Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31](=[O:34])[CH2:32][CH3:33])[CH2:27][CH2:26]2)=[C:21]([C:35]([F:38])([F:37])[F:36])[CH:20]=1.[OH-].[Na+]>O1CCOCC1.CCOC(C)=O>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:2]2[NH:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31](=[O:34])[CH2:32][CH3:33])[CH2:27][CH2:26]2)=[C:21]([C:35]([F:38])([F:37])[F:36])[CH:20]=1
Reactant: CCOC(=O)c1cnc2ccc(Cl)cc2c1Cl
Reactant: CCC(=O)N1CCN(c2ccc(N)cc2C(F)(F)F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2ccc(Cl)cc2c1Nc1ccc(N2CCN(C(=O)CC)CC2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 93.5 %

Procedure:
To a solution of 5.0 ethyl 4,6-dichloroquinoline-3-carboxylate (1.08 g, 4 mmol, 1 equiv.) in 1,4-dioxane (10 mL) at room temperature was added compound 5.1 1-(4-(4-amino-2-(trifluoromethyl)phenyl)piperazin-1-yl)propan-1-one (1.2 g, 4 mmol, 1 equiv.). The resulting solution was heated to 80° C. and stirred 4 h before cooling to room temperature. NaOH ON aqueous solution, 3 mL) was added. The solution was diluted with EtOAc (30 mL) and washed with water (30 mL×2) and brine (30 mL). The organic phase was dried over Na2SO4. After removal of solvents, the residue was purified via flash chromatography (CH2Cl2: MeOH=20:1) to afford the desired product 5.2 ethyl 6-chloro-4-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenylamino)quinoline-3-carboxylate (2 g; 93%). LC-MS: (M+H): 622.20
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[Br:13]Br>ClCCl>[Br:13][CH:3]1[C:2](=[O:1])[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4]1
Reactant: BrBr
Reactant: CCOC(=O)C1CCC(=O)CC1
Solvent: ClCCl
Product: CCOC(=O)C1CCC(=O)C(Br)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 4-oxocyclohexanecarboxylate (3.0 g) in dichloromethane (20 mL) was treated with bromine (2.82 g) in dichloromethane (10 mL) dropwise at 0° C. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed, and the product was used without further purification.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:19]=[CH:18][C:8]([C:9]([N:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)=[O:10])=[CH:7][C:6]=1[O:20][CH3:21])([CH3:3])[CH3:2].[Si]([O:29][C:30](=[CH2:36])/[CH:31]=[CH:32]/N(C)C)(C(C)(C)C)(C)C.C(Cl)(=O)C>CC(O)CC>[CH:1]([O:4][C:5]1[CH:19]=[CH:18][C:8]([C:9]([N:11]2[CH2:16][CH2:15][C:14]3([O:17][CH:32]=[CH:31][C:30](=[O:29])[CH2:36]3)[CH2:13][CH2:12]2)=[O:10])=[CH:7][C:6]=1[O:20][CH3:21])([CH3:3])[CH3:2]
Reactant: C=C(/C=C/N(C)C)O[Si](C)(C)C(C)(C)C
Reactant: COc1cc(C(=O)N2CCC(=O)CC2)ccc1OC(C)C
Solvent: CC(=O)Cl
Solvent: CCC(C)O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)C=CO3)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 591.2 %

Procedure:
A suspension of 1-(4-isopropoxy-3-methoxy-benzoyl)piperidin-4-one (12.8 g, 44.0 mmol) in 2-butanol (100 mL) was purged with argon gas for 5 minutes. (1E)-3-[tert-butyl(dimethyl)silyl]oxy-N,N-dimethyl-buta-1,3-dien-1-amine (10.0 g, 4.0 mmol) was added dropwise at room temperature under argon gas. The reaction mixture was stirred at room temperature overnight. The mixture turned to a dark brown clear solution. Solvent was removed. The residue was redissolved in THF (200 mL) and cooled to −78° C. Acetyl chloride (3.75 mL, 52.8 mmol) was added dropwise. The mixture was stirred at −78° C. for 30 min. The reaction was quenched with saturated sodium bicarbonate (25 mL). The organic layer was separated. The aqueous layer was extracted with diethyl ether (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by column chromatography (40-60% ethyl acetate-Hex) to provide 3-(4-isopropoxy-3-methoxy-benzoyl)-11-oxa-3-azaspiro[5.5]undec-9-en-8-one (8.5 g) as a light yellow thick oil. 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J=6.1 Hz, 1H), 6.99 (d, J=1.9 Hz, 1H), 6.94 (dd, J=8.2, 1.9 Hz, 1H), 6.87 (d, J=8.3 Hz, 1H), 5.44 (d, J=6.1 Hz, 1H), 4.57 (dt, J=12.2, 6.1 Hz, 1H), 4.25-4.00 (m, 2H), 3.87 (s, 3H), 3.34 (s, 2H), 2.56 (s, 2H), 2.15 (d, J=14.1 Hz, 2H), 1.62 (s, 2H), 1.39 (t, J=5.3 Hz, 6H). ESI-MS m/z calc. 359.17, found 360.3 (M+1)+; Retention time: 1.18 minutes (3 minute run).
