Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=1)[CH2:10][C:9]2([CH3:24])[CH3:23])=[O:5])[CH3:2].[CH3:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:36]3[CH2:37][CH2:38][N:33]([C:27]4[CH:28]=[CH:29][C:30]([CH3:32])=[CH:31][C:26]=4[CH3:25])[CH2:34][CH2:35]3)[CH:17]=1)[CH2:10][C:9]2([CH3:24])[CH3:23])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(Br)c1)N2
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(N3CCN(c4ccc(C)cc4C)CC3)c1)N2
Temperature: 120 °C
Yield: 56.3 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.39 g, 1.0 mmol), 1-(2,4-dimethyl-phenyl)-piperazine (0.29 g, 1.5 mmol), palladium (II) acetate (6.73 mg, 0.03 mmol), xantphos (23 mg, 0.04 mmol) and cesium carbonate (0.65, 2.0 mmol) in toluene (10 mL) was heated for 3 h at 120° C. After colling to room temperature, the mixture was treated with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (50% ethyl acetate/hexanes) to afford 2-{3-[4-(2,4-dimethyl-phenyl)-piperazin-1-yl]-phenyl}-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.28 g, 56%) as a white solid: MS (ESI) M+1=498.3.
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]=[C:2]2[C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1.[CH:18]1[CH:19]=[CH:20][N:21]2[CH2:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[NH:24][CH2:23][C:22]=12>>[CH:18]1[CH:19]=[CH:20][N:21]2[CH2:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[N:24]([C:13]([C:12]3[CH:16]=[CH:17][C:9]([C:2]4[CH:1]5[CH2:8][CH:5]([CH2:4][CH:3]=4)[CH2:6][CH2:7]5)=[CH:10][CH:11]=3)=[O:14])[CH2:23][C:22]=12
Reactant: O=C(O)c1ccc(C2=CCC3CCC2C3)cc1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Product: O=C(c1ccc(C2=CCC3CCC2C3)cc1)N1Cc2cccn2Cc2ccccc21
Yield: 86.1 %

Procedure:
4-Bicyclo[3.2.1]oct-2-en-2-yl-benzoic acid of Step B (0.270 g, 1.18 mmol) and 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.240 g, 1.30 mmol) were reacted in the manner of Example 15, Step D. Purification by flash column chromatography on silica gel, eluting with 20% ethyl acetate in hexane, followed by recrystallization from petroleum ether afforded the title compound (0.401 g) as white crystals, m.p. 157° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[Cl-].[Al+3].[Cl-].[Cl-].[Br:17]Br.[OH-].[Na+]>>[Br:17][C:3]1[C:2]([F:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH3:12])=[N:8]2
Reactant: Cc1ccc2cc(F)ccc2n1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Product: Cc1ccc2c(Br)c(F)ccc2n1
Temperature: 80 °C
Yield: 76.6 %

