Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2](C)C(Cl)=O.[Br:7][C:8]1[C:9]([Cl:15])=[N+:10]([O-])[CH:11]=[CH:12][CH:13]=1.C[Si](C#N)(C)C>ClCCl>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:1]#[N:2])=[N:10][C:9]=1[Cl:15]
Reactant: CN(C)C(=O)Cl
Reactant: [O-][n+]1cccc(Br)c1Cl
Agent: C[Si](C)(C)C#N
Solvent: ClCCl
Product: N#Cc1ccc(Br)c(Cl)n1

Procedure:
The reaction was also performed using the acylating agent dimethylcarbamoyl chloride. A solution of dimethylcarbamoyl chloride (12.9 mL, 0.14 mol) in dichloromethane (23 mL) was added drop-wise to a stirred solution of 3-bromo-2-chloropyridine 1-oxide (C27) (11.23 g, 53.9 mmol) and trimethylsilyl cyanide (17.5 mL, 0.14 mol) in dichloromethane (200 mL). The reaction mixture was heated under reflux for 3 days, then diluted with dichloromethane (450 mL) and washed with saturated aqueous sodium bicarbonate solution (2×200 mL), then with water (200 mL), dried over magnesium sulfate and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 15% to 20% ethyl acetate in heptane) provided the title compound, contaminated with dimethylcarbamoyl cyanide (12.73 g, 100%) as an off-white solid. The impurity was reduced by repeatedly washing with aqueous sodium hydroxide solution (2 N) and a second chromatography on silica gel. Although the impurity could not be completely removed, the material was used in the next step without any detrimental effects. Yield: 7.83 g, 36.0 mmol, 67%. 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J=7.8 Hz, 1H), 8.12 (d, J=7.8 Hz, 1H).
Reaction SMILES: [CH:1]([Si:4](Cl)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([I:21])=[C:17]([CH:20]=1)[CH2:18][OH:19].N1C=CN=C1>CN(C=O)C>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([I:21])=[C:17]([CH:20]=1)[CH2:18][O:19][Si:4]([CH:8]([CH3:10])[CH3:9])([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: OCc1cc(Cl)ccc1I
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](OCc1cc(Cl)ccc1I)(C(C)C)C(C)C
Yield: 8345.5 %

Procedure:
Triisopropylsilylchloride (14.59 mL, 68.16 mmol) was added to a stiffed solution of 5-chloro-2-iodobenzyl alcohol (12.2 g, 45.44 mmol) and imidazole (4.64 g, 68.16 mmol) in DMF (45 mL). After 1 h the mixture was partitioned between hexanes and water. The organic layer was dried (Na2SO4) and evaporated in vacuo to an oil which was purified by flash column chromatography on silica (eluting with 5% methylene chloride/hexanes) to give [(5-chloro-2-iodobenzyl)oxy](triisopropyl)silane as an oil (1611 g): 1H NMR (CDCl3, 400 MHz) δ 1.11 (d, J=6.8 Hz, 18H), 1.20 (septet, J=6.8 Hz, 3H), 4.65 (s, 2H), 6.96 (dd, J=2.6, 8.4 Hz, 1H), 7.56 (d, J=2.8 Hz, 1H), 7.66 (d, J=8.2 Hz, 1H).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[F:20]>CN(C)C=O.O>[F:20][C:12]1[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]=1[O:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2)c(F)c1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 43.7 %

