Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[Cl-].[Cl-].[Al+3].O>C1(C)C=CC=CC=1>[CH:1]1([C:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:7])=[CH:2][CH:3]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(C(=O)C2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 199.9 %

Procedure:
Dissolve cyclohexanecarbonyl chloride (2 g, 13.6 mmol) in anhydrous toluene (30 mL). Cool the solution to 0° C., add aluminum trichloride (2.72 g, 20.46 mmol) in three portions and stir the reaction mixture at ambient temperature overnight Cool to 0° C., add slowly water and extract the mixture with EtOAc. Dry the organic layer over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1) to give the desired intermediate (2.75 g, 100%).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=2)[NH2:9])[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][O:23][CH2:24][C:25](O)=[O:26])=[C:16]([C:29]([O:31]C)=[O:30])[CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][O:23][CH2:24][C:25](=[O:26])[NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:6]([N:1]3[CH:2]=[CH:3][CH:4]=[CH:5]3)[CH:7]=2)=[C:16]([CH:15]=1)[C:29]([OH:31])=[O:30]
Reactant: Nc1cccc(-n2cccc2)c1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(-n2cccc2)c1

Procedure:
Using the same method as in Example 15-(i), 3-(1H-pyrrol-1-yl)aniline was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-oxo-2-([3-(1H-pyrrol-1-yl)phenyl]amino)ethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 60%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9]1[C:10]([C:26]2[O:30][C:29]([C:31]3[CH:32]=[C:33]([CH2:37][NH:38]C(=O)OC(C)(C)C)[CH:34]=[CH:35][CH:36]=3)=[N:28][N:27]=2)=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:25])[N:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=2)=[CH:13][N:14]=1.C(=O)(O)[O-]>ClCCl.CO>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([N:22]([CH3:24])[CH3:23])=[O:25])=[CH:19][CH:20]=2)=[N:11][C:10]=1[C:26]1[O:30][C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][NH2:38])[CH:32]=2)=[N:28][N:27]=1
Reactant: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4cccc(CNC(=O)OC(C)(C)C)c4)o3)n2)cc1
Agent: O=C([O-])O
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4cccc(CN)c4)o3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
TFA (131.1 mg, 88.58 μL, 1.150 mmol) was added to a solution of tert-butyl N-[[3-[5-[3-amino-6-[4-(dimethylcarbamoyl)phenyl]pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]carbamate (60 mg, 0.1150 mmol) in dichloromethane (2 mL) and the resulting solution stirred at room temperature overnight. The reaction mixture was passed through a bicarbonate cartridge, which was flushed further with methanol (5 mL). The filtrate was concentrated in vacuo to leave a yellow/orange solid. The solid was taken up in a mixture of methanol and dichloromethane and passed through an SCX cartridge. The cartridge was washed initially with methanol and then the product eluted with 2M ammonia in methanol solution over 4 fractions. A yellow solid crystallised out of the filtrate which was isolated by filtration to give the product (44 mg, 90% yield) 1H NMR (400 MHz, DMSO) d 2.98 (m, 6H), 3.87 (s, 2H), 7.55 (m, 2H), 7.59-7.66 (m, 2H), 7.81 (br s, 2H), 8.00 (m, 1H), 8.17 (m, 3H) and 8.99 (s, 1H) ppm; MS (ES+) 416.26
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[F:47][C:48]1[CH:49]=[C:50](B(O)O)[CH:51]=[CH:52][C:53]=1[F:54].CO.[CH2:60]([N:67]1[CH2:71][CH:70]=[C:69]([C:72](=[O:74])[CH3:73])[CH2:68]1)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>O>[CH2:60]([N:67]1[CH2:71][C@H:70]([C:50]2[CH:51]=[CH:52][C:53]([F:54])=[C:48]([F:47])[CH:49]=2)[C@@H:69]([C:72](=[O:74])[CH3:73])[CH2:68]1)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: CC(=O)C1=CCN(Cc2ccccc2)C1
