Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH:7]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH:15]=[C:14]([CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])[C:13]=2[CH:23]=1)=C>CC(O)(C)C.O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH:7]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH:15]=[C:14]([CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])[C:13]=2[CH:23]=1)=[O:2]
Reactant: C=Cc1ccc2occ(CCNC(C)=O)c2c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Product: CC(=O)NCCc1coc2ccc(C=O)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.10 g of osmium tetroxide in 2-methyl-2-propanol and then 8.70 g of sodium periodate are added at room temperature to a solution of 10 mmol of the product obtained in Step C in a mixture of 50 ml of dioxane and 25 ml of water. After stirring overnight at room temperature, the suspension is filtered and the filtrate is concentrated under reduced pressure. The resulting residue is taken up in dichloromethane. The organic phase is washed with water, dried and evaporated. The residue is purified by chromatography over silica gel to yield the title product.
Reaction SMILES: FC(F)(F)S([O:6][C:7]1[N:12]=[C:11]2[C:13]3[N:20]([CH3:21])[N:19]=[C:18]([C:22](=[O:27])[N:23]([O:25][CH3:26])[CH3:24])[C:14]=3[CH2:15][CH2:16][CH2:17][C:10]2=[CH:9][N:8]=1)(=O)=O.[Cl:30][C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=1O>C1COCC1>[Cl:30][C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=1[O:6][C:7]1[N:12]=[C:11]2[C:13]3[N:20]([CH3:21])[N:19]=[C:18]([C:22]([N:23]([O:25][CH3:26])[CH3:24])=[O:27])[C:14]=3[CH2:15][CH2:16][CH2:17][C:10]2=[CH:9][N:8]=1
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: CON(C)C(=O)c1nn(C)c2c1CCCc1cnc(OS(=O)(=O)C(F)(F)F)nc1-2
Solvent: C1CCOC1
Product: CON(C)C(=O)c1nn(C)c2c1CCCc1cnc(Oc3ccc(Cl)cc3Cl)nc1-2
Temperature: 60 °C
Reaction time: 48 h
Yield: 2 %

Procedure:
To a solution of 3-[methoxy(methyl)carbamoyl]-1-methyl-1,4,5,6-tetrahydropyrazolo[4′,3′:6,7]cyclohepta[1,2-d]pyrimidin-9-yl trifluoromethanesulfonate (73 mg, 0.17 mmol) in THF (3 mL), 2,4-dichlorophenol was added in a microwave vial flushed with argon. The reaction mixture was stirred at 60° C. for 48 h. The solvent was removed under reduced pressure, the crude was purified by preparative HPLC to give 2 mg (2% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH:15]3[CH2:20][CH2:19][Si:18]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(OCC)[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[AlH4-].[Li+].Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][CH2:13][C@H:12]([C@H:15]3[CH2:20][CH2:19][Si@H:18]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCCCC[Si]1(OCC)CCC([C@H]2CC[C@H](c3ccc(F)c(F)c3)CC2)CC1
Agent: Cl
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCC[Si@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(F)c(F)c3)CC2)CC1

Procedure:
