Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH2:8][CH2:7]C=CCCC=1.[C]=O.[CH2:11]([O:13][SiH:14]([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])[CH3:12].[CH2:21]([NH2:24])[CH:22]=[CH2:23]>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Rh].[Rh].[Rh].[Rh].C1(C)C(C)=CC=CC=1>[CH2:21]([NH2:24])[CH:22]=[CH2:23].[NH2:24][CH:8]([CH3:7])[CH2:1][Si:14]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])[O:13][CH2:11][CH3:12]
Reactant: C1=CCCC=CCC1
Reactant: CCO[SiH](OCC)OCC
Agent: [Rh]
Agent: [C-]#[O+]
Agent: [C]=O
Solvent: Cc1ccccc1C
Solvent: C=CCN
Product: CCO[Si](CC(C)N)(OCC)OCC
Temperature: 120 °C
Reaction time: 2.5 h

Procedure:
A 200 ml. flask equipped with a stirrer, thermometer, dropping funnel, CO inlet tube and reflux condenser having a CO outlet tube, was flushed with carbon monoxide and charged with 1.9 milligrams of tetrarhodium dodecacarbonyl (2.5×10-6 mole), 0.027 gram of 1,5-cyclooctadiene (2.5×10-4 mole) and 60 ml. of xylene. While passing carbon monooxide through the flask at a rate of 10 ml./min., the mixture was heated to a temperature of 120° C. under stirring. To the mixture a mixture of 41 grams of triethoxy silane (0.25 mole) and 14 grams of allylamine (0.25 mole) was dropwise added over a period of 30 minutes. After the addition of the reactants, the reaction was carried out at a temperature of 120° C. for 2.5 hours under CO flush and stirring. It was revealed by gas chromatography that gamma-aminopropyl triethoxy silane was obtained in a yield of 75% on an allylamine basis, while the yield of beta-aminopropyl triethoxy silane was 7.5% on an allylamine basis.
Reaction SMILES: S=C1[N:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:20])[CH3:19])=[C:13]([O:21][CH3:22])[CH:12]=2)=[O:8])[CH2:5][CH2:4]S1.[O:23](CCN)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[C:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][O:9][C:7](=[O:8])[NH:6][CH2:5][CH2:4][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:12][C:13]=1[O:21][CH3:22])(=[O:20])[CH3:19]
Reactant: NCCOc1ccccc1
Reactant: COc1cc(COC(=O)N2CCSC2=S)ccc1OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(COC(=O)NCCOc2ccccc2)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.6 %

