Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].O.[Br:11]Br>C(O)(=O)CC>[BrH:11].[Br:11][C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:2]([CH3:1])[C:3]=1[NH2:4]
Reactant: Cc1ccc(N)c(C)c1
Reactant: BrBr
Solvent: O
Solvent: CCC(=O)O
Product: Br
Product: Cc1cc(C)c(N)c(Br)c1
Temperature: 25 °C

Procedure:
A 1 1, 3-necked round-bottom flask, equipped with an overhead stirrer, thermometer, and addition funnel was placed in a heating mantle and charged with 2,4-dimethylaniline (60 g, 0.495 mol), propionic acid (450 ml) and water (2 ml). Rapid stirring was initiated as a solution of bromine (93 g, 0.582 mol) in propionic acid (50 ml) was added over 5 minutes. The resulting slurry was stirred at 85°-90° C. for 40 minutes while monitoring the progress of the reaction by high pressure liquid chromatography (HPLC). After cooling to ambient temperature, ethylene was bubbled through the mixture to discharge the color. After cooling to 10° C. and a 15 minute age, the mixture was filtered. The product was washed with chilled propionic acid (150 ml) then hexane (400 ml) added portionwise. The white to cream colored solid was air dried with final drying accomplished under vacuum. The Compound 1a was obtained as a fine white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:33])[CH:31]=[CH2:32].C(=O)(O)[O-].[Na+]>CN(C=O)C.C1COCC1>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=1)=[CH:3][C:2]([NH:1][C:30](=[O:33])[CH:31]=[CH2:32])=[CH:11][CH:10]=2)#[N:13]
Reactant: C=CC(=O)Cl
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(F)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(F)c(F)c3)c2c1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 28.1 %

