Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([OH:9])([CH2:6][CH:7]=[CH2:8])[CH3:5].[CH2:10](Br)[CH:11]=[CH2:12]>CN(C)C=O>[CH2:12]([O:9][C:4]([CH3:5])([CH3:3])[CH2:6][CH:7]=[CH2:8])[CH:11]=[CH2:10]
Reactant: C=CCBr
Reactant: C=CCC(C)(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC(C)(C)CC=C
Temperature: 0 °C
Reaction time: 1 h
Yield: 156.9 %

Procedure:
To a suspension of sodium hydride (60%, 24 g, 60 mmol) in N,N-dimethylformamide (150 mL) at 0° C. was slowly added 2-methylpent-4-en-2-ol (20.0 g, 200 mmol). After 1 hour at 0° C., allyl bromide (48.0 g 400 mmol) was slowly added at 0˜5° C., and the reaction mixture was stirred at 0° C. for another 1 hour. The reaction was quenched with aq. ammonium chloride solution and extracted with tert-butyl methyl ether. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (44 g, crude) as a yellow oil, which was directly used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].C(=O)([O-])[O-].[K+].[K+].[NH:18]1[CH:22]=[N:21][CH:20]=[N:19]1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: c1nc[nH]n1
Reactant: Cc1cc(Br)cc(C#N)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Br)cc(C#N)c1-n1cncn1
Temperature: 140 °C
Yield: 24.2 %

Procedure:
To a stirred solution of 5-bromo-2-fluoro-3-methylbenzonitrile (1.0 g, 47.716 mmol), in DMF (10.0 mL) was added potassium carbonate (1.95 g, 14.14 mmol) followed by 1H-1,2,4-triazole (0.811 g, 9.433 mmol) at ambient temperature. The reaction mixture was heated to 140° C. for 18 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with ethyl acetate (2×100 mL). The combined ethyl acetate layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure to afford the crude compound purified by flash column chromatography (SiO2, 100-200 mesh; eluting with 30% ethyl acetate/pet ether) to afford the title compound as a pink solid (0.6 g, 49%): 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 8.23 (s, 1H), 7.91 (d, J=2.4 Hz, 2H), 2.21 (s, 3H), ESIMS m/z 262.57 ([M+H]+); IR (thin film) 2231, 554 cm−1.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:18][CH3:19])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[N:29]1[CH:33]=[N:32][C:31]([CH3:34])=[N:30]1)[NH2:25].OS(O)(=O)=O.C([O-])(O)=O.[Na+]>CN1CCCC1=O.O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH:8]2[C:6]3[N:7]=[C:2]([NH:25][C:24]4[CH:26]=[CH:27][C:28]([N:29]5[CH:33]=[N:32][C:31]([CH3:34])=[N:30]5)=[C:22]([O:21][CH3:20])[CH:23]=4)[N:3]=[C:4]([NH:18][CH3:19])[C:5]=3[CH2:10][CH2:9]2)=[CH:12][CH:13]=1
Reactant: CNc1nc(Cl)nc2c1CCC2c1ccc(F)cc1
Reactant: COc1cc(N)ccc1-n1cnc(C)n1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CNc1nc(Nc2ccc(-n3cnc(C)n3)c(OC)c2)nc2c1CCC2c1ccc(F)cc1
Temperature: 100 °C