Procedure:
Sodium hydride (1.51 g, 62.92 mmol, 2.00 equiv) was added in small portions to a solution of phenol (3.25 g, 34.53 mmol, 1.10 equiv) in N,N-dimethylformamide (50 mL) maintained under nitrogen at 0-5° C. After stirring for 30 min at 0-5° C., 1,2-difluoro-4-nitrobenzene (5 g, 31.43 mmol, 1.00 equiv) was added. The reaction mixture was stirred overnight at room temperature and then diluted with 200 mL of water. The resulting solution was extracted with 3×100 mL of ethyl acetate. The combined organic layers was washed with 3×150 mL of brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified on a silica gel column eluted with 0-2% ethyl acetate in petroleum ether to afford 3.2 g (44%) of 2-fluoro-4-nitro-1-phenoxybenzene as a yellow solid. 1H-NMR (400 MHz, CDCl3): δ 8.10-8.07 (m, 1H), 7.99-7.94 (m, 1H), 7.46-7.41 (m, 2H), 7.30-7.26 (m, 1H), 7.12-7.04 (m, 2H), 7.02-6.93 (m, 1H) ppm.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:35]=[CH:34][C:6]([CH2:7][C:8]2[N:9]=[C:10]([O:30][CH2:31][CH2:32][CH3:33])[C:11]3[N:16]=[C:15]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH2:25][CH:26]5[CH2:28][O:27]5)=[C:19]([CH3:29])[CH:18]=4)[O:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1>CO>[NH2:1][CH2:28][CH:26]([OH:27])[CH2:25][O:24][C:20]1[C:19]([CH3:29])=[CH:18][C:17]([C:15]2[O:14][C:12]3[N:13]=[C:8]([CH2:7][C:6]4[CH:34]=[CH:35][C:3]([Cl:2])=[CH:4][CH:5]=4)[N:9]=[C:10]([O:30][CH2:31][CH2:32][CH3:33])[C:11]=3[N:16]=2)=[CH:22][C:21]=1[CH3:23]
Reactant: N
Reactant: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OCC4CO4)c(C)c3)nc12
Solvent: CO
Product: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OCC(O)CN)c(C)c3)nc12
Temperature: 60 °C

Procedure:
5 ml of a 7 N solution of ammonia in methanol were added to 100 mg of crude 5-(4-chloro-benzyl)-2-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-7-propoxy-oxazolo[5,4-d]pyrimidine. The mixture was heated to 60° C. for 6 h. Then the solvent was removed in vacuo and the residue was purified by silica gel chromatography (method SC1) to give 44 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6](OCC)=[O:7])=[CH:4][CH:3]=1.O.[NH2:14][NH2:15]>CCOCC>[F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([NH:14][NH2:15])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: NN
Solvent: CCOCC
Solvent: O
Product: NNC(=O)c1ccc(F)cc1

Procedure:
The p-fluorobenzoic acid hydrazide is prepared as follows. Ethyl p-fluorobenzoate (8.4 g) is refluxed with hydrazine hydrate (3.75 g) for 3 hours. The mixture is then cooled, ether is added and the precipitate of p-fluorobenzoic acid hydrazide (3.2 g) is removed by filtration, washed with ether and desiccated, m.p. 149°-151° C.
Reaction SMILES: [CH3:1][C:2]1([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][C:9]2[C:4](=[C:5]([O:13]C)[C:6]([CH3:12])=[CH:7][C:8]=2[CH3:11])[C:3]1=[O:15].[I-].[Na+].[Cl-].[Al+3].[Cl-].[Cl-]>C(#N)C>[CH3:1][C:2]1([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][C:9]2[C:4](=[C:5]([OH:13])[C:6]([CH3:12])=[CH:7][C:8]=2[CH3:11])[C:3]1=[O:15]
Reactant: COc1c(C)cc(C)c2c1C(=O)C(C)(Cc1ccccc1)C2
Agent: [Al+3]
Agent: [Cl-]
Agent: [I-]
Solvent: CC#N
Product: Cc1cc(C)c2c(c1O)C(=O)C(C)(Cc1ccccc1)C2
Reaction time: 1 h

