=[O:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:21][C:22]([CH3:26])([CH3:27])[C:23]([O:25][CH2:67][Cl:66])=[O:24])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(C)(C)C(=O)O
Reactant: ClCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCCCCC(=O)OC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(C)(C)C(=O)OCCl
Reaction time: 0.08 h
Yield: 64.5 %

Procedure:
To a solution of 5-(N-CBz-L-valyloxy)-4-stearoyloxy-2,2-dimethylvaleric acid (16.0 g, 24 mmol) in dioxane (500 mL), was added dropwise a 40% aqueous solution of tetrabutylammonium hydroxide (14.3 mL). After stirring for 5 min, the solution was evaporated to dryness through co-evaporation with dioxane and toluene. The residue was dissolved in dichloromethane (500 mL) and then chloroiodomethane (17.5 mL, 240 mmol) was added and the solution was stirred for 6 h at room temperature. The solution was concentrated under reduced pressure and the residue was shaken with hexane/ethyl acetate (1:1 v/v, 400 mL). The yellow crystalline solid was filtered off and the filtrate was washed with aqueous solution of sodium thiosulfate (0.1 M) and the filtered through anhydrous sodium sulfate and evaporated to dryness. The residue was column chromatographed (silica gel, 1% MeOH in CH2Cl2), to give 11.0 g of chloromethyl 5-(N-CBz-L-valyloxy)-4-stearoyloxy-2,2-dimethylvalerate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[N:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:29][C:26]1[CH:27]=[N:28][C:23]([N:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)=[CH:24][CH:25]=1
Reactant: CN1CCN(c2ccc(N)cn2)CC1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Product: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCN(C)CC2)nc1
Yield: 29 %

Procedure:
Following general procedure B, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (200 mg, 0.704 mmol) was reacted with 6-(4-methylpiperazin-1-yl)pyridin-3-amine (163 mg, 0.845 mmol) to afford the desired product (90 mg, 29%) as a yellow solid: ESI MS m/z 440, [C21H22BrN5O+H]+
Reaction SMILES: [Br:1]Br.[C:3]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]2[O:13][CH2:14][O:15][C:8]=12)#[N:4].C([O-])(=O)C.[K+]>C(O)(=O)C.O>[Br:1][C:12]1[C:7]([CH2:6][CH2:5][C:3]#[N:4])=[C:8]2[O:15][CH2:14][O:13][C:9]2=[CH:10][CH:11]=1
Reactant: BrBr
Reactant: N#CCCc1cccc2c1OCO2
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: N#CCCc1c(Br)ccc2c1OCO2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
16.4 ml of bromine dissolved in 35 ml of acetic acid are poured at 18° C. onto 53.6 g of nitrile obtained in Stage C dissolved in 179 ml of acetic acid. The mixture is stirred for 1 hour, then left overnight at room temperature and hydrolysed with 31.5 g of potassium acetate dissolved in 150 ml of water and 196.5 g of ice. The mixture is extracted with diethyl ether and the ethereal phase is washed several times with water and dried.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])[O:6][C:7](Cl)(Cl)Cl)Cl.[O:13]([CH2:20]CO)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH2:23][C:24]1[CH:42]=[CH:41][C:27]([C:28]([N:30]2[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:29])=[C:26]([Cl:43])[CH:25]=1.N1CCCCC1>C(Cl)(Cl)Cl>[O:13]([CH2:20][CH2:7][O:6][C:5]([NH:23][C:24]1[CH:42]=[CH:41][C:27]([C:28]([N:30]2[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:29])=[C:26]([Cl:43])[CH:25]=1)=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1ccc(C(=O)N2CCCCc3ccccc32)c(Cl)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCCOc1ccccc1
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(C(=O)N2CCCCc3ccccc32)c(Cl)c1)OCCOc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 115.2 %