Procedure:
To a solution of 2-chloro-7-(4-fluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (Preparation Hh) (141.2 mg, 0.508 mmol) and 3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (Preparation D) (208 mg, 1.017 mmol) in N-Methyl-2-pyrrolidinone (4067 μL) was added H2SO4 (43.4 μL, 0.813 mmol). The solution was heated to 100° C. When the reaction was complete, water and NaHCO3 were added. After extraction into CH2Cl2, the organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. Applied the residue to SG and eluted with a EtOAc/Hex gradient, which yielded 7-(4-fluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (Example 44).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=O)[CH2:4][C:5]([O:7]CC)=O.C(O)(=O)C.[C:17]1([NH:23][NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[OH:7][C:5]1[N:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:24]=[C:3]([C:2]([F:1])([F:11])[F:12])[CH:4]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Solvent: O
Solvent: CC(=O)O
Product: Oc1cc(C(F)(F)F)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
Ethyl 4,4,4-trifluoroacetoacetate (18.4 g (0.1 mol)) was dissolved in 12.0 g (0.2 mol) of acetic acid. The resulting solution was cooled to 10° C. or less with stirring, and 11.8 g (0.11 mol) of phenylhydrazine was added dropwise thereto over 0.5 hours. After the dropwise addition, the solution was stirred at room temperature for 1 hour and subsequently at 80° C. for 5 hours. When the reaction was completed, the reaction solution was cooled to room temperature, and 100 mL of water was added thereto. The produced crystal was collected by filtration, washed twice with 50 mL of water and dried by a hot air drier to obtain 22.3 g (yield: 98.0%) of the title compound as a pale yellow crystal.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:10]([N:15]2[CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][C:17](=[O:25])[NH:16]2)=[N:11][CH:12]=[CH:13][CH:14]=1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClCCl.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(N(CC)CC)C>[Cl:8][C:9]1[C:10]([N:15]2[CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][C:17]([O:25][S:32]([C:29]3[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=3)(=[O:34])=[O:33])=[N:16]2)=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)C1CC(=O)NN1c1ncccc1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CC(OS(=O)(=O)c2ccc(C)cc2)=NN1c1ncccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
Triethylamine (3.75 g, 37.1 mmol) was added dropwise to a mixture of ethyl 2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e. the product of Example 8, Step A) (10.0 g, 37.1 mmol) and p-toluenesulfonyl chloride (7.07 g, 37.1 mmol) in dichloromethane (100 mL) at 0° C. Further portions of p-toluenesulfonyl chloride (0.35 g, 1.83 mmol) and triethylamine (0.19 g, 1.88 mmol) were added. The reaction mixture was then allowed to warm to room temperature and was stirred overnight. The mixture was then diluted with dichloromethane (200 mL) and washed with water (3×70 mL). The organic phase was dried and evaporated to leave the title product as an oil (13.7 g, 87% yield), which slowly formed crystals. Product recrystallized from ethyl acetate/hexanes melted at 99.5-100° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:26][NH:27][O:28][CH3:29]>C(Cl)Cl.CCOCC>[CH3:29][O:28][N:27]([CH3:26])[C:10](=[O:12])[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CSc1ccc(CC(=O)O)cc1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCOCC
Product: CON(C)C(=O)Cc1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.8 %

Procedure:
To a solution of 4-(methylthio)phenylacetic acid (18.3 g, 0.100 mol) in methylene chloride (200 mL) was added 1,1'-carbonyldiimidazole (16.3 g, 0.100 mol) portionwise. The mixture was stirred at room temperature for 20 minutes, and N,O-dimethylhydroxylamine hydrochloride (9.8 g, 0.100 mol) was added. The reaction mixture was stirred overnight at room temperature, diluted with ether (500 mL) and washed successively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated in vacuo to give 20.9 g of N-methoxy-N-methyl-4-(methylthio)-benzeneacetamide as a clear oil (93%).
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[C:9]([CH2:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:18]([C:20]3[N:21]=[C:22]([CH3:32])[S:23][C:24]=3[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:19])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C[CH2:34][N:35](C1C=CC(C(C2C(S([O-])(=O)=O)=CC(S([O-])(=O)=O)=C(O)C=2)=C2C=CC(=[N+](CC)CC)C=C2)=CC=1)CC.CCN(C1C=CC(C(C2C(S([O-])(=O)=O)=CC(S([O-])(=O)=O)=C(O)C=2)=C2C=CC(=[N+](CC)CC)C=C2)=CC=1)CC.[Ca+2].[Cu]C#N>>[C:34]([C:2]1[C:7]2[CH:8]=[C:9]([CH2:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:18]([C:20]3[N:21]=[C:22]([CH3:32])[S:23][C:24]=3[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:19])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)#[N:35]
Reactant: CCN(CC)c1ccc(C(=C2C=CC(=[N+](CC)CC)C=C2)c2cc(O)c(S(=O)(=O)[O-])cc2S(=O)(=O)[O-])cc1
Reactant: Cc1nc(C(=O)N2CCCCC2Cc2cc3c(Br)cccc3o2)c(-c2ccc(F)cc2)s1
Agent: N#C[Cu]
Agent: [Ca+2]
Product: Cc1nc(C(=O)N2CCCCC2Cc2cc3c(C#N)cccc3o2)c(-c2ccc(F)cc2)s1

Procedure:
The title compound (80 mg) was prepared from (RS)-1-[2-(4-bromo-benzofuran-2-ylmethyl)-piperidin-1-yl]1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone, E131 (400 mg) and copper(I)cyanide according to a procedure similar to that described for Example 67.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[NH2:9].C(N(CC)CC)C.[C:28](Cl)(=[O:32])[C:29](Cl)=[O:30]>C(Cl)Cl>[OH:30][C:29]1[C:28](=[O:32])[N:2]([CH3:1])[C:3]2[C:8]([N:9]=1)=[CH:7][CH:6]=[C:5]([C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=1)[CH:4]=2
Reactant: CNc1cc(-c2ccc(OC(F)(F)F)cc2)ccc1N
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(=O)c(O)nc2ccc(-c3ccc(OC(F)(F)F)cc3)cc21
Yield: 46.2 %

