Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[C:4]([I:12])[C:3]=1[OH:13].[CH:14]#[C:15][CH2:16][CH3:17]>N1C=CC=CC=1.Cl>[CH2:16]([C:15]1[O:13][C:3]2[C:4]([I:12])=[CH:5][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=2[CH:14]=1)[CH3:17]
Reactant: CS(=O)(=O)c1cc(I)c(O)c(I)c1
Reactant: C#CCC
Agent: Cl
Solvent: c1ccncc1
Product: CCc1cc2cc(S(C)(=O)=O)cc(I)c2o1
Temperature: 130 °C
Reaction time: 3 h
Yield: 48.4 %

Procedure:
To a solution of 2,6-diiodo-4-methylsulfonylphenol (1.00 g, 2.36 mmol) in pyridine (10 mL) at 25° C. was added but-1-yne (128 mg, 2.36 mmol) and Cu2O (135 mg, 0.944 mmol). The mixture was stirred at 130° C. for 3 h under a nitrogen atmosphere. The residue was cooled to 25° C., diluted with 1N HCl (200 ml) and extracted with EtOAc (30 mL×2). The combined organic layers were washed by brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (PE:EA=10:1 to 5:1) to afford the title compound (400 mg, 48%) as a solid. 1H NMR (CDCl3, 400 MHz) δ 8.14 (d, J=1.6 Hz, 1H), 8.06 (d, J=1.6 Hz, 1H), 6.62 (s, 1H), 3.09 (s, 3H), 2.90 (q, J=7.6 Hz, 2H), 1.38 (t, J=7.6 Hz, 3H). LCMS: 350.9 (M+H+)
Reaction SMILES: [CH2:1]([O:3][CH2:4][C@H:5]([NH:12][C:13](=[O:44])[C@@H:14]([CH:41]([CH3:43])[CH3:42])[NH:15][C:16](=[O:40])[C@H:17]([CH:29](CC1C=CC=CC=1)[C:30](=[O:32])[OH:31])[NH:18]C(OCC1C=CC=CC=1)=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:2]>CO.O.[Pd].[C]>[CH2:1]([O:3][CH2:4][C@H:5]([NH:12][C:13](=[O:44])[C@@H:14]([CH:41]([CH3:43])[CH3:42])[NH:15][C:16](=[O:40])[C@H:17]([CH2:29][C:30](=[O:31])[OH:32])[NH2:18])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC[C@H](NC(=O)[C@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Cc1ccccc1)C(=O)O)C(C)C)c1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CCOC[C@H](NC(=O)[C@H](NC(=O)[C@@H](N)CC(=O)O)C(C)C)c1ccccc1
Temperature: 40 °C
Yield: 50.3 %

Procedure:
To a suspension of 1.20 g (1.99 mmols) of N-benzyloxycarbonyl-β-benzyl-L-aspartyl-D-valine (R)-α-ethoxymethylbenzylamide in 50 ml of methanol and 10 ml of water was added 0.30 g of 10% Pd-carbon (water content 50%). The mixture was reduced under hydrogen under heat at 40°C., 40 ml of water was added thereto, the catalyst was removed by filtration, and the resulting filtrate was concentrated under reduced pressure to 5 ml. The crystal thus precipitated was removed by filtration and dried to obtain 0.38 g (1.00 mmol, 50.3%) of α-L-aspartyl-D-valine (R)-α-ethoxymethylbenzylamide.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@@H:11]1[CH2:15][CH2:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].I[CH3:20].Cl>O1CCCC1.CN(C)C=O>[C:3]([O:7][C:8]([N:10]([CH3:20])[C@@H:11]1[CH2:15][CH2:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](C(=O)O)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CC[C@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 30.5 %