Procedure:
To a stirred yellow solution of VII (371.8 mg, 1.089 mmol) in anhydrous THF (10 mL) was added 2-phenoxyethylamine (165 mg, 157 μL, 1.1×1.089 mmol) and then, dropwise, triethylamine (121 mg, 168 μL, 1.1×1.089 mmol). The solution was stirred for 1.5 hours at room temperature. The colorless solution was then diluted with CH2Cl2 and washed with 1N HCl, distilled water, and saturated NaCl. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated. The crude product was purified by column chromatography on silica gel using hexanes/ethyl acetate (1:1, v/v) to yield 260.6 mg (67%) of a 11 as a clear light yellow oil: Rf=0.39 (hexanes/ethyl acetate, 1:1, v/v); 1HNMR (CDCl3) δ 7.26 (td, 3J=8.0 Hz, 4J=1.1 Hz, 2H), 6.98 (d, 3J=8.0 Hz, 1H), 6.96 (m, 1H), 6.94 (d, 4J=1.0 Hz, 1H), 6.92 (dd, 3J=8.7 Hz, 1H), 6.86 (d, 3J=8.1 Hz, 2H), 5.21 (bs, 1H, NH), 5.06 (s, 2H), 4.03 (t, 3J=5.0 Hz, 2H), 3.80 (s, 3H), 3.59 (q, 3J=5.2 Hz, 2H, NCH2) and 2.29 (s, 3H). Exact mass (EST) calculated for C19H22NO6 [M+H]=360.1442. found 360.1443.
Reaction SMILES: C([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([CH2:16][OH:17])[C:13]([C:18]#[N:19])=[CH:12]2)=[CH:7][CH:6]=1)C.[CH2:21](N(CC)CC)[CH3:22].CS(Cl)(=O)=O>O1CCCC1>[C:18]([C:13]1[C:14]([CH2:16][O:17][CH2:21][CH3:22])=[CH:15][N:11]([C:8]2[CH:7]=[CH:6][C:5]([C:4]([OH:3])=[O:20])=[CH:10][CH:9]=2)[CH:12]=1)#[N:19]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c(CO)c2)cc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CCOCc1cn(-c2ccc(C(=O)O)cc2)cc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
To a solution of 4-(3-cyano-4-hydroxymethylpyrrole-1-yl)benzoic acid ethyl ester (0.022 g) in tetrahydrofuran (1 mL) were added triethylamine (0.0082 g) and methane sulfonylchloride (0.0093 g) under ice-cooling. After warming to ambient temperature, this mixture was stirred for 30 minutes. The insoluble material of this reaction mixture was removed by filtration, and this filtrate was added to a mixture of ethanol (1.125 g) and sodium hydride (60%, 0.13 g), and this mixture was stirred for 5 hours. To this reaction mixture was added water, and this mixture was stirred at room temperature for 1 hours. To this reaction mixture was added 2 mol/L hydrochloric acid (3 mL), this mixture was extracted with ethyl acetate. This organic layer was washed with brine, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=88/12-81/19) to give the title compound (0.010 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:19][C:20]2[CH:24]=[C:23]([O:25][CH3:26])[NH:22][N:21]=2)=[N:4][C:5]([NH:9][C@H:10]([C:12]2[N:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=2)[CH3:11])=[N:6][C:7]=1Cl.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.CCN(C(C)C)C(C)C>CCCCO>[Cl:1][C:2]1[C:3]([NH:19][C:20]2[CH:24]=[C:23]([O:25][CH3:26])[NH:22][N:21]=2)=[N:4][C:5]([NH:9][C@H:10]([C:12]2[N:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=2)[CH3:11])=[N:6][C:7]=1[N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: COc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)nc(Cl)c2Cl)n[nH]1
Reactant: C1COCCN1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)nc(N3CCOCC3)c2Cl)n[nH]1
Temperature: 150 °C

Procedure:
A mixture of 5,6-dichloro-N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N4-(5-methoxy-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (Example 30, 100 mg), morpholine (0.026 mL) and DIPEA (0.066 ml) in n-BuOH (2.0 ml) was charged into a microwave reaction vessel. The vessel was sealed and heated at 150° C. for 24 hours. The solvent was removed under reduced pressure and the residue was purified by Gilson 2%-40% MeCN/H2O, 15 minutes) to give the titled compound as solid (21.8 mg). 1H NMR δ 11.99 (s, 1H) 9.30 (s, 1H) 8.82 (s, 2H) 7.89 (d, 1H) 5.49 (s, 1H) 4.93-5.14 (m, 1H) 3.75 (s, 3H) 3.44-3.62 (m, 4H) 3.09-3.27 (m, 4H) 1.47 (d, 3H) m/z 450.
Reaction SMILES: [H-].[Na+].[CH:3]([O:5][CH3:6])=[O:4].[F:7][C:8]([F:22])([F:21])[C:9]1[N:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](OC)=[O:18])=[CH:11][N:10]=1>COCCOC>[OH:18]/[CH:17]=[C:16](/[CH2:15][C:12]1[CH:11]=[N:10][C:9]([C:8]([F:22])([F:21])[F:7])=[N:14][CH:13]=1)\[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC=O
Reactant: COC(=O)CCc1cnc(C(F)(F)F)nc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)/C(=C\O)Cc1cnc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
To a solution of NaH (360 mg, 9.00 mmol) in DME (20 mL) was added a solution of methyl formate (0.254 mL, 4.10 mmol) and methyl 3-[2-(trifluoromethyl)-5-pyrimidinyl]propanoate (800 mg, 3.42 mmol) in DME (20 mL) at 0° C. The mixture was stirred at room temperature overnight, and quenched with MeOH. Purification via reverse phase flash chromatography afforded the title compound (730 mg, 2.78 mmol, 82% yield) as yellow solid. LCMS: rt=2.03 min, [M+H+]=263.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10](=[O:12])[NH:9][C@@H:8]3[CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][C@H:7]3[C:6]=2[CH:5]=[C:4]([CH2:23][CH2:24][CH3:25])[CH:3]=1.Br[C:27]1C=CC(C(N(CC)CC)=O)=C(Cl)C=1>>[ClH:1].[Cl:1][C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:27])[C@@H:8]3[CH2:13][NH:14][CH2:15][C@H:7]3[C:6]=2[CH:5]=[C:4]([CH2:23][CH2:24][CH3:25])[CH:3]=1
Reactant: CCN(CC)C(=O)c1ccc(Br)cc1Cl
Reactant: CCCc1cc(Cl)c2c(c1)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1NC2=O
Product: CCCc1cc(Cl)c2c(c1)[C@@H]1CNC[C@H]1N(C)C2=O
Product: Cl