Reactant: OB(O)c1ccc(F)c(F)c1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: O
Solvent: CO
Product: CC(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Temperature: 55 °C
Yield: 39.6 %

Procedure:
A two necked flask was charged under argon with rhodium(acac)bis ethylene (0.239 g, 0.05 eq.), (R)-BINAP (0.575 g, 0.05 eq.) and 3,4-difluoro-phenylboronic acid (7.3 g, 2.5 eq.). 400 mL of MeOH and 40 mL of H2O were added followed by 1-(1-benzyl-2,5-dihydro-1H-pyrrol-3-yl)-ethanone (3.72 g). The reaction mixture was heated at 55° C. for 8 hours, cooled down to RT and concentrated under vacuo. Purification by flash chromatography (SiO2, EtOAc/Heptane 2/1) afforded 2.31 g (40%) of the title product as a light yellow oil. ES-MS m/e: 316.1 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C[Mg]Br.[CH2:13]([C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:34]2[CH:39]=[CH:38][C:37]([CH2:40][CH:41]([CH3:43])[CH3:42])=[CH:36][CH:35]=2)[CH2:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[CH:14]([CH3:16])[CH3:15].Cl>O1CCCC1.CCOCC.C(OCC)(=O)C>[CH2:40]([C:37]1[CH:38]=[CH:39][C:34]([CH:23]([C:20]2[CH:19]=[CH:18][C:17]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:22][CH:21]=2)[CH2:24][C:25]2[CH:33]=[CH:32][C:28]([C:29]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)=[O:30])=[CH:27][CH:26]=2)=[CH:35][CH:36]=1)[CH:41]([CH3:43])[CH3:42]
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(C)Cc1ccc(C(Cc2ccc(C(=O)Cl)cc2)c2ccc(CC(C)C)cc2)cc1
Agent: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)Cc1ccc(C(Cc2ccc(C(=O)c3c[nH]c4ccccc34)cc2)c2ccc(CC(C)C)cc2)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 16.9 %

Procedure:
To a solution of indole (366 mg) in tetrahydrofuran (5 ml) was added 3M solution of methyl magnesium bromide in ether (1.5 ml) at 20° C., and the mixture was stirred at 20° C. for 1 hour. A solution of 4-[2,2-bis(4-isobutylphenyl)ethyl]benzoyl chloride (450 mg) in tetrahydrofuran (5 ml) was added to the mixture at 20° C. After stirred at 20° C. for 30 minutes, the mixture was poured into a mixture of 1N hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water, aqueous sodium bicarbonate and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel (10 g) eluting with a mixture of hexane and ethyl acetate (20:1) to give 3-[4-[2,2-bis(4-isobutylphenyl)ethyl]benzoyl]indole (90 mg) as colorless crystals.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:11]=[C:12]([CH:27]=[CH:28][CH:29]=2)[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[CH:17][CH:16]=2)=[CH:2]1.[OH-].[K+]>O1CCCC1.C(O)C.C(OCC)(=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:11]=[C:12]([CH:27]=[CH:28][CH:29]=2)[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:17][CH:16]=2)=[CH:2]1
Reactant: COC(=O)CCc1ccc(OCc2cccc(-c3csc4ccccc34)c2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)CCc1ccc(OCc2cccc(-c3csc4ccccc34)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.5 %

Procedure:
Methyl 3-(4-{[3-(1-benzothiophen-3-yl)benzyl]oxy}phenyl)propanoate (0.80 g, 1.99 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and ethanol (10 mL). An aqueous solution (5 mL) of 85% potassium hydroxide (0.28 g, 4.24 mmol) was added to the solution, and the mixture was stirred at room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, and the mixture washed successively with aqueous citric acid solution, water and aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with diethyl ether-hexane to give the title compound (0.70 g, yield 91%) as colorless prism crystals. MS: m/z 371 (M−OH), 1H NMR (CDCl3) δ: 2.65 (2H, t, J=7.4 Hz), 2.92 (2H, t, J=7.4 Hz), 5.13 (2H, s), 6.93 (2H, d, J=8.8 Hz), 7.14 (2H, d, J=8.8 Hz), 7.34-7.98 (9H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH:9](=O)[CH:10]([CH3:12])[CH3:11].[CH:14](=O)[CH3:15].C(O)(=O)C>[Pt].CO>[CH2:14]([N:1]([C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1)[CH2:9][CH:10]([CH3:12])[CH3:11])[CH3:15]