Procedure:
Dissolved 1.00 g (3.37 mmol) 6-amino-4-[(3,4-difluorophenyl)amino]-3-quinolinecarbonitrile in 2 ml DMF, added 12 ml THF, and chilled to 0° C. under N2. Added 517 μl (3.71 mmol) triethylamine and 310 μl (3.72 mmol) acryloyl chloride. Removed ice bath a 15 minutes. At 3.5 hours stripped solvent and slurried residue with dilute sodium bicarbonate. Collected solids, washed with water, and air dried. Boiled in ethyl acetate, collected solids and dried in vacuo, giving 332 mg of yellow solid: mass spectrum (electrospray m/e): M+H=351.1.
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:14][C@@H:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[O:12][C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5]1)[CH3:2].[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[C:32]([OH:35])([CH3:34])[CH3:33])[C:26](O)=[O:27].CCN=C=NCCCN(C)C.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:1]([O:3][C@H:4]1[CH2:14][C@@H:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[O:12][C:6]2([CH2:7][CH2:8][N:9]([C:26]([C:25]3[CH:29]=[CH:30][C:31]([C:32]([OH:35])([CH3:34])[CH3:33])=[C:23]([F:22])[CH:24]=3)=[O:27])[CH2:10][CH2:11]2)[CH2:5]1)[CH3:2]
Reactant: CC(C)(O)c1ccc(C(=O)O)cc1F
Reactant: CCO[C@H]1C[C@@H](c2ccc(F)cc2)OC2(CCNCC2)C1
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCO[C@H]1C[C@@H](c2ccc(F)cc2)OC2(CCN(C(=O)c3ccc(C(C)(C)O)c(F)c3)CC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
To a solution of cis-8-ethoxy-10-(4-fluorophenyl)-11-oxa-3-azaspiro[5.5]undecane (75 mg, 0.26 mmol) and 3-fluoro-4-(1-hydroxy-1-methyl-ethyl)benzoic acid (56 mg, 0.28 mmol) in CH2Cl2 (1 mL) was added EDCI (54 mg, 0.28 mmol). Diisopropylethylamine (134 μL, 0.767 mmol) was added last. The reaction mixture was allowed to stir at room temperature for 1 hour. The reaction mixture was purified by column chromatography (0-50% EtOAc-Hex) to provide [cis-8-ethoxy-10-(4-fluorophenyl)-11-oxa-3-azaspiro[5.5]undecan-3-yl]-[3-fluoro-4-(1-hydroxy-1-methyl-ethyl)phenyl]methanone (28.3 mg). 1H NMR (400 MHz, CDCl3) δ 7.60 (t, J=8.1 Hz, 1H), 7.34 (dd, J=8.5, 5.4 Hz, 2H), 7.14 (dd, J=8.0, 1.6 Hz, 1H), 7.11-7.00 (m, 3H), 4.60-4.30 (m, 2H), 3.77 (br s, 1H), 3.65-3.05 (m, 6H), 2.27 (br s, 2H), 2.23-2.07 (m, 1H), 1.64 (s, 6H), 1.62-1.30 (m, 5H), 1.22 (dd, J=16.6, 9.6 Hz, 3H). ESI-MS m/z calc. 473.24, found 474.5 (M+1)+; Retention time: 1.63 minutes (3 minute run).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[S:18]1[CH:22]=[CH:21][N:20]=[C:19]1[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:27][C:26]2[CH:25]=[CH:24][C:23]([C:19]3[S:18][CH:22]=[CH:21][N:20]=3)=[CH:30][CH:29]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(-c2nccs2)cc1
Reactant: CC(C)(C)OC(=O)COc1cccc(CN)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3nccs3)cc2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
A solution of (3-aminomethyl-phenoxy)-acetic acid tert-butyl ester (0.14 g, 0.59 mmol) and 4-thiazol-2-yl-benzaldehyde (0.105 g, 0.55 mmol) in 2 mL MeOH was stirred at room temperature for 1.5 hours. After cooling to 0° C., NaBH4 (0.033 g, 0.88 mmol) was added and the reaction was stirred for 10 minutes. The mixture was quenched with aqueous saturated NaHCO3:H2O (1:1) and the MeOH was removed in vacuo. The product was extracted into CH2Cl2 and the organic solution was dried over MgSO4, filtered, and concentrated in vacuo to afford a brown oil. The product was purified via flash chromatography on silica gel (6/4 EtOAc/Hexanes) to afford the title compound of Step A (0.140 g). 1H NMR (400 MHz, CDCl3) δ 7.91 (d, 2H), 7.82 (s, 1H), 7.40 (d, 2H), 7.23–7.38 (m, 2H), 6.94 (m, 2H), 6.78 (d, 1H), 4.49 (s, 2H), 3.80 (s, 2H), 3.76 (s, 2H), 1.45 (s, 9H); MS 411 (M+1).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:16]O)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:18]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[CH2:16][Br:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CBr)c1
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a solution of (3-tert-butyldimethylsilyloxymethylphenyl)methanol (528 mg) and tetrabromomethane (694 mg) in dichloromethane (10 mL) was added triphenylphosphine (549 mg) at room temperature, and the mixture was stirred for 2 hours. The reaction mixture was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give the title compound (660 mg).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:8]=1[C:16]#[N:17])(=O)=O.[CH3:20][C:21]([CH3:26])=[CH:22]B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.CCOC(C)=O>[N+:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([CH:20]=[C:21]([CH3:26])[CH3:22])[C:8]=1[C:16]#[N:17])([O-:15])=[O:14]
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)cccc1[N+](=O)[O-]
Reactant: CC(C)=CB(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)=Cc1cccc([N+](=O)[O-])c1C#N
Temperature: 25 °C
Yield: 61.3 %

Procedure:
A suspension of 2-cyano-3-nitrophenyl trifluoromethanesulfonate (Example 129d) (4.80 g; 16.21 mmol), 2-methyl-1-propenylboronic acid (2.43 g; 24.32 mmol), tetrakis(tiphenylphosphine)palladium(0) (1.87 g; 1.62 mmol), sodium carbonate (1.89 g; 17.83 mmol) and water (33.0 mL) in dimethoxyethane (DME) (132.0 mL) was heated at reflux for 4 h, under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and diluted with water (100 mL) and EtOAc (250 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (3×100 mL). The combined extract was washed with brine and dried with anhydrous MgSO4. The filtrate was evaporated and the residue was purified by chromatography on silica gel using gradient hexanes to hexanes/EtOAc (7:3), to give 2.01 g (61%) of the title compound as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 8.19-8.23 (m, 1H), 7.83-7.93 (m, 2H), 6.45 (broad s, 1H), 1.95-1.98 (m, 3H), 1.75-1.79 (m, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3]1.[CH2:8]([CH2:12][C:13](=O)[CH3:14])[C:9]([CH3:11])=O.O>C1(C)C=CC=CC=1.CC(O)=O>[CH3:14][C:13]1[N:7]([C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)[C:9]([CH3:11])=[CH:8][CH:12]=1
Reactant: Cn1ccc(N)n1
Reactant: CC(=O)CCC(C)=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(C)n1-c1ccn(C)n1