Procedure:
Following the procedures described in Example 24, Parts A and B, (3aS,9bR)-tert-butyl 6-chloro-5-oxo-8-propyl-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate, the second eluting compound from Example 23, Part J, was converted to the title compound of Example 26 as an off-white solid. 1H NMR (DMSO-D6): δ 9.77 (broad s, 2H), 7.33 (s, 1H), 7.05 (s, 1H), 3.96-3.90 (m, 1H), 3.80-3.65 (overlapping m, 2H), 3.48-3.20 (overlapping m, 3H), 2.99 (s, 3H), 2.58 (t, 2H, J=7.7 Hz), 1.65-1.55 (m, 2H), 0.89 (t, 3H, J=7.3 Hz). LRMS (ESI): 279.09/281.07 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.Cl.[CH3:23][NH2:24]>CO.C(Cl)Cl>[CH3:23][NH:24][CH2:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CNCc1ccc2[nH]c(C(N)=O)c(Sc3ccccc3)c2c1

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph) (50 mg, 0.17 mmol) with methylamine HCl (2.0 equiv, 23 mg, 0.34 mmol) as described in General Procedure X to afford 5-methylaminomethyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide, Ic (18 mg, 34.6%) as a yellow solid, tlc Rf=0.2 (15% MeOH/CH2Cl2), m/z obs=312 (M+1).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH2:14][CH2:15][CH2:16][N:17]([C:19](=[O:25])[CH2:20][O:21]C(=O)C)[CH:18]=3)=[C:9]([F:26])[CH:8]=2)[CH2:5][C@H:4]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:3]1.C(=O)([O-])[O-].[K+].[K+].Cl>CO>[OH:21][CH2:20][C:19]([N:17]1[CH:18]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([N:6]3[CH2:5][C@H:4]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:3][C:2]3=[O:1])=[CH:8][C:9]=2[F:26])[CH2:14][CH2:15][CH2:16]1)=[O:25]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CN(C(=O)COC(C)=O)CCC3)c(F)c2)C(=O)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CN(C(=O)CO)CCC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (S)-N-[[2-Oxo-3-[3-fluoro-4-[1-[(acetoxy)acetyl]-3,4-dihydro-2H-pyridin-5-yl]phenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 72, Step 6, 238 mg) and anhydrous potassium carbonate (151 mg) in methanol (27 mL) is stirred under N2 at ambient temperature for 2 hrs and is then neutralized with hydrochloric acid (1M) and concentrated under reduced pressure. The residue is then diluted with methylene chloride (100 mL) and saline (50 mL) and the resultant insoluble product is removed by filtration and dried under reduced pressure. The layers in the filtrate are separated and the organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to give additional quantities of the title compound, mp 171-173° C.
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][C:5]=2[S:4][C:3]=1CC1C(F)=CC=CC=1Cl.O.[C:22]([O-:25])(O)=[O:23].[Na+].[CH3:27][C:28](O)=O>[Zn]>[CH2:27]([O:25][C:22]([N:8]1[CH2:9][CH2:10][C:11]2[C:2]([Br:1])=[CH:3][S:4][C:5]=2[CH2:6][CH2:7]1)=[O:23])[CH3:28]
Reactant: CC(=O)O
Reactant: O=C([O-])O
Reactant: Fc1cccc(Cl)c1Cc1sc2c(c1Br)CCNCC2
Agent: [Na+]
Agent: [Zn]
Solvent: O
Product: CCOC(=O)N1CCc2scc(Br)c2CC1
Temperature: 22 °C
Yield: 68 %