Reaction SMILES: [Cl:1][C:2]1[C:21](I)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.C(OC([N:30]1[C:34]([C:35](=[O:39])[N:36]([CH3:38])[CH3:37])=[CH:33][CH:32]=[C:31]1B(O)O)=O)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[Cl:1][C:2]1[C:21]([C:31]2[NH:30][C:34]([C:35](=[O:39])[N:36]([CH3:38])[CH3:37])=[CH:33][CH:32]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1
Reactant: CN(C)C(=O)c1ccc(B(O)O)n1C(=O)OC(C)(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN(C)C(=O)c1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cnc2Cl)[nH]1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
6-Chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-iodonicotinamide (Stage 48.3, 257 mg, 0.560 mmol), (1-(tert-butoxycarbonyl)-5-(dimethylcarbamoyl)-1H-pyrrol-2-yl)boronic acid (Stage 73.2, 200 mg, 0.709 mmol), Pd(Ph3P)4 (64.7 mg, 0.056 mmol), Na2CO3 (237 mg, 2.240 mmol), water (560 μL) and DME (2.240 mL) were added to a MW vial, which was sealed, evacuated/purged with argon and stirred at 80° C. for 16 h. The RM was diluted with MeOH (1 mL)/DCM (2 mL), treated with Si-Thiol (194 mg, 0.280 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® Silica gel column, 12 g, cyclohexane-DCM (4:1)/EtOAc, from 5% to 50% EtOAc) to yield the title product as a white solid. UPLC-MS (Condition 3) tR=1.16 min, m/z=469.1 [M+H]+, m/z=513.0 [M+FA+H]−; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.98-3.28 (m, 6H) 6.69-6.75 (m, 1H) 6.76-6.81 (m, 1H) 7.40 (d, J=9.17 Hz, 2H) 7.85-7.93 (m, 2H) 8.62 (d, J=2.32 Hz, 1H) 8.81 (d, J=2.32 Hz, 1H) 10.65 (s, 1H) 11.89 (br. s, 1H).
Reaction SMILES: O[CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:43]I>C(OCC)(=O)C.C(Cl)Cl.CCCCCC.C(Cl)Cl.C1C=CC=CC=1>[I:43][CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]1
Reactant: II
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CI)OC(C)(C)O1
Yield: 99.2 %

Procedure:
To a solution of 1.0 g (3.84 mmol) of tert-butyl [(4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxane-4-yl]acetate, 2.01 g (7.68 mmol) of triphenylphosphine, 0.523 g (7.68 mmol) of imidazole and 11.5 ml of anhydrous benzene was added 1.46 g (5.8 mmol) of iodine with stirring and cooling with ice, and then reacted for 2.5 hours at room temperature. The deposited crystal was filtered, and the obtained crystal was washed with ether. The filtrate and the washings were combined and distilled away under reduced pressure. The residue was purified by subjecting to silica gel column chromatography [eluent: hexane-methylene chloride (1:1), successively ethyl acetate-methylene chloride (1:9)]to give 1.41 g of tert-butyl [(4R,6S)-6-(iodomethyl)-2,2-dimethyl-1,3-dioxane-4-yl]acetate as syrups (yield: 99%).