Subsequently, the reaction mixture was concentrated, to which 200 ml of hexane was added thereby permitting secondarily produced urea hydrochloride to be precipitated and separated. The residual solution was concentrated to obtain 33.8 g of 4-(trans-4-(3,4-difluorophenyl)cyclohexyl)-1-n-pentyl-1-ethoxy-1-silacyclohexane. This silacyclohexane product was dissolved in 100 ml of THF and was added to 100 ml of a THF solution of 10.0 g of lithium aluminohydride, followed by agitation under reflux for 1 hour. The cis-trans isomer mixture was subjected to quantitative gas-chromatographic analysis in the same manner as set out in Example 1, revealing that a ratio of the cis isomer (retention time: 9.56 minutes) and the trans isomer (retention time: 9.66 minutes) was 11:89. The reaction mixture was poured into 200 ml of 5% hydrochloric acid and extracted with ethyl acetate. The extract was subjected to ordinary procedures of washing with brine, drying and concentration, followed by purification through silica gel chromatography to obtain 25.2 g of the intended product (yield: 80.2%). This product exhibited nematic liquid crystal properties at a temperature between 14.3° and 71.6° C. and was found to be very useful as a liquid crystal substance. The results of IR analysis of the product are shown below.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].Cl.[NH2:15][CH2:16][C:17]1[CH:18]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:20]=[CH:21][CH:22]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.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]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:15][CH2:16][C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:20]=[CH:21][CH:22]=3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: CC(=O)Nc1cccc(CN)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1cccc(CNc2ccc3c(=O)[nH]nc(Cl)c3c2)c1
Yield: 2.3 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (100 mg, 0.385 mmol), N-[3-(aminomethyl)phenyl]acetamide hydrochloride (90 mg, 0.448 mmol), Pd2(dba)3 (40 mg, 0.044 mmol), rac-BINAP (81 mg, 0.130 mmol) and NaOtBu (101 mg, 1.05 mmol) in DMA (6 mL) was heated at 80° C. for 3 h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography on silica (EtOAc/hexanes) afforded N-{3-[(4-chloro-1-oxo-1,2-dihydro-phthalazin-6-ylamino)-methyl]-phenyl}-acetamide (3 mg) as a light brown solid, 1H (400 MHz, CDCl3) δ: 2.09 (s, 3H), 4.38 (s, 2H), 6.85 (d, 1H), 7.00 (m, 2H), 7.21 (t, 1H), 7.38 (m, 1H), 7.53 (m, 1H), 7.61 (s, 1H), 8.05 (d, 1H), 8.75 (bs, 1H), 10.90 (bs, 1H) ppm; m/z (M+1) 342.98.
Reaction SMILES: [ClH:1].Cl.[Cl:3][CH2:4][C:5]1[CH:10]=[C:9]([CH2:11][N:12]([CH3:14])[CH3:13])[CH:8]=[CH:7][N:6]=1.[NH2:15][C:16]([NH2:18])=[S:17]>C(O)C>[ClH:3].[ClH:1].[ClH:3].[CH3:13][N:12]([CH2:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:4][S:17][C:16](=[NH:15])[NH2:18])[CH:10]=1)[CH3:14]
Reactant: CN(C)Cc1ccnc(CCl)c1
Reactant: NC(N)=S
Agent: Cl
Solvent: CCO
Product: CN(C)Cc1ccnc(CSC(=N)N)c1
Yield: 125 %

Procedure:
2-Chloromethyl-4-(dimethylaminomethyl)pyridine dihydrochloride (14.67 g) was added to a refluxing solution of thiourea (4.34 g) in ethanol (120 ml) and the solution refluxed for 3 hours, whereupon solid precipitated. After cooling the mixture (ice bath), the solid was filtered and recrystallised from methanolethanol to give S-(4-dimethylaminomethyl-2-pyridylmethyl)isothiourea trihydrochloride (11.88 g), m.p. 175°-9° C.
