Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH:12]3[CH2:14][CH2:13]3)[CH:11]=1)[O:8][C:7]([CH3:16])([CH3:15])[CH2:6][C:5]2([CH3:18])[CH3:17].[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[CH:12]1([C:10]2[CH:11]=[C:2]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])[CH:3]=[C:4]3[C:9]=2[O:8][C:7]([CH3:16])([CH3:15])[CH2:6][C:5]3([CH3:18])[CH3:17])[CH2:14][CH2:13]1
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)CC(C)(C)c2cc(Br)cc(C3CC3)c2O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC1(C)CC(C)(C)c2cc(C#C[Si](C)(C)C)cc(C3CC3)c2O1

Procedure:
Following general procedure D and using 6-bromo-8-cyclopropyl-2,2,4,4-tetramethyl chroman (Intermediate 32, 0.376 g, 1.22 mmol), (trimethylsilyl)acetylene (4 mL, 28 mmol), triethyl amine (3 mL), anhydrous tetrahydrofuiran (5 mL), copper(I)iodide (0.025 g, 0.13 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.075 g, 0.11 mmol), the title compound was obtained as an oil (0.173 g, 43%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[N:13]=[C:12]([C:23]3[NH:27][C:26](=[O:28])[C:25]([CH3:30])([CH3:29])[N:24]=3)[C:11]=2[CH3:31])=[CH:6][CH:5]=1.[CH3:32]I.O>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[N:13]=[C:12]([C:23]3[N:27]([CH3:32])[C:26](=[O:28])[C:25]([CH3:29])([CH3:30])[N:24]=3)[C:11]=2[CH3:31])=[CH:6][CH:5]=1
Reactant: CI
Reactant: Cc1c(C2=NC(C)(C)C(=O)N2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C2=NC(C)(C)C(=O)N2C)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
To a solution of sodium hydride (14.4 mg, 0.66 mole) in DMF (3 mL) at 0° C. was added compound 23 (100 mg, 0.22 mmol) in one portion. The mixture was allowed to warm to room temperature and stirred for 30 min, at which time methyl iodide (2 g, 14.08 mmol) was added. After the mixture was stirred for 2 h, water was added and the resulting mixture was extracted with ethyl acetate (2×50 mL). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the crude residue by flash chromatography on silica gel with hexanes/ethyl acetate (1:1) gave the product 27 (70 mg, 0.15 mmol, 68%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.45 (d, 1H), 7.30 (d, 2H), 7.26 (dd, 1H), 7.18 (d, 1H), 7.07 (d, 2H), 3.28 (s, 3H), 2.24 (s, 3H), 1.87 (s, 6H); ESMS m/: 461.1 (M+1).
Reaction SMILES: [CH:1]12[CH2:9][CH:5]3[CH2:6][CH:7]([CH2:8]1)[C:3]([NH:10][C:11]([NH2:13])=[S:12])([CH2:4]3)[CH2:2]2.Br[CH:15]([CH:21]([CH3:23])[CH3:22])[C:16](OCC)=[O:17]>>[CH:21]([CH:15]1[S:12][C:11]([NH:10][C:3]23[CH2:4][CH:5]4[CH2:9][CH:1]([CH2:8][CH:7]2[CH2:6]4)[CH2:2]3)=[N:13][C:16]1=[O:17])([CH3:23])[CH3:22]
Reactant: NC(=S)NC12CC3CC(CC1C3)C2
Reactant: CCOC(=O)C(Br)C(C)C
Product: CC(C)C1SC(NC23CC4CC(CC2C4)C3)=NC1=O

Procedure:
Synthesis was performed from N-tricyclo[3.3.1.0˜3,7˜]non-3-ylthiourea and ethyl 2-bromo-3-methylbutanoate according to Method C.
Reaction SMILES: [C-:1]#[N:2].[K+].[Cl:4][C:5]1[C:10]([CH2:11]Cl)=[CH:9][CH:8]=[CH:7][N:6]=1>CCO.O>[Cl:4][C:5]1[C:10]([CH2:11][C:1]#[N:2])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: ClCc1cccnc1Cl
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCc1cccnc1Cl
Temperature: 25 °C

