Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([NH:8]N)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([CH:13]([CH3:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=O)[CH3:11]>C(O)(=O)C>[CH3:11][C:10]1[C:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])([CH3:22])[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1
Reactant: NNc1ccccc1
Reactant: CC(=O)C(C)CCCCCC(=O)O
Agent: Cl
Solvent: CC(=O)O
Product: CC1=Nc2ccccc2C1(C)CCCCCC(=O)O
Yield: 61.7 %

Procedure:
To a stirred solution of phenylhydrazine hydrochloride (Aldrich, 7.2 g, 0.05 mol) in acetic acid (50 ml) was added 7-acetyloctanoic acid (11 g, 0.06 mol). The reaction mixture was heated under reflux for 4 hrs. The solution was cooled. (No clear precipitate was observed). Acetic acid was removed under reduced pressure. The resulting yellow liquid was chromatographed on a silica gel column using chloroform/methanol mixture as solvent. Pure 6-(2,3-dimethyl-3H-indol-3-yl)hexanoic acid (8.0 g, 61%) was obtained as pale yellow oil which crystallized on standing, m.p. 115-118° C.; IR νcm−1=2927, 2860, 2526, and 1709. 1H NMR, CDCl3, δ, 7.6 (d, 1H, J=7 Hz, 4-H); 7.2-7.4 (m, 3H, aromatic protons); 2.25 (s, 3H, —CH3); 2.1-2.2(t, —CH2COOH); 1.72-1.94 (m 2H, —CH2); 1.4-1.45 (m, 2H, —CH2); 1.23-1.05 (m, singlet merged in m, 5H, —CH2, —CH3); 0.55-0.85 (m, 2H, —CH2). TLC, Rf=0.22 (silica gel, methanol-chloroform, 5:95).
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[NH:6][C:5]1=[O:24])[CH:2]=[CH2:3].[H-].[Na+].Br[CH:28]([CH2:33][CH3:34])[C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C>[CH2:1]([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:28]([CH2:33][CH3:34])[C:29]([O:31][CH3:32])=[O:30])[C:5]1=[O:24])[CH:2]=[CH2:3]
Reactant: CCC(Br)C(=O)OC
Reactant: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)OC)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.3 g (3.61 mmol) of (3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 42, Step A) in DMF (14.43 mL) at 0° C. was added a dispersion of 60% sodium hydride in mineral oil (0.361 g, 9.02 mmol). The grey slurry was stirred at 0° C. for 30 minutes. Then methyl 2-bromobutanoate (1.246 mL, 10.83 mmol) was added. The mixture was warmed to room temperature and stirred at room temperature for 1 h. The mixture was quenched with sat. NH4Cl. The mixture was extracted with ethyl acetate. The organic layer was washed with water, 1 M LiCl (2×), and sat. aq. NaCl solution. The organic layer was dried over Na2SO4 filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (80 g column; eluent: 10 to 35% EtOAc in hexanes) to give the title compound as the less polar, major diastereomer.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]=[CH:6][CH:7]=[CH:8][CH2:9][CH:10]([O:19][CH3:20])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)C.[Li+].[OH-]>CO>[CH3:20][O:19][CH:10]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH2:9][CH:8]=[CH:7][CH:6]=[CH:5][C:4]([OH:21])=[O:3]
Reactant: CCOC(=O)C=CC=CCC(OC)c1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(CC=CC=CC(=O)O)OC)cc1
Temperature: 40 °C
Reaction time: 16 h
Yield: 92.2 %