Procedure:
23.0 Grams of 2,3-dihydro-2,4,6-trimethyl-7-methoxy-2-benzyl-1H-inden-1-one and 25.8 g of sodium iodide were dissolved in 90 ml of acetonitrile. To this solution was added 22.9 g of aluminium chloride at room temperature and stirred for 1 hour. Then the solvent was removed by evaporation under a reduced pressure, and the residue thus obtained was extracted with ethyl acetate. The extract was washed with an aqueous solution saturated with sodium chloride, an aqueous solution of sodium thiosulfate and an aqueous solution saturated with sodium chloride in this order, and the insoluble matters were removed by filtration. The solvent was removed by evaporation and the residue thus obtained was recrystallized from n-hexane to obtain 19.7 g of 2,3-dihydro-2,4,6-trimethyl-7-hydroxy-2-benzyl-1H-indene-1-one. Colorless prism-like crystals. Melting point: 86°-87° C.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].N1C=CC=CC=1.[C:13]([OH:17])([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl>[C:1]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)(C)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of isobutyryl chloride (47 g, 0.44 mol) in CH2Cl2 (75 ml) and tert-butanol (75 ml) at 0° C., pyridine (39.3 ml, 486 mmol) was added slowly by syringe. The mixture was allowed to warm to room temperature, stirred overnight, diluted with CH2Cl2 (400 ml) and washed with H2O, HCl (2N, two times), H2O (two times) and saturated NaHCO3. The organic phase was dried over MgSO4 and filtered. The filtrate was then concentrated under reduced pressure without heat. The resulting oil was simply distilled, collecting the fraction boiling at 128-129° C. to give tert-butyl isobutyrate, 21 (35.9 g, 56%).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[N:12]=[C:11]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:10]2=[CH:9][CH:8]=1.[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1.O>CCCCCC.C1(C)C=CC=CC=1>[N:12]1[C:7]([CH2:6][CH:23]([C:22]2[CH:25]=[CH:26][C:19]([CH3:18])=[CH:20][CH:21]=2)[OH:24])=[CH:8][CH:9]=[C:10]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:11]=12
Reactant: Cc1ccc(C=O)cc1
Reactant: Cc1ccc2c(n1)CCCCC2
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCCC
Product: Cc1ccc(C(O)Cc2ccc3c(n2)CCCCC3)cc1
Temperature: -20 °C
Reaction time: 0.75 h

Procedure:
To a solution of 1.6M n-butyl lithium in n-hexane (7.2 ml) in toluene (25 ml), at -20° C. under nitrogen, was added a solution of 2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine (1.7 g 0.01 m) in toluene (5 ml). The solution was left to stir at -20° C. for 0.75 hours, then blown over into a solution of 4-methylbenzaldehyde (1.5 g). The solution was allowed to warm to room temperature and water added. The toluene phase was extracted with 2N hydrochloric acid and this was basified with solid potassium carbonate and then extracted with dichloromethane. The combined dichloromethane extracts were washed with water, dried (MgSO4) and evaporated to give an oil. This was purified by chromatography on basic alumina using diisopropyl ether as eluent to give the title compound as an oil. This was dissolved in ether and treated with ethereal HCl to give a crystalline hydrochloride salt (1.2 g) m.p. 184°-6° C.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:16]1([NH:22][C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=2[N+:13]([O-:15])=[O:14])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: NC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc(NC2CCCCC2)c([N+](=O)[O-])c1

Procedure:
Ethyl 4-fluoro-3-nitrobenzoate (5.73 g, 0.0269 mol) was dissolved in 25 mL of DMF. While stirring under an atmosphere of nitrogen, cyclohexanamine in 5 mL of DMF (3.4 mL, 0.030 mol) and N,N-diisopropylethylamine (14 mL, 0.080 mol) were added simultaneously via two seperate syringes. The reaction mixture turned immediately into a deep yellow/orange gel and was diluted with another 5 mL of DMF. The reaction mixture was slightly exothermic and stirring was maintained until the reaction was complete as determined by LC/MS. The reaction mixture was then diluted with ethyl acetate and washed with 5% citric acid then brine. The organic phase was collected, dried over sodium sulfate and concentrated to a yellow oil which solidified under high vacuum to yield 8.47 g of the title compound.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:43][CH2:44][CH:45]4[CH2:47][CH2:46]4)=[C:24]([NH:27][C:28](=[O:42])[CH:29]=[CH:30][CH2:31][N:32]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:33][CH2:34][OH:35])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[F:15]>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:43][CH2:44][CH:45]4[CH2:47][CH2:46]4)=[C:24]([NH:27][C:28](=[O:42])[CH:29]=[CH:30][CH2:31][N:32]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:33][CH2:34][O:35][C:1]([CH3:2])=[O:3])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: CCOC(=O)CN(CC=CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1)CCO
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CCOC(=O)CN(CC=CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1)CCOC(C)=O
Reaction time: 8 h