Procedure:
In a 3 L reactor, set for reflux under positive nitrogen pressure and using a bleach scrubber, was prepared a solution of potassium cyanide (68.32 g, 1.04M) in EtOH (136 mL) and water (255 mL). The mixture was heated to reflux, at which point a solution of 2-chloro-3-(chloromethyl)pyridine (Intermediate 1; 170.0 g, 1.04M) in EtOH (170 mL) was added dropwise over 30 minutes. The whole mixture was maintained at reflux for a further 150 minutes. The mixture was then allowed to cool just below boiling point and the equipment set for distillation. A total of 8.5 volumes of EtOH were removed. On cooling, half a volume of water was added. At a temperature of 40° C., the solution was seeded and crystallised instantaneously. The thick beige slurry was allowed to cool to ambient temperature and then to 0° C. This mixture was filtered, rinsed with cold water (2 vols) and dried at 45° C. in a vacuum oven overnight. The title compound was afforded as a beige solid in excellent yield and purity (126.9 g, 80%). δH (d6-DMSO, 300 MHz) 8.45 (1H, dd), 8.00 (1H, dd), 7.50 (1H, dd), 4.15 (2H, s). LCMS (ES)+ RT 2.15 min, m/e 153.01 & 155.01 (M+1 & M+3, Product).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]([NH:13][C:14]1[C:15]([C:19]2[CH:32]=[CH:31][C:22]([CH2:23][S:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:21][CH:20]=2)=[N:16][O:17][CH:18]=1)=[O:12])[CH3:9].CCCCCC>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11]([NH:13][C:14]1[C:15]([C:19]2[CH:32]=[CH:31][C:22]([CH2:23][S:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:21][CH:20]=2)=[N:16][O:17][CH:18]=1)=[O:12])[CH3:9]
Reactant: COC(=O)CCSCc1ccc(-c2nocc2NC(=O)OC(C)c2ccccc2Cl)cc1
Solvent: CCO
Solvent: CCCCCC
Product: COC(=O)CCSCc1ccc(-c2nocc2NC(=O)O[C@H](C)c2ccccc2Cl)cc1
Yield: 49 %

Procedure:
Methyl 3-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfanyl)propionate (110 mg, 0.232 mmol) was subjected to optical resolution by high performance liquid chromatography (HPLC) (hexane:ethanol=8:2) using CHIRALCEL OD column (2 cm I.D.×25 cm L; DAICEL CHEMICAL IND., LTD) to give the title compound (R form, 54 mg, 49%) along with its S form (55 mg, 50%). The optical purity was determined by HPLC analysis using an optically active column.
Reaction SMILES: [C:1]([C:3](=[CH:6][N:7]([CH3:9])[CH3:8])[CH:4]=O)#[N:2].[NH2:10]OS(O)(=O)=O.[OH-].[Na+]>O>[CH3:8][N:7]([CH:6]=[C:3]([C:4]#[N:10])[C:1]#[N:2])[CH3:9]
Reactant: CN(C)C=C(C#N)C=O
Reactant: NOS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)C=C(C#N)C#N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a slurry of 12.4 g. of 2-cyano-3-dimethylaminoacrolein in 50 ml. of water was added in small portions 13.6 g. of hydroxylamine-0-sulfonic acid (91% pure). The resulting clear solution was stirred for an additional 10 minutes, then cooled to 0° and adjusted to pH 6.0 by addition of approximately 26 ml. of 5N sodium hydroxide solution. The mixture was heated for 20 minutes in a water bath at 70°. A pH 3 was maintained over this period by dropwise addition of 5N sodium hydroxide solution. After cooling to room temperature, the mixture was extracted with 3 × 100 ml. of methylene chloride. The combined extracts were washed with 50 ml. of water, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. Thus, dimethylaminomethylenemalononitrile was obtained. After recrystallization from isopropanol, the material had a melting point of 93°-95°.
Reaction SMILES: [CH2:1]([C:5]1[N:13]2[C:8]([C:9](=[CH:31][C:32]([O:34]C(C)(C)C)=[O:33])[CH2:10][CH2:11][CH:12]2[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O>>[CH2:1]([C:5]1[N:13]2[C:8]([C:9](=[CH:31][C:32]([OH:34])=[O:33])[CH2:10][CH2:11][CH:12]2[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:27][N:28]=[N:29][N:30]=3)=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CCC2=CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1ccc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CCC2=CC(=O)O
Temperature: 25 °C