Reactant: Nc1cccc(O)c1
Reactant: CC=O
Reactant: CC(C)C=O
Agent: [Pt]
Solvent: CO
Solvent: CC(=O)O
Product: CCN(CC(C)C)c1cccc(O)c1

Procedure:
3-(N-Ethyl-N-isobutylamino)phenol was synthesized by following the procedure of Examples 1 to 4. In a 500 cc-volume SUS-made autoclave equipped with a stirrer were charged 32.7 g (0.30 mole) of m-aminophenol, 185.5 g of methanol, and 1.6 g of a commercially available catalyst comprising 5% by weight of platinum supported on activated carbon containing 0.1 part by weight of lead per part by weight of platinum, and 47.6 g of a methanol solution containing 50% by weight of isobutyraldehyde (isobutyraldehyde content: 0.33 mole) was introduced over a period of 30 minutes at constant conditions of 40° C. and 10 kg/cm2G. After completion of the introduction of isobutyraldehyde, the mixture was maintained at the same temperature for an additional 60 minutes, after which 41.1 g of a methanol solution containing 45% by weight of acetaldehyde (acetaldehyde content: 0.42 mole) and 0.20 g (0.0033 mole) of acetic acid were continuously introduced over a period of 30 minutes. After completion of the introduction of acetaldehyde, the mixture was maintained at the same temperature for an additional 70 minutes and allowed to cool. The catalyst was removed by filtration, and the resulting filtrate was analyzed by gas chromatography, liquid chromatography, and GPC. The catalyst recovered was reused in the next reaction. The results are as shown in Table 7.
Reaction SMILES: [Cl-].[Li+].[CH:3](NC(C)C)(C)[CH3:4].C([Li])CCC.[OH:15][CH:16]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:17]([N:19]([CH3:29])[C:20](=[O:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:18].C(I)C.[Si](O[Si](C)(C)C)(C)(C)C>O1CCCC1>[CH2:3]([CH:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:20]([N:19]([CH:17]([CH3:18])[CH:16]([OH:15])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:29])=[O:28])[CH3:4]
Reactant: CC(C)NC(C)C
Reactant: CC(C(O)c1ccccc1)N(C)C(=O)Cc1ccccc1
Agent: [Cl-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCI
Solvent: C[Si](C)(C)O[Si](C)(C)C
Product: CCC(C(=O)N(C)C(C)C(O)c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
A dry 500 mL round-bottomed flask was charged with lithium chloride (4.24 g, 100 mmol, 10.0 equiv), diisopropylamine (3.1 mL, 22.1 mmol, 2.21 equiv), and tetrahydrofuran (35 mL). The suspension was cooled to -78° C., and n-butyllithium (2.04M in hexanes, 10.20 mL, 20.8 mmol, 2.08 equiv) was added via cannula, and the mixture was briefly warmed to 0° C. and then recooled to -78° C. [1S-[1R*, 2R*]]-N-(2-hydroxy-1-methyl-2-phenylethyl)-N-methyl benzeneacetamide (2.83 g, 10.0 mmol, 1.0 equiv) was added as a solution in tetrahydrofuran (50 mL), and the mixture was stirred at -78° C. for 1 hour, 0° C. for 10 minutes, and 23° C. for 4 minutes, then cooled to 0° C. Ethyl iodide (3.2 mL, 40 mmol, 4.0 equiv) was added, and the reaction was quenched after 40 minutes with saturated ammonium chloride. The amide was extracted from saturated ammonium chloride (800 mL) with ethyl acetate (3×100 mL), and the combined organic extracts were dried over sodium sulfate. After removal of the solvent under reduced pressure, flash column chromatography (50% ethyl acetate/hexanes) of the oily residue afforded a colorless oil which slowly solidified (2.85 g, 92 % yield). GC analysis of the TMS ether indicated a diastereomeric purity of the amide of greater than 98% de: mp 65°-66° C.; 1H NMR (300 MHz, C6D6) δ6.9-7.4 (m, 5H), 4.95 (br, 1H), 4.51 (t, 1H, J=6.9 Hz), 4.03 (m, 1H), 3.82 (m, 1H), 3.11 (dd, 1H, J=7.5 Hz, 7.0 Hz), 2.78 (s, 3H), 2.48 (m, 2H), 2.25 (m, 1H), 2.12 (s, 3H), 1.90 (m, 1H), 1.73 (m, 2H), 0.98 (d, 3H, J=6.8 Hz), 0.97 (m, 3H), 0.82 (t, 3H, J =7.3 Hz), 0.30 (d, 3H, J=6.5 Hz); 13C NMR (75.5 MHz, CDCl3) δ 175.4, 174.2, 142.3, 141.3, 140.5, 139.6, 128.8, 128.7, 128.7, 128.3, 128.2, 127.8, 127.7, 127.4, 126.9, 126.7, 126.6, 126.3; FTIR (neat film) cm-1: 3384 (br, m), 3027 (m), 2966 (m), 2922 (m), 2873 (m), 1620 (s), 1491 (m), 1453 (m), 1406 (m), 761 (m), 701 (m); HRMS (FAB) Calcd for C20H26NO2 (MH+): 312. 