Procedure:
To chloroform (5 ml) is added triphosgen (0.72 g), and thereto is added with stirring 2-phenoxyethanol (1.0 g) under ice-cooling, during which the temperature of the reaction solution is kept at below 10° C., and the mixture is stirred at 0° C. for one hour. To the reaction solution are added with stirring dropwise 1-(4-amino-2-chlorobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (1.9 g) and a solution of piperidine (2.5 g) in chloroform (30 ml) under ice-cooling. The mixture is stirred at room temperature for three hours, washed with a saturated aqueous potassium hydrogen sulfate solution, distilled water and a saturated aqueous sodium hydrogen carbonate solution, and dried over magnesium sulfate, filtered, and evaporated to remove the solvent. The residue is recrystallized from diethyl ether to give 1-[4-(2-phenoxyethoxy-carbonylamino)-2-chlorobenzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.3 g) as white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[C:12]([Cl:21])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:24][C:25]([O:27][CH3:28])=[O:26].N1C(C)=CC=CC=1C>CC#N>[C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][N:9]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:19])([F:20])[F:18])=[C:12]([Cl:21])[CH:11]=1)[CH2:24][C:25]([O:27][CH3:28])=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)CCNc1ccc(OC(F)(F)F)c(Cl)c1
Solvent: Cc1cccc(C)n1
Solvent: CC#N
Product: COC(=O)CN(CCC(=O)OC(C)(C)C)c1ccc(OC(F)(F)F)c(Cl)c1
Temperature: 115 °C
Yield: 64.1 %

Procedure:
A neat solution of 8.50 g (22.5 mmol) of 3-(3-chloro-4-trifluoromethoxy-phenylamino)-propionic acid tert-butyl ester, 10.71 ml (112.6 mmol) of methyl bromoacetate and 13.07 ml (112.6 mmol) of 2,6-lutidine was stirred 14 h at 60° C., diluted with 30 ml of CH3CN and heated at 115° C. for 20 h. The reaction was then partitioned between aqueous 10% KHSO4 solution and EtOAc (3×). The organic phases were washed with aqueous 10% NaCl, dried over Na2SO4 evaporated and purified by flash silica gel column (n-heptane:EtOAc 95:5 to 85:1) to yield 5.94 g (64%) of the title compound as light yellow oil. MS: 412.11 (MH+, Cl).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2(O)[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[CH:23]=3)[NH:18][C:17]2=[O:26])=[C:12]([O:28][CH3:29])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[OH:37][C@H:38]1[CH2:42][NH:41][C@H:40]([C:43]([N:45]([CH3:47])[CH3:46])=[O:44])[CH2:39]1>>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([N:41]3[CH2:42][C@H:38]([OH:37])[CH2:39][C@H:40]3[C:43]([N:45]([CH3:47])[CH3:46])=[O:44])[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[CH:23]=3)[NH:18][C:17]2=[O:26])=[C:12]([O:28][CH3:29])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1
Reactant: COc1cc(CO[Si](C)(C)C(C)(C)C)ccc1C1(O)C(=O)Nc2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(CO[Si](C)(C)C(C)(C)C)ccc1C1(N2C[C@H](O)C[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.64 g of the compound obtained in Step 237-3 and (4R)-4-hydroxy-N,N-dimethyl-L-prolinamide trifluoroacetate (5.67 mmol) as starting materials, respectively 901 mg (Isomer A: colorless solid) and 288 mg (Isomer B: colorless amorphous) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 28-2.
Reaction SMILES: [CH3:1][C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=1[I:23]>>[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[C:8]([C:9]([F:10])([F:11])[F:12])[C:2]=2[CH3:1])=[O:19])=[CH:16][C:15]=1[I:23]
Reactant: Cc1c(N)cccc1C(F)(F)F
Reactant: O=C(Cl)c1ccc(Cl)c(I)c1
Product: Cc1c(NC(=O)c2ccc(Cl)c(I)c2)cccc1C(F)(F)F

Procedure:
4-Chloro-3-iodo-N-(2-methyl-3-(trifluoromethyl)phenyl)benzamide was synthesized from 2-methyl-3-(trifluromethyl)aniline and 4-chloro-3-iodobenzoyl chloride according to the procedure described in Example 183. 4-Chloro-3-iodo-N-(2-methyl-3-(trifluoromethyl)phenyl)benzamide was obtained as a white solid. MS (M−H+) 437.8; Calculated for C15H10ClF3INO: 439.