Procedure:
To a stirred suspension of sodium hydride (89 mg, 2.24 mmol) in tetrahydrofuran (10 mL) and dimethyl formamide (10 mL) cooled in an ice bath was added (1S,3R)-3-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (427 mg, 1.86 mmol, WO2006/011035) and iodomethane (128 microL, 2.05 mmol). The mixture was allowed to warm to room temperature and stirred for 20 h. Sodium hydride (178 mg, 4.474 mmol) and idomethan (256 microL, 4.102 mmol) were added, and the reaction mixture was stirred at 20 h at room temperature. Reaction mixture was acidified to pH 3.5 with 1 mol/L hydrochloric acid and extracted with ethyl acetate. Organic layer was dried over sodium sulfate and concentrated under reduced pressure. Crude material was purified by column chromatography (50% ethyl acetate in hexane containing 1.5% acetic acid) to give the desired compound as a colorless solid (138.0 mg, 31%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[CH2:11]([NH2:14])[C:12]#[CH:13].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][NH:14][CH2:11][C:12]#[CH:13]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: C#CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: C#CCNCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 59.6 %

Procedure:
To a solution of 3,4-difluorobenzaldehyde (5 g, 35.2 mmol) in 200 mL dichloroethane was added mono-propargyl amine (4.85 mL, 70.7 mmol, 2 eq.) followed by Na(OAc)3BH (9 g, 42.5 mmol) and the mixture was stirred for 2 days at room temperature. The solution was diluted with 100 mL of dichloromethane, washed with 2×100 mL aq. NaHCO3, 100 mL brine, dried over Na2SO4, filtered and concentrated. The crude product was chromatographed with 20:80 ethyl acetate-hexanes to provide 3.8 g of (3,4-difluoro-benzyl)-prop-2-ynyl-amine as an oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][C:10]2([O:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[NH:15]([CH2:11][C:10]1([OH:12])[CH2:13][CH2:14][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(CN2CCC3(CO3)C2)cc1
Reactant: Nc1ccccc1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: OC1(CNc2ccccc2)CCN(Cc2ccccc2)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
5-Benzyl-1-oxa-5-azaspiro[2.4]heptane (946 mg) was dissolved in acetonitrile (30 mL), and aniline (0.55 mL) and lithium perchlorate (640 mg) were added. After stirring at 80° C. overnight, the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed twice with aqueous sodium hydrogen carbonate solution. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using basic silica gel (20% ethyl acetate/hexane to 60% ethyl acetate/hexane) to give the object product (768 mg, 54%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]([NH2:15])=[NH:14])[CH2:2][CH2:3][CH3:4].C([O:18][CH:19]=[C:20]([C:26](OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])C.O>CN(C=O)C>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]1[NH:15][C:19](=[O:18])[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][N:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCCCOc1ccccc1NC(=N)N
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1ccccc1Nc1ncc(C(=O)OCC)c(=O)[nH]1
Temperature: 100 °C
Yield: 86.8 %

Procedure:
A mixture of N-(2-butoxyphenyl)guanidine (11.6 g) and diethyl ethoxymethylenemalonate (12.1 g) in DMF (70 ml) is heated at 100° C. for 9 hours. After cooling, water (50 ml) is added to the reaction mixture, and the precipitate is collected by filtration, washed with ethanol and recrystallized from a mixture of DMF and water to give ethyl 2-(2-butoxyanilino)-1,6-dihydro-6-oxo-5-pyrimidinecarboxylate (16.1 g). M.p. 211°-213° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10].CC1C=CC(S(O[CH:22]2[CH2:25][CH2:24][CH2:23]2)(=O)=O)=CC=1.O>CN(C=O)C>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH:22]1[CH2:25][CH2:24][CH2:23]1
Reactant: Cc1ccc(S(=O)(=O)OC2CCC2)cc1
Reactant: Sc1ccccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccccc1SC1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.4 %

