Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3](=[O:13])[CH:4]([C:6]1([OH:12])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH3:5].[CH2:15](Br)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[OH:12][C:6]1([CH:4]([CH3:5])[C:3]([N:2]([CH3:1])[CH3:14])=[O:13])[CH2:7][CH2:8][N:9]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:11]1
Reactant: BrCCc1ccccc1
Reactant: CC(C(=O)N(C)C)C1(O)CCNCC1
Solvent: CCO
Product: CC(C(=O)N(C)C)C1(O)CCN(CCc2ccccc2)CC1

Procedure:
2-(4-hydroxy-4-piperidyl)propionic acid N,N-dimethylamide and phenethyl bromide are reacted in a manner analogous to that described in Example 3. The resulting crude title compound is dissolved in ethanol, the calculated amount of furmaric acid is added and subsequently ether is added until the solution becomes turbid. The resulting hydrogen fumarate form of the title compound has a M.P. of 188°-189° after recrystallization from ethanol/ether.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1>O1CCOCC1>[C:1]1([NH:7][C:8](=[O:9])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc(O)cc1
Solvent: C1COCCO1
Product: O=C(Nc1ccccc1)Nc1ccc(O)cc1
Reaction time: 2 h

Procedure:
Phenyl isocyanate and 4-aminophenol were added to dioxane solvent, and stirred for 2 hours to obtain 4-(N'-phenylureido)phenol (hereinafter, referred to simply as "Compound 8").
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:26][C:27]([OH:29])=[O:28])=[O:5])[CH3:2].[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:35]3[CH:36]=[CH:37][C:32]([C:31]([F:42])([F:41])[F:30])=[CH:33][CH:34]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:26][C:27]([OH:29])=[O:28])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CC(=O)O)n(-c2ccc(CC(=O)O)cc2)c2ccc(O)cc12
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CCOC(=O)c1c(CC(=O)O)n(-c2ccc(CC(=O)O)cc2)c2ccc(Oc3ccc(C(F)(F)F)cc3)cc12

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-carboxymethyl-1-(4-carboxymethyl-phenyl)-5-hydroxyindole-3-carboxylic acid ethyl ester (235 mg, 0.5 mmol, see step (b) Example 7) and 4-trifluoromethylphenylboronic acid (143 mg, 0.75 mmol). Yield 122 mg, 41%.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5]2[C:7]([OH:11])=[CH:8][CH:9]=[CH:10][C:4]=2[CH2:3]1.[CH3:13][N:14]=[C:15]=[O:16]>>[CH3:1][C:2]1([CH3:12])[O:6][C:5]2[C:4](=[CH:10][CH:9]=[CH:8][C:7]=2[O:11][C:15]([NH:14][CH3:13])=[O:16])[CH2:3]1
Reactant: CC1(C)Cc2cccc(O)c2O1
Reactant: CN=C=O
Product: CNC(=O)Oc1cccc2c1OC(C)(C)C2

Procedure:
The carbofuran phenol from Examples 3 and 4 is then reacted with methyl isocyanate in the presence of a tertiary amine catalyst to give carbofuran (2,3-dihydro-2,2-dimethyl-7-benzofuranyl-N-methyl carbamate).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:8]([C:15]3[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=3)=[N:9][N:10]([CH3:14])[C:11]=2[CH:12]=[O:13])=[C:5]([CH3:23])[O:4][N:3]=1.[Li+].[BH4-].S(C)C>C(OCC)C>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:9][N:10]([CH3:14])[C:11]=2[CH2:12][OH:13])=[C:5]([CH3:23])[O:4][N:3]=1
Reactant: COc1ccc(-c2nn(C)c(C=O)c2-c2c(C)noc2C)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CSC
Product: Cc1noc(C)c1-c1c(-c2ccc(O)cc2)nn(C)c1CO
Temperature: 25 °C
Yield: 69.2 %

