Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]#[CH:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)=[O:13].[OH:23][CH2:24][CH2:25][O:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O>[OH:23][CH2:24][CH2:25][O:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]#[CH:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:15]=[CH:16][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:18][CH:19]=1)=[O:13]
Reactant: O=Cc1ccccc1OCCO
Reactant: C#CCOc1ccc(N)c(C(=O)c2ccc(C(C)C)cc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C#CCOc1ccc(NCc2ccccc2OCCO)c(C(=O)c2ccc(C(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 100 mg (0.341 mmol) (2-amino-5-propargyloxy-phenyl)-(4-isopropyl-phenyl)-methanone in 1.5 ml CH2Cl2 is added 61 mg (0.36 mmol) 2-(2-hydroxyethoxy)benzaldehyde and 84 mg (0.38 mmol) sodium triacetoxyborohydride. The mixture is stirred at r.t. for two days, diluted with water and extracted with CH2Cl2. Purification of the crude product by chromatography (ethyl acetate/hexanes 1:1) affords a yellow solid.
Reaction SMILES: Cl[C:2]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:7][CH2:6][CH2:5][N:4]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]4)=[C:13]([O:23][CH3:24])[N:12]=3)=[N:9][N:10]=[C:3]12.[F:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][C:32]=1[C:38]([F:41])([F:40])[F:39].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C=O)C>[F:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:2]2([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:7][CH2:6][CH2:5][N:4]3[C:8]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]5)=[C:13]([O:23][CH3:24])[N:12]=4)=[N:9][N:10]=[C:3]23)=[CH:33][C:32]=1[C:38]([F:39])([F:40])[F:41]
Reactant: CCOC(=O)C1(Cl)CCCn2c(-c3ccc(-n4cnc(C)c4)c(OC)n3)nnc21
Reactant: Oc1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(Oc2ccc(F)c(C(F)(F)F)c2)CCCn2c(-c3ccc(-n4cnc(C)c4)c(OC)n3)nnc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 40.2 %

Procedure:
A mixture of ethyl 8-chloro-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (200 mg), 4-fluoro-3-(trifluoromethyl)phenol (91 mg) and potassium carbonate (199 mg) in DMF (2 mL) was stirred at 100° C. for 2 hr. The reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (108 mg).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[N+:16]([C:19]1[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=1[OH:31])[CH2:22][C@@H:23]([C:25]([OH:27])=[O:26])[NH2:24])([O-:18])=[O:17]>>[C:25]([C@@H:23]([NH:24][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:22][C:21]1[CH:28]=[CH:29][C:30]([OH:31])=[C:19]([N+:16]([O-:18])=[O:17])[CH:20]=1)([OH:27])=[O:26]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: N[C@@H](Cc1ccc(O)c([N+](=O)[O-])c1)C(=O)O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(O)c([N+](=O)[O-])c1)C(=O)O
Yield: 10 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 3-nitro-L-tyrosine to provide the title compound in 10% yield as yellow needles.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.CC(C)([O-])C.[Na+].Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[CH3:16][C:13]1([CH3:17])[N:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:11]([CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)[C:14]1=[O:15]
Reactant: Brc1ccccc1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1c1ccccc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
Under an argon atmosphere, a solution of 2-(adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one (50.0 mg, 0.213 mmol) prepared in Process 3 of Example 12 in toluene (1 mL) was added with palladium acetate (II) (1.00 mg, 0.00445 mmol), tri-t-butylphosphine (0.700 mg, 0.00346 mmol), sodium t-butoxide (30.8 mg, 0.320 mmol) and bromobenzene (67.0 mg, 0.427 mmol) sequentially at room temperature, and the resultant was stirred under microwave irradiation at 110° C. for 1 hour. The reaction solution was added with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, the obtained residue was purified using Preparative Thin-Layer chromatography (hexane:ethyl acetate=5:1), and the title compound (42.0 mg, 64.4%) was obtained as a pale yellow amorphous solid.
Reaction SMILES: FC1C=CC(CC(=O)[CH2:10][NH:11][C:12]([C:14]2[N:15]=[C:16]3[CH:32]=[CH:31][C:30]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[CH:29][N:17]3[C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:13])=CC=1.CN1CC[O:44][CH2:43]C1.ClC(OCC)=O.CN(C)O>C1COCC1.C(Cl)Cl>[CH3:43][O:44][N:11]([CH3:10])[C:12]([C:14]1[N:15]=[C:16]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:29][N:17]2[C:18](=[O:28])[C:19]=1[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:13]
Reactant: O=C(CNC(=O)c1nc2ccc(N3CCOCC3)cn2c(=O)c1OCc1ccccc1)Cc1ccc(F)cc1
Reactant: CN1CCOCC1
Agent: CCOC(=O)Cl
Agent: CN(C)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CON(C)C(=O)c1nc2ccc(N3CCOCC3)cn2c(=O)c1OCc1ccccc1
Temperature: -12 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
3-Benzyloxy-7-morpholin-4-yl-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid (product of example 5, 100 mg, 0.263 mmol) was dissolved in THF (1 mL) and DCM (11 mL) and cooled to −20° C. N-Methylmorpholine (30 μL, 0.265 mmol) was added and the temperature was raised to −12° C. Ethyl chloroformate was added and after 2 minutes, the solution of dimethylhydroxylamine. The reaction was warmed to room temperature and stirred for one hour. After this time, the mixture was quenched by addition of 0.2 M HCl. The layers were separated and the organic layer was washed sequentially with 0.2 M HCl, 0.5 M NaOH (2×) and brine. Then dried and concentrated. The product was isolated as a yellow solid (112 mg, 100% yield) and was used without further purification.
Reaction SMILES: [CH2:1]1[C@H:5]2[CH2:6][CH2:7][C@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C@H:4]2[CH2:3][NH:2]1.Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C(O)(CC)(C)C.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:25][C:24]([F:27])([F:26])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:2]1[CH2:3][C@@H:4]2[C@@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:7][CH2:6][C@@H:5]2[CH2:1]1
Reactant: FC(F)(F)c1ccccc1Br
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCC(C)(C)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H]2CN(c3ccccc3C(F)(F)F)C[C@@H]21
Temperature: 80 °C