Procedure:
To a suspension of sodium hydride (60% in oil, 390 mg, 9.75 mmol) in anhydrous DMF (20 mL) was added 2-bromobenzenethiol (1.03 mL, 8.37 mmol) dropwise over 5 minutes. After stirring for 10 minutes at room temperature a solution of cyclobutyl 4-methylbenzenesulfonate (2.0 g, 8.85 mmol) in dry DMF (3 mL) was added dropwise. The resulting solution was then stirred for 2 hours at room temperature, and 2 hours at 50° C. Water was then added, and the mixture extracted with ethyl acetate (×3). The combined organics were washed with brine (×3), then dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with neat petrol) to give (2-bromophenyl)(cyclobutyl)sulfane (1.19 g, 4.89 mmol, 58%) as a colourless oil.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.NCC1CCN([NH:27][C:28](=[O:36])[NH:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)CC1>>[CH:30]1([NH:29][C:28]([N:27]2[CH2:7][CH2:6][CH:18]([CH2:10][NH:11][CH2:3][C@H:2]([OH:1])[CH2:4][O:5][C:6]3[C:18]4[C:17]5[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]=4[CH:9]=[CH:8][CH:7]=3)[CH2:17][CH2:16]2)=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Reactant: NCC1CCN(NC(=O)NC2CCCCC2)CC1
Product: O=C(NC1CCCCC1)N1CCC(CNC[C@H](O)COc2cccc3[nH]c4ccccc4c23)CC1
Yield: 0.1 %

Procedure:
Prepared from 4-[(2S)-oxiranylmethoxy]-9H-carbazole (0.175 g, 0.73 mmol) and 3-(4-aminomethyl-1-piperidinyl)-1-cyclohexyl urea (0.360 g, 1.5 mmol) according to the procedure used in example 2 to give 0.095 mg of the title compound as an off white solid.
Reaction SMILES: [OH:1][CH:2]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:17]([C:27]#[N:28])[CH:16]=1)[C:3]([O:5]CC1C=CC=CC=1)=[O:4].Cl.[H][H]>[Pd].[C].C(O)(=O)C>[OH:1][CH:2]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:17]([C:27]#[N:28])[CH:16]=1)[C:3]([OH:5])=[O:4]
Reactant: N#Cc1cc(CCC(O)C(=O)OCc2ccccc2)ccc1C1CCCCC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: N#Cc1cc(CCC(O)C(=O)O)ccc1C1CCCCC1

Procedure:
A solution of 0.01 moles of benzyl α-hydroxy-γ-(3-cyano-4-cyclohexylphenyl)butyrate dissolved in 100 ml. of acetic acid and containing 0.01 mole of hydrogen chloride is shaken with hydrogen over a 5% Pd carbon catalyst until 0.01 moles of hydrogen is absorbed. The catalyst is then filtered and the solution is evaporated to dryness and crystallized to obtain α-hydroxy-γ-(3-cyano-4-cyclohexylphenyl)butyric acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[C:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[CH2:33][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31]3)=[CH:26][CH:25]=2)[N:14]=1>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3](=[O:41])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][C:13]1[C:18]([C:19]([F:21])([F:22])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[CH2:31][N:32]([C:34]([O:36][C:37]([CH3:39])([CH3:40])[CH3:38])=[O:35])[CH2:33]3)=[CH:26][CH:25]=2)[N:14]=1
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(C3CN(C(=O)OC(C)(C)C)C3)cc2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CN(C(=O)OC(C)(C)C)C3)cc2)ncc1C(F)(F)F
Reaction time: 18 h

Procedure:
A suspension of tert-butyl 3-(4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate (A79) (570 mg, 1.00 mmol) and 10% Pd/C (0.600 g) in EtOAc (13 mL) was stirred under a hydrogen atmosphere for 18 hours. The resulting mixture was filtered through a pad of Celite, washing with EtOAc and the filtrate concentrated in vacuo to give the title compound A80 as a light yellow foam (521 mg, 90%); 1H NMR (300 MHz, d6-DMSO) δ 8.56 (s, 1H), 7.64 (d, J=8.5 Hz, 2H), 7.57 (s, 1H), 7.33 (d, J=8.5 Hz, 2H), 7.28-7.25 (m, 4H), 4.35 (t, J=8.7 Hz, 2H), 3.99 (dd, J=8.4, 6.7 Hz, 2H), 3.77 (m, 3H), 3.70 (brs, 3H), 3.13 (m, 4H), 1.44 (s, 9H). LCMS-B: rt 9.374 min; m/z 571 [M+H]+.
Reaction SMILES: [CH3:1][Mg]Cl.[CH3:4][O:5][C:6](=[O:17])[C:7](=[C:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:8]([O:10][CH3:11])=[O:9].[NH4+].[Cl-]>O1CCCC1.[Cu]I>[CH3:11][O:10][C:8](=[O:9])[CH:7]([C:12]([CH2:15][CH3:16])([CH3:1])[CH2:13][CH3:14])[C:6]([O:5][CH3:4])=[O:17]
Reactant: C[Mg]Cl
Reactant: CCC(CC)=C(C(=O)OC)C(=O)OC
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(C)(CC)C(C(=O)OC)C(=O)OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.5 %

