Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH2:11][CH2:12][CH2:13][CH3:14].O(C1C=CC=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:54][C:55]1([CH3:62])[C:59]([CH3:61])([CH3:60])[O:58][BH:57][O:56]1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:11]([O:10][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[B:57]1[O:58][C:59]([CH3:61])([CH3:60])[C:55]([CH3:62])([CH3:54])[O:56]1)[CH2:12][CH2:13][CH3:14]
Reactant: CC1(C)OBOC1(C)C
Reactant: CCCCOc1ccc(OC)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2Oc2ccccc2P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCCCOc1ccc(OC)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 95 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
A mixture of 2-bromo-1-butoxy-4-methoxybenzene (1.2 g, 4.7 mmol), TEA (2.6 mL, 19 mmol), (oxydi-2,1-phenylene)bis(diphenylphosphine) (0.51 g, 0.95 mmol) (Aldrich, CAS# 166330-10-5), palladium(II) acetate (0.11 g, 0.47 mmol), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.1 mL, 14 mmol) (Aldrich, CAS# 25015-63-8) in 1,4-dioxane (5.0 mL) was stirred overnight at 95° C. The mixture was cooled to room temperature, quenched with saturated aqueous ammonium chloride, and extracted with ether. The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by silica gel flash chromatography (0-10% EtOAc/hexane) to afford compound C.3 (0.60 g, 41% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.16 (d, J=3.1 Hz, 1H), 6.91 (dd, J=3.1, 9.0 Hz, 1H), 6.79 (d, J=9.0 Hz, 1H), 3.91 (t, J=6.3 Hz, 2H), 3.78 (s, 3H), 1.75 (m, 2H), 1.54 (m, 2H), 1.34 (s, 12H), 0.96 (t, J=7.4, 3H).
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].[C:31]([O:35][CH2:36][CH3:37])(=[O:34])[CH2:32]O>>[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][CH2:32][C:31]([O:35][CH2:36][CH3:37])=[O:34])=[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: CCOC(=O)CO
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1Cl
Product: CCOC(=O)COC(=O)c1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1C1CCCC1

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 ethyl glycolate according to Method E. 1H NMR (400 MHz, CDCl3) δ ppm 1.32 (t, J=7.12 Hz, 4H), 1.40-1.67 (m, 6H) 1.72-1.83 (m, 1H), 1.96 (ddd, J=26.25, 13.09, 4.16 Hz, 1H), 2.06-2.20 (m, 1H), 2.25-2.36 (m, 1H), 2.84-2.99 (m, 1H), 3.12 (ddd, J=16.18, 3.36, 3.02 Hz, 1H), 3.49 (ddd, J=13.76, 9.33, 4.83 Hz, 1H), 4.28 (q, J=7.25 Hz, 2H), 4.64 (dd, J=9.67, 5.37 Hz, 1H), 4.87 (s, 2H), 7.03 (dd, J=8.73, 2.01 Hz, 1H), 7.31 (d, J=2.15 Hz, 1H), 7.46 (d, J=8.59 Hz, 1H), 7.93-8.02 (m, 2H), 8.17 (d, J=8.86 Hz, 1H). ES-MS m/z 506 (M+H).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12]O)[CH:4]=1)#[N:2].S(Cl)([Cl:16])=O>ClCCl>[Cl:16][CH2:12][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([C:1]#[N:2])=[CH:4]1
Reactant: O=S(Cl)Cl
Reactant: N#Cc1cn(CO)c2ccccc12
Solvent: ClCCl
Product: N#Cc1cn(CCl)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.69 g of 3-cyano-1H-indole-1-ylmethanol was dissolved to 30 ml of dichloromethane. 1.4 ml of thionyl chloride was added to the solution, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain 1.70 g of 1-(chloromethyl)-3-cyano-1H-indole.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([CH2:11][O:12][C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[C:16]([C:22](O)=[O:23])[NH:17]4)=[CH:9][O:10][C:6]=2[CH2:5][CH2:4][CH2:3]1.[NH2:25][CH:26]1[CH2:31][CH2:30][C:29]([CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][C@H:38]([OH:41])[C@@H:37]([CH3:42])[CH2:36]2)([OH:32])[CH2:28][CH2:27]1>>[OH:32][C:29]1([CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][C@H:38]([OH:41])[C@@H:37]([CH3:42])[CH2:36]2)[CH2:30][CH2:31][CH:26]([NH:25][C:22]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[C:13]([O:12][CH2:11][C:8]2[C:7]4[C:2](=[O:1])[CH2:3][CH2:4][CH2:5][C:6]=4[O:10][CH:9]=2)[CH:21]=[CH:20][CH:19]=3)=[O:23])[CH2:27][CH2:28]1
Reactant: O=C(O)c1cc2c(OCc3coc4c3C(=O)CCC4)cccc2[nH]1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Product: C[C@H]1CN(CCC2(O)CCC(NC(=O)c3cc4c(OCc5coc6c5C(=O)CCC6)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized analogously to example 1 from 4-(4-oxo-4,5,6,7-tetrahydro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid 16f and amine 14.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9](Cl)=[O:10])=[CH:5][CH:4]=1.[CH3:14][CH2:15][O:16][C:17]([C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=1)=[O:18].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([C:17]([O:16][CH2:15][CH3:14])=[O:18])=[CH:24][CH:23]=2)=[O:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COc1ccc(C=CC(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(NC(=O)C=Cc2ccc(OC)cc2)cc1
Reaction time: 19 h