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7]C(C)([O-])C.[K+].[C:13]([CH:15]=[C:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:32][C@H:31]([CH2:33][NH:34][C:35](=[O:37])[CH3:36])[O:30][C:29]3=[O:38])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)#[N:14].[Cl-].[NH4+]>CS(C)=O>[C:13]([CH:15]1[C:16]2([CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:32][C@H:31]([CH2:33][NH:34][C:35](=[O:37])[CH3:36])[O:30][C:29]4=[O:38])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)[CH2:7]1)#[N:14]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=CC#N)CC3)cc2)C(=O)O1
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)(C)=O
Agent: [Cl-]
Agent: [I-]
Solvent: CS(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CC4C#N)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
A mixture of trimethyloxosulphonium iodide (10 mol), potassium tert-butoxide (10 mol) and (S)-N-[3-{4-[4-cyanomethylidenepiperidin-1-yl]-phenyl}-2-oxo-1,3-oxazolidin-5-ylmethyl]-acetamide (8 mmol, Example A) in 20 ml dimethylsulfoxide, was stirred overnight at room temperature. The reaction mixture was worked up with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried evaporated to dryness to afford a residue, which was purified by column chromatography over silica gel to give solid in 47% yield.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:15]=[C:14]([CH2:16][CH2:17][NH2:18])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:19][CH3:20])[CH:12]=2)[N:7]=1.C(N(CC)CC)C.O>O1CCCC1>[Cl:5][C:6]1[CH:15]=[C:14]([CH2:16][CH2:17][NH:18][C:1](=[O:3])[CH3:2])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:19][CH3:20])[CH:12]=2)[N:7]=1
Reactant: COc1ccc2nc(Cl)cc(CCN)c2c1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc2nc(Cl)cc(CCNC(C)=O)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
Acetyl chloride (0.37 g, 4.7 mmol) was added dropwise gradually under ice-cooling to a solution of 2-(2-chloro-6-methoxyquinolin-4-yl)ethylamine (1.0 g, 4.2 mmol) and triethylamine (0.87 g, 8.6 mmol) in tetrahydrofuran (50 ml). The reaction mixture was stirred at room temperature for 1 hour and poured into water. The organic materials were extracted with a mixed solvent of 5% methanol/ethyl acetate. The extract was washed with saturated brine and water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was recrystallized from ethyl acetate to obtain the title compound (0.96 g, 80%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.CN(C1C=CC=CN=1)C.[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:10][C@@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.5 g, 6.5 mmol) was dissolved in 20 mL DMF, added imidazole (1.1 g, 16 mmol), dimethylaminopyridine (80 mg, 0.65 mmol), and tert-butyldimethylsilyl chloride (1.08 g, 7.1 mmol). Stirred at ambient temperature overnight, dissolved in 150 mL EtOAc, washed with 10% citric acid (3×100 mL), water (2×100 mL), brine, dried with MgSO4, filtered, and concentrated. Redissolved in 50 mL CHCl3 and reconcentrated to yield title compound as a clear oil. (1.54 g, 69%) APCI (AP−): 344.2 (M−H)−.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:11][C:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[N:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)CCC>>[N:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:2]1[S:6][C:5]([N:7]2[CH2:11][C:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[N:4][CH:3]=1
Reactant: O=C1OC2(CN3CCC2CC3)CN1c1ncc(Br)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Product: O=C1OC2(CN3CCC2CC3)CN1c1ncc(-c2ccccn2)s1

Procedure:
The title compound was prepared by a method analogous to that described in Example 14 from 3′-(5-bromothiazol-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 2-(tri-n-butylstannyl)pyridine. The title compound (35 mg) was obtained as a pale solid, m/z 343 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1.[CH3:23][C:24]1[O:28][C:27]([CH:29]=O)=[CH:26][CH:25]=1>CCO>[CH3:22][N:7]1[C:6]2=[C:5]3[CH:29]([C:27]4[O:28][C:24]([CH3:23])=[CH:25][CH:26]=4)[NH:1][CH2:2][CH2:3][N:4]3[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:11]2[C:10](=[O:19])[N:9]([CH3:20])[C:8]1=[O:21]