Procedure:
47 μl of acetic anhydride and catalytic amounts of 4-dimethyl-aminopyridine are added to 250 mg of 4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{N-[(ethoxycarbonyl)methyl]-N-(2-hydroxyethyl)amino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxy-quinazoline in 2 ml of methylene chloride. The reaction mixture is stirred overnight at ambient temperatures and then evaporated to dryness. The crude product is purified by chromatography on a silica gel column with methylene chloride, followed by methylene chloride/methanol (9:1) as eluant. Yield: 150 mg (56% of theory), Melting point: 90-92° C. Mass spectrum (ESI+): m/z=614, 616 [M+H]+
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8](Cl)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:12][NH2:13]>>[Br:1][C:2]1[C:10]2[S:9][C:8]([NH:13][CH3:12])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc2cccc(Br)c2s1
Reactant: CN
Product: CNc1nc2cccc(Br)c2s1
Temperature: 60 °C
Yield: 67.7 %

Procedure:
7-Bromo-2-chlorobenzothiazole (85 mg, 0.34 mmol) and methylamine (2 M in THF, 3 mL, 6 mmol) were mixed and heated to 60° C. overnight. The solvent was evaporated. The residue was purified by ISCO chromatography (0 to 30% EtOAc:heptane) to afford 56 mg (67%) of the title compound. MS (ESI): 243.30, 245.26 [M+H]+; HPLC tR=1.09 min (HPLC: Anayltical—2 min).
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:3]\[CH2:4]O.N1C(C)=CC(C)=CC=1C.[Cl-].[Li+].CS([Cl:27])(=O)=O>CN(C=O)C>[Cl:27][CH2:4]/[CH:3]=[C:2](\[CH3:1])/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Product: CC(C)=CCC/C(C)=C/CCl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89.4 %

Procedure:
To a stirred solution of 30.0 g (0.194 mol) of (E)-3,7-dimethyl-2,6-octadien-1-ol and 28.27 mL (0.213 mol) of 2,4,6-collidine under argon at room temperature was added dropwise 8.23 g (0.194 mol) of lithium chloride in 100 mL of DMF. The mixture was cooled to 0° C. and treated with 16.56 mL (0.213 mol) of methanesulfonyl chloride dropwise over 10 minutes. The reaction was stirred at 0° C. for 1.5 hours (solid present), then was poured into 500 mL of ice/water. The aqueous solution was washed three times with 200 mL portions of hexane, the organic layers were combined and washed with 5% KHSO4, water, NaHCO3, brine, dried (MgSO4) and evaporated to provide 29.95 g of a pale yellow oil. Rapid flash chromatography was performed on 400 g of silica gel, eluting with 3:9 EtOAc/hexane. Pure product fractions were combined and evaporated to provide 25.20 g (75%) of title compound as a pale yellow oil.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].COC(C1NN=C(OC[C:33]2[C:34]([C:39]3[CH:44]=CC=CC=3)=[N:35][O:36][C:37]=2C)C=1)=O.NC1CCOCC1>>[O:36]1[CH2:44][CH2:39][CH:34]([NH:35][C:3]([C:5]2[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:4])[CH2:33][CH2:37]1
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)[nH]n1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)n[nH]1
Agent: NC1CCOCC1
Product: CCCCc1noc(C)c1COc1cc(C(=O)NC2CCOCC2)[nH]n1
Yield: 19 %