Procedure:
To a microwave vial under nitrogen was added tert-butyl(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-ylcarbamate from Example 216 step B (290 mg, 1.281 mmol), 1-bromo-2-(trifluoromethyl)benzene (0.183 mL, 1.345 mmol), potassium phosphate, tribasic (446 mg, 2.56 mmol), tris(dibenzylideneacetone)dipalladium(0) (23.47 mg, 0.026 mmol) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-PHOS, 48.9 mg, 0.103 mmol) in t-amyl alcohol (2.0 mL). The reaction was heated at 80° C. for 18 hours. The reaction was diluted with ethyl acetate (35 mL) and quenched with water (75 mL). The organic phase was removed, and the aqueous layer extracted with 50 mL of ethyl acetate. The solvent was removed in vacuo. The crude material was applied to a 24 g silica gel cartridge with ether and purified using 1-50% ethyl acetate/hexanes to give tert-butyl (3aR,4S,6aS)-2-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrol-4-ylcarbamate: 1H NMR (400 MHz, pyridine-d5) δ ppm 7.66 (d, J=7.8, 1H), 7.45 (t, J=7.6, 1H), 7.25 (d, J=8.1, 1H), 7.11 (t, J=7.5, 1H), 4.21 (s, 1H), 3.40 (d, J=9.1, 1H), 3.11 (dd, J=9.1, 6.9, 1H), 3.03-2.88 (m, 2H), 2.69 (d, J=11.5, 2H), 2.17 (dt, J=11.4, 5.7, 1H), 2.04-1.91 (m, 1H), 1.67 (dd, J=18.5, 7.9, 1H), 1.60-1.46 (m, 11H); MS (ESI+) m/z 371 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N+:15]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C1COCC1.[Ni]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH2:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cnccc1OCc1ccccc1
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cnccc1OCc1ccccc1

Procedure:
4-(benzyloxy)-3-nitropyridine (15 g, 65 mmol, 1 eq) was dissolved in THF, then Raney Nickel (2.25 g, 10% w/w) (washed with THF) was added under nitrogen atmosphere and the reaction was stirred at room temperature with 2 kg hydrogen pressure for 6 h. The reaction solution was filtered through celite and the filtrate was concentrated under vacuum to get brown oil. The product was taken to the next step without purification. Yield: 12.3 g (94%). 1HNMR (400 MHz, DMSO-d6): δ 4.86 (s, 2H), 5.18 (s, 2H), 6.88 (d, 1H, J=5.32 Hz), 7.31 (t, 1H, J=3.90 Hz), 7.4 (t, 2H, J=5.08 Hz), 7.5 (t, 2H, J=8.08 Hz), 7.71 (d, J=2.05 Hz, 1H), 7.89 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[S:10][C:11]([C:14]#[N:15])=[CH:12][N:13]=2)[CH:5]=[C:4]([CH2:16]O)[CH:3]=1.CN(C)C=O.P(Cl)(Cl)([Cl:25])=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[S:10][C:11]([C:14]#[N:15])=[CH:12][N:13]=2)[CH:5]=[C:4]([CH2:16][Cl:25])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cnc(Nc2cc(CO)cc(Cl)n2)s1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cnc(Nc2cc(CCl)cc(Cl)n2)s1