1965. Found: 312. 1962.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[C:5]([Br:7])[N:6]=1.C([Li])CCC.O>C(OCC)C>[Br:7][C:5]1[N:6]=[CH:2][S:3][C:4]=1[CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:11])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)OCc1sc(Br)nc1Br
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCc1scnc1Br
Temperature: -78 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
To a −78° C. solution of 2,4-dibromo-5-{[(tert-butyldimethylsilyl)oxy]methyl}-1,3-thiazole (2.44 g, 6.3 mmol) in anhydrous diethyl ether (120 mL) was added a solution of n-butyl lithium (2.5M in hexanes, 2.5 mL, 6.3 mmol). The reaction mixture was stirred at −78° C. for 1 hour. Water (75 mL) was added, and the mixture was warmed to room temperature then extracted with EtOAc (3×75 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo, affording 4-bromo-5-{[(tert-butyldimethylsilyl)oxy]methyl}-1,3-thiazole (1.77 g, 90%). The product was used without further purification.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[N:11]12[CH2:18][CH2:17][CH:14]([CH2:15][CH2:16]1)[C@@H:13]([NH:19][C:20](=[O:37])[O:21][CH:22]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH2:12]2>C(OCC)(=O)C>[Cl-:1].[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH:22]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[O:21][C:20]([NH:19][C@@H:13]2[CH:14]3[CH2:17][CH2:18][N+:11]([CH2:2][C:3](=[O:4])[C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)([CH2:16][CH2:15]3)[CH2:12]2)=[O:37])=[CH:31][CH:32]=1
Reactant: O=C(N[C@H]1CN2CCC1CC2)OC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: O=C(CCl)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1C[N+]2(CC(=O)c3ccccc3)CCC1CC2)OC(c1ccc(F)cc1)c1ccc(F)cc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
2-Chloro-1-phenylethanone (13 mg, 0.09 mmol) was added to a solution of (R)-bis(4-fluorophenyl)methyl quinuclidin-3-ylcarbamate (32.0 mg, 0.09 mmol, prepared as in example 3) in ethyl acetate (2 ml). The reaction was stirred at room temperature overnight. Then more 2-chloro-1-phenylethanone (2.7 mg, 0.02 mmol) was added to the solution, and the reaction was stirred for additional 24 hours. The reaction was evaporated to dryness, and the residue was triturated in Et2O. Then isopropyl ether was added, and the product was sonicated and the precipitate was collected by suction filtration to obtain (R)-3-((bis(4-fluorophenyl)methoxy)carbonylamino)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane chloride (32.4 mg)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8]([Br:19])=[CH:9][CH:10]=[C:11]([C:16]([NH2:18])=[O:17])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C1COCC1>[C:20]([NH:1][CH2:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8]([Br:19])=[CH:9][CH:10]=[C:11]([C:16]([NH2:18])=[O:17])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: NCc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Solvent: C1CCOC1