Procedure:
A solution of the product from example 3, step a) (148 mg, 0.39 mmol) in AcOH (80 μl) and H2O (1.92 ml) was treated with Zn (76 mg, 1.17 mmol) at 105° C. for 4.5 hours. Next, the contents were cooled to 22° C., poured into sat. NaHCO3 (25 ml) and extracted with EtOAc (2×25 ml). The organic layer was dried (MgSO4) and concentrated providing 80 mg (68%) of the subtitle compound, which was used without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@H:12]([O:14]C(OCC)C)[CH2:11][C@H:10]([C:20]([O:22][CH3:23])=[O:21])[C@H:9]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.Cl.[OH-].[Na+]>C1COCC1.CCOC(C)=O>[CH2:1]([N:8]1[CH2:13][C@H:12]([OH:14])[CH2:11][C@H:10]([C:20]([O:22][CH3:23])=[O:21])[C@H:9]1[C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(C)O[C@@H]1C[C@H](C(=O)OC)[C@@H](C(=O)OCc2ccccc2)N(Cc2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@H]1C[C@@H](O)CN(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a solution of 2-benzyl 3-methyl(2S,3S,5R)-1-benzyl-5-(1-ethoxyethoxy)piperidine-2,3-dicarboxylate (5.70 g, 0.0125 mol) in 100 mL of THF was added 20 mL of water followed by 20 mL of 1N HCl. The mixture was stirred at rt fro 1 h. After diluted with EtOAc, the mixture was neutralized with 1N NaOH, washed with brine, dried. The residue obtained after concentration was applied on silical, eluting with 0 to 50% EtOAc in hexane, to provide the alcohol compound (4.80 g, 89.6%). MS (ESI): (M+H)+=384.2.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:6][C:5]([C:15]#[N:16])=[CH:4][C:3]=1[NH:17]C(=O)OC(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:17][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([CH2:8][N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[C:2]=1[Cl:1])[C:15]#[N:16]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(CN2CCOCC2)c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(N)c(Cl)c(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
A solution of tert-butyl (2-chloro-5-cyano-3-(morpholinomethyl)phenyl)carbamate (45 mg, 0.128 mmol) in a mixture of DCM (2 mL) and TFA (2 mL) was left stirring at RT for 1 hr. The solvent was removed and the residue was dissolved in MeOH and applied onto an SCX column. This was washed with MeOH and the product was eluted with 2N NH3 in MeOH. The solvent was removed to leave 3-amino-4-chloro-5-(morpholinomethyl)benzonitrile (32 mg, 100% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[N:14][CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[BH4-].[Na+]>O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[CH:15]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:14][CH2:13][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(cc1OCc1ccccc1)CCN=C2c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc2c(cc1OCc1ccccc1)CCNC2c1ccccc1
Temperature: 55 °C
Reaction time: 3 h

Procedure:
A suspension of 38 parts of 6-benzyloxy-7-methoxy-1-phenyl-3,4-dihydroisoquinoline in 435 parts of ethanol is heated to approximately 55°C. 32 Parts of sodium borohydride is added portionwise over a 45 minute period, while maintaining the reaction temperature at 50°-60°C. The mixture is stirred for an additional 3 hours at approximately 50°C. and a precipitate forms. The reaction mixture is then poured into water and the precipitate is separated by filtration, giving 6-benzyloxy-7-methoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline, melting at about 118°-119°C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[C:9](Cl)[N:8]=2)[N:5]=[CH:4][C:3]=1[C:19]#[N:20].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1.C(Cl)Cl>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[C:9]([NH:28][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:8]=2)[N:5]=[CH:4][C:3]=1[C:19]#[N:20]
Reactant: N#Cc1cnn(-c2nc(Cl)c(C(F)(F)F)cc2Cl)c1N
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: N#Cc1cnn(-c2nc(NCc3ccccc3)c(C(F)(F)F)cc2Cl)c1N
Temperature: 25 °C
Yield: 40.2 %