Procedure:
To a stirred solution of diene ester 3 (0.36 g, 1.24 mmol) in methanol (10 mL) at rt was added aqueous LiOH 0.5 N solution (3.4 mL, 1.7 mmol). After being stirred at 40° C. for 16 h, methanol was removed under reduced pressure and the resulting aqueous solution was acidified with 3N HCl (pH=ca. 4), extracted with ethyl acetate (25×3 mL), dried (MgSO4), and concentrated under reduced pressure to give the desired carboxylic acid 4 (0.30 g, 92% yield). Without further purification, the crude product was used in the next step: 1H NMR (300 MHz, CD3OD): δ 7.23 (d, J=9.0 Hz, 2H), 7.00 (dd, J=15.3, 10.5 Hz, 1H), 6.93 (d, J=9.0 Hz, 2H), 6.17 (dd, J=15.3, 10.5 Hz, 1H), 5.93 (dd, J=15.3, 10.5 Hz, 1H), 5.85 (d, J=15.3 Hz, 1H), 4.20 (br t, J=6.6 Hz, 1H), 3.82 (s, 3 H ), 3.20 (s, 3H), 2.61 (m, 1H), 2.48 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[CH:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20].C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[CH3:16][CH:7]([O:6][C:5]1[CH:17]=[CH:18][C:2]([C:24]2[CH:25]=[CH:26][C:21]([CH:19]=[O:20])=[CH:22][CH:23]=2)=[CH:3][CH:4]=1)[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(C=O)cc2)cc1
Yield: 30.3 %

Procedure:
The title compound (82 mg, 30%, yellow foam) was prepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (252 mg, 0.749 mmol, prepared in example 1), 4-formylbenzeneboronic acid (135 mg, 0.900 mmol), dichlorobis(triphenylphosphine)palladium(II) (21 mg, 0.030 mmol), 2 M sodium carbonate (270 mg in 1.3 mL water), and 1,2-dimethoxyethane (5 mL) in a manner analogous to the procedure described in Example 8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[CH:27]=[C:26]([C:28]([C:30]2[CH:40]=[C:39]([CH3:41])[C:33]3[N:34]([CH3:38])[C:35](=[O:37])[O:36][C:32]=3[CH:31]=2)=[O:29])[C:25]([CH3:42])=[CH:24][N:23]=1>CN(C=O)C>[CH3:38][N:34]1[C:33]2[C:39]([CH3:41])=[CH:40][C:30]([C:28]([C:26]3[C:25]([CH3:42])=[CH:24][N:23]=[C:22]([N:17]4[CH2:18][CH2:19][CH:14]([N:10]5[CH2:9][CH2:8][C:7]6[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=6[NH:12][C:11]5=[O:13])[CH2:15][CH2:16]4)[CH:27]=3)=[O:29])=[CH:31][C:32]=2[O:36][C:35]1=[O:37]
Reactant: Cc1cnc(Cl)cc1C(=O)c1cc(C)c2c(c1)oc(=O)n2C
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)c(C)cn3)CC1)C(=O)N2
Temperature: 300 °C

Procedure:
0.33 g (1.2 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 0.13 g (0.40 mmol) 6-(2-chloro-5-methyl-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one (mixture) were combined and heated to 300° C. for approx. 10 min. Then the mixture was dissolved in DMF and purified by preparative HPLC-MS. The fractions containing the product were combined and the organic solvent was evaporated down. The residue was neutralised with 1N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried i. vac.
Reaction SMILES: [CH2:1]([C:8]1[C:16]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[N:18]=2)=[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][N:10]2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].C(Cl)(Cl)(Cl)[Cl:38]>O1CCCC1>[CH2:1]([C:8]1[C:16]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)[N:18]=2)=[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([Cl:38])[N:10]2[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: c1ccc(Cc2nn3ccccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Clc1cccc2c(-c3ccnc(NC4CCCC4)n3)c(Cc3ccccc3)nn12
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 26.5 %

