Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH3:16][S:17][CH2:18][C:19]#[N:20].C(OCl)(C)(C)C.C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:4](=[O:5])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:12][CH:13]=[CH:14][C:15]=1[CH:18]([S:17][CH3:16])[C:19]#[N:20]
Reactant: CSCC#N
Reactant: Nc1ccccc1C(=O)c1ccccc1
Agent: CC(C)(C)OCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSC(C#N)c1cccc(C(=O)c2ccccc2)c1N
Temperature: -69 °C
Reaction time: 1 h
Yield: 106.7 %

Procedure:
To a slurry of 29.6 g (0.15 mole) of 2-aminobenzophenone and 13.1 g (0.15 mole) of (methylthio)acetonitrile in 400 ml of methylene dichloride at a temperature of -68° C. was added dropwise 16.8 g (0.155 mole) of t-butyloxychloride at a rate to ensure that the reaction temperature did not exceed -64° C. The resulting solution was stirred at -69° C. for one hour, treated with 15.7 g (0.155 mole) of triethylamine and allowed to warm to ambient temperature. The solution obtained was washed twice with water, dried over sodium sulphate, and concentrated to give 45.2 g of a dark oil as the residue. This residue was chromatographed on 1 kg of silica gel to yield 22.5 g (53%) of the title compound as tan crystals, m.p. 107°-108° C.
Reaction SMILES: [C:1]([CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=O)([O:3]CC)=O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[C:17]([F:23])[CH:16]=1.C1(C)C=CC=CC=1.C(O)(=O)C>O>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:1](=[O:3])[C:6]3[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]=3[NH:22]2)=[C:17]([F:23])[CH:16]=1
Reactant: CCOC(=O)C1CCCCCC1=O
Reactant: NNc1ccc(Cl)cc1F
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=c1c2c([nH]n1-c1ccc(Cl)cc1F)CCCCC2

Procedure:
A mixture of 9.3 parts of 2-carbethoxycycloheptanone [prepared by the method of G. Stork, et al., J. Am. Chem. Soc., 85, 207 (1963)], 8.1 parts of 4-chloro-2-fluorophenyl hydrazine, 100 parts of toluene and 0.5 parts of acetic acid was refluxed for 4 hours until all water was evolved. The resulting solution was cooled to -50° and filtered to yield 12 parts of 2-(4-chloro-2-fluorophenyl)-1,4,5,6,7,8-hexahydrocycloheptapyrazol-3(2H)-one melting at 197°-201°. Four parts of the pyrazolone was mixed with 4.4 parts of phosphorous oxybromide and 2.2 parts of N,N-diethylaniline in 200 parts of xylene and the mixture refluxed for 3 hours. 0.5 Part of N,N-dimethyl formamide was added and the mixture refluxed for 1 hour. The mixture was poured over 100 parts of ice and the phases separated. The organic phase was evaporated under reduced pressure of 50 mm. Hg at 70° to a crude product. The product was dissolved in 100 parts of chloroform, washed with 100 parts of 10% aqueous sodium carbonate, dried with anhydrous magnesium sulfate and evaporated to an oil under reduced pressure of 500 mm. Hg at 40°. Purification by chromatography on alumina using 3% ether in hexane as the eluent gave 0.8 parts of 3-bromo-2-(4-chloro-2-fluorophenyl)-2,4,5,6,7,8-hexahydrocycloheptapyrazole melting at 59°-60°.