Procedure:
A solution of N3-methyl-4′-(trifluoromethoxy)biphenyl-3,4-diamine (1 g) in methylene chloride (35 ml) was cooled in an ice bath, and triethylamine (1.5 ml) was added, followed by dropwise addition of oxalyl chloride (670 mg). After 1 hour the solvent was removed under reduced pressure, and the residue was crystallized from methanol, to provide 3-hydroxy-1-methyl-7-(4-(trifluoromethoxy)phenyl)quinoxalin-2(1H)-one (550 mg).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:23][O:24][CH3:25])=[C:10](/[CH:19]=[CH:20]/[CH2:21]O)[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C1(P(=[CH:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O-2].[O-2].[Mn+4].C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:23][O:24][CH3:25])=[C:10](/[CH:19]=[CH:20]/[CH:21]=[CH:45]/[C:46]([O:48][CH2:49][CH3:50])=[O:47])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c(-c3cncc(C)c3)c(/C=C/CO)c(COC)nc21
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCOC(=O)/C=C/C=C/c1c(COC)nc2c(cnn2CC)c1-c1cncc(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.3 %

Procedure:
A mixture of (2E)-3-[1-ethyl-6-(methoxymethyl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-2-propen-1-ol (40 mg), ethyl (triphenylphosphanylidene)-acetate (49 mg), manganese dioxide (103 mg) and DCM (2 ml) was stirred at room temperature for 1 h. The reaction mixture was filtrated through celite pad. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel (CHCl3-MeOH 95:5) to give ethyl (2E,4E)-5-[1-ethyl-6-(methoxymethyl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-2,4-pentadienoate (53 mg) as a colorless solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][CH2:19][C:20]2[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]=2)[C:13]2[CH:34]=[CH:35][C:36]([Cl:39])=[C:37]([CH3:38])[C:12]1=2)=[O:10])([CH3:7])[CH3:6].N1C=CC=CC=1>ClCCl>[CH:5]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH:14]([N:18]([C:1](=[O:3])[CH3:2])[CH2:19][C:20]2[CH:21]=[C:22]([C:30]([F:33])([F:31])[F:32])[CH:23]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:25]=2)[C:13]2[CH:34]=[CH:35][C:36]([Cl:39])=[C:37]([CH3:38])[C:12]1=2)=[O:10])([CH3:7])[CH3:6]
Reactant: Cc1c(Cl)ccc2c1N(C(=O)OC(C)C)CCCC2NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c1ccc(Cl)c2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.6 %

Procedure:
Inject titanium isopropoxide (0.176 mL, 0.60 mmol) to a mixture of 8-chloro-9-methyl-5-oxo-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (90 mg, 0.30 mmol) and 3,5-bis(trifluoromethyl)benzylamine (137 mg, 0.45 mmol) at room temperature under an atmosphere of nitrogen and stir the solution for 14 h. Add methanol (1.3 mL) and sodium borohydride (28 mg, 0.75 mmol) and stir the mixture under nitrogen at room temperature for 2 h. Add 0.1M NaOH, stir for 30 min. Filter through celite and wash the residue with AcOEt. Separate organic layer, extract aqueous with AcOEt. Wash organic layer with brine and dry the organic layers over anhydrous sodium sulfate. Filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford (+/−)-5-(3,5-Bis-trifluoromethyl-benzylamino)-8-chloro-9-methyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (90 mg, 57%). Add acetyl chloride (0.025 mL, 0.34 mmol) dropwise to a solution of the amine (90 mg, 0.17 mmol) and pyridine (0.025 mL, 0.34 mmol) in dichloromethane (1.2 mL) at 0° C. Stir under nitrogen at room temperature for 1 h 30 min. Add water and extract with dichloromethane. Dry the organic layer over anhydrous magnesium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (40 mg, 42%); MS (ES+): 565 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[NH:13][CH:14]=[CH:15][N:16]=2)=[O:9])[CH:5]=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.[H-].[Na+].[CH3:24]I.O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[N:13]([CH3:24])[CH:14]=[CH:15][N:16]=2)=[O:9])[CH:5]=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1
Reactant: CI
Reactant: Nc1nc(C(=O)NCc2ncc[nH]2)cc(-c2ccco2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccnc1CNC(=O)c1cc(-c2ccco2)nc(N)n1
Reaction time: 0.33 h
Yield: 56.9 %