Procedure:
20.1 g (0.125 mole) of 6-fluoro-2-methylquinoline was added to 25.3 g (0.189 mole) of aluminum chloride at a temperature of 60° C. 19.98 g (0.125 mole) of bromine was added as a gas. The reaction mixture was heated overnight at 80° C. The reaction mixture was then poured onto ice, and 50% aqueous sodium hydroxide was added until the bulk of the solids had dissolved. The mixture was then extracted with toluene. The toluene extract was dried with magnesium sulfate and evaporated under vacuum to give 23 g of 5-bromo-6-fluoro-2-methylquinoline as a light tan solid. The structure was confirmed by nuclear magnetic resonance spectral analysis.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:30])[N:4]([C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][C:20]=2[F:29])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].CO.O.[OH-].[Na+]>O1CCCC1>[Br:1][C:2]1[C:3](=[O:30])[N:4]([C:19]2[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=2[F:29])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: COC(=O)c1ccc(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1ccc(C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound of Example 604 (4.1 g, 8.5 mmol) was suspended in tetrahydrofuran (30 mL), methanol (15 mL), water (15 mL) and 2.5 N NaOH (6.8 mL, 17 mmol)). After stirring at room temperature for 2 hour, the reaction was complete and the organics were removed. The aqueous layer was acidified to pH 1 with 3N HCl, the solids were suspended in water, filtered, and washed with diethyl ether. The title compound was obtained as a white powder and used without further purification (4.4 g). 1H NMR (400 MHz, CD3OD) δ 8.00 (dd, J=1.8 and 8.8 Hz, 1H), 7.93 (dd, J=1.48 and 10 Hz, 1H), 7.64 (q, J=8 and 14.8 Hz, 1H), 7.49 (t, J=7.6 Hz, 1H), 7.05 (t, J=10 Hz, 2H), 6.66 (s, 1H), 5.36 (s, 2H), 2.08 (s, 3H) ppm. 19F NMR (400 MHz, CD3OD) δ −111.48 (1F), −115.96 (1F), −123.35 (1F) ppm. ES-HRMS m/z 468.9987 (M+H calcd for C20H14BrF3NO4 requires 469.0086).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[N:21]([CH2:24][CH2:25][CH2:26]/[C:27](/[C:43]1O[C:45]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=2)=[N:46][N:47]=1)=[CH:28]\[C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]2)=[C:31]([O:41][CH3:42])[CH:30]=1)=[N+]=[N-]>C1COCC1>[F:55][C:52]1[CH:53]=[CH:54][C:49]([CH2:48][C:45]2[N:21]3[CH2:24][CH2:25][CH2:26]/[C:27](=[CH:28]\[C:29]4[CH:34]=[CH:33][C:32]([N:35]5[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]5)=[C:31]([O:41][CH3:42])[CH:30]=4)/[C:43]3=[N:47][N:46]=2)=[CH:50][CH:51]=1
Reactant: COc1cc(/C=C(\CCCN=[N+]=[N-])c2nnc(Cc3ccc(F)cc3)o2)ccc1-n1cnc(C)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(/C=C2\CCCn3c(Cc4ccc(F)cc4)nnc32)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 88.2 %

Procedure:
Triphenylphosphine (28 mg) and water (0.3 mL) were added to a solution of 2-{4-azido-1-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene}butyl}-5-(4-fluorobenzyl)[1,3,4]oxadiazole (50 mg) in THF (5 mL), and the reaction solution was heated under reflux for four hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. A solution of the residue in acetic acid (2 mL) was heated under reflux for three hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: ethyl acetate→ethyl acetate:methanol=5:1) to obtain 40 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:10])[C:7]([CH3:9])=[CH2:8])[CH:2]1[O:4][CH2:3]1.C[O:12]C1C=CC(O)=CC=1.S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O>[C:6]([O:5][CH2:1][CH:2]([CH2:3][OH:12])[OH:4])(=[O:10])[C:7]([CH3:9])=[CH2:8]
Reactant: COc1ccc(O)cc1
Reactant: C=C(C)C(=O)OCC1CO1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C=C(C)C(=O)OCC(O)CO
Reaction time: 18 h
Yield: 80 %

Procedure:
Into a two phase mixture of 86 g (0.6 mol) of comercial glycidylmethacrylate containing 200 ppm of MEHQ and 500 ml of water is added 2 ml of concentrated sulfuric acid at ambient temperature. After stirring approximately 18 hours, the mixture appeared as a clear homogenous solution. To the resultant solution is added sufficient sodium sulfate to cause separation of an oil. The 2 phase mixture is extracted sequentially with 5 portions of 150 ml each of chloroform and the combined chloroform extracts are dried over solid sodium sulfate. After filtering the solid sodium sulfate, the solvent is removed by evaporation to give 77 g (80%) of glycerol mono-methacrylate as a clear colorless oil. The monomer can be used without further purification or can be further purified by chromatography to separate trace amounts of glycerol di-methacrylate.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34]([C@@H:37]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:38]Br)=[CH:33][C:32]=1[NH:48][CH:49]=[O:50])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[I-].[Na+].C(=O)([O-])O.[Na+]>CS(C)=O.O>[C:1]12([CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][CH2:38][C@@H:37]([C:34]4[CH:35]=[CH:36][C:31]([O:30][CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[C:32]([NH:48][CH:49]=[O:50])[CH:33]=4)[O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:42])[CH3:43])=[CH:16][CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: NCCc1ccc(OCCC23CC4CC(CC(C4)C2)C3)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(NC=O)c1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCc1ccc(OCCC23CC4CC(CC(C4)C2)C3)cc1)c1ccc(OCc2ccccc2)c(NC=O)c1
Temperature: 130 °C