Procedure:
To a solution of 4-(3,5-dimethylisoxazol-4-yl)-3-(4-methoxyphenyl)-1-methyl-1H-pyrazole-5-carbaldehyde (4.1 mg, 0.013 mmol) in diethyl ether (3 mL) was added LiBH4 (12 mg, 0.55 mmol) and stirred at room temperature over night. The reaction was then quenched with water and extracted with EtOAc, filtered through a phase separator and concentrated. To the raw product in DCM (1 mL) was added BF3.Me2S (1 M solution in DCM, 0.2 mL, 0.2 mmol) and stirred over night at room temperature. The formed precipitate was twice washed with 0.5 mL DCM, dissolved in MeOH and purified on preparative HPLC to give E11 4-(4-(3,5-dimethylisoxazol-4-yl)-5-(hydroxymethyl)-1-methyl-1H-pyrazol-3-yl)phenol (2.8 mg, 0.009 mmol, 71%). ES/MS m/z: 299.6 (M+H), 297.7 (M−H); 1H NMR (MeOD, 500 MHz): 7.18 (m, 2H), 6.71 (m, 2H), 3.98 (s, 3H), 3.74 (s, 2H), 2.20 (s, 3H) and 1.87 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[C:11]([O:15]C(=O)CC)(=[O:14])[CH2:12][CH3:13].C([O-])(=O)CC.[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[C:12]([CH3:13])[C:11]([OH:15])=[O:14]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: CCC(=O)OC(=O)CC
Agent: CCC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC(=Cc1ccc(F)c(F)c1)C(=O)O
Temperature: 135 °C

Procedure:
A mixture of 2.88 g (0.02 mol) of 3,4-difluorobenzaldehyde, 3.24 g (0.025 mol) of propionic anhydride and 0.92 g (0.02 mol) of sodium propionate under nitrogen is heated at 135° C. with a magnetic stirrer for 20 hours. The reaction mixture is poured onto 50 ml of water. A solid precipitates that dissolves when 50 ml of saturated K2CO3 is added with stirring. The basic solution is extracted with ether (2×100 ml). The aqueous phase is then poured into an excess of concentrated HCl and ice. The precipitated white solid is filtered and dried to give 3,4-difluoro-a-methylcinnamic acid, M.P. 122-125° C.
Reaction SMILES: Cl.[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12](=[O:35])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([O:28][C@@H:29]4[CH2:33][CH2:32][NH:31][CH2:30]4)=[CH:24][N:23]=3)=[CH:16][CH:15]=2)[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].Cl.F[CH2:38][C:39](C1ON=C(NC(=O)NC2C=CC(NC(=O)C3C=CC(OC4CCNCC4)=CN=3)=CC=2)C=1)(C)[CH2:40]F>>[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12](=[O:35])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([O:28][C@@H:29]4[CH2:33][CH2:32][N:31]([CH:39]([CH3:40])[CH3:38])[CH2:30]4)=[CH:24][N:23]=3)=[CH:16][CH:15]=2)[CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(O[C@@H]4CCNC4)cn3)cc2)no1
Reactant: CC(CF)(CF)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCNCC4)cn3)cc2)no1
Agent: Cl
Product: CC(C)N1CC[C@@H](Oc2ccc(C(=O)Nc3ccc(NC(=O)Nc4cc(C(C)(C)C)on4)cc3)nc2)C1
Yield: 94 %

Procedure:
(R)-N-(4-(3-(5-tert-Butylisoxazol-3-yl)ureido)phenyl)-5-(1-isopropylpyrrolidin-3-yloxy)picolinamide (95 mg, 94%) was prepared using a procedure analogous to that described in Example 20, substituting (R)-N-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenyl)-5-(pyrrolidin-3-yloxy)picolinamide hydrochloride from Step 1 of this example for N-(4-(3-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenyl)-5-(piperidin-4-yloxy)picolinamide hydrochloride used in Example 20. LC-MS (ESI) m/z 507 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[C:9](#[N:12])[CH:10]=[CH2:11]>CC([O-])=O.CC([O-])=O.[Cu+2]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:11][CH2:10][C:9]#[N:12])[CH:5]=[CH:6][CH:7]=1
Reactant: C=CC#N
Reactant: Nc1cccc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Product: N#CCCNc1cccc(Cl)c1
Reaction time: 3 h
Yield: 67 %