Procedure:
To a cold (−78° C.) solution of 4-(2-benzylpyrazolo[1,5-a]pyridin-3-yl)-N-cyclopentyl-2-pyrimidinamine (207 mg, 0.560 mmol) in tetrahydrofuran (7 mL) was added lithium diisopropylamide (17.5 mL, 0.16 M in tetrahydrofuran, 2.80 mmol). The reaction mixture was stirred at −78° C. for 45 minutes, then carbon tetrachloride (542 μl, 5.60 mmol) was added. The reaction mixture was stirred for an additional 30 minutes at −78° C. The reaction mixture was quenched with water, warmed to room temperature, and extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration, followed by flash chromatography (4:1 hexanes:ethyl acetate) provided 4-(2-benzyl-7-chloropyrazolo[1,5-a]pyridin-3-yl)-N-cyclopentyl-2-pyrimidinamine (60 mg, 27%) as a yellow solid. 1H NMR (CDCl3) δ 8.35 (d, 1H), 8.21 (d, 1H), 7.35–7.16 (m, 6H), 7.04 (d, 1H), 6.64 (d, 1H), 5.20 (d, 1H), 4.60 (s, 2H), 4.37 (m, 1H), 2.09 (m, 2H), 1.82–1.48 (m, 6H); MS m/z 404 (M+1).
Reaction SMILES: [CH2:1]([Si:3]([CH2:18][CH3:19])([CH2:16][CH3:17])[O:4][C:5]1([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:9][C:8](=[O:11])[CH:7]=[CH:6]1)[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:16]([Si:3]([CH2:1][CH3:2])([CH2:18][CH3:19])[O:4][C:5]1([C:12]([F:14])([F:13])[F:15])[CH2:6][CH2:7][C:8](=[O:11])[CH2:9][CH2:10]1)[CH3:17]
Reactant: CC[Si](CC)(CC)OC1(C(F)(F)F)C=CC(=O)C=C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC[Si](CC)(CC)OC1(C(F)(F)F)CCC(=O)CC1

Procedure:
A solution of 291 mg of 4-triethylsiloxy-4-trifluoromethyl-2,5-cyclohexadien-1-one in 2 mL of absolute ethanol was treated with a few mg of 5% palladium on carbon, hydrogenated in a Parr shaker for one hour under 50 psig of hydrogen, and filtered. Concentration of the filtrate gave 4-triethylsiloxy-4-trifluoromethylcyclohexanone: 1H NMR (CDCl3) δ 0.45-1.16 (m, 15H), 1.92-2.89 (m, 8H); mass spectrum (70 eV) m/z (relative intensity) 267 (19, M-C2H5), 115 (45), 105 (33), 87 (100), 81 (22), 77 (67), 73 (20), 67 (29), 59 (57), 55 (84), 47 (20).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12](N(C)OC)=[O:13].CC(C[AlH]CC(C)C)C>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[CH:12]=[O:13]
Reactant: CON(C)C(=O)C1OCCc2c(Br)cccc21
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: O=CC1OCCc2c(Br)cccc21
Temperature: -30 °C
Reaction time: 1 h

Procedure:
A solution of 5-bromo-N-methyl-N-(methyloxy)-3,4-dihydro-1H-isochromene-1-carboxamide (3.0 g, 10 mmol) in 60 mL of anhydrous THF was cooled to −30° C. and then DIBAL-H (20 mmol) was added. The mixture was stirred at −30° C. for 1 hours. The reaction was quenched with water, extracted with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude 5-bromo-3,4-dihydro-1H-isochromene-1-carbaldehyde was used for next step without purification.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[S:11][C:5]=2[C:4]([CH2:23][CH:24]([CH3:26])[CH3:25])=[N:3]1.C1(C)C=CC(S(=O)([S:35][CH2:36][CH2:37][CH2:38][O:39][Si](C(C)(C)C)(C)C)=O)=CC=1>>[OH:39][CH2:38][CH2:37][CH2:36][S:35][C:9]1[C:6]2[C:7](=[O:8])[N:2]([CH3:1])[N:3]=[C:4]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:5]=2[S:11][C:10]=1[CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)Cc1nn(C)c(=O)c2cc(Cc3cccc4ccccc34)sc12
Reactant: Cc1ccc(S(=O)(=O)SCCCO[Si](C)(C)C(C)(C)C)cc1
Product: CC(C)Cc1nn(C)c(=O)c2c(SCCCO)c(Cc3cccc4ccccc34)sc12