Procedure:
To a solution of 10 g. of p-methoxycinnamoyl chloride in 200 ml. of dichloromethane is slowly added a solution of 0.24 g. of benzocaine and 7.1 ml. of triethylamine in 200 ml. of dichloromethane. The mixture is stirred for 19 hours, then the organic layer is washed with 200 ml. of 10% hydrochloric acid followed by 200 ml. of brine, dried over magnesium sulfate, and condensed to a solid. This solid is crystallized from 100 ml. of ethanol, giving 10.6 g. of the desired product as yellow crystals, m.p. 163°-165.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[C:5](=[C:10]([CH3:17])[C:11]([CH2:15][CH3:16])=[CH:12][C:13]=1[OH:14])[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:18])[C:4]1[C:5](=[C:10]([CH3:17])[C:11]([CH2:15][CH3:16])=[CH:12][C:13]=1[O:14][CH2:27][CH:26]=[CH2:25])[C:6]([O:8][CH3:9])=[O:7]
Reactant: CCc1cc(O)c(C(=O)OC)c(C(=O)OC)c1C
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(CC)c(C)c(C(=O)OC)c1C(=O)OC
Temperature: 60 °C
Reaction time: 14 h
Yield: 83.1 %

Procedure:
4-Ethyl-6-hydroxy-3-methyl-phthalic acid dimethyl ester (1.01 g, 4.02 mmol) was dissolved in DMF (5 mL). Potassium carbonate (3.33 g, 24.14 mmol) was added, followed by allylbromide (2.92 g, 24.14 mmol). The suspension was heated at 60° C. After 14 hrs, the reaction was cooled to room temperature and filtered. The solvents were removed in vacuo and the crude material was purified by silica gel chromatography to provide 0.976 g (83%) of the desired product as a colorless oil. 1H NMR (300 MHz, CDCl3): δ=1.16 (t, J=7.2 Hz, 3H), 2.20 (s, 3H), 2.62 (q, J=7.2 Hz, 2H), 3.83 (s, 3H), 3.84 (s, 3H), 4.57 (m, 2H), 5.26 (dd, J=9.3, 1.5 Hz, 1H), 5.41 (dd, J=13.5, 1.5 Hz, 1H), 5.98 (m, 1H), 6.82 (s, 1H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[S:5][C:6]=1[Br:7].ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.[NH2:31][CH2:32][CH2:33][CH2:34][S:35][C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:31][CH2:32][CH2:33][CH2:34][S:35][C:36]2[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=2)=[O:10])[S:5][C:6]=1[Br:7]
Reactant: NCCCSc1ccncc1
Reactant: O=C(O)c1cc(Br)c(Br)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: O=C(NCCCSc1ccncc1)c1cc(Br)c(Br)s1
Yield: 71.8 %