Procedure:
A solution of 2-amino-6-(2-furyl)-N-(1H-imidazol-2-ylmethyl)pyrimidine-4-carboxamide (300 mg, 1.06 mmol) in DMF (15 mL) at room temperature was treated with NaH (44 mg, 1.11 mmol), stirred for 20 min, treated with MeI (99 μl, 1.58 mmol) and stirred at room temperature for 16 h. The mixture was poured into water (30 mL), extracted with EtOAc (3×10 mL) and the combined organic phase was dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; EtOAc] to give the title compound (180 mg, 57%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][OH:13].[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][O:13][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][O:14]1
Reactant: Cc1cc(Cl)c(CO)cc1[N+](=O)[O-]
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1cc(Cl)c(COC2CCCCO2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 11 h

Procedure:
To a solution of (2-chloro-4-methyl-5-nitrophenyl)methanol (23 g, 114 mmol) and 3,4-dihydro-2H-pyran (20.9 mL, 228 mmol) in CH2Cl2 (500 mL) was added pyridinium p-toluenesulfonate (5.7 g, 22.8 mmol), and then the mixture was stirred at room temperature for 11 h. The reaction was quenched by 5% aq. NaHCO3. The layers were separated and the aqueous layer was extracted with CH2Cl2. The organic layers were combined and washed with H2O and brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by SiO2 column chromatography (heptane/EtOAc=96/4, isocratic) to give the title compound. 1H NMR (400 MHz, ACETONITRILE-d3) δ 8.10 (s, 1H), 7.49 (s, 1H), 4.81 (d, J=13.64 Hz, 1H), 4.72-4.78 (m, 1H), 4.59 (d, J=13.64 Hz, 1H), 3.77-3.92 (m, 1H), 3.34-3.60 (m, 1H), 2.54 (s, 3H), 1.68-1.91 (m, 2H), 1.43-1.68 (m, 4H).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([C@@H:10]3[CH2:12][C@H:11]3[NH:13]C(=O)OC(C)(C)C)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>ClCCl>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([C@@H:10]3[CH2:12][C@H:11]3[NH2:13])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(C2CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1C[C@H]1c1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
To a solution of tert-butyl (trans-2-(4-cyclopropylphenyl)cyclopropyl)carbamate (260 mg, 0.951 mmol) in dichloromethane (DCM) (3 mL) was added TFA (500 μl, 6.49 mmol) and the mixture was stirred at room temperature for 3 h. The mixture was concentrated and the residue was treated with saturated NaHCO3 aqueous solution and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated to give 148 mg of product as pale yellow oil. MS: (M+H)+=174.1. 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.57-0.70 (m, 2H), 0.86-1.04 (m, 4H), 1.78-1.93 (m, 2H), 2.37-2.48 (m, 1H), 6.86-7.00 (m, 4H).
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][C@H:5]([C:13]([OH:15])=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].C(N(CC)CC)C>O1CCCC1>[CH3:3][N:4]([C:16](=[O:18])[CH3:17])[C@H:5]([C:13]([OH:15])=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1
Reactant: CN[C@@H](Cc1ccncc1)C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N(C)[C@@H](Cc1ccncc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
Methyl-3-(4-pyridinyl)alanine, dihydrochloride (1.4 g, 0.0053 mol) is stirred in dry tetrahydrofuran (20 mL) with acetic anhydride (0.9 mL, 0.0095 mol) and triethylamine (3.3 mL, 0.0233 mol) at room temperature. After stirring at room temperature overnight the mixture is diluted with 20 mL tetrahydrofuran and filtered and the solids washed with tetrahydrofuran. The filtrate is concentrated to a dark oil, dissolved in dichloromethane (50 mL) and washed with dilute sodium bicarbonate solution (50 mL). The organic layer is dried over magnesium sulfate and concentrated. The residue is triturated with diethyl ether, filtered, and dried to afford 0.83 g of the title compound as a tan solid; mp 86-88° C.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6]Br.[CH3:8][C:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=O)[CH2:11][CH:10]=1.S(=O)(=O)(O)O>O1CCCC1>[CH3:8][C:9]1[CH2:14][CH2:13][CH:12]([C:15]2([OH:17])[CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:11][CH:10]=1
Reactant: CC1=CCC(C(=O)O)CC1
Reactant: BrCCCCBr