Procedure:
2-{[6-Chloro-4-(hydroxymethyl)pyridin-2-yl]amino}-1,3-thiazole-5-carbonitrile 11-7 (0.132 g, 0.49 mmol) was stirred in anhydrous CH2Cl2 (2 mL) under N2. N,N-Dimethylformamide (0.038 mL, 0.49 mmol) was added followed by the addition of phosphorous oxychloride (0.046 mL, 0.49 mmol). After 2.5 hours the reaction was concentrated and quenched by the addition of saturated NaHCO3 (aq). A precipitate formed which was filtered and washed with water to afford 2-{[6-chloro-4-(chloromethyl)pyridin-2-yl]amino}-1,3-thiazole-5-carbonitrile as a yellow solid. 1H NMR (DMSO-d6) δ 12.63 (bs, 1H), 8.34 (s, 1H), 7.24 (s, 1H), 7.17 (s, 1H), 4.82 (s, 2H).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].CC(C)([O-])C.[K+].Br[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1>O1CCCC1>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.17 h

Procedure:
To a solution of diethyl malonate (320 mg, 2 mmol) in tetrahydrofuran (15 ml) was added a solution of potassium tert-butoxide in tetrahydrofuran (1 M, 2.2 ml, 2.2 mmol). After stirring for 10 minutes, 4-bromonitrobenzene (404 mg, 2 mmol) was added. After stirring for 12 hours, the reaction was quenched by addition of saturated aqueous ammonium chloride solution (50 ml) and extracted with ethyl acetate (2×50 ml). The combined extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide crude 2-(4-nitro-phenyl)-malonic acid diethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](Cl)(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].Cl>[OH-].[Na+].C1(C)C=CC=CC=1>[OH:8][C:4]1[CH:3]=[C:2]([NH:1][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(O)c1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)Nc1cccc(O)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 3-amino-phenol (60 g, 6.55 mol) in 2 N NaOH (1 l), cooled to 10° C., pivaloyl chloride (68 ml, 0.55 mol) in toluene (200 ml) is added within 1 h. After stirring for 15 h at 25° C., the mixture is cooled to 0° C. and acidified to pH 1 with conc. HCl. Extraction with EtOAc washing with water, 10% NaHCO3, water, and brine, followed by drying (Na2SO4), evaporation of volatiles, and crystallization (EtOAc/hexanes) gives N-(3-hydroxy-phenyl)-2,2-dimethyl-propionamide.
Reaction SMILES: C(OC(=O)CCCNC(NC1SC(C2C=CC(S(C)(=O)=O)=C(F)C=2)=C(C)N=1)=O)C.[N:30]1([C:35]2[CH:36]=[C:37]([C:45]3[S:49][C:48]([NH2:50])=[N:47][C:46]=3[CH3:51])[CH:38]=[CH:39][C:40]=2[S:41]([CH3:44])(=[O:43])=[O:42])[CH:34]=[CH:33][N:32]=[CH:31]1.[CH2:52]([O:54][C:55](=[O:61])[CH2:56][CH2:57][N:58]=[C:59]=[O:60])[CH3:53]>>[CH2:52]([O:54][C:55](=[O:61])[CH2:56][CH2:57][NH:58][C:59]([NH:50][C:48]1[S:49][C:45]([C:37]2[CH:38]=[CH:39][C:40]([S:41]([CH3:44])(=[O:43])=[O:42])=[C:35]([N:30]3[CH:34]=[CH:33][N:32]=[CH:31]3)[CH:36]=2)=[C:46]([CH3:51])[N:47]=1)=[O:60])[CH3:53]
Reactant: CCOC(=O)CCN=C=O
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(-n2ccnc2)c1
Agent: CCOC(=O)CCCNC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Product: CCOC(=O)CCNC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(-n3ccnc3)c2)s1