Product: CC(=O)NCc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Step 1 A suspension of 7-(aminomethyl)-4-bromo-9H-carbazole-1-carboxamide (prepared according to Step 2 of Example 33-1, 168 mg, 0.528 mmol) and TEA (0.184 mL, 1.320 mmol) in THF (18 mL) was treated with acetic anhydride (0.080 mL, 0.845 mmol). The mixture was stirred at rt for 2 h, then was partitioned between EtOAc and 1 M hydrochloric acid. The organic phase was washed with NaHCO3 (aq) and brine, dried and concentrated to provide 7-(acetamidomethyl)-4-bromo-9H-carbazole-1-carboxamide as an off-white solid. Mass spectrum m/z 359.9 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6](C)=[CH:5][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C@@H:16]([N:18]3[CH2:23][CH2:22][C@:21]([CH2:30][C:31]([OH:34])([CH3:33])[CH3:32])([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:20][C:19]3=[O:35])[CH3:17])=[CH:12][CH:11]=2)=[N:3]1.ClC1C=CC(=O)N(C[CH:44]2[CH2:46][CH2:45]2)N=1>>[CH:44]1([CH2:1][N:2]2[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:10]3[CH:11]=[CH:12][C:13]([C@@H:16]([N:18]4[CH2:23][CH2:22][C@:21]([CH2:30][C:31]([OH:34])([CH3:33])[CH3:32])([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[O:20][C:19]4=[O:35])[CH3:17])=[CH:14][CH:15]=3)=[N:3]2)[CH2:46][CH2:45]1
Reactant: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)nn(C)c1=O
Reactant: O=c1ccc(Cl)nn1CC1CC1
Product: C[C@@H](c1ccc(-c2ccc(=O)n(CC3CC3)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from 3-{(S)-1-[4-(1,5-dimethyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-phenyl]-ethyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one and 6-chloro-2-(cyclopropylmethyl)pyridazin-3(2H)-one following a procedure analogous to that described in Example 17. Mass spectrum (ESI+): m/z=502 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]=[C:9]=[O:10])=O)=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:20][C:19]=1[NH:32][NH:33]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:20][C:19]=1[N:32]1[C:9](=[O:10])[NH:8][C:6]([C:5]2[CH:11]=[CH:12][C:2]([F:1])=[C:3]([C:13]([F:16])([F:15])[F:14])[CH:4]=2)=[N:33]1
Reactant: O=C=NC(=O)c1ccc(F)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NNc1cc(CNC(=O)C(C)(C)C)ccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(F)c(C(F)(F)F)c3)[nH]c2=O)c1
Yield: 45.5 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 4-fluoro-3-(trifluoromethyl)benzoyl isocyanate (Intermediate-101, 0.196 g, 0.84 mmol), tert-butyl 2-(2-chloro-5-(((2,2-dimethylpropanoyl)amino)methyl)phenyl)hydrazinecarboxylate (Intermediate-94, 0.150 g, 0.420 mmol), DCM (15 mL), and trifluoro acetic acid (3.0 mL) to afford 0.090 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.12 (s, 9H), 4.29 (d, J=5.7 Hz, 2H), 7.35 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.60 (d, J=8.7 Hz, 1H), 7.70-7.76 (m, 1H), 8.19-8.23 (m, 3H), 12.76 (s, 1H); MS (m/z): 471.32 (MA-H)+.
Reaction SMILES: O[CH2:2][C:3]1(CO)[CH2:6][O:5][CH2:4]1.C(N(CC)CC)C.[C:16](Cl)(=O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]CCC.C1C[O:35]CC1>>[C:4]([O:5][CH3:6])(=[O:35])[CH2:3][CH2:2][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16]
Reactant: C1CCOC1
Reactant: OCC1(CO)COC1
Reactant: CCCCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCC(=O)OC
Temperature: 0 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
Oxetane 2 (5 g, 41 mmol) was dried in vacuo at 100° C. for 1 h and then dissolved in THF (120 mL). To the solution at room temperature was added freshly distilled triethylamine (10 mL, 72 mmol) and N,N-(dimethylamino)pyridine (400 mg, 3.3 mmol) and the reaction was cooled to 0° C. Myristoyl chloride (8.9 mL, 33 mmol) was added via cannula to the reaction mixture, and the resulting yellowish solution was stirred at 0° C. for 4 h and then warmed to room temperature and stirred an additional 4 h. The reaction was quenched by addition of diethyl ether and washing with sat'd aq. NaHCO3, followed by washing with brine. The organic layer was separated and dried (Na2SO4). The solvents were removed by rotary evaporation, and the crude product was purified by silica gel column chromatography to yield 8 g (74%) of the ester 3 as white powder.