Procedure:
Prepared from 5-methyl-7-(2-methylpropyl)-2-(1-naphthalenylmethyl)thieno[2,3-d]-pyridazin-4(5H)-one (385 mg) prepared as described in Example 7 above and S-{3-[(1,1-dimethylethyl)dimethylsilyl]oxypropyl} paratoluenethiosulfonate (600 mg) (J. Med. Chem., 1995, 38, 2557) following the method of Example 3. Yield 370 mg.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:12]([C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][C:15]=1[CH3:23])#[N:13].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[C:12]([C:14]1[CH:22]=[CH:21][C:17]([C:18]([N:1]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:19])=[CH:16][C:15]=1[CH3:23])#[N:13]
Reactant: c1ccc2c(c1)CCCCN2
Reactant: Cc1cc(C(=O)O)ccc1C#N
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1C#N

Procedure:
To a solution of 2,3,4,5-tetrahydro-1H-1-benzazepine (0.80 g, 5.44 mmol) in dichloromethane (40 ml) were added 4-cyano-3-methylbenzoic acid from example C (0.96 g, 5.95 mmol), triethylamine (0.76 g, 5.44 mmol), 4-(dimethylamino)pyridine (0.66 g, 5.44 mmol) and WSCDI (2.17 g, 10.88 mmol). The mixture was stirred at reflux for 18 h, cooled and evaporated in vacuo. The residue was partitioned between EtOAc and 1M KHSO4. The organic layer was washed with saturated sodium bicarbonate solution and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 30:70); yield 1.10 g (70%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[N:9]=[N:10][N:11]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]=1[C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[Cl:42])=[O:35].[C:43](OC(=O)C)(=[O:45])[CH3:44].C([O-])(=O)C.[Na+]>>[F:32][C:30]([F:31])([F:33])[C:22]1[CH:21]=[C:20]([CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=1)[CH2:19][N:11]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:8]([C:4]2[C:3]([C:34](=[O:35])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[Cl:42])=[C:2]([NH:1][C:43](=[O:45])[CH3:44])[CH:7]=[CH:6][N:5]=2)[N:9]=[N:10]1
Reactant: Nc1ccnc(-c2nnn(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2-c2ccccc2)c1C(=O)c1ccccc1Cl
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CC(=O)Nc1ccnc(-c2nnn(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2-c2ccccc2)c1C(=O)c1ccccc1Cl
Temperature: 80 °C
Reaction time: 13 h

Procedure:
Combine {4-amino-2-[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-pyridin-3-yl}-(2-chloro-phenyl)-methanone (840 mg, 0.067 mmol) and 2.0 ml of acetic anhydride and sodium acetate (18.2 mg, 0.134 mmol). Seal the reaction mixture in a pyrex tube and heat to 80° C. After 13 hours, cool to RT. Pour the mixture through a plug of Celite® (1 cm) and silica gel (2 cm). Concentrate the clear liquid to 1.0 mL and apply to a 2 mm chromatotron plate and elute with a EtOAc/hexane gradient to provide 26 mg of the title compound: Exact Mass 643.1; mass spectrum (IS): m/z=643.9 (M+1), m/z=641.8 (M−1); 1H NMR (250 MHz, CDCl3) 9.69 (s, 0.6H), 8.39 (s, 1H), 7.74 (s, 1H), 7.15-7.49 (m, 5H), 7.27 (s, 2H), 6.80-7.05 (m, 5H), 5.26 (s, 2H), 2.16 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[O:12][CH3:13])=[C:9]([CH:14]1[CH2:16][CH2:15]1)[CH:8]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[C:6]2=[O:21].[NH2:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1>>[NH2:22][C:23]1[N:24]=[CH:25][C:26]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[O:12][CH3:13])=[C:9]([CH:14]2[CH2:16][CH2:15]2)[CH:8]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[C:6]3=[O:21])=[CH:27][CH:28]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: COC(=O)c1cc(C2CC2)c2c(OC)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(OC)c(-c3ccc(N)nc3)ccn2c1=O
Yield: 59.9 %

Procedure:
Methyl 8-(6-amino-pyridin-3-yl)-1-cyclopropyl-9-methoxy-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methoxy-4-oxo-4H-quinolizine-3-carboxylate (50 mg, 0.16 mmol), and 2-aminopyridine-5-boronic acid pinacol ester (42.9 mg, 0.20 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as an orange solid (35 mg, 57%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH2:12](O)[CH3:13].O=S(Cl)Cl>C(OCC)(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: CCO
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1ccc(O)cc1