Procedure:
As described for example 1b, 5-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.34 mmol), instead of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester, was converted, using 4-aminotetrahydropyran instead of morpholine, to the title compound (23 mg, 19%) which was obtained as a white solid. MS: m/e=363.0 [M+H]+.
Reaction SMILES: C([O-])CCC.C([O-])CCC.C([O-])CCC.C([O-])CCC.[Zr+4:21].C(OCCOCCO)CCC.COC1C=CC(O)=CC=1.[C:42]([OH:46])(=[O:45])[CH:43]=[CH2:44]>C(O)CCC>[C:42]([O-:46])(=[O:45])[CH:43]=[CH2:44].[C:42]([O-:46])(=[O:45])[CH:43]=[CH2:44].[C:42]([O-:46])(=[O:45])[CH:43]=[CH2:44].[C:42]([O-:46])(=[O:45])[CH:43]=[CH2:44].[Zr+4:21]
Reactant: C=CC(=O)O
Agent: [Zr+4]
Agent: CCCC[O-]
Agent: COc1ccc(O)cc1
Solvent: CCCCO
Solvent: CCCCOCCOCCO
Product: C=CC(=O)[O-]
Temperature: 45 °C

Procedure:
Into the flask described hereinabove there were placed 509.3 g of zirconium tetrabutanolate, 498.6 g of diethylene glycol monobutyl ether, and 2.8 g of 4-methoxyphenol. To this mixture there were quickly added in drops using a dropping funnel 382.7 grams of acrylic acid. The temperature thereby increased to 45° C. The product remained liquid and stable so that it could be heated to 90° C. during 30 minutes. The co-product butanol was expelled during 1 hour using vacuum up to 200 mbar.
Reaction SMILES: [C:1]1([C@@H:7]([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:13]1([C:19]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:27]3[C@H:23]([CH2:24][NH:25][CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[C:29]1([C:19]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:27]3[C@H:23]([CH2:24][N:25]([C:8](=[O:10])[C@@H:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH3:11])[CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Reactant: C[C@@H](C(=O)O)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](C(=O)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1)c1ccccc1
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
N,N'-Carbonyldiimidazole (0.66 g) is added to a solution of (R)-2-phenylpropionic acid (0.62 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 30 minutes at +5° C. and a solution of (3aR,7aR)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (1.35 g) and triethylamine (0.57 cc) in dichloromethane (40 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is dissolved in ethyl acetate (100 cc) and the solution is washed with water (2×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (4 kPa). The residue is chromatographed on a silica gel column (0.2-0.04 mm, diameter 2.8 cm, height 15 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (60/40 by volume) and collecting 50 cc fractions. Fractions 4 to 8 are concentrated to dryness under reduced pressure (4 kPa) to give (3aR,7aR)-7,7-diphenyl-2-[(R)-2-phenylpropionyl]-4-perhydroisoindolone (1.4 g) in the form of a white meringue, the infrared spectrum of which is identical to that of the product from Example 68; [α]D20 =-278° (c=1, methanol).
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)=[CH:13][S:12][C:11]=1[N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32])=[O:9])C.Cl>O>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]([C:8]([OH:9])=[O:7])=[C:11]([N:22]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]3=[O:32])[S:12][CH:13]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1c(-c2ccc(Br)cc2)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1c(-c2ccc(Br)cc2)csc1N1C(=O)c2ccccc2C1=O