Procedure:
To a solution of 1-methyl-1H-pyrazol-3-amine (9.5 g, 98 mmol) and acetonylacetone (11.2 g, 98 mmol) in toluene (150 mL), AcOH (1.5 mL) is added, heated to reflux with a water separator until the formation of water ceased. Concentrated to dry. The residue is purified by flash column to give product.
Reaction SMILES: [CH:1]([CH:3]1[CH:8]([CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:7][O:6][CH:5]([CH3:19])[O:4]1)=O.[C:20]1([NH:26][C:27](=[S:30])[NH:28][NH2:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C.C(O)(=O)C.C(Cl)(Cl)Cl>[CH3:18][O:17][C:15]([CH2:14][CH2:13][CH2:12]/[CH:11]=[CH:10]\[CH2:9][C@H:8]1[CH2:7][O:6][C@@H:5]([CH3:19])[O:4][C@H:3]1[CH:1]=[N:29][NH:28][C:27]([NH:26][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[S:30])=[O:16]
Reactant: COC(=O)CCC/C=C\CC1COC(C)OC1C=O
Reactant: NNC(=S)Nc1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1C=NNC(=S)Nc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 114.3 %

Procedure:
To a mixture of 2R,4R, 5S)-4-formyl-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-1,3-dioxane (62 mg) and 4-phenyl-3-thiosemicarbazide (46 mg) in ethanol (2 ml) was added acetic acid (1 drop) and the solution was stirred at room temperature for 4 hours. The mixture was diluted with chloroform (15 ml) and the solution was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to give (2R,4R,5S)-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-4-[4-(phenyl)thiosemicarbazonomethyl]-1,3-dioxane (110 mg) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH:7]([CH2:13][C:14]#[N:15])[CH2:6]2.[C:16]([O-])(=[O:18])[CH3:17].[Na+].[H][H]>[Ni].C(OC(=O)C)(=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH:7]([CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])[CH2:6]2
Reactant: COc1ccc2c(c1)CC(CC#N)CO2
Reactant: CC(=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)CC(CCNC(C)=O)CO2

Procedure:
0.812 g (4 mmol) of the nitrile obtained in Step C is added to a suspension of 0.35 g (6 mmol) of Raney nickel and 0.5 g (6 mmol) of sodium acetate in 40 ml of acetic anhydride. The reaction medium is then subjected to hydrogen pressure of 50 psi at a temperature of 50° C. for 5 hours. After cooling of the mixture, the salts are filtered off and the filtrate is concentrated under reduced pressure. The residue obtained is then taken up in ethyl acetate; the organic phase is then washed with a saturated solution of sodium hydrogen carbonate. After drying over magnesium sulphate and filtration, the solvent is evaporated in vacuo. Chromatography on a silica column (eluant: AcOEt) results in the title amide in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:3]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CN(C1C=CC=CN=1)C>ClCCl>[F:14][C:11]1[CH:10]=[CH:9][C:8]([C:4]2[C:3]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[C:2]([NH:1][C:28]([NH:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:29])[N:6]([CH3:7])[N:5]=2)=[CH:13][CH:12]=1
Reactant: Cn1nc(-c2ccc(F)cc2)c(-c2ccncc2)c1N
Reactant: O=C=Nc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: Cn1nc(-c2ccc(F)cc2)c(-c2ccncc2)c1NC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
150 mg of 5-amino-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole was dissolved in 5 ml of dichloromethane. Then, 80 mg of phenyl isocyanate and 80 mg of dimethylaminopyridine were added thereto, followed by stirring at room temperature overnight. After the reaction mixture was washed with water and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography using 20 g of silica gel and eluted with chloroform-methanol (50:1). Thus, 70 mg of the title compound was obtained and crystallized from ether.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8](=[C:11]([S:14][CH3:15])SC)[C:9]#[N:10])=O.[CH3:16][O:17][CH2:18][CH2:19][N:20]([CH2:22][C:23]1[CH:34]=[CH:33][C:26]([C:27]([NH:29][C:30]([NH2:32])=[NH:31])=[O:28])=[CH:25][CH:24]=1)[CH3:21].C(N(CC)CC)C>CN(C=O)C>[C:9]([C:8]1[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[N:31][C:30]([NH:29][C:27](=[O:28])[C:26]2[CH:25]=[CH:24][C:23]([CH2:22][N:20]([CH2:19][CH2:18][O:17][CH3:16])[CH3:21])=[CH:34][CH:33]=2)=[N:32][C:11]=1[S:14][CH3:15])#[N:10]
Reactant: CSC(SC)=C(C#N)C(=O)c1ccco1
Reactant: COCCN(C)Cc1ccc(C(=O)NC(=N)N)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCN(C)Cc1ccc(C(=O)Nc2nc(SC)c(C#N)c(-c3ccco3)n2)cc1