Reaction SMILES: [CH2:1]([N:4]([C@@H:28]([CH3:33])[C:29]([F:32])([F:31])[F:30])[S:5]([C:8]1[CH:9]=[N:10][C:11]([C:14]2[NH:15][C:16]3[C:21]([C:22]=2[C:23]#[N:24])=[CH:20][CH:19]=[C:18]([CH:25]2[CH2:27][CH2:26]2)[CH:17]=3)=[CH:12][CH:13]=1)(=[O:7])=[O:6])[CH:2]=[CH2:3].Br[C:35]1[N:40]=[CH:39][CH:38]=[CH:37][N:36]=1.CN[C@@H]1CCCC[C@H]1NC.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[CH2:1]([N:4]([C@@H:28]([CH3:33])[C:29]([F:31])([F:30])[F:32])[S:5]([C:8]1[CH:9]=[N:10][C:11]([C:14]2[N:15]([C:35]3[N:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[C:16]3[C:21]([C:22]=2[C:23]#[N:24])=[CH:20][CH:19]=[C:18]([CH:25]2[CH2:26][CH2:27]2)[CH:17]=3)=[CH:12][CH:13]=1)(=[O:6])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCN([C@@H](C)C(F)(F)F)S(=O)(=O)c1ccc(-c2[nH]c3cc(C4CC4)ccc3c2C#N)nc1
Reactant: Brc1ncccn1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: C=CCN([C@@H](C)C(F)(F)F)S(=O)(=O)c1ccc(-c2c(C#N)c3ccc(C4CC4)cc3n2-c2ncccn2)nc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 84.5 %

Procedure:
A mixture of (S)-N-allyl-6-(3-cyano-6-cyclopropyl-1H-indol-2-yl)-N-(1,1,1-trifluoropropan-2-yl)pyridine-3-sulfonamide (140 mg, 0.30 mmol), 2-bromo-pyrimidine (98 mg, 0.59 mmol), copper (I) iodide (11 mg, 0.06 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (0.02 mL, 0.12 mmol), and K3PO4 (134 mg, 0.60 mmol) in toluene was stirred at 100° C. for 16 hrs. The mixture was then filtered through celite and the solvent evaporated. The residue was purified on silica gel eluting with 0 to 10% ethyl acetate in CH2Cl2 to provide (S)-N-allyl-6-(3-cyano-6-cyclopropyl-1-(pyrimidin-2-yl)-1H-indol-2-yl)-N-(1,1,1-trifluoropropan-2-yl)pyridine-3-sulfonamide (140 mg, 86%). MS m/z 553.3 M+H+; 1H NMR (500 MHz, CDCl3): δ 8.65 (1H, d, J=3.0 Hz), 8.62 (2H, d, J=4.0 Hz), 8.14 (1H, dd, J=4.0, 8.0 Hz), 8.01 (1H, d, J=9.0 Hz), 7.75 (1H, s), 7.64 (1H, d, J=7.5 Hz), 7.21-7.19 (1H, m), 7.04 (1H, d, J=9.0 Hz), 5.60 (1H, m), 5.28-5.25 (2H, m), 4.50 (1H, m), 3.86 (1H, d, J=6.5 Hz), 2.02-1.96 (1H, m), 1.32 (3H, d, J=8.5 Hz), 0.98-0.96 (2H, m), 0.75-0.72 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:29][CH2:30][CH3:31])=[C:17]([NH:20][C:21](=[O:28])[CH:22]=[CH:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:32]#[N:33])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:34][C@@H:35]([CH2:39][CH2:40][C:41]([NH:43][C@H:44]([C:47]([NH:49][CH2:50][C:51]([OH:53])=[O:52])=[O:48])[CH2:45][SH:46])=[O:42])[C:36]([OH:38])=[O:37].C(N(CC)CC)C.CO>O1CCCC1.O>[NH2:34][C@H:35]([CH2:39][CH2:40][C:41]([NH:43][CH:44]([CH2:45][S:46][CH:23]([CH2:24][N:25]([CH3:27])[CH3:26])[CH2:22][C:21]([NH:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[O:29][CH2:30][CH3:31])[N:13]=[CH:12][C:11]([C:32]#[N:33])=[C:10]2[NH:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)=[O:28])[C:47]([NH:49][CH2:50][C:51]([OH:53])=[O:52])=[O:48])=[O:42])[C:36]([OH:38])=[O:37]
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Reactant: CCOc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)CC(CN(C)C)SCC(NC(=O)CC[C@@H](N)C(=O)O)C(=O)NCC(=O)O
Reaction time: 7 h
Yield: 97.6 %

Procedure:
A mixture of 0.50 g (1.07 mmol) of 4-dimethylamino-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-ethoxy-quinolin-6-yl]-amide, 0.328 g (1.07 mmol) of glutathione, and 0.2 mL of triethylamine in a solvent mixture consisting of 10 mL of methanol, 4 mL of water, and 4 mL of tetrahydrofuran was stirred for 7 h and then stored overnight in the refrigerator. The solvents were remove at reduced pressure at 30° C. Ethanol was added and removed three times giving 0.81 g of the title compound as a tan powder. A sample of this was purified by HPLC. The product was then isolated as the trifluoroacetate salt. Analysis for C34H40N8O8CIFS+(C2HF3O2)3; calcd: C, 43.00, H, 3.88, N, 10.03, Cl, 3.17; found: C, 42.23, H, 4.17, N, 10.03, Cl, 3.23.