Procedure:
A stirred solution of 6.0 grams (0.019 mole) of 5-amino- 1-(3,6-dichloro-5-trifluoromethylpyridin-2-yl)-4-cyanopyrazole and 15.4 grams (0.144 mole) of benzylamine in 100 mL of tetrahydrofuran was heated at reflux for 3.5 hours. The reaction mixture was cooled and filtered. The filtrate was evaporated under reduced pressure, leaving a residue. This residue was dissolved in methylene chloride, and the organic solution was washed in succession with water, dilute hydrochloric acid, and water. The washed organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure, leaving a pale yellow solid residue. This residue, in 200 mL of petroleum ether, was heated to reflux and then allowed to cool to room temperature. The mixture was filtered, and the filter cake was dried to yield 3.0 grams of 5-amino-1-(3-chloro-5-trifluoromethyl-6-phenylmethylaminopyridin-2-yl)-4-cyanopyrazole. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[OH:6][CH2:7][CH:8]([CH2:42][OH:43])[CH2:9][CH2:10][N:11]1[C:19](NC(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:18][C:17]2[C:12]1=[N:13][C:14](OC)=[N:15][CH:16]=2.C(=O)(O)[O-].[Na+].[N:49]1C=CC=CC=1>O>[NH2:49][C:14]1[N:13]=[C:12]2[C:17]([N:18]=[CH:19][N:11]2[CH2:10][CH2:9][CH:8]([CH2:7][OH:6])[CH2:42][OH:43])=[CH:16][N:15]=1
Reactant: COc1ncc2nc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n(CCC(CO)CO)c2n1
Reactant: c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1ncc2ncn(CCC(CO)CO)c2n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To an ice-cooled solution of phosphorus oxychloride (93 μl, 1.0 mmol) in pyridine (2 ml) was added dropwise over 45 minutes a solution of 9-(4-hydroxy-3-hydroxymethylbut-1-yl)-2-monomethoxytritylaminopurine (0.46 g, 0.9 mmol) in pyridine (4 ml). The solution was stirred for a further 20 minutes at room temperature and was then added dropwise to a solution of sodium bicarbonate (0.34 g, 4.0 mmol) in water (6 ml). The solvent was removed and the residue was taken up in 80% acetic acid (9 ml) and the solution was stirred at 70° for 25 minutes. The solvent was removed and the residue was taken up in water and brought to pH 6 by addition of ammonia. The solution was extracted twice with chloroform and the solvent was removed. The residue was purified by preparative high pressure liquid chromatography on a C18 reverse-phase μ-Bondapack column eluting with 4% methanol in ammonium acetate buffer (pH 4.5, 50 mM) to afford 2-amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl) purine 4':4"-phosphate as a white powder (225 mg, 75%); λmax (H2O) 220, 242, and 303 nm; νmax (KBr) 2900-3200 (br), 1705, 1615, and 1580 cm-1 ; δH [(CD3)2SO] 1.63 (1H, m, 3'-H), 1.74 (2H, q, J 7.0 Hz, 2'-H), 3.80 (2H, q, J 9.2 Hz, 2×Hax), 3.98 (2H, ddd, J 14.3, 10.9, and 3.5 Hz, 2×Heq), 4.08 (2H, t, J 7.1 Hz, 1'-H), 6.51 (2H, s, D2O exchangeable, 2-NH2), 8.10 (1H, s, 8-H), and 8.56 (1H, s, 6-H); (Found: C, 36.41; H, 5.18; N, 22.38%. C10H14N5O4P.0.3 NH3. 1.5H2O requires C, 36.25; H, 5.45; N, 22.40%).
Reaction SMILES: C1C=CC2C(=O)[C:14]3[C:9](=[C:10]([OH:18])[CH:11]=[CH:12][C:13]=3[OH:17])C(=O)C=2C=1.[C:19]([O-])([O-])=[O:20].[K+].[K+]>C1C=CC=CC=1.[Ag]=O>[CH3:19][O:20][C:14]1[CH:9]=[C:10]([OH:18])[CH:11]=[CH:12][C:13]=1[OH:17]
Reactant: O=C([O-])[O-]
Reactant: O=C1c2ccccc2C(=O)c2c(O)ccc(O)c21
Agent: O=[Ag]
Agent: [K+]
Solvent: c1ccccc1
Product: COc1cc(O)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.5 %

Procedure:
A mixture of 1.00 g (7.10 mmol) of methoxyhydroquinone (3), 2.50 g (10.7 mmol) of silver oxide, and 1.20 g (8.50 mmol) of K2CO3 in 50 mL of benzene was stirred under argon at 25° C. for 3 h, the mixture was filtered through Celite, and washed with 5 mL of dichloromethane. The filtrate was concentrated to give 0.970 g (99% yield) of methoxybenzoquinone (6): 1H NMR d 6.72 (s, 2H), 5.95 (s, 1H), 3.84 (s, 3H). 13CNMR d 187.4, 181.6, 137.1, 134.4, 111.5, 107.6, 56.2. This material was used in the next step without purification.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([CH3:13])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[C-:14]#[N:15].[Na+]>O>[CH3:13][C:12]1[C:3]([CH2:2][C:14]#[N:15])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: [C-]#N
Reactant: Cc1cc2ccccc2cc1CBr
Agent: [Na+]
Solvent: O
Product: Cc1cc2ccccc2cc1CC#N
Temperature: 25 °C
Yield: 98.6 %