Reaction SMILES: FC1C=CC(C2C=NC(N3CCN(S(C[C@H](C(C)C)C(O)=O)(=O)=[O:21])CC3)=NC=2)=CC=1.C([C@@H]1COC(=O)N1[C:44](=[O:72])[C@H:45]([CH2:49][S:50]([N:53]1[CH2:58][CH2:57][CH:56]([C:59]2[N:64]=[CH:63][C:62]([C:65]3[CH:70]=[CH:69][C:68]([Cl:71])=[CH:67][CH:66]=3)=[CH:61][N:60]=2)[CH2:55][CH2:54]1)(=[O:52])=[O:51])[CH:46]([CH3:48])[CH3:47])C1C=CC=CC=1>>[Cl:71][C:68]1[CH:67]=[CH:66][C:65]([C:62]2[CH:61]=[N:60][C:59]([CH:56]3[CH2:57][CH2:58][N:53]([S:50]([CH2:49][C@H:45]([CH:46]([CH3:48])[CH3:47])[C:44]([OH:21])=[O:72])(=[O:51])=[O:52])[CH2:54][CH2:55]3)=[N:64][CH:63]=2)=[CH:70][CH:69]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)O
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCC(c2ncc(-c3ccc(Cl)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Product: CC(C)[C@@H](CS(=O)(=O)N1CCC(c2ncc(-c3ccc(Cl)cc3)cn2)CC1)C(=O)O
Yield: 90 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-3-methylbutyric acid, from 4-(R)-benzyl-3-(2-(R)-{4-[5-(4-chlorophenyl)pyrimidin-2-yl]piperidine-1-sulfonylmethyl}-3-methylbutyryl)oxazolidin-2-one (0.275 g), to give the title compound as a white solid (0.184 g, 90%).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([C:18]([O:20]CC)=[O:19])=[C:9]2[C:15]=1[O:14][CH2:13][C:12]([F:17])([F:16])[CH2:11][O:10]2)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[F:17][C:12]1([F:16])[CH2:11][O:10][C:9]2=[C:8]([C:18]([OH:20])=[O:19])[S:7][C:6]([C:4]([OH:5])=[O:3])=[C:15]2[O:14][CH2:13]1
Reactant: CCOC(=O)c1sc(C(=O)OCC)c2c1OCC(F)(F)CO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1sc(C(=O)O)c2c1OCC(F)(F)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 71571.5 %

Procedure:
953 mg (3.67 mmol) of 3,3-Difluoro-3,4-dihydro-2H-thieno[3,4-b][1,4]-dioxepine-6,8-dicarboxylic acid diethyl ester in 75 mL of ethanol was mixed with 1.10 g (27.5 mmol) of sodium hydroxide granules and stirred for 2 hours under nitrogen at room temperature. After acidifying the resulting mixture with 2N hydrochloric acid, the ethanol was largely evaporated off using a rotary evaporator, the solids filtered off, the filtrate washed three times with water and then dried in air. 736 g of 3,3-difluoro-3,4-dihydro-2H-thieno[3,4-b][1,4]-dioxepine-6,8-dicarboxylic acid was obtained corresponding to a yield of 92% yield with a melting point of 288–293° C., as characterized by:
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.Cl>C1COCC1>[C:1]1([N:7]2[C:11]([B:17]([OH:22])[OH:18])=[CH:10][CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-n2cccn2)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccnn1-c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
To a solution of 1-phenyl-1H-pyrazole (12.8 g, 88.9 mmol) in THF (355 mL) was dropwise added n-BuLi (1.63 M solution in hexane, 57.2 mL, 93.3 mmol) at −78° C. under N2. The mixture was stirred at −78° C. for 1 h. To the mixture was added B(Oi-Pr)3 (82.0 mL, 355 mmol) at −78° C. The mixture was stirred at −78° C. for 1 h, gradually warmed to room temperature and stirred at room temperature overnight. The pH of the mixture was adjusted to 5 with 1 M HCl aqueous solution. The mixture was concentrated in vacuo, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, concentrated in vacuo and crystallized with MeOH/EtOAc/hexane to yield the title compound (12.6 g, 76% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 6.73 (1H, brs), 7.28-7.39 (1H, m), 7.39-7.54 (4H, m), 7.66 (1H, s).