Procedure:
A solution of 3-chlorobenzenamine (10 g, 0.079 mol), Cu(OAc)2 (0.5 g, 5% by weight of m-chloroaniline), and acrylonitrile, was heated to reflux. Refluxing was continued for 3 h with the temperature rising to about 130° C. After the reaction was complete, acrylonitrile was stripped under reduced pressure and the residue purified by column chromatography to afford the pure product 3-(3-chlorophenylamino)propanenitrile (8 g, yield 67%). 1HNMR δ 2.6 (m, 2H), 3.5 (m, 2H), 4.1 (m, 1H), 6.45 (m, 1H), 6.55 (m, 1H), 7.1 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:19]O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([O:11][CH3:19])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(C)(C)C(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)(C)c1ccc(C)cc1

Procedure:
A solution of 2-(4-methylphenyl)-2-methylpropionic acid (60.0 g), sulfuric acid (0.6 ml) and methanol (300 ml) was refluxed for 19 hr. The solvent was evaporated, and water (200 ml) was added and the mixture was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the title compound (61.52 g) as a pale-brown oil. 1H-NMR(CDCl3)δ:1.56(6H, s), 2.32(3H, s), 3.64(3H, s), 7.13(2H, d, J=8.6 Hz), 7.22(2H, d, J=8.6 Hz). MS(EI): 192(M+).
Reaction SMILES: [OH-].[Na+].[F:3][CH:4]([F:17])[CH2:5][O:6][C:7]1[N:8]=[CH:9][C:10]([C:13]([O:15]C)=[O:14])=[N:11][CH:12]=1.Cl.C(OCC)(=O)C>C(O)C.[Cl-].[Na+].O>[F:17][CH:4]([F:3])[CH2:5][O:6][C:7]1[N:8]=[CH:9][C:10]([C:13]([OH:15])=[O:14])=[N:11][CH:12]=1
Reactant: COC(=O)c1cnc(OCC(F)F)cn1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)c1cnc(OCC(F)F)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 5 N sodium hydroxide solution (266 μL) was added to a solution of methyl 5-(2,2-difluoroethoxy)pyrazine-2-carboxylate obtained in Preparation Example 51-(1) (145 mg) in ethanol (4 mL), and the mixture was stirred at room temperature for one hour. 5 N hydrochloric acid was added to the reaction solution to prepare an acidic solution. Ethyl acetate and brine were added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to obtain the title compound (92 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:12][CH:11]=2)[OH:9])=[CH:4][C:3]=1[S:23]([NH2:26])(=[O:25])=[O:24].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:9])[C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:14][CH:15]=2)=[CH:4][C:3]=1[S:23]([NH2:26])(=[O:25])=[O:24]
Reactant: CCCCCCOc1ccc(C(O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCOc1ccc(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1
Reaction time: 0.5 h

Procedure:
2-Chloro-5-[(4-hexyloxy-phenyl)-hydroxy-methyl]-benzenesulfonamide is dissolved in acetone (10 mL), and treated with a solution of Jones reagent (3 M in water, 0.91 mmol). The reaction is allowed to stir for 30 minutes. The reaction is diluted with water and extracted with dichloromethane. The organic phase is separated and concentrated in vacuo. The residue is purified by silica gel chromatography (gradient of ethyl acetate in hexanes 25-75%) followed by recrystallization from ether affording 30 mg of the title compound. 1H NMR (DMSO) δ 0.88 (t, 3H, J=6.78 Hz), 1.28-1.45 (m, 6H), 1.70-1.79 (m, 2H), 4.09 (t, 2H, J=6.4 Hz), 7.10 (d, 2H, J=9.04 Hz), 7.75-7.90 (m, 4H), 8.24 (d, 1H, J=1.89). MS (m/z): 396 (M+1).
Reaction SMILES: [Cl:1][CH:2]([CH2:6][CH3:7])[C:3](Cl)=[O:4].[CH2:8]([NH:10][CH2:11][CH3:12])[CH3:9]>C(Cl)Cl.[OH-].[Na+]>[Cl:1][CH:2]([CH2:6][CH3:7])[C:3]([N:10]([CH2:11][CH3:12])[CH2:8][CH3:9])=[O:4]
Reactant: CCNCC
Reactant: CCC(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCC(Cl)C(=O)N(CC)CC
Yield: 65.7 %