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 4-(4-bromophenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 21, Part C). The mixture is heated to reflux for 90 minutes, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][C:15]([O:21]C)=[CH:16][CH:17]=3)[CH2:12]2)=[O:10])=[CH:4][C:3]=1[C:23]([F:26])([F:25])[F:24].B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][C:15]([OH:21])=[CH:16][CH:17]=3)[CH2:12]2)=[O:10])=[CH:4][C:3]=1[C:23]([F:24])([F:25])[F:26]
Reactant: COc1ccc2c(c1)CC(C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)C1CCc2ccc(O)cc2C1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
To a solution of N-[4-chloro-3-(trifluoromethyl)phenyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide (3.65 g mg, 9.53 mmol) in DCM (100 mL) at 0° C. was added a 1.0M solution of BBr3 in DCM (14.3 mL) dropwise. The reaction mixture was allowed to warm to rt overnight. The reaction mixture was poured onto ice and extracted with EtOAc. The organic solution was dried over Na2SO4, filtered and evaporated. The residue was triturated with DCM to give N-[4-chloro-3-(trifluoromethyl)phenyl]-7-hydroxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide as a beige solid (3.25 g, 92.4%). LCMS: (FA) ES+ 370.2, ES− 368.1.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)[CH3:2].C1(CN)CCCCC1.[O:18]=[C:19]1[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:39][C:40]1[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=1[C:42](O)=[O:43].O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:42](=[O:43])[C:41]2[CH:45]=[CH:46][CH:47]=[CH:48][C:40]=2[CH2:39][N:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]3([CH2:31][O:30][C:29]4[CH:32]=[C:33]5[C:37](=[CH:38][C:28]3=4)[CH2:36][CH2:35][O:34]5)[C:19]2=[O:18])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(N)cc1
Reactant: O=C(O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: CCc1ccc(NC(=O)c2ccccc2CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 4-ethylaniline to replace cyclohexanemethylamine, and 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(4-ethylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (87%) as a colorless solid: mp>230° C.; 1H NMR (300 MHz, DMSO-d6) δ10.50 (s, 1H), 7.68-7.55 (m, 3H), 7.49-7.35 (m, 2H), 7.23-7.10 (m, 5H), 6.99 (dd, J=7.5, 7.5 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 6.51 (s, 1H), 6.39 (s, 1H), 5.15-4.99 (m, 2H), 4.83 (d, J=8.9 Hz, 1H), 4.68 (d, J=8.9 Hz, 1H), 4.46 (t, J=8.7 Hz, 2H), 2.99-2.85 (m, 2H), 2.54 (q, J=7.5 Hz, 2H), 1.14 (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ177.8, 167.4, 161.6, 161.2, 142.8, 139.7, 137.2, 136.7, 134.4, 132.7, 130.8, 129.1, 129.3, 127.8, 127.1, 124.1, 123.6, 120.9, 120.4, 120.3, 119.6, 109.7, 92.9, 80.4, 72.6, 57.4, 41.5, 28.8, 28.1, 16.3; MS (ES+) m/z 517.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]2[N:17]=[C:18]([CH3:22])[N:19]=[C:20](Cl)[C:15]=2[C:14]([CH3:23])=[C:13]1[CH3:24].[NH:25]1[CH2:30][CH2:29][CH2:28][CH:27]([C:31]#[N:32])[CH2:26]1.C(N(CC)C(C)C)(C)C>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]2[N:17]=[C:18]([CH3:22])[N:19]=[C:20]([N:25]3[CH2:30][CH2:29][CH2:28][CH:27]([C:31]#[N:32])[CH2:26]3)[C:15]=2[C:14]([CH3:23])=[C:13]1[CH3:24]
Reactant: Cc1nc(Cl)c2c(C)c(C)n(-c3ccc(C(F)(F)F)cc3Br)c2n1
Reactant: N#CC1CCCNC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N2CCCC(C#N)C2)c2c(C)c(C)n(-c3ccc(C(F)(F)F)cc3Br)c2n1
Temperature: 25 °C
Yield: 13.2 %

Procedure:
A mixture of 7-(2-bromo-4-trifluoromethylphenyl)-4-chloro-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidine (400 mg), piperidine-3-carbonitrile (290 mg), N,N-diisopropylethylamine (309 mg) in ethanol (2 mL) was heated at reflux for 6 days. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: hexane/ethyl acetate=5:1) to obtain two diastereoisomers (low polar diastereoisomer: 62 mg and high polar diastereoisomer: 36 mg) of 1-[7-(2-bromo-4-trifluoromethylphenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl]piperidine-3-carbonitrile.