Procedure:
From 2-(furan-2-carbonyl)-3,3-bis-methylsulfanyl-acrylonitrile, N-(4-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-benzoyl)-guanidine and triethylamine in DMF. ES-MS m/e (%): 438 (M+H+, 100).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.Cl.[NH2:43][C@@H:44]1[CH2:49][CH2:48][C@H:47]([OH:50])[CH2:46][CH2:45]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:43][C@H:44]5[CH2:49][CH2:48][C@@H:47]([OH:50])[CH2:46][CH2:45]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@H]1CC[C@@H](O)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N[C@H]2CC[C@@H](O)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.08 g (0.18 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.13 mL (0.72 mmole) of ethyldiisopropyl amine and 0.030 g (0.20 mmole) of cis-4-amino-cyclohexanol hydrochloride in 2.0 mL of dimethylformamide was added 0.085 g (0.2 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-90:10) gave 0.066 g of cis-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(4-hydroxy-cyclohexyl)-3-methoxy-benzamide (I-68) as a white solid.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.CN(C)CCN(C)C.[Cl:22][C:23]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:24]=1[C:25]([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)=[O:26]>O1CCCC1.O>[Cl:22][C:23]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:24]=1[C:25]([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)([C:10]1[N:9]([CH2:8][O:7][CH3:6])[CH:13]=[CH:12][N:11]=1)[OH:26]
Reactant: O=C(c1ccc(F)cc1)c1ccc(Cl)cc1Cl
Reactant: COCn1ccnc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COCn1ccnc1C(O)(c1ccc(F)cc1)c1ccc(Cl)cc1Cl
Reaction time: 1 h

Procedure:
At -60° C. and under a nitrogen atmosphere, 44 ml. (0.072 mol) of n-butyl lithium (15% solution in n-hexane) was added dropwise under stirring to a solution of 7.8 g (0.07 mol) of 1-(methoxymethyl)imidazole and 8.1 g (0.072 mol) of N,N,N',N'-tetramethylethylenediamine in 100 ml of anhydrous tetrahydrofuran. The mixture was stirred for one hour and then 18.9 g (0.070 mol) of 2,4-dichloro-4'-fluorobenzophenone in 100 ml of anhydrous tetrahydrofuran were added at -60° C. The solution was stirred for one hour at -60° C. and kept standing overnight at room temperature. Then 50 ml of water were added and the solid matter formed was filtered off. The filtrate was extracted with tetrahydrofuran and diethyl ether. The organic phase was dried over sodium sulphate and the solvents were distilled off. Diethyl ether was added to the semisolid residue and the solid matter was filtered off. This product was combined with the solid matter obtained after the addition of water. The substance was twice crystallised from acetone with a small amount of dimethylformamide. α-(2,4-Dichlorophenyl)-α-(p-fluorophenyl)-1-(methoxymethyl)imidazole-2-methanol was obtained. Melting point 179° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[C:22]([F:25])=[N:23][CH:24]=1.C([O-])(=O)C.[K+].O>C1COCC1>[Cl:18][C:19]1[CH:20]=[C:21]([C:2]2[N:10]=[C:9]([CH3:11])[N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[C:22]([F:25])=[N:23][CH:24]=1
Reactant: Cc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Reactant: OB(O)c1cc(Cl)cnc1F
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2cc(Cl)cnc2F)c2ncn(C3CCCCO3)c2n1
Temperature: 90 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
6-Chloro-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.500 g, 1.979 mmol) and 5-chloro-2-fluoropyridin-3-ylboronic acid (1.388 g, 7.91 mmol) (Combi-Blocks, Inc., San Diego, Calif.) in THF (25 ml) were added to a 100 mL round-bottomed flask. Potassium acetate (0.583 g, 5.94 mmol) was added to the mixture, followed by water (1 mL). The mixture was evacuated, then backfilled with Nitrogen gas. Then bis(di-tert-butyl (4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.050 g) (Aldrich, St. Louis, Mo.) was added into the mixture. The mixture was evacuated, then backfilled with nitrogen gas. The flask was fitted with a reflux condenser, then placed into a pre-heated (90° C.) oil bath and allowed to stir under inert atmosphere for 2 h. The progress of the reaction was monitored by LCMS, which showed mostly desired product. The reaction mixture was allowed to cool to room temperature, diluted with water (10 mL) and extracted with CH2Cl2 (3×25 mL). The organic extracts were washed with satd aqueous Na2CO3 (1×20 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a tan oil. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep RediSep®, Teledyne ISCO, Lincoln, Nebr., pre-packed silica gel column (120 g), eluting with a gradient of 1% to 40% EtOAc in CH2Cl2, to give 6-(5-chloro-2-fluoropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.502 g, 1.443 mmol, 73.0% yield) as yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.37-8.45 (m, 1H); 8.27-8.33 (m, 2H); 5.79-5.92 (m, 1H); 4.14-4.26 (m, 1H); 3.74-3.91 (m, 1H); 2.89 (s, 3H); 1.96-2.25 (m, 3H); 1.63-1.91 (m, 3H). m/z (ESI, +ve) 348 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[CH3:12][NH:13][CH2:14][CH2:15][OH:16].C(N(CC)CC)C>CN1CCCC1=O>[CH3:8][C:6]1[CH:7]=[C:2]([N:13]([CH2:14][CH2:15][OH:16])[CH3:12])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: CNCCO
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1cc(N(C)CCO)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 5-fluoro-2-nitrotoluene (1.5 g, 9.6 mmol), N-methylethanolamine (0.90 mL, 0.012 mol) and triethylamine (1.6 mL, 0.012 mol) in N-methyl-2-pyrrolidone (15 mL) was stirred at 60° C. for 12 h. Cooled to ambient temperature, the reaction mixture was poured into ice water, extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated to afford 2-[(3-methyl-4-nitrophenyl)-N-methylamino]ethanol as solid (2.0 g, y. 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[CH2:12]([O:14][C:15]([C:17]1([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)[CH2:21][CH2:20][NH:19][CH2:18]1)=[O:16])[CH3:13]>>[CH2:12]([O:14][C:15]([C:17]1([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[CH:26][CH:25]=2)[CH2:21][CH2:20][N:19]([C:10](=[O:11])[NH:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:18]1)=[O:16])[CH3:13]
Reactant: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCNC1
Reactant: COc1ccc(N=C=O)cc1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCN(C(=O)Nc2ccc(OC)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 71 using 4-methoxy phenyl isocyanate and 3-(4′-fluoro-biphenyl-4-yloxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 65) to afford the racemate as a yellow liquid (78, mg, 88%)
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[CH2:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]1=O)C.O.[NH2:14]N>C(O)C>[CH3:10][C:7]1([CH3:11])[C:6]2[C:5](=[CH:4][NH:2][N:14]=2)[CH2:9][CH2:8]1
Reactant: NN
Reactant: CN(C)C=C1CCC(C)(C)C1=O
Solvent: CCO
Solvent: O
Product: CC1(C)CCc2c[nH]nc21
Temperature: 25 °C
Yield: 102.8 %