Procedure:
Following the procedure of Kem K. M.; Nguyen N. V.; Cross D. J. J. Org. Chem. 1981;46:5188 for the preparation of chloroacetamides, a solution of 2-chlorobutyryl chloride (61.91 mmol, 8.73 g, Lancaster) in 28 mL of CH2Cl2 was added to diethylamine (56.28 mol, 4.12 g, Aldrich) in a mixture of CH2Cl2 (56 mL) and NaOH (56 mL, 20% aqueous) at −25° C. to furnish 2-chloro-N,N-diethyl-butyramide (7.23 g, 72%). 1HNMR (400 MHz, CDCl3) δ 0.98 (t, J=7.33 Hz, 3H, CH2CH3), 1.12 (t, J=7.08 Hz, 3H, CH2CH3), 1.19-1.23 (m, 3H, CH2CH3), 1.89-2.00 (m, 1H, CH2CH3), 2.03-2.14 (m, 1H, CH2CH3), 3.22-3.38 (m, 2H, NCH2CH3), 3.41-3.52 (m, 2H, NCH2CH3), 4.26 (t, J=7.08 Hz, 1H, CHCl); MS(APCI+): m/z 177.9 (M+1), 179.9 (M+3).
Reaction SMILES: COC1C=CC(C(Cl)=O)=CC=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][C:28]=1[F:34].[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([N:45]=[C:46]=[S:47])=[O:44])=[CH:39][CH:38]=1>C1(C)C=CC=CC=1.C(O)C>[CH3:35][O:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]([N:45]=[C:46]=[S:47])=[O:44])=[CH:41][CH:42]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:46]([NH:45][C:43](=[O:44])[C:40]2[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[CH:38][CH:39]=2)=[S:47])=[CH:29][C:28]=1[F:34]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: COc1ccc(C(=O)Cl)cc1
Agent: COc1ccc(C(=O)N=C=S)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
4-Methoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-methoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-methoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (70 mg, yield 87%).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[N:14]=[C:13]([NH:15][C@@H:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][OH:19])[C:12]([CH2:23][C:24]2[CH:45]=[CH:44][C:27]([O:28][CH2:29][CH2:30][CH2:31][N:32]3[CH2:36][CH2:35][CH2:34][C@@H:33]3[C:37]([O:39]C(C)(C)C)=[O:38])=[CH:26][C:25]=2[O:46][CH3:47])=[C:11]([CH3:48])[N:10]=1>>[NH2:8][C:9]1[N:14]=[C:13]([NH:15][C@@H:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][OH:19])[C:12]([CH2:23][C:24]2[CH:45]=[CH:44][C:27]([O:28][CH2:29][CH2:30][CH2:31][N:32]3[CH2:36][CH2:35][CH2:34][C@@H:33]3[C:37]([OH:39])=[O:38])=[CH:26][C:25]=2[O:46][CH3:47])=[C:11]([CH3:48])[N:10]=1
Reactant: CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(OCCCN2CCC[C@@H]2C(=O)OC(C)(C)C)cc1OC
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(OCCCN2CCC[C@@H]2C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 14 h
Yield: 98.8 %

Procedure:
Trifluoroacetic acid (6 mL) was added to the product from step (x) (505 mg) and the mixture was stirred at RT for 14 h. After the reaction mixture was concentrated, 1M-sodium hydroxide (20 mL) and methanol (10 mL) was added to the residue and the mixture was stirred in methanol for 30 mins. The reaction mixture was concentrated, diluted with water and washed with chloroform. The aqueous layer was neutralized with 6M-hydrogen chloride and sat. sodium hydrogen dicarbonate and extracted with chloroform/EtOH (3/1). The combined organic layer was dried and concentrated. The residue was diluted with chloroform, filtered, concentrated and diluted with chloroform/EtOAc. The precipitate was collected by filtration, washed with EtOAc and dried to give 450 mg of the sub-title compound as a white solid; 1H NMR (CDCl3); 6.78 (1H, d), 6.48 (1H, d), 6.38 (1H, dd), 5.35-5.20 (1H, m), 4.20-3.97 (3H, m), 3.86 (3H, s), 3.55 (2H, s), 3.63-3.47 (1H, m), 3.40-3.09 (4H, m), 2.91-2.75 (1H, m), 2.60-2.45 (1H, m), 2.35 (3H, s), 2.30-2.02 (4H, m), 2.02-1.70 (3H, m), 1.50-1.33 (1H, m), 1.33-0.95 (5H, m), 0.77 (3H, t); LC-MS: m/z 516.
Reaction SMILES: [NH2:1][C@H:2]([CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C@@H:3]([C:5]1[CH:14]=[CH:13][C:8]2OCCO[C:7]=2[CH:6]=1)[OH:4].[CH3:21][O:22]C1C=CC=CC=1C=O>>[NH2:1][C@H:2]([CH2:15][N:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1)[C@@H:3]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:13][C:14]=1[O:22][CH3:21])[OH:4]
Reactant: N[C@H](CN1CCCC1)[C@H](O)c1ccc2c(c1)OCCO2
Reactant: COc1ccccc1C=O
Product: COc1ccccc1[C@@H](O)[C@H](N)CN1CCCC1