Procedure:
To a solution of Intermediate 22 (0.4 g, 1.34 mmol) and (R)—N-(2-(benzyloxy)-5-(2-bromo-1-(tert-butyldimethylsilyloxy)ethyl)phenyl)formamide (0.62 g, 0.82 mmol) in dimethyl sulfoxide (3 mL) was added sodium iodide (0.59 g, 3.99 mmol) and sodium hydrogen carbonate (0.67 g, 8.03 mmol). The reaction mixture was heated under argon at 130° C. for 1 hour. The mixture was poured into water and extracted with ether. The organic layer was washed with water and brine and the solvent was removed under reduced pressure. The title compound was obtained as yellow foam (0.84 g, 73%) and used in the next step without further purification. MS (M+): 684.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:2]=1.C(O)(=O)C>CO>[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17])[CH2:2]1
Reactant: CC(C)(C)OC(=O)Nc1cnc2ccccc2c1
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CNc2ccccc2C1
Reaction time: 16 h
Yield: 75.4 %

Procedure:
To a solution of 3-quinolinylcarbamic acid, 1,1-dimethylethyl ester (6.0 g, 24.56 mmol) in MeOH (150 mL) was added acetic acid (18 mL). The mixture was bubbled with argon for 15 min, then palladium hydroxide (20 weight % palladium on carbon) (1.2 g) was added. The resulting suspension was subjected to hydrogenation under 45 psi of pressure for 16 h, then filtered. The filtrate was concentrated and the residue taken in CH2Cl2. The resulting CH2Cl2 solution was washed with saturated aqueous NaHCO3, saturated aqueous NaCl, dried (Na2SO4) and concentrated. The residue was chromatographed (silica gel) eluting with EtOAc (0 to 50%) in hexanes to give 1A (4.6 g, 75% yield) as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[NH:22][C:21](=[O:23])[O:20][N:19]=2)=[C:14]([Cl:24])[CH:13]=1)[CH2:2][CH:3]=[CH2:4].[OH-:35].[Na+].OO.O>O1CCCC1>[Cl:24][C:14]1[CH:13]=[C:12]([O:11][CH2:10][C:9]2[S:8][C:7]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:32])[F:34])=[CH:27][CH:26]=3)=[N:6][C:5]=2[CH2:1][CH2:2][CH2:3][CH2:4][OH:35])[CH:17]=[CH:16][C:15]=1[C:18]1[NH:22][C:21](=[O:23])[O:20][N:19]=1
Reactant: C=CCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(-c2noc(=O)[nH]2)c(Cl)c1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c(-c2ccc(OCc3sc(-c4ccc(C(F)(F)F)cc4)nc3CCCCO)cc2Cl)no1
Temperature: 25 °C

Procedure:
To a solution of 50 mg of 3-{4-[4-but-3-enyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-chloro-phenyl}-4H-[1,2,4]oxadiazol-5-one in 2 ml of tetrahydrofuran at 0° C. was added 0.3 ml of a 2M solution of borane-methylsulfide complex in tetrahydrofuran. The resulting mixture was stirred allowing it to warm up to room temperature than stirred at room temperature for 30 minutes. After cooling to 0° C., 0.1 ml of a 5M aqueous solution of sodium hydroxide and 0.1 ml of a 30% aqueous solution of hydrogen peroxide were added. The resulting mixture was stirred allowing it to warm up to room temperature over 1 hour. It was then poured into water, extracted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient of dichloromethane/methanol from 100/0 to 95/5) followed by crystallization from dichloromethane/pentane to give 28 mg of 3-{2-chloro-4-[4-(4-hydroxy-butyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-4H-[1,2,4]oxadiazol-5-one.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([NH:19][S:20]([C:23]2[S:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)(=[O:22])=[O:21])[CH2:10][C:9]1([CH2:17][NH2:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]([CH3:38])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.C(O)(=O)C>[C:1]([O:5][C:6]([C:8]1([NH:19][S:20]([C:23]2[S:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)(=[O:22])=[O:21])[CH2:10][C:9]1([CH2:17][NH:18][CH:36]([CH3:38])[CH3:35])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)=O
Reactant: CC(C)(C)OC(=O)C1(NS(=O)(=O)c2ccc(-c3ccc(Cl)cc3)s2)CC1(CN)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)NCC1(c2ccccc2)CC1(NS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)s1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 66.8 %