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]([CH3:29])[CH:21]=3)[CH:17]=[CH:16][N:15]=2)[C:10]([O:30][CH3:31])=[CH:9][C:8]=1[N:32]([CH3:44])[CH2:33][CH2:34][N:35]([CH3:43])[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39].CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[CH3:31][O:30][C:10]1[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]([CH3:29])[CH:21]=3)[CH:17]=[CH:16][N:15]=2)=[CH:12][C:7]([NH:6][C:1](=[O:4])[CH:2]=[CH2:3])=[C:8]([N:32]([CH3:44])[CH2:33][CH2:34][N:35]([CH3:43])[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:39])[CH3:40])[CH:9]=1
Reactant: COc1cc(N(C)CCN(C)C(=O)OC(C)(C)C)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cn(C)c4ccccc34)n2)c(OC)cc1N(C)CCN(C)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
Acryloyl chloride (0.069 mL, 0.85 mmol) in CH2Cl2 (2.5 mL) was added dropwise over 5 minutes to a solution of tert-butyl N-[2-[[2-amino-5-methoxy-4-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]-methylamino]ethyl]-N-methylcarbamate (Intermediate 171, 377 mg, 0.71 mmol) and DIPEA (0.234 mL, 1.42 mmol) in CH2Cl2 (8 mL) cooled in an ice/methanol bath. The mixture was stirred for 0.5 h. The mixture was then diluted with 10% CH3OH in CH2Cl2. The resulting solution was washed with sat. NaHCO3, dried (MgSO4) and then concentrated in vacuo. Purification by FCC, eluting with 0-3% CH3OH in CH2Cl2 gave the title compound (325 mg, 78%) as a yellow foam; 1H NMR: 1.38 (9H, s), 2.71 (3H, s), 2.77 (3H, s), 3.00 (2H, t), 3.34 (2H, t), 3.88 (3H, s), 3.91 (3H, s), 5.73-5.78 (1H, m), 6.27 (1H, dd), 6.67 (1H, dd), 6.99 (1H, s), 7.17 (1H, t), 7.21-7.27 (2H, m), 7.53 (1H, d), 7.87 (1H, s), 8.26 (1H, d), 8.33 (1H, d), 8.62 (1H, s), 8.99 (1H, s), 9.10 (1H, s); m/z: ES+ MH+ 584.73.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:17]([N:24]1[CH2:32][C:31]2([C:33]([O:35][CH3:36])=[O:34])[CH:26]([C:27](I)=[CH:28][CH2:29][CH:30]2[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[O:43][CH3:44])[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO.C1(C)C=CC=CC=1.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>[CH2:17]([N:24]1[CH2:32][C:31]2([C:33]([O:35][CH3:36])=[O:34])[CH:26]([C:27]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)=[CH:28][CH2:29][CH:30]2[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[O:43][CH3:44])[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(I)=CCC2c1ccccc1OC
Reactant: Cc1ccc(B(O)O)cc1
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: Cc1ccccc1
Solvent: CO
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(c1ccc(C)cc1)=CCC2c1ccccc1OC
Yield: 95 %

Procedure:
A solution of 0.41 g (2.99 mmol) of 4-methylphenylboronic acid in 13 cm3 of methanol and 30 cm3 of a 2N aqueous sodium carbonate solution were successively added to a solution of 1.37 g (2.7 mmol) of methyl (3aRS,4SR,7aRS)-2-benzyl-7-iodo-4-(2-methoxyphenyl)-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate and of 0.15 g (0.13 mmol) of tetrakis(triphenylphosphine)palladium in 30 cm3 of toluene and then the mixture was brought to reflux for two hours. After returning to a temperature in the region of 20° C., the reaction mixture was extracted with 100 cm3 of ethyl acetate, washed with two times 50 cm3 of distilled water, dried over magnesium sulphate and then concentrated under reduced pressure. The brown residue obtained was purified by flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (95/05 by volume) mixture. 