Reaction SMILES: [CH:1]1([CH2:5][N:6]2[C:15](=[O:16])[C:14]3[NH:13][CH:12]=[N:11][C:10]=3[N:9]([CH2:17][CH:18]3[CH2:21][CH2:20][CH2:19]3)[C:7]2=[O:8])[CH2:4][CH2:3][CH2:2]1.Cl[CH2:23][CH2:24][CH3:25]>>[CH:1]1([CH2:5][N:6]2[C:15](=[O:16])[C:14]3[N:13]([CH2:23][CH2:24][CH3:25])[CH:12]=[N:11][C:10]=3[N:9]([CH2:17][CH:18]3[CH2:21][CH2:20][CH2:19]3)[C:7]2=[O:8])[CH2:4][CH2:3][CH2:2]1
Reactant: O=c1c2[nH]cnc2n(CC2CCC2)c(=O)n1CC1CCC1
Reactant: CCCCl
Product: CCCn1cnc2c1c(=O)n(CC1CCC1)c(=O)n2CC1CCC1

Procedure:
1,3-Di-cyclobutylmethyl-7-n-propyl xanthine was prepared from 1,3-di-cyclobutylmethyl xanthine and 1-chloropropane using an analogous procedure to that described in Example 5. The title compound was isolated as a crystalline solid, m.p. 91° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][N:11]3[C:15]4=[N:16][C:17]([CH3:21])=[CH:18][C:19]([CH3:20])=[C:14]4[N:13]=[C:12]3[CH2:22][CH3:23])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[C:26]1(=[O:36])[O:31][C:29](=[O:30])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12>CN(C=O)C>[C:29]([C:28]1[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=1[C:26]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][N:11]3[C:15]4=[N:16][C:17]([CH3:21])=[CH:18][C:19]([CH3:20])=[C:14]4[N:13]=[C:12]3[CH2:22][CH3:23])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)=[O:36])([OH:31])=[O:30]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2[nH]ccc2c1
Reactant: O=C1OC(=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(ccn2C(=O)c2ccccc2C(=O)O)c1
Reaction time: 16 h
Yield: 46.9 %

Procedure:
To a solution of the product of Step A (75 mg, 0.25 mmol) in 3 mL of DMF was added 11 mg (0.27 mmol, 1.1 eq) of 60% NaH, followed by 45 mg (0.30 mmol, 1.2 eq) of phthalic anhydride. This mixture was stirred for 16 hours and the DMF removed in vacuo. The resultant oil was flash column chromatographed with 15% of (10/1) mixture of methanol/NH4OH in CHCl3 to yield the titled compound (53 mg, 47%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[Cs+].[Cs+].[O:18]1[CH2:21][CH:20](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:19]1>CN(C=O)C>[N+:9]([C:3]1[CH:4]=[C:5]([O:8][CH:20]2[CH2:21][O:18][CH2:19]2)[CH:6]=[CH:7][C:2]=1[NH2:1])([O-:11])=[O:10]
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)OC2COC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1ccc(OC2COC2)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a stirred solution of 4-amino-3-nitrophenol (1.37 g, 8.91 mmol) in DMF (15 mL) at rt was added cesium carbonate (5.79 g, 17.82 mmol) and the mixture was stirred for 30 min. Oxetan-3-yl-4-methylbenzenesulfonate (3.05 g, 13.36 mmol) was added and the mixture was heated at 80° C. for 6 h. The mixture was cooled to rt and partitioned between EtOAc and water. The organic layer was separated, and the aqueous layer was extracted with additional EtOAc. The combined organic layers were washed with brine. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The solid residue was purified by trituration with diethyl ether to afford 2-nitro-4-(oxetan-3-yloxy)aniline (1.33 g, 71%) as a brown solid. 1H NMR (500 MHz, DMSO-d6) δ 7.29 (br s, 2H), 7.15 (dd, J=9.2, 3.0 Hz, 1H), 7.10 (d, J=3.0 Hz, 1H), 7.02 (d, J=9.2 Hz, 1H), 5.24 (pentet, J=4.9 Hz, 1H), 4.87-4.93 (m, 2H), 4.51-4.53 (m, 2H); LCMS (ESI) m/z 211 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](O)([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[CH:4][CH2:3]1.O=S(Cl)Cl.[NH:33]1[CH2:38][CH2:37][S:36][CH2:35][CH2:34]1.CCOC(C)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:16])([N:33]3[CH2:38][CH2:37][S:36][CH2:35][CH2:34]3)[CH3:15])[CH:11]=[CH:10][C:9]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[CH:4][CH2:3]1