Procedure:
To the obtained 2-aminomethyl-1-[5-(4-chloro-phenyl)-thiophene-2-sulfonylamino]-2-phenyl-cyclopropanecarboxylic acid t-butyl ester (60 mg, 0.12 mmol) in tetrahydrofuran (1.0 mL) were added acetone (13 μL, 0.17 mmol) and sodium triacetoxyborohydride (37 mg, 0.17 mmol) at 0° C. under argon atmosphere, and the mixture was stirred at room temperature for 20 hours. To the obtained solution was added acetic acid (50 μL), and the mixture was further stirred for 21 hours. Then saturated aqueous sodium hydrogen carbonate solution (2.0 mL) was added and the aqueous layer was extracted with ethyl acetate (3.0 mL). The organic layer was washed with water (2.0 mL) and saturated aqueous sodium chloride solution (2.0 mL), and dried over magnesium sulfate. After filtration and evaporation, the obtained residue was purified by silica gel chromatography (chloroform:methanol=25:2) to give the title compound (45 mg, yield 69%) as a pale-yellow oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C([O-])(=O)C.[Na+].[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=1.C([BH3-])#N.[Na+]>CO>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH:6][CH2:23][C:19]1[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)[C@H](N)CC(C)C
Reactant: O=Cc1cccnc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: COC(=O)[C@@H](CC(C)C)NCc1cccnc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
D-Leucine methyl ester hydrochloride (20 g, 110.43 mmol) is dissolved in methanol. To this is added sodium acetate (22.64 g, 276 mmol) followed by 3-pyridine carboxaldehyde (10.9 mL, 115.5 mmol). The mixture is allowed to stir at room temperature for 15 minutes and then sodium cyanoborohydride (4.15 g, 66 mmol) is added slowly over 15 minutes. After stirring for 16 hours at room temperature methanol is evaporated under reduced pressure and the resulting oil is taken up in ethyl acetate and washed with water (2×). The organics are dried over sodium sulfate and concentrated to an oil. The product is purified by silica gel flash chromatography (100% ethyl acetate) to give N-(3-picolyl) D-leucine methyl ester as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[Cl:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:9][C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=2)=[CH:12][CH:11]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Clc1cncc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Clc1ccc(Nc2cncc(Cl)n2)cc1
Temperature: 100 °C
Yield: 19.5 %

Procedure:
A mixture of 2,6-dichloropyrazine (2.0 g, 13.4 mmol), 4-chloroaniline (1.88 g, 14.8 mmol) and sodium tert-butoxide (1.71 g, 17.6 mmol) in toluene (45 mL) were degassed with argon for 20 minutes. (±)-2,2′-Bis(diphenylphosphino-)1,1′-binaphthalene ((±)-BINAP) (502 mg, 0.81 mmol) and palladium(II)-acetate (90.4 mg, 0.40 mmol) were added followed by degassing for 5 minutes. The reaction mixture was stirred at 100° C. over night. The mixture was filtrated and the filtrate evaporated. Flash chromatography (ethyl acetate/heptane as eluent) gave (4-chloro-phenyl)-(6-chloro-pyrazin-2-yl)-amine (628 mg, 18%) as a brown oil.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[C:17]12([CH2:27][C:28](Cl)=[O:29])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2>>[C:17]12([CH2:27][C:28]([NH:1][N:2]3[N:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]3=[O:16])=[O:29])[CH2:24][CH:23]3[CH2:22][CH:21]([CH2:20][CH:19]([CH2:25]3)[CH2:18]1)[CH2:26]2
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1nc(C(F)(F)F)c2ccccc2c1=O
Yield: 77 %