Procedure:
To a solution of unsaturated tert-butyl ester (0.0627 mmol, the title compound of Example 1924) in 2 mL of CDCl3 at room temperature is added 0.5 mL of TFA, and the progress of the reaction is monitored by 1H NMR. The resulting yellow solution is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo. The crude product is purified to give the title compound of Example 1925.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[N+:11]([O-])=O.[H][H]>[Ni].CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[NH2:11]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(Cl)c(N)c1

Procedure:
A mixture of 1-chloro-2,4-dinitrobenzene (40.0 g, 0.197 mole), methanol (100 g), and 3.0 g of modified Raney nickel catalyst consisting of about 83.1% Ni, 9.3% Co, 7.1% Al and 0.5% Mo was charged into an autoclave. The autoclave was sealed, pressurized with hydrogen to 700 psig, and the hydrogenation carried out at about 30° C. Hydrogen uptake was observed by monitoring the pressure change. After the hydrogen uptake ceased (approximately 6.0 hrs.), the reaction mixture was heated for a short time longer and then the autoclave was vented. A sample of the reaction mixture was taken and analyzed by liquid chromatography after being separated from the solid catalyst. The desired product 1-chloro-2,4-diaminobenzene was formed in high yield and good purity. Liquid chromatography indicated an area % of 92.4% (excluding the methanol solvent) for the product. Very little dechlorination had occurred.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:32])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:20]([C:22]4[C:23]([O:29][CH3:30])=[N:24][CH:25]=[C:26]([F:28])[CH:27]=4)[OH:21])=[C:14]([C:16]([O:18]C)=O)[N:15]=[C:7]3[C:6]=2[CH:31]=1.C[O-].[Na+].C([NH2:38])=O>>[Br:1][C:2]1[C:3]([F:32])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:20]([C:22]4[C:23]([O:29][CH3:30])=[N:24][CH:25]=[C:26]([F:28])[CH:27]=4)[OH:21])=[C:14]([C:16]([NH2:38])=[O:18])[N:15]=[C:7]3[C:6]=2[CH:31]=1
Reactant: NC=O
Reactant: COC(=O)c1nc2n(c1C(O)c1cc(F)cnc1OC)C1CC(C1)c1cc(F)c(Br)cc1-2
Agent: C[O-]
Agent: [Na+]
Product: COc1ncc(F)cc1C(O)c1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
10-bromo-9-fluoro-3-((5-fluoro-2-methoxypyridin-3-yl)(hydroxy)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was prepared similarly to as described in General Procedure L. Methyl 10-bromo-9-fluoro-3-((5-fluoro-2-methoxypyridin-3-yl)(hydroxy)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was reacted with sodium methoxide and formamide to afford the crude title compound which was carried forward without further purification.
Reaction SMILES: [C:1](=[O:17])([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([N+:14]([O-])=O)[CH:7]=1)[O:2][CH2:3][CH3:4].C(O)(=O)C>CCOC(C)=O.[Pd]>[C:1](=[O:17])([O:2][CH2:3][CH3:4])[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([NH2:14])[CH:7]=1
Reactant: CCOC(=O)Oc1ccc(OC)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)Oc1ccc(OC)c(N)c1
Reaction time: 2 h
Yield: 95 %

Procedure:
Ethyl 4-methoxy-3-nitrophenyl carbonate (0.720 g, 2.99 mmol) was dissolved in EtOAc (20 ml), and glacial acetic acid (0.200 ml, 3.49 mmol) was added followed by 10% palladium on carbon (0.100 g, 0.094 mmol). The mixture was stirred in a Parr apparatus under hydrogen atmosphere (25 psi) for 2 hours. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure. The resulting crude 3-amino-4-methoxyphenyl ethyl carbonate (0.600 g, 2.84 mmol, 95% yield, MS/ESI+ 212.3 [MH]+), was used for the next step without any further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.[BH4-].[Na+]>CO>[CH3:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10]2)=[CH:18][CH:17]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Cc1ccc(CN)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(CNC2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-benzyl-4-piperidone (1.74 g, 9.2 mmol) and 4-methylbenzylamine (0.97 g, 8 mmol) in methanol (30 ml) was added sodium borohydride (525 mg) in small portions over 30 min. The reaction mixture was stirred at room temperature. After 16 h, the mixture was concentrated. Water (30 ml) was added, and the mixture was extracted with dichloromethane (2×20 ml). The combined organic layers were dried (Na2SO4), filtered, and concentrated to give 4-((4-methylphenyl)methyl)amino-1-phenylmethylpiperidine. The crude product was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.[NH:23]1[CH2:27][CH2:26][C@H:25]([NH2:28])[CH2:24]1>>[NH2:28][C@H:25]1[CH2:26][CH2:27][N:23]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=3[NH:12][C:13](=[O:21])[CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[N:3]=2)[CH2:24]1
Reactant: N[C@H]1CCNC1
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Product: N[C@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Yield: 59.3 %