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(CCN)cc2n(C)c1=O
Reactant: Cc1ccc(C=O)o1
Solvent: CCO
Product: Cc1ccc(C2NCCn3c(-c4ccccc4)c4c(=O)n(C)c(=O)n(C)c4c32)o1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
6-(2-Amino-ethyl)-1,3-dimethyl-5-phenyl-1,6-dihydro-pyrrolo[3,4-d]pyrimidine-2,4-dione (Intermediate A) (519 mg, 1.740 mmol) in EtOH (3 mL) was treated with 5-methylfuran-2-carbaldehyde (commercial) (0.173 mL, 1.740 mmol) and heated at 100° C. for 30 min using microwave irradiation. A further portion of 5-methylfuran-2-carbaldehyde (0.173 mL, 1.740 mmol) was added and heating continued at 100° C. for 10 min. The solvent was removed under reduced pressure and purification by chromatography on silica eluting with 40-80% EtOAc in iso-hexanes afforded the title compound as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH2:11][CH3:12].[Li]C(C)(C)C.[C:18](=[O:20])=[O:19]>C(OCC)C>[CH2:11]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:18]([OH:20])=[O:19])[CH:3]=2)[NH:7][N:6]=1)[CH3:12]
Reactant: O=C=O
Reactant: CCc1n[nH]c2ccc(Br)cc12
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CCc1n[nH]c2ccc(C(=O)O)cc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To a −78° C. solution of 5-bromo-3-ethyl-1H-indazole (5 g, 22 mmol) in diethyl ether (150 mL) was added t-BuLi (4.84 g, 75.6 mmol). The mixture was stirred at −78° C. for 1 hour. Dry CO2 gas was passed through the reaction mixture at −78° C. for 1 hour and the temperature was slowly raised to room temperature for 2 hours. The reaction mixture was stirred at room temperature for 1 hour and quenched with saturated NH4Cl solution. The ether layer was separated and concentrated to recover unreacted starting material. The pH of the aqueous layer was made acidic with 2 N HCl, which was filtered to afford the title compound (2 g, 47%) as a pale brown solid. 1H NMR (DMSO-d6): δ12.6-13.0 (br, 2H), 8.4 (s, 1H), 7.9 (d, 1H), 7.5 (d, 1H), 3.0 (q, 2H), 1.4 (t, 3H).
Reaction SMILES: [CH3:1][C:2](C)([O-:4])C.[K+].[CH3:7][C:8]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12](=[O:13])[N:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]([S:21][CH3:22])=[N:9]1.[Cl-].O>O1CCCC1>[CH3:7][C:8]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12](=[O:13])[N:11]([N:14]([C:2](=[O:4])[CH3:1])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]([S:21][CH3:22])=[N:9]1
Reactant: CSC1=NC(C)(c2ccccc2)C(=O)N1Nc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CSC1=NC(C)(c2ccccc2)C(=O)N1N(C(C)=O)c1ccccc1
Temperature: 0 °C
Yield: 22.1 %

Procedure:
0.4 g (3.5 mmol) of potassium tert-butoxide is added to a solution of 4-methyl-1-phenylamino-2-methylthio-4-phenyl-2-imidazolin-5-one (Compound 9) (1 g, 3.2 mmol) in anhydrous tetrahydrofuran (30 ml), cooled beforehand to 0° C. The mixture is left to react for 0.5 hour at 0° C. 0.25 g (3.5 mmol) of acetyle chloride is then added and the mixture is left to react for 0.5 hour at room temperature. The reaction mixture is poured into 100 ml of water and the product is extracted with 100 ml of diethyl ether. The ethereal solution is washed with water to neutrality. The solution is dried over magnesium sulfate and then concentrated. A honey-like product is obtained which is purified by chromatography on a silica column. The purified product crystallizes from diisopropyl ether. 0.25 g of Compound 23 is obtained in the form of a white powder melting at 132° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:13]([NH:21][C:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[O:23])[C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].C1COCC1.[Li+].[OH-].Cl>O.CO>[F:1][C:2]1[CH:3]=[C:4]([C@H:13]([NH:21][C:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)=[O:23])[C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10]