Procedure:
The title compound is prepared by the same procedure as 4-{3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-butyric acid ethyl ester (Example 164) by replacing 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72) with 5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 148) and replacing ethyl-4-isocyanatobutyrate with 3-isocyanato-propionic acid ethyl ester.
Reaction SMILES: [OH-].[K+].C(N)CCN.[CH3:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:16].[H][H]>CC(O)C>[CH3:8][O:9][C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16]
Reactant: COC1CCCCC1=O
Reactant: [H][H]
Agent: NCCCN
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CO[C@H]1CCCC[C@H]1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In a 100 ml autoclave were charged 1.75 ml of a 0.2M solution of potassium hydroxide (0.35 mmol) in 2-propanol, 0.2 ml of a 0.1M solution of 1,3-propanediamine (0.02 mmol) in 2-propanol, 1.28 g (10.0 mmol) of 2-methoxycyclohexanone, 8.4 mg (0.005 mmol) of Ru2Cl4 [(S)-BINAP]2NEt3, and 8 ml of 2-propanol in a nitrogen atmosphere, and hydrogen was introduced therein to 50 atm. The mixture was stirred at room temperature for 1.5 hours. The disappearance of the starting material was confirmed by gas chromatography. The solvent was evaporated under reduced pressure, and the residue was distilled under reduced pressure to obtain (1R,2S)-2-methoxycyclohexanol. The optical purity of the product was found to be 93% d.e. and 91% e.e. by gas chromatography.
Reaction SMILES: [C:1]([C:9]([OH:11])=[O:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([O:15][CH2:16][CH:17](O)[CH2:18][OH:19])[CH:13]=[CH2:14]>>[O:8]=[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([O:11][CH:17]([CH2:16][O:15][CH2:12][CH:13]=[CH2:14])[CH2:18][O:19][C:9](=[O:10])[C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: C=CCOCC(O)CO
Product: C=CCOCC(COC(=O)C(=O)c1ccccc1)OC(=O)C(=O)c1ccccc1

Procedure:
The compound of Example A.8 is prepared by the method described in Example A.7 using 2.2 mole equivalents of benzoylformic acid (glyoxalic acid) and 1 mole equivalent of 3-allyloxy-1,2-propanediol.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[CH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2[CH:18]=[C:19]([NH:24][C:25]([C:27]4[CH:32]=[CH:31][C:30]([CH:33]5[CH2:37][CH2:36][N:35]([C:38](OC(C)(C)C)=O)[CH2:34]5)=[CH:29][CH:28]=4)=[O:26])[CH:20]=[CH:21][C:22]=2[CH3:23])[CH:11]=3)=[O:5])[CH2:3][CH2:2]1.C(Cl)Cl.Cl.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.CI>O1CCOCC1.C(OCC)(=O)C>[CH:1]1([C:4]([NH:6][C:7]2[N:8]=[CH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2[CH:18]=[C:19]([NH:24][C:25](=[O:26])[C:27]4[CH:28]=[CH:29][C:30]([CH:33]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34]5)=[CH:31][CH:32]=4)[CH:20]=[CH:21][C:22]=2[CH3:23])[CH:11]=3)=[O:5])[CH2:3][CH2:2]1
Reactant: Cc1ccc(NC(=O)c2ccc(C3CCN(C(=O)OC(C)(C)C)C3)cc2)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccc(C3CCN(C)C3)cc2)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 9 %