Procedure:
Prepared according to the method of example 30, using N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1(a)) (0.166 g) and (3S)-3-pyrrolidinamine (0.127 g) to afford the title compound (0.113 g).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])=[O:5].[C:20]1(C)C=CC(S(O)(=O)=O)=CC=1>C(OC)(OC)OC>[CH3:19][C:17]1[CH:18]=[C:2]2[C:3]([C:4](=[O:5])[N:6]([CH:7]3[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]3=[O:14])[CH:20]=[N:1]2)=[CH:15][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1ccc(C(=O)NC2CCC(=O)NC2=O)c(N)c1
Solvent: COC(OC)OC
Product: Cc1ccc2c(=O)n(C3CCC(=O)NC3=O)cnc2c1
Yield: 223.4 %

Procedure:
A solution of 2-amino-N-(2,6-dioxo-piperidin-3-yl)-4-methyl-benzamide (1.0 g, 3.8 mmol) and trimethyl orthoformate (10 mL) and p-toluene sulfonic acid (250 mg) was heated to 160° C. in a microwave oven for 30 minutes. The suspension was filtered and washed with methanol (20 mL), water (20 mL) and methanol (20 mL) to give 3-(7-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as an off-white solid (880 mg, 85% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 20/80 CF3CN/0.1% H3PO4, 5.14 min (97.1%); mp: 313-315° C.; 1H NMR (DMSO-d6) δ 2.11-2.18 (m, 1H, CHH), 2.48 (s, 3H, CH), 2.61-2.74 (m, 2H, 2CHH), 2.82-2.92 (m, 1H, CHH), 5.46 (br, 1H. NCH), 7.41 (dd, J=1, 8 Hz, 1H, Ar), 7.53 (s, 1H, Ar), 8.03 (d, J=8 Hz, 1H, Ar), 8.33 (s, 1H, CH), 11.15 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.23, 22.51, 30.91, 56.74, 118.95, 125.93, 126.74, 128.66, 145.27, 147.35, 147.59, 159.54, 169.88, 172.44; LCMS: MH=272; Anal Calcd for C14H13N3O3+0.1H2O: C, 61.58; H, 4.87; N, 15.39. Found: C, 61.41; H, 4.87; N, 15.15.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].[F:14][C:15]1[CH:16]=[C:17]([N:29]2[CH2:33][C@H:32]([CH2:34][NH:35][C:36](=[O:38])[CH3:37])[O:31][C:30]2=[O:39])[CH:18]=[C:19]([F:28])[C:20]=1[CH:21]1[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]1.CN1CCOCC1>ClCCl>[O:27]=[S:24]1(=[O:4])[CH:25]=[CH:26][CH:21]([C:20]2[C:19]([F:28])=[CH:18][C:17]([N:29]3[CH2:33][C@H:32]([CH2:34][NH:35][C:36](=[O:38])[CH3:37])[O:31][C:30]3=[O:39])=[CH:16][C:15]=2[F:14])[CH2:22][CH2:23]1
Reactant: CC(=O)NC[C@H]1CN(c2cc(F)c(C3CCS(=O)CC3)c(F)c2)C(=O)O1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(=O)NC[C@H]1CN(c2cc(F)c(C3C=CS(=O)(=O)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
Trifluoroacetic anhydride (2.24 ml, 15.8 mmol) was added dropwise at room temperature to a solution of N-[[(5S)-3-[3,5-difluoro-4-(tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (2.04 g, 5.28 mmol and N-methylmorpholine (2.90 ml, 26.4 mmol) in dichloromethane (50 ml). The reaction mixture was stirred overnight at room temperature and then evaporated to dryness. The resulting crude N-({(5S)-3-[4-(3,4-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (1.95 g) was dissolved in tetrahydrofuran (100 ml) and peracetic acid (5.6 ml of a 32% solution in acetic acid, 26.4 mmol) added dropwise at 0° C. The reaction mixture was allowed to warm to room temperature, stirred overnight, and then evaporated to dryness. The residue was purified by flash column chromatography (ethyl acetate) to give white solid (1.80 g, 85%).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)#[CH:2].I[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=1>>[C:19]1([CH3:23])[CH:20]=[CH:21][CH:22]=[C:17]([C:2]#[C:1][C:3]2[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=2)[CH:18]=1
Reactant: C#Cc1ccc(OCC(=O)OCC)cc1
Reactant: Cc1cccc(I)c1
Product: CCOC(=O)COc1ccc(C#Cc2cccc(C)c2)cc1