Reactant: C1CSCCN1
Reactant: CC1(C)CC=C(c2cc(C(C)(C)O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: CC1(C)CC=C(c2cc(C(C)(C)N3CCSCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a suspension of 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-amide (as prepared in the previous step, 65 mg, 0.17 mmol) in 1.5 mL of DCM at 0° C. was added SOCl2 (38 μL, 0.52 mmol) under Ar. After stirring at RT for 1 h, the mixture was cooled back to 0° C. To the reaction was added thiomorpholine (172 μL, 1.72 mmol) and the resulting mixture was stirred at 0° C. for 1 h. After warming to RT, the mixture was treated with EtOAc (30 mL) and washed with H2O (2×10 mL) and brine (10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (5% EtOAc/DCM then 1-2% MeOH/DCM) to afford the title compound (70 mg, 88%) as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 11.90 (s, 1H), 9.65 (s, 1H), 8.28 (d, 1H, J=8.6 Hz), 7.74 (s, 1H), 7.45 (dd, 1H, J=8.6, 2.3 Hz), 7.33 (d, 1H, J=2.3 Hz), 5.78 (m, 1H), 2.77 (m, 4H), 2.65 (m, 4H), 2.29 (m, 2H), 2.12 (m, 2H), 1.60 (t, 2H, J=6.3 Hz), 1.33 (s, 6H), 1.12 (s, 6H). Mass spectrum (ESI-neg, m/z): Calcd. for C26H33N5OS, 462.2 (M−H). found 462.4.
Reaction SMILES: [N:1]([O-])=O.[Na+].[Cl:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][C:7]=1[O:13][CH3:14].[Sn](Cl)(Cl)(Cl)Cl>O.Cl>[Cl:5][C:6]1[CH:12]=[CH:11][C:9]([NH:10][NH2:1])=[CH:8][C:7]=1[O:13][CH3:14]
Reactant: COc1cc(N)ccc1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Product: COc1cc(NN)ccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Concentrated hydrochloric acid (12 mL) and a solution of sodium nitrite (1.7 g, 24.4 mmol) in water (8 mL) were added to a solution of 4-chloro-3-methoxy aniline (3.86 g, 24.4 mmol) in water (8 mL), at −10° C. The mixture was stirred for 30 minutes and was then added to solution of tin chloride (14.89 g, 66 mmol) in concentrated hydrochloric acid (24 mL) and water (24 mL), cooled to 0° C. The reaction mixture was stirred for 18 hours, allowing the temperature to rise to 25° C. The resulting precipitate was filtered off and the solid was re-crystallised from heptanes/ethyl acetate (33:66) to afford the title compound the title compound as white solid in 72% yield, 3 g
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.[Si:8]([O:15][CH2:16][C@@H:17]([N:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][N:35]=[C:34](S(C)(=O)=O)[N:33]=2)=[CH:28][C:27]1=[O:42])[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[Si](OC[C@@H](N1C=CC(C2C=CN=C(S(C)(=O)=O)N=2)=CC1=O)C1C=CC(Cl)=C(F)C=1)(C(C)(C)C)(C)C>>[Si:8]([O:15][CH2:16][C@@H:17]([N:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([NH:7][C@H:4]3[CH2:3][CH2:2][C@H:6]([OH:1])[CH2:5]3)[N:33]=2)=[CH:28][C:27]1=[O:42])[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)([C:11]([CH3:14])([CH3:12])[CH3:13])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(Cl)c1)n1ccc(-c2ccnc(S(C)(=O)=O)n2)cc1=O
Reactant: NC1CCOCC1
Agent: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(F)c1)n1ccc(-c2ccnc(S(C)(=O)=O)n2)cc1=O
Product: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(Cl)c1)n1ccc(-c2ccnc(N[C@H]3CC[C@H](O)C3)n2)cc1=O

Procedure:
1-((S)-2-(tert-Butyldimethylsilyloxy)-1-(3,4-dichlorophenyl)ethyl)-4-(2-((1S,3S)-3-hydroxycyclopentylamino)pyrimidin-4-yl)pyridin-2(1H)-one was prepared according to the general procedure of Example 2, Step A, substituting (1S,3S)-3-aminocyclopentanol for tetrahydro-2H-pyran-4-amine and (S)-1-(2-(tert-butyldimethylsilyloxy)-1-(3,4-dichlorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one for (S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one. m/z (APCI-pos) M+1=575.2, 577.1.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH:9]1)=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:11]2([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:35])([CH3:33])[CH3:34])[NH:9][CH:8]([C:6]([OH:7])=[O:5])[CH:12]2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])=[C:24]([F:30])[CH:25]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(F)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(F)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 100 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-3-(2,3-difluoro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 62b (1.8 g, 3.6 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-3-(2,3-difluoro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2 g, 100%).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:7][Si:8]([Si:11]([Si:19]([CH3:22])([CH3:21])[CH3:20])([Si:15]([CH3:18])([CH3:17])[CH3:16])[CH2:12][CH2:13][OH:14])([CH3:10])[CH3:9].N1C=CC=CC=1>O1CCCC1.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[C:1]([O:14][CH2:13][CH2:12][Si:11]([Si:19]([CH3:22])([CH3:21])[CH3:20])([Si:15]([CH3:18])([CH3:17])[CH3:16])[Si:8]([CH3:7])([CH3:9])[CH3:10])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)Cl
Reactant: C[Si](C)(C)[Si](CCO)([Si](C)(C)C)[Si](C)(C)C
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCC[Si]([Si](C)(C)C)([Si](C)(C)C)[Si](C)(C)C
Temperature: 25 °C
Yield: 63 %

Procedure:
Methacryloyl chloride (2.50 grams, 0.024 mole) in 25 ml tetrahydro-furan was added dropwise into a solution of 2-tris(trimethylsilyl) silyl ethanol (6.5 grams, 0.022 mole), pyridine (2.0 grams, 0.025 mole) and 25 mg of phenothiazine in 50 ml tetrahydrofuran at room temperature. Stirred at room temperature for two more hours. The solids were filtered off and the solution was washed with 100 ml brine. The solution was then diluted with 100 ml ether and washed with 5% hydrochloric acid, followed by deionzed water, and then with brine. It was dried over anhydrous magnesium sulfate and was concentrated in vacuo. Fractional distillation under reduced pressed gave 5 grams of the product at 105-115° C. at 0.5 mm.
Reaction SMILES: [Cl:1][C:2]1[C:10](OS(C(F)(F)F)(=O)=O)=[CH:9][C:8]([C:19]2[N:20]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:23][CH:22]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:42].B1(C=C)OB([CH:49]=[CH2:50])OB(C=C)O1.C1C=CN=CC=1.C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC>[Cl:1][C:2]1[C:10]([CH:49]=[CH2:50])=[CH:9][C:8]([C:19]2[N:20]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:23][CH:22]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:42]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(OS(=O)(=O)C(F)(F)F)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: C=CB1OB(C=C)OB(C=C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: c1ccncc1
Solvent: O
Product: C=Cc1cc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c(c1Cl)CNC2=O
Yield: 59.8 %

Procedure:
In a similar manner to Step 1 of Example 152, 4-chloro-5-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (70.0 mg, 0.111 mmol) was dissolved in dimethoxyethane (3.5 mL), and the solution was treated with 2,4,6-trivinylcyclotriboroxane-pyridine complex (53.6 mg, 0.222 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium (7.3 mg, 0.0090 mmol), potassium carbonate (76.7 mg, 0.355 mmol) and water (0.060 mL), followed by purification by preparative thin-layer chromatography (chloroform/methanol=9/1) to obtain 4-chloro-5-vinyl-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (33.6 mg, yield 60%).