Procedure:
Step A To a suspension of CuI (5.7 g, 30 mmol) in anhydrous tetrahydrofuran (100 mL) at −50° C. was added methylmagnesium chloride (3 M, 20 mL, 60 mmol) during a period of 15 min. After the addition was finished, the reaction mixture was gradually warmed room temperature and stirred for 20 min. Then the temperature of the mixture was lowered to −50° C., a tetrahydrofuran solution (20 mL) of 2-(1-ethyl-propylidene)-malonic acid dimethyl ester (3 g, 15 mmol) prepared in Example 106a Step A was added. The reaction mixture was allowed to slowly warmed to room temperature and stirred for 1 h. Aqueous saturated NH4Cl solution was added to quench the reaction. The mixture was filtered, and the filtrate was concentrated to remove most of tetrahydrofuran. The residue was extracted with ethyl acetate twice. The organic layers were combined, concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:30) to give 2-(1-ethyl-1-methyl-propyl)-malonic acid dimethyl ester as a colorless oil (3 g, 93%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([OH:17])=O)=[C:13]([CH3:18])[NH:12][C:11](=[O:19])[NH:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[F:20][C:21]1[CH:22]=[C:23]([NH:28][C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[C:35]([NH2:38])[CH:36]=3)[NH:31][N:30]=2)[CH:24]=[C:25]([F:27])[CH:26]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:20][C:21]1[CH:22]=[C:23]([NH:28][C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[C:35]([NH:38][C:15]([C:14]4[CH:9]([C:4]5[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=5)[NH:10][C:11](=[O:19])[NH:12][C:13]=4[CH3:18])=[O:17])[CH:36]=3)[NH:31][N:30]=2)[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: CC1=C(C(=O)O)C(c2cc(F)cc(F)c2)NC(=O)N1
Reactant: Nc1ccc2[nH]nc(Nc3cc(F)cc(F)c3)c2c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Nc4cc(F)cc(F)c4)c3c2)C(c2cc(F)cc(F)c2)NC(=O)N1

Procedure:
The titled compound was prepared following the procedure of Example 175 using 4-(3,5-Difluoro-phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, N3-(3,5-difluoro-phenyl)-1H-indazole-3,5-diamine, PyBroP and diisopropylethylamine in methylene chloride. MS (ESI) m/z 511 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]4[C:16]([CH3:22])=[N:17][N:18]([CH2:20][CH3:21])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:25][O:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][N:28]=1>>[CH2:20]([N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:30]5[CH:29]=[N:28][C:27]([O:26][CH3:25])=[N:32][CH:31]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:24])[C:13]2=[O:23])[C:16]([CH3:22])=[N:17]1)[CH3:21]
Reactant: COc1ncc(B(O)O)cn1
Reactant: CCn1cc(-n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)c(C)n1
Product: CCn1cc(-n2c(=O)n(C)c3cnc4ccc(-c5cnc(OC)nc5)cc4c32)c(C)n1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate F, 49 mg, 0.126 mmol) and 2-methoxy-5-pyrimidineboronic acid (ABCR, Karlsruhe, Germany, 25 mg, 0.162 mmol) to give the title compound as a white solid. (HPLC: tR 2.47 min (Method A); M+H=416 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.98 (s, 1H), 8.76-8.68 (m, 2H), 8.23-8.16 (m, 1H), 8.16-8.09 (m, 1H), 7.99-7.93 (m, 1H), 7.52-7.45 (m, 1H), 4.19 (q, 2H), 3.96 (s, 3H), 3.59 (s, 3H), 1.97 (s, 3H), 1.42 (t, 3H))
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][C@H:26]1[CH2:31][CH2:30][C@H:29]([C:32]([OH:34])=[O:33])[CH2:28][CH2:27]1.C[O-].[Na+]>COCCO>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][C@H:26]2[CH2:31][CH2:30][C@H:29]([C:32]([OH:34])=[O:33])[CH2:28][CH2:27]2)=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: N[C@H]1CC[C@H](C(=O)O)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: N#Cc1nc(C(=O)N[C@H]2CC[C@H](C(=O)O)CC2)c(O)c2ccc(Oc3ccccc3)cc12