Procedure:
The title compound was prepared from ethyl (4-ethynylphenoxy)acetate (42 mg, 0.21 mmol) and iodo-3-methylbenzene (0.04 mL, 0.31 mmol) according to the general procedure ID to give 56 mg (93%) of an orange oil after purification by flash chromatography (SiO2, EtOAc/hexanes, 1:10). Rf: 0.44 (EtOAc:hexanes, 1:5); 1HNMR (CDCl3) δ 7.61-7.56 (m, 2H), 7.51-7.31 (m, 4H), 7.03-6.88 (m, 2H), 4.75 (s, 2H), 4.43-4.36 (dq, 2H, J=7.2 Hz, 2.1 Hz), 2.47 (s, 3H), 1.44-1.38 (tt, 3H, J=7.2 Hz, 1.5 Hz); 13CNMR (CDCl3) δ 168.6, 157.7, 138.0, 133.1, 132.0, 128.9, 128.5, 128.2, 123.2, 116.2, 114.7, 88.6, 88.6, 65.4, 61.5, 21.2, 14.1; EI-MS m/z 294 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11](O)[CH2:10][C@@H:9]1[CH3:19])=[O:7].[NH:25]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([N:25]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:10][CH:9]1[CH3:19])=[O:7]
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](O)C[C@@H]2C)cc1OC
Reactant: c1ccc2c(c1)CCCCN2
Product: COc1ccc(C(=O)N2c3ccccc3C(N3CCCCc4ccccc43)CC2C)cc1OC
Yield: 8.5 %

Procedure:
Starting with cis-1-(3,4-dimethoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinol (280 mg, 0.82 mmol) prepared in Reference Example 1 and 2,3,4,5-tetrahydro-1H-1-benzazepine (362 mg, 2.46 mmol), the same procedure as shown in Example 1 was repeated to give the titled compound (32 mg, yield: 9%) as a colorless oil. (cis:trans=1:1.5)
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([C:10]2[C:11]([NH:16][C:17]3[C:26]([CH3:27])=[CH:25][CH:24]=[C:23]4[C:18]=3[CH:19]=[CH:20][NH:21][C:22]4=O)=[N:12][CH:13]=[CH:14][CH:15]=2)=[N:3][CH:2]=1.P(Cl)(Cl)([Cl:31])=O>>[N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([C:10]2[C:11]([NH:16][C:17]3[C:18]4[CH:19]=[CH:20][N:21]=[C:22]([Cl:31])[C:23]=4[CH:24]=[CH:25][C:26]=3[CH3:27])=[N:12][CH:13]=[CH:14][CH:15]=2)=[N:3][CH:2]=1
Reactant: Cc1ccc2c(=O)[nH]ccc2c1Nc1ncccc1-c1ncnc2[nH]ccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc2c(Cl)nccc2c1Nc1ncccc1-c1ncnc2[nH]ccc12
Yield: 67.3 %

Procedure:
5-(3-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)pyridin-2-ylamino)-6-methylisoquinolin-1(2H)-one (750 mg, 2036 μmol) was suspended in phosphorous oxychloride (9.5 mL, 10.2 mmol). The reaction vessel was flushed with N2 and sealed. The reaction was heated in an oil bath for 5 h. The excess reagent was removed in vacuo. The residue was azeotroped with toluene times and then put under high vacuum overnight. The residue was suspended with 50 g of ice. The suspension was neutralized with NaHCO3 (aq., sat.). The resulting mixture was extracted with DCM. The DCM solution was concentrated in vacuo and the residue was purified via flash column on silica (Hexane:EtOAc gradient of 50-10%) to give N-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyridin-2-yl)-1-chloro-6-methylisoquinolin-5-amine as a yellow solid (530 mg, 67% yield). MS (ESI, pos. ion) m/z: 387 [M+H]+
Reaction SMILES: C([O-])(=O)C.[NH4+].[Cl:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH:16]=O)=[CH:12][NH:13]2)=[CH:9][C:8]=1[C:18]([F:21])([F:20])[F:19].[N+:22]([CH3:25])([O-:24])=[O:23]>>[Cl:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11](/[CH:16]=[CH:25]/[N+:22]([O-:24])=[O:23])=[CH:12][NH:13]2)=[CH:9][C:8]=1[C:18]([F:21])([F:20])[F:19]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1c[nH]c2cc(Cl)c(C(F)(F)F)cc12
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: O=[N+]([O-])/C=C/c1c[nH]c2cc(Cl)c(C(F)(F)F)cc12
Yield: 49 %