Procedure:
A mixture of 4-hydroxyphenylacetic acid (g.12 g, 0.06 mol), absolute ethanol (50 mL) and SOCl2 (2 mL, 0.028 mol) was refluxed for 3 hours. The residue was cooled, diluted with ethyl acetate (200 L), washed first with dilute aqueous sodium bicarbonate (100 mL) and then twice with water (100 mL), then was dried over anhydrous MgSO4, filtered and evaporated in vacuo. Ethyl 4-hydroxyphenylacetate was obtained as an oil.
Reaction SMILES: C([O:8][C:9](=[O:39])[CH2:10][CH:11]([N:22]1[CH:26]=[CH:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)[CH2:23]1)[C:12]([NH:14][C@H:15]([CH2:20][OH:21])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])C1C=CC=CC=1>CCO>[C:30]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:29]=[CH:28][C:27]([N:24]2[CH:25]=[CH:26][N:22]([CH:11]([C:12]([NH:14][C@H:15]([CH2:20][OH:21])[C:16]([CH3:17])([CH3:19])[CH3:18])=[O:13])[CH2:10][C:9]([OH:39])=[O:8])[CH2:23]2)=[CH:32][CH:31]=1
Reactant: CC(C)(C)[C@@H](CO)NC(=O)C(CC(=O)OCc1ccccc1)N1C=CN(c2ccc(-c3ccccc3)cc2)C1
Solvent: CCO
Product: CC(C)(C)[C@@H](CO)NC(=O)C(CC(=O)O)N1C=CN(c2ccc(-c3ccccc3)cc2)C1

Procedure:
According to the procedure described in Example 1(a), a suspension of 3(RS)-(3-biphenyl-4-yl-1H-imidazol-1-yl)-N-(2,2-dimethyl-1(S)-hydroxymethylpropyl)succinamic acid benzyl ester in EtOH was hydrogenated to provide 3(RS)-(3-biphenyl-4-yl-1H-imidazol-1-yl)-N-(2,2-dimethyl-1(S)-hydroxymethylpropyl)succinamic acid as a solid, mp 145-50° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[OH:9]O>C(O)(=O)C.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N+:3]=1[O-:9]
Reactant: Cc1ccc(C)nc1
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(C)[n+]([O-])c1
Temperature: 90 °C
Reaction time: 48 h

Procedure:
A mixture of 2,5-dimethylpyridine (12.5 g, 0.12 mol) and 30% hydrogen peroxide (30 mL) in acetic acid (25 mL) was stirred at 90° C. for 48 h. The reaction mixture was diluted with water (50 mL) and concentrated to a volume of approximately 25 mL. The concentrated solution was neutralized with solid sodium carbonate, extracted with DCM (100 mL×3), dried with anhydrous sodium sulfate, and concentrated to give 14.4 g of the product as a yellow oil. MS (ESI): m/z 124.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[H-].[Na+].[CH3:15]I>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[C:11]([NH:12][CH3:15])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: Nc1cc2ccccc2cc1N
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNc1cc2ccccc2cc1N
Temperature: 2.5 °C
Reaction time: 0.12 h
Yield: 30.9 %