Procedure:
To a solution of tert-butyl 3-(4-(3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylphenylcarbamoyl)phenyl)pyrrolidine -1-carboxylate (prepared following the procedures described for Example 15) (0.135 mmol) in methylene chloride (3.0 mL, 47 mmol) was added 4.0 M of hydrogen chloride in 1,4-dioxane (0.50 mL). The reaction mixture was stirred at room temperature for three hours, and then evaporated in vacuo. To this crude product was added potassium carbonate (53.6 mg, 0.388 mmol), N,N-dimethylformamide (3.0 mL, 39 mmol), and methyl iodide (9.0 uL, 0.14 mmol). The reaction mixture was stirred at room temperature for 18 hours, and then potassium carbonate (33.1 mg, 0.239 mmol) and methyl iodide (7.0 uL, 0.11 mmol) were added. The reaction mixture was stirred at room temperature for 24 hours, and then poured into ethyl acetate, washed with 2M aqueous Na2CO3, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 5-20% 1M NH3/MeOH in dichloromethane) to yield 6.0 mg (9%) of N-(3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylphenyl)-4-(1-methylpyrrolidin-3-yl)benzamide. LCMS (ESI): RT (Min)=4.104, M+H=505.2, method=E; 1H NMR (400 MHz, DMSO) δ 10.90 (s, 1H), 10.18 (s, 1H), 9.19 (s, 1H), 8.50 (s, 1H), 8.02 (s, 1H), 7.92 (t, J=9.3 Hz, 3H), 7.81-7.67 (m, 3H), 7.44 (d, J=8.1 Hz, 2H), 7.32 (d, J=8.4 Hz, 1H), 3.52-3.40 (m, 2H), 3.01 (unresolved, 1H), 2.82 (unresolved, 2H), 2.44 (s, 3H), 2.26 (s, 3H), 2.08 (m, 1H), 1.84 (m, 2H), 0.85 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=CC=CC=4)[CH:27]=3)[C:6]3[C:11]([C:12]=2[C:16]2[CH:25]=[CH:24][C:23]4[C:18](=CC=CC=4)[CH:17]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.C([Li])CCC.C[O:42][B:43]([O:46]C)OC>C1COCC1>[C:26]1([C:5]2[C:6]3[C:11]([C:12]([C:16]4[CH:17]=[CH:18][CH:23]=[CH:24][CH:25]=4)=[C:13]4[C:4]=2[CH:3]=[C:2]([B:43]([OH:46])[OH:42])[CH:15]=[CH:14]4)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:35]=[CH:34][CH:33]=[CH:28][CH:27]=1
Reactant: COB(OC)OC
Reactant: Brc1ccc2c(-c3ccc4ccccc4c3)c3ccccc3c(-c3ccc4ccccc4c3)c2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
In an argon atmosphere, 100 mL of dehydrated THF were added to 10 g (20 mmol) of 2-bromo-9,10-di(2-naphtyl)anthracene, and the temperature of the mixture was cooled to −78° C. Then, 14 mL of n-butyllithium (in hexane, 1.6 mol/L) were dropped. After the mixture had been stirred at −78° C. for 1 hour, the temperature of the mixture was increased to 0° C. The temperature of the mixture was cooled to −78° C. again, and 6.6 mL (60 mmol) of trimethoxyborane were added. The mixture was stirred at −78° C. for 1 hour, and was then stirred at room temperature for 2 hours. 100 mL of 10-mass % hydrochloric were added, and the whole was stirred for 1 hour, followed by filtration. The resultant solid was washed with toluene to obtain 4.7 g of 9,10-diphenylanthracene-2-boronic acid (50% yield).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:28]([NH:32][S:33]([C:36]1[S:37][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:39][CH:40]=1)(=[O:35])=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([NH:32][S:33]([C:36]1[S:37][C:38]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=4)[N:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:39][CH:40]=1)(=[O:34])=[O:35])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(-c3ccnc(I)c3)n2)cc1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)ccn2)s1

Procedure:
The title compound was prepared from 2′-iodo-4-trifluoromethyl-6-(4-trifluoromethylphenyl)-[2,4′]bipyridinyl (example E.98) (0.494 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.380 g, 1.1 mmol) according to the general procedure VI. Obtained as a white solid (0.360 g, 62%). MS (ISP) 586.2 [(M+H)+]; mp 220° C.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[I:24](O)(=O)(=O)=O.II.S(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[I:24][C:4]1[CH:3]=[CH:2][C:1]([C@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])=[CH:6][CH:5]=1
Reactant: [O-][I+3]([O-])([O-])O
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccccc1
Agent: II
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(I)cc1
Temperature: 60 °C
Yield: 54.2 %

Procedure:
(+,−) Cis-propane-2-sulfonic acid (2-phenyl-cyclopentyl)-amide (1.8 g, 6.7 mmol, prepared in example 16) was dissolved in 20 mL of glacial acetic acid and 0.7 mL (7.1 mmol) of concentrated sulfuric acid added followed by 2 mL of water. To this solution was added periodic acid (0.35 g, 1.6 mmol) and iodine (0.77 g, 3.0 mmol). The resulting mixture was heated to 60° C. for 3 hours. The reaction was cooled to room temperature and 20 mL of a 10% aqueous solution of sodium bisulfite was added. The product was extracted into ethyl acetate then washed with water, dilute sodium bicarbonate, and dried over magnesium sulfate. Filtered and concentrated in vacuo to 2.2 g of crude yellow oil. This oil was purified by reverse phase chromatography to give 341 mg (13%) of the title compound as a white solid. The NMR was consistent with the assigned structure.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].C(Cl)(Cl)Cl.[C:14](Cl)(=[O:16])[CH3:15]>C(N(CC)CC)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(C)c(O)c1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1cc(C)ccc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.3 %

Procedure:
At 0° C., to a mixture of 2,5-dimethylphenol 20 g and chloroform 150 ml was added acetyl chloride 15 g and triethylamine 49 g. The resulting mixture was raised to room temperature and was stirred for four hours. Then, the reaction mixture was extracted with chloroform. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give acetic acid 2,5-dimethylphenyl ester 24 g.