Procedure:
Prepared in a manner similar to (1R,2R)-2-amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol as described in U.S. Pat. No. 6,855,830 and starting with 2-methoxy-benzaldehyde. Clear oil. HPLC system A 98% (tR=4.52 min) NMR (500 MHz, CDCl3) δ 7.47-7.48 (d, 1H), 7.25-7.29 (1H, M), 6.80-7.02 (m, 1H), 6.87-6.88 (d, 1H), 5.065 (s, 1H), 3.83 (s, 3H), 3.71-3.73 (1H, M), 3.22-3.24 (m, 1H), 2.80-2.84 (m, 1H), 2.55-2.58 (m, 5H), 1.80 (m, 4H).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[N:8]2[C:16](=[S:19])[NH:17][N:18]=[C:7]12)[CH2:2][CH2:3][CH2:4][CH3:5].S(OC)(O[CH3:24])(=O)=O.[OH-].[Na+]>O>[CH3:24][S:19][C:16]1[N:8]2[C:9](=[O:15])[C:10]3[NH:11][CH:12]=[N:13][C:14]=3[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]2=[N:18][N:17]=1
Reactant: COS(=O)(=O)OC
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(=S)[nH]nc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(SC)nnc12
Yield: 85.1 %

Procedure:
A solution of 9-pentyl-3-thioxo-2,3,6,9-tetrahydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (1.90 g, 6.83 mmol), dimethyl sulfate (1.03 g, 8.19 mmol) and 1 m of sodium hydroxide in water (25 ml) was stirred at room temperature for 1 hour. The mixture was neutralized to pH=7. The solid formed was filtered and dried to provide the desired product (1.70 g, 85.2%). 1HNMR (300 MHz, CD3OD): δ 4.29 (t, J=7.2 Hz, 2H), 2.65 (s, 3H), 1.89 (m, 2H), 1.40 (m, 4H), 0.92 (m, 3H). LCMS calculated for: C12H17N6OS (M+H) 294.1. Found: 294.1.
Reaction SMILES: [C:1]([C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[C:5]([CH3:10])[N:4]=1)#[CH:2].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](I)[CH:13]=1>C(N(CC)CC)C.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]([C:2]#[C:1][C:3]2[C:8]([NH2:9])=[CH:7][CH:6]=[C:5]([CH3:10])[N:4]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: Clc1cccc(I)c1
Reactant: C#Cc1nc(C)ccc1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(N)c(C#Cc2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.6 %