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Product: CC1=CCC(C2(O)CCCC2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred suspension of 46.8 g of magnesium in 250 ml of tetrahydrofuran was added 182 g of 1,4-dibromobutane in 700 ml of dry tetrahydrofuran over 1 hour. The gently refluxing reaction mixture was maintained at reflux for 2 more hours and then cooled to room temperature. A solution of 100 g of the methyl ester of 4-methyl-3-cyclohexene-1-carboxylic acid in 20 ml of dry tetrahydrofuran was added at 20°-30° C. with cooling by an ice bath. The reaction mixture was stirred at room temperature for 2 days, and the excess Grignard reagent was decomposed by careful addition of dilute sulfuric acid. Most of the tetrahydrofuran was evaporated, and the reaction product was extracted with ether. The ether phase was washed successively with water and saturated NaCl solution, dried with MgSO4, and stripped to give 120 g of crude product as an oil. Multiple redistillation of the oil gave 32 g of product b.p. 90°-92° C. (0.5 mm).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH2:5][CH:4]([CH3:9])[O:3]1.[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([Mg]Br)[CH:21]=[CH:22][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(OC1C=C(Br)C=CC=1)C1C=CC=CC=1.[Mg].Cl>O1CCCC1>[CH2:10]([O:17][C:18]1[CH:23]=[C:22]([C:6]2([OH:8])[CH2:5][CH:4]([CH3:9])[O:3][CH:2]([CH3:1])[CH2:7]2)[CH:21]=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Br[Mg]c1cccc(OCc2ccccc2)c1
Reactant: CC1CC(=O)CC(C)O1
Agent: Brc1cccc(OCc2ccccc2)c1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CC1CC(O)(c2cccc(OCc3ccccc3)c2)CC(C)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2,6-dimethyltetrahydropyran-4-one (2.2 g) in tetrahydrofuran (5 ml) was added to a solution of 3-benzyloxyphenylmagnesium bromide [prepared by heating a mixture of 3-benzyloxybromobenzene (5 g), magnesium (0.5 g) and tetrahydrofuran (20 ml)] in tetrahydrofuran and the mixture was stirred at ambient temperature for 3 hours. The mixture was cooled to 5° C., ice (5 ml) and 2N hydrochloric acid solution (25 ml) were added, and the mixture was extracted with ethyl acetate. The organic phase was washed with a saturated sodium chloride solution, dried (MgSO4) and evaporated. The residue was purifed by column chromatography using increasingly polar mixtures of toluene and ethyl acetate as eluent. There were thus obtained two isomers of 4-(3-benzyloxyphenyl)-4-hydroxy-2,6-dimethyltetrahydropyran: a less polar isomer (2.41 g, 45%),
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][C:15]([F:16])([F:18])[F:17])[CH2:10][C:11]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:13])=[CH:5][C:4]=1[C:19]([F:20])([F:21])[F:22])#[N:2]
Reactant: N#Cc1ccc(N(CC(=O)O)CC(F)(F)F)cc1C(F)(F)F
Reactant: Nc1ccccc1
Product: N#Cc1ccc(N(CC(=O)Nc2ccccc2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described for Example 91C using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(2,2,2-trifluoroethyl)glycine and aniline: MS (APCI) m/z 402 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17](=[O:18])[C:16]3[C@@H:15]4[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]4)[C:11]=3[NH:10]2)=[CH:5][CH:4]=1.I[CH2:24][CH3:25]>CN(C)C=O.ClCCl>[CH2:24]([N:10]1[C:11]2[C@@:12]3([CH3:22])[C:19]([CH3:21])([CH3:20])[C@H:15]([CH2:14][CH2:13]3)[C:16]=2[C:17](=[O:18])[N:9]1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH3:25]
Reactant: COc1ccc(-n2[nH]c3c(c2=O)[C@H]2CC[C@]3(C)C2(C)C)cc1
Reactant: CCI
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCn1c2c(c(=O)n1-c1ccc(OC)cc1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 46.6 %

Procedure:
A mixture of (4S,7R)-2-(4-methoxy-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 40; 300 mg, 1.0 mmol) and iodoethane (405 μL, 5.0 mmol) in dimethylformamide (9 mL) was heated in a sealed tube at ˜100° C. overnight. The reaction mixture was allowed to cool to room temperature, diluted with dichloromethane (100 mL), transferred to a round-bottomed flask and evaporated. Ethyl acetate (100 mL) was added and the solution was washed with water, concentrated aqueous sodium thiosulfate (50 mL; 50% w/v), saturated aqueous sodium hydrogen carbonate (50 mL) and brine (50 mL). The solution was dried (magnesium sulfate), filtered, evaporated, and purified using a Biotage 40S system, eluting with 3% methanol/dichloromethane. Fractions homogeneous for the product were evaporated, co-evaporated with ethanol and dried under high vacuum to give (4S,7R)-1-ethyl-2-(4-methoxy-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (152 mg, 46%) as a light yellow solid. APCI(+)-MS (M+H) 327.