Procedure:
To a solution of 2-[(dimethylamino)methylene]-5,5-dimethylcyclopentanone (12.5 g, 75 mmol) in ethanol (100 mL) at room temperature was added hydrazine hydrate (4 mL, 82.3 mmol). The reaction mixture was heated at reflux overnight. It was then cooled to room temperature and concentrated. Water (700 mL) was added to the residue, and the resulting solution was extracted twice with diethyl ether (2×250 mL). The organic extracts were combined, dried over MgSO4 and concentrated to give the title compound as an oil (10.5 g). 1H NMR indicated the oil to be ˜60% pure. It was used directly for Step C.
Reaction SMILES: [C@@H:1]12[C:10](=O)[O:9][C:7](=[O:8])[C@@H:2]1[CH2:3][CH:4]=[CH:5][CH2:6]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.O.C(Cl)(Cl)Cl>O1CCCC1>[OH:8][CH2:7][C@H:2]1[C@@H:1]([CH2:10][OH:9])[CH2:6][CH:5]=[CH:4][CH2:3]1
Reactant: O=C1OC(=O)[C@@H]2CC=CC[C@H]12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: OC[C@@H]1CC=CC[C@@H]1CO
Temperature: 0 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
A solution of 25 g of cis-4-cyclohexene-1,2-dicarboxylic acid anhydride in 140 ml of tetrahydrofuran is instilled in a suspension of 10 g of lithium aluminum hydride in 140 ml of tetrahydrofuran at room temperature and the mixture is then stirred for 3 hours at reflux temperature. It is cooled to 0° C. a mixture of tetrahydrofuran/water (1+1) is instilled slowly, stirred for 30 minutes, mixed with 150 ml of chloroform, filtered and the filtrate is concentrated by evaporation in a vacuum. The residue is distilled at 0.2 mm/Torr and 150° C. on a bulb tube. After recrystallization of the distillate from toluene/pentane, 21 g of cis-1,6-dihydroxymethyl-3-cyclohexene is obtained as colorless crystals, melting point 33°-35° C.