Procedure:
To a solution of Cul (5.0 mg, 28 μmol) in triethylamine (5 ml) were added (2-ethynyl-6-methyl-pyridin-3-yl)amine (75 mg, 0.57 mmol described in Example 7), (PPh3)2PdCl2 (20 mg, 28 μmol), and 1-chloro-3-iodobenzene (135 mg, 0.57 mmol). The reaction mixture was stirred at room temperature for 4 h. The solvent was evaporated to afford a brown oil which was taken up in DCM and the solution was washed with water. The aqueous phase was extracted twice with DCM. The organic phases were dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography (hexane/ethyl acetate 7:3) to yield 54 mg (0.22 mmol, 39%) of (2-(3-chloro-phenylethynyl)-6-methyl-pyridin-3-yl)amine as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH:12]=O)=[N:6][C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][C:16]=1[F:23].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:6]([CH:12]=[N:11][CH:10]=2)[C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][C:16]=1[F:23])=[O:24]
Reactant: COC(=O)c1ccc(CNC=O)nc1Nc1ccc(SC)cc1F
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2cncn2c1Nc1ccc(SC)cc1F
Temperature: 95 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
To a suspension of 2-(2-fluoro-4-methylsulfanyl-phenylamino)-6-formylaminomethyl-nicotinic acid methyl ester (309 mg, 0.89 mmol) in toluene (15.6 mL) was added phosphorous oxychloride (91 μl, 0.98 mmol) and the reaction mixture heated to 95° C. and stirred for 1 hour. The cooled reaction mixture was quenched by the addition of water (ca. 2 mL) then concentrated in vacuo. The resultant residue was taken up in ethyl acetate and washed with water followed by a saturated aqueous solution of sodium bicarbonate and brine. The organic phase was isolated, dried (Na2SO4), filtered, concentrated in vacuo, and the residue subjected to flash chromatography (Si-PPC, gradient 0% to 40%, ethyl acetate in hexane) to afford the title compound as a yellow solid (150 mg, 51%). LCMS (method B): RT=3.44 min, [M+H]+=332.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:32]=[CH:31][C:18]([CH2:19][O:20][C:21]2[C:22]([C:27](OC)=[O:28])=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1.[BH4-].[Na+].O1CCCC1.CO>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:32]=[CH:31][C:18]([CH2:19][O:20][C:21]2[C:22]([CH2:27][OH:28])=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1ncccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2cccnc2CO)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a mixture of methyl 3-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-2-pyridinecarboxylate (0.30 g), sodium borohydride (0.13 g) and tetrahydrofuran (10 mL) was dropwise added methanol (2 mL) at 50° C., and the mixture was stirred at 50° C. for 1 hr. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give crystals (0.23 g, 82%) of [3-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-2-pyridyl]methanol. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 118-119° C.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH3:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][N:9]=1.F[C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21]>CN(C=O)C.[NH4+].[Cl-]>[CH3:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:18]2[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=2[C:20]#[N:21])[N:9]=1
Reactant: N#Cc1ccccc1F
Reactant: Cc1n[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccccc2C#N)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.3 %

Procedure:
Cs2CO3 (1.56 g, 4.8 mmol) was added to a solution of 3-methyl indazole (0.634 g, 4.8 mmol) and 2-fluorobenzonitrile (1 mL, 9.6 mmol) in DMF (20 mL) and the mixture stirred at RT for 12 h. The mixture was diluted with sat. NH4Cl and a precipitate formed. The solid was filtered, washed with H2O, hexane and dried under vacuum to give 2-(3-methyl-1H-indazol-1-yl)benzonitrile (1 g, 89%) which was used without purification.
Reaction SMILES: [CH3:1][Li].[CH3:3][CH:4]([CH2:6][CH2:7][CH2:8][C@H:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C:15]3[CH2:16][CH2:17][C:18]4[C@:23]([C:25]=3[CH2:26][CH2:27]2)([CH3:24])[CH2:22][CH2:21][C:20](=[O:30])[CH:19]=4)[CH2:13][CH2:12]1)[CH3:10])[CH3:5].[Cl-].[NH4+]>C(OCC)C>[CH3:1][C@@:18]12[CH2:19][C:20](=[O:30])[CH2:21][CH2:22][C@:23]1([CH3:24])[C:25]1[CH2:26][CH2:27][C@@:28]3([CH3:29])[C@@H:14]([CH2:13][CH2:12][C@@H:11]3[C@H:9]([CH3:10])[CH2:8][CH2:7][CH2:6][CH:4]([CH3:3])[CH3:5])[C:15]=1[CH2:16][CH2:17]2
Reactant: [Li]C
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CCC(=O)C=C1CC3
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CCC(=O)C[C@@]1(C)CC3
Reaction time: 0.5 h

Procedure:
0.85 ml of a methyllithium solution (1.6 N, in diethyl ether) are added to a suspension of 130 mg cuprous iodide in diethyl ether at 0° C. The resulting mixture is stirred for one hour before a solution of 130 mg cholesta-4,8-dien-3-one in 1 ml diethyl ether is added. After being stirred for 30 minutes the reaction mixture is poured into saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer is separated, washed with brine, dried over anhydrous sodium sulphate and filtered. After evaporation of the solvent the residue is chromatographed with mixture of hexane and ethyl acetate to give 80 mg 5-methyl-5β-cholest-8-en-3-one as a white solid.