1.2 g (93%) of methyl (3aRS,4SR,7aRS)-2-benzyl-4-(2-methoxyphenyl)-7-(4-methylphenyl)-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate were thus obtained in the form of a yellow oil, the characteristics of which were as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:13]([CH2:14][NH:15][C:16]3[N:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=3)[CH2:12][N:11]([C:26]([C:28]3[CH:33]=[C:32]([CH3:34])[N:31]=[N:30][CH:29]=3)=[O:27])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].[CH3:37]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:13]([CH2:14][N:15]([CH3:37])[C:16]3[N:17]=[CH:18][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:20][N:21]=3)[CH2:12][N:11]([C:26]([C:28]3[CH:33]=[C:32]([CH3:34])[N:31]=[N:30][CH:29]=3)=[O:27])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1cc(C(=O)N2C[C@H](CNc3ncc(C(F)(F)F)cn3)[C@@H](c3ccc(Cl)c(Cl)c3)C2)cnn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2C[C@H](CN(C)c3ncc(C(F)(F)F)cn3)[C@@H](c3ccc(Cl)c(Cl)c3)C2)cnn1
Yield: 57.1 %

Procedure:
{(3S,4S)-3-(3,4-Dichloro-phenyl)-4-[(5-trifluoromethyl-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl)-(6-methyl-pyridazin-4-yl)-methanone (50.0 mg, 0.1 mmol) were dissolved in DMF (1 mL) and treated with NaH (55% dispersion in oil) (5 mg, 0.11 mmol) at ambient temperature. After 5 min methyl iodide (7.3 μL, 0.12 mmol) were added and the reaction mixture was stirred over night. After quenching with water and extraction with ethyl acetate (3×10 mL) the combined organic phases were dried on sodium sulfate and filtered. After evaporation of the solvent the crude product was subjected to column chromatography (silica gel, dichloro methane, dichloro methane/methanol 4:1) to yield the title product (30 mg, 58%) as a brown foam. ES-MS m/e: 525.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:24](=[O:36])[NH:25][CH2:26][C:27]2[C:28](=[O:35])[NH:29][C:30]([CH3:34])=[CH:31][C:32]=2[CH3:33])[C:5]([CH3:23])=[C:6]([N:8]([CH3:22])[CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([N:8]([CH3:22])[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:5]([CH3:23])=[C:4]([CH:3]=1)[C:24]([NH:25][CH2:26][C:27]1[C:28](=[O:35])[NH:29][C:30]([CH3:34])=[CH:31][C:32]=1[CH3:33])=[O:36]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)c2C)c(=O)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCNCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
A stirred solution of tert-butyl 4-((5-bromo-3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methylphenyl)(methyl)amino)piperidin-1-carboxylate (1.3 g, 2.39 mmol) in DCM (10 mL) was cooled to 0° C. and TFA (2 mL) was added to it. Reaction mass was stirred at room temperature for 1 h. On completion, reaction was concentrated to dryness. Residue was basified with aqueous sodium bicarbonate till pH 8 and aqueous layer extracted with 20% MeOH/DCM. Combined organic layers were dried over sodium sulfate and concentrated to afford the desired compound (0.9 g, 85%). LCMS: 461.15 (M+1)+; HPLC: 98.52% (@ 254 nm) (Rt; 4.673; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 8.22 (t, 1H), 7.19 (s, 1H), 7.01 (s, 1H), 5.85 (s, 1H), 4.23 (d, 2H, J=4 Hz), 2.91 (d, 2H, J=11.6 Hz), 2.78 (bs, 1H), 2.55 (s, 3H), 2.32-2.35 (m, 2H), 2.18 (s, 3H), 2.10 (s, 6H), 1.44-1.50 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH2:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[O:8][CH:7]([C:18]([F:21])([F:20])[F:19])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2.C1([C@H](N)C)C2C(=CC=CC=2)C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH2:12][CH2:13][C:14]([CH3:17])([CH3:15])[CH3:16])[O:8][C@@H:7]([C:18]([F:21])([F:19])[F:20])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2
Reactant: CC(C)(C)CCc1cc2c(cc1Cl)C=C(C(=O)O)C(C(F)(F)F)O2
Agent: C[C@@H](N)c1cccc2ccccc12
Product: CC(C)(C)CCc1cc2c(cc1Cl)C=C(C(=O)O)[C@H](C(F)(F)F)O2

Procedure:
A racemic mixture of the compound prepared in Example 9b, Step 3 was chirally resolved using the same protocol as for Example 609e, Step 1, R-enantiomer was identified as peak 1 with retention time 4.26 min: ESHRMS m/z 361.0797 (M−H, C17H17ClF3O3 Calc'd 361.0813). 1HNMR (DMSO-d6/400 MHz) 13.23 (brs, 1H), 7.80 (s, 1H), 7.55 (s, 1H), 7.01 (s, 1H), 5.89 (q, 1H, J=7.1 Hz), 3.30 (m, 2H), 2.56-2.60 (m, 2H), 1.31-1.37 (m, 2H), 0.91 (s, 9H). 19FNMR (d6-benzene; 6 eq of (R)-(+)-1-(1-naphthyl)ethylamine) d−77.80 (d, 3F, J=6.8 Hz, R-enantiomer), −77.77 (d, 3F, J=6.8 Hz, S-enantiomer).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[CH:19]=[C:18]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH:25]=2)=[O:21])[CH:17]=[C:16]([CH3:38])[C:12]=1[C:13]([OH:15])=O.Cl.[CH3:40][C:41]([CH3:54])([O:43][C:44]([NH:46][CH2:47][C@@H:48]([C:50]([O:52][CH3:53])=[O:51])[NH2:49])=[O:45])[CH3:42].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl.C(OCC)(=O)C>[Cl:10][C:11]1[CH:19]=[C:18]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][Si:31]([C:34]([CH3:36])([CH3:35])[CH3:37])([CH3:32])[CH3:33])[CH:25]=2)=[O:21])[CH:17]=[C:16]([CH3:38])[C:12]=1[C:13]([NH:49][C@H:48]([C:50]([O:52][CH3:53])=[O:51])[CH2:47][NH:46][C:44]([O:43][C:41]([CH3:54])([CH3:42])[CH3:40])=[O:45])=[O:15]
Reactant: Cc1cc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc(Cl)c1C(=O)O
Reactant: COC(=O)[C@@H](N)CNC(=O)OC(C)(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1c(C)cc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.4 %

Procedure:
Diisopropylethylamine (2.11 mL, 12.1 mmol) was added to a solution of 2-chloro-4-[[[[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]phenyl]methyl]amino]carbonyl]-6-methylbenzoic acid (Example 33; 1.32 g, 3.04 mmol) and 3-[[(1,1-dimethylethoxy)carbonyl]amino]-L-alanine, methyl ester, hydrochloride (1.54 g, 6.05 mmol) in dichloromethane (15 mL). Benzotriazol-1-yloxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent; 1.48 g, 3.35 mmol) was added and the mixture was stirred at room temperature for 4 h. The solution was diluted with ethyl acetate, washed with 1 M HCl, water, saturated aqueous sodium hydrogen carbonate, and water. The solution was then dried (MgSO4), filtered, evaporated, and chromatographed (40% ethyl acetate/petroleum ether) to give N-[2-chloro-4-[[[[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]phenyl]methyl]amino]carbonyl]-6-methylbenzoyl]-3-[[(1,1-dimethylethoxy) carbonyl]amino]-L-alanine, methyl ester (1.57 g, 81%) as a white foam
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[OH:11].[Cl-].[NH4+]>O1CCCC1.CO.[Zn]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([OH:11])=[C:2]([F:1])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-fluoro-4-nitrophenol (Avacado, 1.00 g, 6.37 mmol) in 4 mL of tetrahydrofuran and 6 mL of methanol at 0° C. was added zinc dust (2.08 g, 31.8 mmol, <10 micron) followed by ammonium chloride (1.70 g, 31.8 mmol). The mixture was stirred at room temperature overnight. The heterogeneous mixture was filtered through a thin pad of Celite® with methanol and the filtrate was concentrated in vacuo to give 4-amino-2-fluorophenol as a brown solid which was used without further purification (656 mg, 81%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:19]=1[CH2:20]Br>CN(C=O)C>[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:19]=1[CH2:20][O:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(O)cc1