Procedure:
Nitromethane (20 ml) and ammonium acetate (1.6 g) were added to 6-chloro-5-(trifluoromethyl)indole-3-carbaldehyde (3.25 g) and the mixture was heated under reflux for 1 hr. The reaction mixture was allowed to cool, and the precipitated solid was collected by filtration, washed with methanol-water (1:1) and dried to give a brown solid. This solid was washed in a suspension state with diethyl ether, collected by filtration and dried to give 6-chloro-3-[(E)-2-nitrovinyl]-5-(trifluoromethyl)-1H-indole (1.86 g, yield 49%).
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:26]([C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[N:38]1[CH2:43][CH2:42][O:41][C:40]2[CH:44]=[C:45]([S:49](Cl)(=[O:51])=[O:50])[C:46]([F:48])=[CH:47][C:39]1=2)#[N:27]>C1COCC1.CCOC(C)=O>[C:26]([C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[N:38]1[CH2:43][CH2:42][O:41][C:40]2[CH:44]=[C:45]([S:49]([NH:8][C:9]3[S:10][CH:11]=[CH:12][N:13]=3)(=[O:51])=[O:50])[C:46]([F:48])=[CH:47][C:39]1=2)#[N:27]
Reactant: COc1ccc(CNc2nccs2)cc1
Reactant: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Cl)c(F)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Nc3nccs3)c(F)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.6 %

Procedure:
To a vial charged with N-(4-methoxybenzyl)thiazol-2-amine (2.83 g, 12.86 mmol) was added THF (38.2 ml) and the mixture cooled in an ice water bath prior to the addition of lithium bis(trimethylsilyl)amide, 1.0M solution in tetrahydrofuran (14.03 ml, 14.03 mmol), faster than dropwise. After 15 min, a solution of 4-(2-cyano-4-(trifluoromethyl)phenyl)-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (4.92 g, 11.69 mmol) in THF (30 ml) was added. The mixture was allowed to warm to rt over 1.5 h, providing a brown solution and product as the primary species according to LC-MS (m/z=605). The solution was added to ice, diluted with EtOAc and extracted with water (brine added to help resolve emulsion). The layers were separated and the aqueous phase was extracted with EtOAc. The combined organics were dried with Na2SO4, filtered, and dried under reduced pressure. To the crude material was added DCM (70 ml) and the resulting light brown solution cooled in an ice water bath prior to the addition of TFA (20 ml) and the mixture stirred at 0° C. for 20 mins and at room temperature for 1 h affording a purplish solution. The mixture was concentrated under reduced pressure and the resulting brownish oil purified with a 330 g ISCO gold column ramping EtOAc in heptane (0-45%, then isocratic at 45% with 10% DCM isocratic throughout, sample loaded with DCM providing product (˜3.9 g) as a slightly off-white solid. The solid was triturated with MeOH to afford a white solid, 4-(2-cyano-4-(trifluoromethyl)phenyl)-6-fluoro-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (3.208 g, 6.62 mmol, 56.6% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.80-3.88 (m, 2 H) 4.28-4.35 (m, 2 H) 6.64 (d, J=11.64 Hz, 1 H) 6.84 (d, J=4.69 Hz, 1 H) 7.23 (d, J=6.75 Hz, 1 H) 7.27 (d, J=4.60 Hz, 1 H) 7.77 (d, J=8.61 Hz, 1 H) 8.09 (dd, J=8.90, 1.96 Hz, 1 H) 8.41 (d, J=1.66 Hz, 1 H) 12.81 (s, 1 H). m/z (ESI) 485.2 (M+H)+.