Procedure:
To a mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (60 mg, 0.19 mmol) and trans-4-amino-cyclohexanecarboxylic acid (107 mg, 0.75 mmol) in 3 mL of 2-methoxyethanol was added NaOMe solid (30 mg, 0.56 mmol). The resultant mixture was microwaved at 140° C. for 1 h. Reaction mixture was concentrated and residue was dissolved in water (60 mL). It was acidified by 1 N HCl to pH=3-4. Precipitate was collected, and rinsed with water and MeOH. Solid was dried to provide the title compound 40 mg (0.093 mmol) in 49% yield. LC-MS ESI−: 430.00 (M−1)−.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:12]=[C:11]([O:13][CH2:14][CH:15]([OH:18])[CH2:16]Cl)[CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[C:1]([C:4]1[O:5][C:6]2[CH:12]=[C:11]([O:13][CH2:14][CH:15]([OH:18])[CH2:16][N:30]3[CH2:29][CH2:28][N:27]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[O:20][CH3:19])[CH2:32][CH2:31]3)[CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: COc1ccccc1N1CCNCC1
Reactant: CC(=O)c1cc2ccc(OCC(O)CCl)cc2o1
Product: COc1ccccc1N1CCN(CC(O)COc2ccc3cc(C(C)=O)oc3c2)CC1

Procedure:
The procedures of Example 2b were repeated except that 1.3 g (0.005 mole) of 2-acetyl-6-(3-choro-2-hydroxypropoxy)benzofuran and 1.1 g (0.0055 mole) of 1-(2-methoxyphenyl)piperazine were employed as starting materials. The obtained concentrated residue was crystallized from ethyl acetate.
Reaction SMILES: [C:1]1([S:7]([C:10]([CH:20]2[CH2:32][C:23]3[NH:24][C:25]4[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][C:30]=4[C:22]=3[CH2:21]2)([F:19])[C:11]2[O:15][N:14]=[C:13]([C:16]([NH2:18])=O)[N:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O>C(#N)C>[C:1]1([S:7]([C:10]([CH:20]2[CH2:32][C:23]3[NH:24][C:25]4[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][C:30]=4[C:22]=3[CH2:21]2)([F:19])[C:11]2[O:15][N:14]=[C:13]([C:16]#[N:18])[N:12]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)c1noc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2ccccc2)n1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1noc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2ccccc2)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 12.5 %