Reaction SMILES: [C:1]([C:3]1[CH:36]=[CH:35][C:6]([CH2:7][N:8]2[C:12]([CH2:13][CH2:14][NH:15][C:16]([C@@H:18]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][N:19]3C(OC(C)(C)C)=O)=[O:17])=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].[C:37]([C:41]([OH:43])=[O:42])([F:40])([F:39])[F:38]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:41]([OH:43])=[O:42].[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]([CH2:13][CH2:14][NH:15][C:16]([C@@H:18]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][NH:19]3)=[O:17])=[CH:11][N:10]=[CH:9]2)=[CH:35][CH:36]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)NCCc1cncn1Cc1ccc(C#N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(Cn2cncc2CCNC(=O)[C@@H]2Cc3ccccc3CN2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-(t-butyloxycarbonyl)-1,2,3,4-tetrahydro-isoquinoline-3(S)-carboxylic acid {2-[3-(4-cyanobenzyl)-3H-imidazol-4-yl]-ethyl}-amide (1.18 g, 2.4 mmol) in CH2Cl2 (6 mL) was added CF3CO2H (4 mL). The reaction was stirred for 0.75 hr at 25° C. Evaporation in vacuo yielded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([O:29][CH3:30])=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=O)[NH:12][CH:11]3[C:32]3[C:37]([F:38])=[C:36]([F:39])[CH:35]=[CH:34][C:33]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:43]>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([O:29][CH3:30])=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=[S:43])[NH:12][CH:11]3[C:32]3[C:37]([F:38])=[C:36]([F:39])[CH:35]=[CH:34][C:33]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2c(C)ccc(F)c2F)C12C(=O)Nc1cc(Cl)ccc12
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=S)NC(c2c(C)ccc(F)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 50 °C
Yield: 91.6 %

Procedure:
A mixture of racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5,6-difluoro-2-methyl-phenyl) spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (40 mg, 0.067 mmol) and P2S5 (45 mg, 0.20 mmol) in THF (2 mL) was heated at 50° C. for 2 h, and then diluted with toluene (10 mL). The mixture was concentrated in vacuo and the residue was washed with DCM twice. The DCM layers were combined and concentrated. The residue was purified by flash chromatography to give the title compound as white solid (38 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[C:10]([CH2:12][C:13]([NH:15][CH:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:14])[CH:9]=[CH:8][C:5]=1[CH2:6]Cl)[CH3:2].[C-:35]#[N:36].[Na+].O>CS(C)=O>[CH2:1]([O:3][C:4]1[CH:11]=[C:10]([CH2:12][C:13]([NH:15][CH:16]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)=[O:14])[CH:9]=[CH:8][C:5]=1[CH2:6][C:35]#[N:36])[CH3:2]
Reactant: [C-]#N
Reactant: CCOc1cc(CC(=O)NC(c2ccccc2)c2ccccc2N2CCCCC2)ccc1CCl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOc1cc(CC(=O)NC(c2ccccc2)c2ccccc2N2CCCCC2)ccc1CC#N
Temperature: 60 °C
Reaction time: 5 h

Procedure:
A solution of 2-ethoxy-4[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzyl chloride (2.6 g, 5.45 mmol) in dimethylsulphoxide (10 ml) is added dropwise at 50°-60° C. to sodium cyanide (0.32 g, 6.5 mmol) in dimethylsulphoxide (40 ml). The mixture is then stirred for 5 hours at 60° C., added to water and extracted with chloroform. The extract is concentrated by evaporation in vacuo. The residue is purified by column chromatography on silica gel (toluene/ethyl acetate=5/1).