Procedure:
A suspension of 2-bromomethyl3-methylnaphthalene (2.87 g, 12.2 mmol) and NaCN (652 mg, 13.3 mmol) in CH3CH/H2O (9:1, 125 mL) was heated to reflux for 1 hour. Upon warming, the suspension became homogeneous. After cooling to room temperature, the volatiles were removed from the reaction mixture in vacuo and the residue was partitioned between 2O (150 mL) and CH2Cl2 (150 mL). The aqueous phase was extracted with CH2Cl2 (1×150 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to give the title compound as a white solid (2.18 g, 99%). This material was of sufficient purity to be used as such in the next step.
Reaction SMILES: O[CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1[CH3:18])[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9].Cl>C1COCC1.CCOC(C)=O>[CH3:17][O:16][C:12]1[C:11]([CH3:18])=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9]
Reactant: COc1cccc(C(O)C2CCCCC2=O)c1C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(CC2CCCCC2=O)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.7 %

Procedure:
To a solution of 2-[hydroxy-(3-methoxy-2-methylphenyl)-methyl]cyclohexanone (1.85 g) in THF (20 ml) was added conc. HCl (0.5 ml) at 5° C. and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc, washed with saturated sodium hydrogen carbonate, water, and brine, dried over magnesium sulfate, evaporated in vacuo. The residue was dissolved in MeOH (30 ml) and 10% Pd/C (wet) (400 mg) was added. The mixture was stirred under hydrogen atmosphere at room temperature for 2 hours. The catalyst was removed by filtration and the filtrate was evaporated. The residue was pufified by silica gel column chromatography (hexane-EtOAc 12:1 to 8:1) to give 2-(3-methoxy-2-methylbenzyl)cyclohexanone (980.6 mg) as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:35]([CH3:37])[CH3:36])[C:6]2[O:10][C:9]([C:11]3[CH:33]=[CH:32][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][C:22]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)=[CH:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:34]=1)#[N:2]>CO.O1CCCC1.[Pd]>[C:1]([C:3]1[CH:4]=[C:5]([CH:35]([CH3:37])[CH3:36])[C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([NH:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([C:25]5[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=5)[CH2:21][CH2:20]4)=[O:16])=[CH:32][CH:33]=3)=[N:8][C:7]=2[CH:34]=1)#[N:2].[C:1]([C:3]1[CH:4]=[C:5]([CH:35]([CH3:37])[CH3:36])[C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([NH:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@@H:22]([C:25]5[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=5)[CH2:21][CH2:20]4)=[O:16])=[CH:32][CH:33]=3)=[N:8][C:7]=2[CH:34]=1)#[N:2]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CC=C(c5ccc(F)cc5)CC4)cc3)oc12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4CC[C@@H](c5ccc(F)cc5)CC4)cc3)oc12
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4CC[C@H](c5ccc(F)cc5)CC4)cc3)oc12
Reaction time: 6 h
Yield: 46.5 %

Procedure:
To a solution of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-{[4-(4-fluorophenyl)cyclohex-3-en-1-yl]methyl}benzamide (30 mg, 0.061 mmol, EXAMPLE 41) in methanol (1 ml) and tetrahydrofuran (1 ml) was added 10% palladium on carbon (10 mg, 0.094 mmol). The mixture was flushed with nitrogen, then flushed with hydrogen and stirred for 6 h under a hydrogen balloon, at which point LC/MS analysis showed no starting material. The mixture was added directly to a 1000-micron plate and then eluted with 1:1 ethyl acetate-hexanes to provide the desired products trans-4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-{[4-(4-fluorophenyl)cyclohexyl]methyl}benzamide (11.9 mg, 0.024 mmol, 39.5% yield) and cis-4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-{[4-(4-fluorophenyl)cyclohexyl]methyl}benzamide (14.0 mg, 0.028 mmol, 46.5% yield).