Procedure:
To a stirred solution of 170 mg (0.35 mmol) of (RS,SR)-5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazole-3-carboxylic acid amide in 2 mL acetonitrile at RT was added 0.5 mL phosphorous oxychloride. The dark brown solution was stirred for 1 hour and then the temperature was raised to 50° C. and stirred overnight. After cooling down to RT, 0.5 mL phosphorous oxychloride were added. The reaction mixture was stirred for 2 hours under reflux condition. The solvent was partially evaporated and the resulting oil was dissolved with EtOAc and washed with saturated NaHCO3 solution. The organic phase was dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel (EtOAc/heptane 1:1) yielded 20 mg (12%) (RS, SR)-5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazole-3-carbonitrile as a light red solid, MS: 457 (MH+).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:19][CH2:20][C:21]([CH:23]2[CH2:27][CH2:26][CH2:25][C:24]2=O)=[O:22])[CH:12]=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16]>C(Cl)(Cl)Cl>[Cl:4][C:24]1[CH2:25][CH2:26][CH2:27][C:23]=1[C:21](=[O:22])[CH2:20][CH2:19][C:11]1[CH:10]=[C:9]([O:8][CH3:7])[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(CCC(=O)C2CCCC2=O)cc(OC)c1OC
Solvent: ClC(Cl)Cl
Product: COc1cc(CCC(=O)C2=C(Cl)CCC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
13 ml of oxalyl chloride were added at ambient temperature to a solution of 23 g of the product of Stage C and 230 ml of chloroform and the mixture was stirred for three hours at ambient temperature, and concentrated under reduced pressure by proceeding with two entrainments with cyclohexane to obtain 28 g of crude product which was crystallized from a mixture of 50 ml of cyclohexane and 50 ml of diisopropyl ether after partial concentration. Separation was carried out, followed by washing with diisopropyl ether and drying under reduced pressure to obtain 16.24 g of the expected product melting at 93° C.
Reaction SMILES: C([CH:6]1[CH:11]([CH2:12][CH2:13][C:14]([O:17][CH3:18])([CH3:16])[CH3:15])[CH2:10][CH2:9][CH2:8][C:7]1=[O:19])(OCC)=O.[OH-].[K+].CO>O>[CH3:18][O:17][C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][CH:11]1[CH2:10][CH2:9][CH2:8][C:7](=[O:19])[CH2:6]1
Reactant: CCOC(=O)C1C(=O)CCCC1CCC(C)(C)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(C)(C)CCC1CCCC(=O)C1
Yield: 19.5 %

Procedure:
Crude 2-carbethoxy-3-(3-methoxy-3-methylbut-1-yl)cyclohexanone (7.0 g) of example 17 was added to a mixture of potassium hydroxide (3.0 g), methanol (50 mL) and water (50 mL) and heated at reflux 4.5 hours. The cooled mixture was extracted with hexane, the extracts were dried (Na2SO4) and concentrated to an oil which was purified by bulb to bulb distillation, airbath temperature 175~C., 0.1 mm Hg to yield 3-(3-methoxy-3-methylbut-1-yl)cyclohexanone (1.0 g); NMR(CDCl3)δ 1.2(s,6H), 1.2-1.5(m,5H), 1.6-1.8(m,2H), 1.9-2.1(m,3H), 2.2-2.4(m,3H), 3.2(s,3H); IR (neat) 2970, 2950, 1720, 1460, 1370, 1230, 1090 cm-1 ; MS (m/e) 41, 55, 73, 110, 133, 151, 183, 184.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][O:11][C:10]2[CH:14]=[C:15]([S:18]([N:21]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[C:22]3[S:23][CH:24]=[CH:25][N:26]=3)(=[O:20])=[O:19])[CH:16]=[CH:17][C:9]1=2.Br[CH2:37][C:38]#[N:39].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:38]([CH2:37][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][O:11][C:10]2[CH:14]=[C:15]([S:18]([N:21]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)[C:22]3[S:23][CH:24]=[CH:25][N:26]=3)(=[O:19])=[O:20])[CH:16]=[CH:17][C:9]1=2)#[N:39]
Reactant: N#CCBr
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2OCC#N)cc1
Temperature: 80 °C
Yield: 33.8 %

Procedure:
To a solution of 4-(2-hydroxyphenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (From Example 256, Step 3; 550 mg, 1.080 mmol) and 2-bromoacetonitrile (194 mg, 1.62 mmol) in DMF (10 mL) was added potassium carbonate (447 mg, 3.24 mmol). The reaction mixture was heated at 80° C. for 12 h. After completion, the reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with water (3×50 mL), dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material which was purified by combiflash column chromatography (column size: 12 g; elution: 0-30% ethyl acetate in hexane) to yield 4-(2-(cyanomethoxy)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (200 mg, 33.8%). MS (ESI, positive ion) m/z; 549.1 (M+1)