Procedure:
The product of Example 11B (50.6 mg) and (adamantan-1-yl)acetyl chloride (54 mg, 0.25 mmol) were treated as in Example 6 to give the title compound (69 mg, 0.17 mmol) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 11.47 (s, 1H), 8.44 (dd, 1H), 8.18-7.98 (m, 3H), 2.08 (s, 2H), 1.99-1.92 (m, 3H), 1.75-1.55 (m, 12H); MS (DCI) M/Z 423.3 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[F:23][C:24]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:25]=1[CH2:26]Br>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:26][C:25]1[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:24]=1[F:23]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3Cl)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccc(F)cc2Cl)n1Cc1ccc(F)cc1F
Temperature: 80 °C
Yield: 65.7 %

Procedure:
A mixture of (4S,7R)-2-(2-chloro-4-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 21; 200 mg, 0.62 mmol), tetrabutylammonium iodide (229 mg, 0.62 mmol) and 2,4-difluorobenzyl bromide (320 μL, 2.5 mmol) in dimethylformamide (4 mL) was heated at 80° C. overnight. The solvent was evaporated and dichloromethane (50 mL) was added. The solution was washed with water (2×20 mL), saturated aqueous sodium thiosulfate (20 mL), and brine (20 mL), dried (magnesium sulfate), filtered, concentrated and purified by chromatography, eluting with 60-70% ethyl acetate/petroleum ether, to give (4S,7R)-2-(2-chloro-4-fluoro-phenyl)-1-(2,4-difluoro-benzyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (182 mg, 68%) as an off-white solid. APCI(+)-MS (M+H) 447.
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.C(N(CC)CC)C.[C:18]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21]([C:24](Cl)=[O:25])=[CH:20][CH:19]=1.O>ClCCl>[C:27]1([C:18]2[CH:19]=[CH:20][C:21]([C:24]([N:7]3[CH2:8][CH2:9][C:10]4[O:2][CH:3]=[CH:4][C:5]=4[CH2:6]3)=[O:25])=[CH:22][CH:23]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: c1cc2c(o1)CCNC2
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(-c2ccccc2)cc1)N1CCc2occc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.26 g (1.2 mmol) of 4-biphenylcarbonyl chloride was added under ice-cooling, followed by overnight stirring at room temperature. This solution was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to yield the desired product.
Reaction SMILES: [O:1]=[C:2]([CH2:9][C:10](=[O:13])[C:11]#[CH:12])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C1C2C(=CC=CC=2)C=CC=1CN1CCC[C@H]1CO>C1COCC1.CO>[OH:1][CH:2]([CH2:9][CH:10]([OH:13])[C:11]#[CH:12])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: C#CC(=O)CC(=O)CC(=O)OCC
Agent: OC[C@@H]1CCCN1Cc1ccc2ccccc2c1
Solvent: C1CCOC1
Solvent: CO
Product: C#CC(O)CC(O)CC(=O)OCC
Reaction time: 20 h

Procedure:
50 mg (0.27 mmol) of ethyl 3,5-dioxo-6-heptynoate was dissolved in 5 ml of THF and 52 ml of methanol. Then, with or without addition of aluminum tri-i-propoxide as a metal reagent, a reaction was conducted at 20° C. for 20 hours using 5.4 ml of a 1.0M BH3 ·THF solution and 6.2 mg (0.027 mmol) of the (S)-N-(β-naphthyl)methyl-2-pyrrolidine methanol (compound (S)-II-1) obtained in Example 1, to obtain ethyl 3,5-dihydroxy-6-heptynoate (VI-2) as oily desired product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:22])([CH3:21])[N:9](CC3C=CC(OC)=CC=3)[C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1.O.CCOC(C)=O>CC#N>[Cl:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:22])([CH3:21])[NH:9][C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1
Reactant: COc1ccc(CN2C(=O)c3ccc(Cl)nc3C2(C)C)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CC1(C)NC(=O)c2ccc(Cl)nc21
Yield: 62.8 %

Procedure:
To solution of 2-chloro-6-(4-methoxy-benzyl)-7,7-dimethyl-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one (1.58 g, 5.0 mmol) in CH3CN (20 mL) was added ceric ammonium nitrate (8.2 g, 15.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours before water and EtOAc was added into the mixture. The organic layer was separated, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by silica gel column chromatography to give title compound (617 mg, 63%) as a solid. MS: 197.2 (M+H+).