Reactant: COC(=O)c1ccc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-methyl 4-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)benzoate (105 mg, 0.225 mmol) and THF (2 mL):MeOH (1 mL) was added 1M LiOH (1 mL). The solution was stirred at room temperature. After 16 h, the reaction was diluted with water. The aqueous solution was acidified with 1 N HCl to a pH of 7 and extracted with EtOAc (3×15 mL). The combined EtOAc layers were dried over MgSO4 and concentrated in vacuo to give the title compound as a white solid. 1H NMR (300 MHz, MeOH-d4) δ ppm 8.49 (d, J=4.7 Hz, 1H), 8.06-8.15 (m, J=8.5 Hz, 2H), 7.89-8.00 (m, J=8.5 Hz, 2H), 7.64 (t, J=9.1 Hz, 1H), 7.31-7.51 (m, 4H), 6.70 (s, 1H). MS (ESI pos. ion) m/z: 453.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:31][CH:32](O)[CH3:33]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([O:30][CH:32]([CH3:33])[CH3:31])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1Cl
Reactant: CC(C)O
Product: CC(C)OC(=O)c1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1C1CCCC1
Yield: 66 %

Procedure:
The title compound was prepared from (±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 15 and propan-2-ol according to Method E (yellow solid, 145 mg, 0.313 mmol, 66% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.14 (d, J=8.1 Hz, 1H), 7.89-7.94 (m, 2H), 7.46 (d, J=8.9 Hz, 1H), 7.30 (d, J=2.1 Hz, 1H), 7.03 (dd, J=8.9, 2.1 Hz, 1H), 5.22-5.32 (m, 1H), 4.63 (dd, J=9.7, 5.4 Hz, 1H), 3.44-3.54 (m, 1H), 3.08-3.16 (m, 1H), 2.86-2.98 (m, 1, 2.25-2.36 (m, 1H), 2.07-2.19 (m, 1H), 1.88-2.03 (m, 1H), 1.73-1.83 (m, 1H), 1.42-1.66 (m, 5H), 1.39 (d, J=6.4 Hz, 6H), 1.20-1.37 (m, 2H). ES-HRMS m/z calc. for C27H29ClN3O2 (M+H) 462.1943, found 462.1897.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2](OCC)=O.[F:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[C:17]([C:23]([NH2:25])=[O:24])[C:18]([NH2:22])=[N:19]2)=[CH:14][CH:13]=1>CCCCCC>[F:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[C:17]3[C:23](=[O:24])[NH:25][C:2]([C:1]([O:8][CH2:9][CH3:10])=[O:7])=[N:22][C:18]3=[N:19]2)=[CH:14][CH:13]=1
Reactant: NC(=O)c1cc2ccc(F)cc2nc1N
Reactant: CCOC(=O)C(=O)OCC
Solvent: CCCCCC
Product: CCOC(=O)c1nc2nc3cc(F)ccc3cc2c(=O)[nH]1
Temperature: 160 °C

Procedure:
Diethyl oxalate (47.5 g., 0.326 mole) and 7-fluoro-2-aminoquinoline-3-carboxamide (3.7 g., 0.015 mole) are mixed together and heated at 160° C. for seven hours. The reaction mixture is cooled to room temperature, hexane (300 ml.) added, and the brown solid which precipitates filtered off, and washed with hexane (60 ml.). It is then slurried in hot chloroform (250 ml.) and the insoluble material removed by filtration. The hot filtrate is decolorized with charcoal, filtered and dried (Na2SO4). The light brown solid which precipitates upon cooling is filtered off and recrystallized from isopropyl alcohol. Yield = 1.04 g. (29.2%) of the title ethyl ester. M.P. 248°-251° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[CH:13][C:8]=3[O:7][C:6]=2[CH:23]=1.C([Li])(C)(C)C.CCCCC.[CH3:34][Sn:35](Cl)([CH3:37])[CH3:36]>C1COCC1.C(Cl)Cl.CCOCC>[CH3:34][Sn:35]([CH3:37])([CH3:36])[C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[CH:13][C:8]=3[O:7][C:6]=2[CH:23]=1
Reactant: C[Sn](C)(C)Cl
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc2c(c1)oc1cc(Br)ccc12
Agent: [Li]C(C)(C)C
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCCCC
Product: CC(C)(C)[Si](C)(C)OCc1ccc2c(c1)oc1cc([Sn](C)(C)C)ccc12
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 68.6 %

Procedure:
To a solution of the dibenzofuran 10 (995 mg, 2.5 mmol) in anhydrous THF (25 mL) at -78° C. under a nitrogen atmosphere was added a 1.7M t-butyllithium in pentane solution (3.0 mL, 5.1 mmol). The resulting yellow solution was stirred from 100 min., then trimethyltin chloride (548 mg, 2.75 mmol) was added as a solid. The mixture was allowed to warm to ambient temperature and then stirred for 3 hours. The reaction mixture was then poured into ether and the organic solution was washed with water (3 times) and then with brine. The organic solution was then dried with magnesium sulfate, filtered and concentrated under vaccum. Flash chromatography of the residue (silica gel, 10% methylene chloride in hexanes) provided 815 mg of the stannane 316 (68% yield) as a crystalline solid.