Reactant: Fc1cccc(F)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCc1ccc(OCc2c(F)cccc2F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-Hydroxybenzyl cyanide (5 g, 37.5 mmol) and K2CO3 (6.74 g, 48.8 mmol) in dry DMF (20 ml) was added 2,6-Difluorobenzyl bromide (7.77 g, 37.5 mmol). The reaction mixture was stirred for 4 hours at room temperature and concentrated in vacuo. The crude residue was taken in EtOAc and washed with water and brine. The aqueous layer was washed one more time with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated to provide the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:3](=[C:6]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[CH2:4][OH:5])[CH3:2]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([C:3](=[C:6]([C:7]1[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=1)[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH:4]=[O:5])[CH3:2]
Reactant: CCC(CO)=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCC(C=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 18 h
Yield: 99.4 %

Procedure:
Activated manganese dioxide (49 g) was added to a solution of 2-ethyl-3,3-bis(4-fluorophenyl)-2-propenol (7 g, 25.5 mmol) in 100 mL of methylene chloride and the mixture stirred for 18 hours. The insolubles were removed and the solution concentrated in vacuo to give 6.9 g of the title compound as an oil. MS(CI): m/e =272 for M+ of C17H14F2O.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]([O:21]CC)=[O:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:24]1[NH:29][C:28](=[O:30])[C:27]2=[C:31]([CH3:39])[N:32]=[C:33]([CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[N:26]2[N:25]=1)[CH3:2].[OH-].[Na+].O>CO.O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:24]1[NH:29][C:28](=[O:30])[C:27]2=[C:31]([CH3:39])[N:32]=[C:33]([CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[N:26]2[N:25]=1)[CH3:2]
Reactant: CCOC(=O)C1CCN(S(=O)(=O)c2ccc(OCC)c(-c3nn4c(C5CCCC5)nc(C)c4c(=O)[nH]3)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOc1ccc(S(=O)(=O)N2CCC(C(=O)O)CC2)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
180 mg (0.323 mmol) of the ester from Example 8 and 50 mg (1.29 mmol) of sodium hydroxide are stirred at room temperature in 20 ml of methanol/water 3:1 for 30 minutes. 10 ml of water are added and the mixture is extracted once with dichloromethane. The aqueous phase is acidified using 2 n HCl and extracted twice with dichloromethane. The combined dichloromethane phases are dried over sodium sulphate and evaporated. The residue is recrystallized from diethyl ether.
Reaction SMILES: C([O:5][C:6]([NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[CH:17]=[N+:16]([CH3:19])[C:15]1[CH:20]=[C:21]([Cl:25])[C:22]([F:24])=[CH:23][C:14]2=1)=[O:7])(C)(C)C.[OH-].[Na+].[O-:28][Mn](=O)(=O)=O.[K+]>C(Cl)Cl.O>[Cl:25][C:21]1[C:22]([F:24])=[CH:23][C:14]2[C:13]3[C:18](=[C:9]([NH:8][C:6](=[O:7])[OH:5])[N:10]=[CH:11][CH:12]=3)[C:17](=[O:28])[N:16]([CH3:19])[C:15]=2[CH:20]=1
Reactant: C[n+]1cc2c(NC(=O)OC(C)(C)C)nccc2c2cc(F)c(Cl)cc21
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cn1c(=O)c2c(NC(=O)O)nccc2c2cc(F)c(Cl)cc21
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 90.1 %

Procedure:
To a stirred solution of 4-((tert-butoxycarbonyl)amino)-8-chloro-9-fluoro-6-methylbenzo[c][2,7]naphthyridin-6-ium (2.6 g, 2.310 mmol) in a mixture of DCM (10 mL) and water (50 mL) was added NaOH (0.370 g, 9.24 mmol) in three portions, followed by the addition of KMnO4 (1.461 g, 9.24 mmol) in five portions and the reaction was heated to 90° C. for 5 h. After cooling, the solvent was removed under reduced pressure. The residue was taken up in EtOAc (50 mL) and MeOH (50 mL) and stirred for 10 min. The reaction mixture was then passed through diatomaceous earth (Celite®), eluting with EtOAc. The filtrate was concentrated to yield (8-chloro-9-fluoro-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-4-yl)carbamic acid (2.35 g, 2.082 mmol, 90% crude yield) as a yellow solid which was taken to the next step without purification. LC/MS (ESI) m/e 322.1 [(M+H)+, calcd for C14H10ClFN3O3 322.0] LC/MS retention time (method E): tR=1.05 min.