Procedure:
A solution of 2,3-diaminonaphthalene (500 mg, 3.16 mmol) in anhydrous dimethylformamide (3 mL) was cooled in an ice bath and treated with sodium hydride (130 mg of a 61% dispersion in mineral oil, 3.31 mmol). The mixture was stirred at 0-5° C. for 7 minutes, then treated with methyl iodide (0.206 mL, 3.31 mmol) and stirred in the cold for an additional 15 minutes. After warming to room temperature, the mixture was diluted with ethyl acetate (30 mL), washed with water (5×30 mL) and brine (20 mL), dried over magnesium sulfate, filtered, and evaporated under vacuum to a dark solid (0.5 g). The crude product was purified by silica gel chromatography (2.75×24 cm column) using 5% ethyl acetate in dichloromethane as eluting solvent. The product fractions were combined and evaporated to afford 2-amino-3-methylamino-naphthalene (168 mg) as a solid.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][C@@H:8]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:7]([CH2:21][C:22]#[N:23])[CH2:6][CH2:5]1)=[N+]=[N-].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[NH2:1][C@@H:4]1[CH2:9][C@@H:8]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:7]([CH2:21][C:22]#[N:23])[CH2:6][CH2:5]1
Reactant: N#CC[C@H]1CC[C@H](N=[N+]=[N-])C[C@H]1NC(=O)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N#CC[C@H]1CC[C@H](N)C[C@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
To a mixture of benzyl [(1R,2R,5S)-5-azido-2-(cyanomethyl)cyclohexyl]carbamate (45 mg, 0.14 mmol) in tetrahydrofuran (1.5 mL) was added water (13 μL, 0.73 mmol) and resin of triphenylphosphine (150 mg, 0.29 mmol). The resulting mixture was stirred overnight at room temperature. The mixture was filtered and dried in vacuo to give 32 mg of crude product. LCMS calculated for C16H22N3O2 (M+H)+: m/z=288.2. Found: 288.0. The crude was used without further purification.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].CO.[H][H]>C(Cl)Cl.[Ru]>[OH:1][C@H:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: CCC(=O)CC(=O)OC
Reactant: [H][H]
Agent: [Ru]
Solvent: ClCCl
Solvent: CO
Product: CC[C@@H](O)CC(=O)OC
Yield: 98.1 %

Procedure:
Into a 200-ml autoclave (made of Hastelloy) were introduced 50 g of methyl 3-oxopentanoate (manufactured by Wacker Chemicals Co., Ltd.) and 75 ml of methanol. The atmosphere in the autoclave was replaced with nitrogen gas. Thereto was added a solution prepared by dissolving 325 mg of Ru2Cl4 ((+)-(T)BINAP)2Et3N as a ruthenium-optically active phosphine complex in 3.8 ml of methylene chloride. Asymmetric hydrogenation was conducted at a reaction temperature of 30° C. and a hydrogen pressure of 30 atm. After the reaction mixture was thus reacted for 50 hours, it was taken out of the autoclave. The methanol was distilled off, and the residue was subjected to vacuum distillation to obtain 49.8 g of methyl (R)-3-hydroxypentanoate. Yield, 98%.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[N:19]=[C:20]([C:23]6[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=O)=[CH:25][CH:24]=6)[CH:21]=[N:22][C:17]5=[N:16][N:15]=4)[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C[Al](C)C.[CH:37]1([CH2:40][NH2:41])[CH2:39][CH2:38]1>C1(C)C=CC=CC=1.CO>[CH:37]1([CH2:40][NH:41][C:27](=[O:29])[C:26]2[CH:25]=[CH:24][C:23]([C:20]3[CH:21]=[N:22][C:17]4[N:18]([C:14]([C:11]5([C:7]6[CH:6]=[C:5]7[C:10](=[CH:9][CH:8]=6)[N:1]=[CH:2][CH:3]=[CH:4]7)[CH2:12][CH2:13]5)=[N:15][N:16]=4)[N:19]=3)=[CH:32][CH:31]=2)[CH2:39][CH2:38]1
Reactant: COC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1
Reactant: NCC1CC1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(NCC1CC1)c1ccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzoate (15 mg, 0.036 mmol) in toluene (0.2 mL) was added 2.0 M of trimethylaluminum in toluene (27 μL) at RT followed by addition of cyclopropylmethylamine (5.0 mg, 0.071 mmol). The mixture was stirred at 70° C. overnight. After cooling the mixture was diluted with methanol, and filtered. The filtrate was purified by RP-HPLC (pH=10) to afford the desired product. Analytical LCMS: (M+H)+=462.4.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=O)=[CH:24][C:23]=1[F:31]>>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)=[CH:24][C:23]=1[F:31]
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: O=C(O)c1ccc(Cl)c(F)c1
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3ccc(Cl)c(F)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 241 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 4-chloro-3-fluorobenzoic acid: MS (ES) m/z 421 (M+1).