Reaction SMILES: [OH:1][C@H:2]([C:13]1[CH:22]=[CH:21][C:16]2[C:17](=[O:20])[O:18][CH2:19][C:15]=2[C:14]=1[CH3:23])[CH2:3][N:4]1[CH:9]2[CH2:10][NH:11][CH2:12][CH:5]1[CH2:6][O:7][CH2:8]2.[CH3:24][C@@H:25]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([CH:35]3[CH2:37][O:36]3)[CH:32]=2)[C:27](=[O:38])[O:26]1>>[OH:36][CH:35]([C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[C:27](=[O:38])[O:26][C@H:25]([CH3:24])[CH2:34]2)[CH2:37][N:11]1[CH2:12][CH:5]2[N:4]([CH2:3][C@H:2]([OH:1])[C:13]3[C:14]([CH3:23])=[C:15]4[C:16](=[CH:21][CH:22]=3)[C:17](=[O:20])[O:18][CH2:19]4)[CH:9]([CH2:8][O:7][CH2:6]2)[CH2:10]1
Reactant: C[C@@H]1Cc2cc(C3CO3)ccc2C(=O)O1
Reactant: Cc1c([C@@H](O)CN2C3CNCC2COC3)ccc2c1COC2=O
Product: Cc1c([C@@H](O)CN2C3COCC2CN(CC(O)c2ccc4c(c2)C[C@@H](C)OC4=O)C3)ccc2c1COC2=O

Procedure:
(3R)-6-(1-Hydroxy-2-(9-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)ethyl)-3-methylisochroman-1-one was prepared initially as a mixture of two diastereomers from 5-[(1R)-1-hydroxy-2-(3-oxa-7,9-diazabicyclo[3.3.1]non-9-yl)ethyl]-4-methyl-2-benzofuran-1(3H)-one [INTERMEDIATE 17] and (3R)-3-Methyl-6-(oxiran-2-yl)-3,4-dihydro-1H-isochromen-1-one [INTERMEDIATE 23, STEP B] in an analogous fashion to that described for the synthesis of EXAMPLE 1. The mixture of diastereomers was separated by preparative SFC-HPLC using a Chiralcel® OD column (30×250 mm) to afford the title single isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]#[N:18])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:19][O-:20].[Na+]>CO>[CH3:19][O:20][C:17]([N:14]1[CH2:13][CH2:12][CH:11]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][N:7]=2)[CH2:16][CH2:15]1)=[NH:18]
Reactant: N#CN1CCC(c2n[nH]c3cc(Cl)ccc23)CC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)N1CCC(c2n[nH]c3cc(Cl)ccc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
To a stirred mixture of cyanogen bromide (1.8 g, 0.017 mol), sodium bicarbonate (2.80 g) and dimethyl sulfoxide (DMSO) (40 ml) was added dropwise 6-chloro-3-(4-piperidinyl)-1H-indazole (4.0 g, 0.017 mol) of Example 52 dissolved in DMSO (50 ml). The reaction was stirred at ambient temperature for 1 hour and poured into water. The resulting solid was collected, dried and weighed 4.0 g. Recrystallization from toluene-hexane afforded 3.1 g (70%) of 4-(6-chloro-1H-indazol-3-yl)piperidine-1-carbonitrile, m.p. 180°-188° C. To a stirred mixture of 4-(6-chloro-1H-indazol-3-yl)-piperidine 1-carbonitrile (3.0 g., 0.015 mol) in methanol (30 ml) was added a solution of 25% sodium methoxide in methanol (2.5 ml). The reaction was warmed on a steam bath to effect solution and then stirred at ambient temperature for 16 hours. Most of the methanol was removed in vacuo and the residue was diluted with water. An initial oil solidified and 3.5 g of a solid was collected. This was recrystallized from methanol-water to yield 2.9 g (66%) of 4-(6-chloro-1H-indazol-3-yl)piperidine-1-carboximidic acid methyl ester, mp 173°-175° C.