Procedure:
To a solution of 2.55 g (8.91 mmol) of 4,5-dibromothiophene-2-carboxylic acid and 1.33 g (11.6 mmol) of N-hydroxysuccinimide in 90 ml of methylene chloride, 2.05 g (10.7 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 1 hour. Further, 1.50 g (8.91 mmol) of 4-(3-aminopropylthio)pyridine was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain powder. The powder thus obtained was washed with ether and dried to obtain 2.79 g of the desired compound (yield: 71.8%, colorless powder).
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH2:8][C:9]1[CH:10]=[C:11]([C:15]([OH:17])=[O:16])[CH:12]=[CH:13][CH:14]=1.[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][OH:36])=[CH:29][CH:28]=2)[C:22]([C:37]#[N:38])=[C:21](SC2C=CC=CC=2)[N:20]=1.Cl>COCCOC.O>[NH2:18][C:19]1[N:20]=[C:21]([O:7][CH2:8][C:9]2[CH:10]=[C:11]([C:15]([OH:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)[C:22]([C:37]#[N:38])=[C:23]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH2:35][OH:36])=[CH:31][CH:32]=2)[C:24]=1[C:25]#[N:26]
Reactant: N#Cc1c(N)nc(Sc2ccccc2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: O=C(O)c1cccc(CO)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1c(N)nc(OCc2cccc(C(=O)O)c2)c(C#N)c1-c1ccc(OCCO)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1.65 g (14.68 mmol) of potassium tert-butoxide were suspended in 15 ml of 1,2-dimethoxyethane. After addition of 0.97 g (5.87 mmol) of 3-(hydroxymethyl)benzenecarboxylic acid (Example 66A) and 1.14 g (2.94 mmol) of 2-amino-4-[4-(2-hydroxyethoxy)phenyl]-6-(phenylsulfanyl)pyridine-3,5-dicarbonitrile (Example 35A), the mixture was stirred at 60° C. overnight. After cooling of the reaction mixture, 50 ml of water were added. With ice-cooling, the clear solution was acidified to pH 1 using conc. hydrochloric acid. The aqueous phase was decanted from the viscous precipitate formed. The residue was purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% trifluoroacetic acid). The aqueous phase was evaporated and the residue was purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% trifluoroacetic acid).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:6]=[CH:5][N:4]=1)#[N:2].[C:19](OC)(=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[SH:22].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:27]=[C:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[S:22][C:1]([C:3]2[CH:8]=[C:7]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH:6]=[CH:5][N:4]=2)=[N:2]1
Reactant: CC(C)(C)OC(=O)NCCc1ccnc(C#N)c1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 71.7 %

Procedure:
tert-Butyl 2-(2-cyano-4-pyridyl)ethylcarbamate (3.0 g, 12 mmol) and methyl thiosalicylate (3.6 g, 21 mmol) were dissolved in toluene (12 ml), and triethylamine (6.0 ml, 43 mmol) was added thereto. The mixture was refluxed for 8 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (2:1, v/v) were collected, concentrated and recrystallized from hexane-ethanol to give the titled compound (3.3 g, 71%) as white crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C@H:20]4[CH2:25][CH2:24][C@H:23]([CH2:26][CH2:27][CH3:28])[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)=[CH:10][N:9]=2)=[CH:4][C:3]=1[F:29].[Cu][C:31]#[N:32].CN1C(=O)CCC1.Cl>O>[C:31]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([C:14]3[CH:15]=[CH:16][C:17]([C@H:20]4[CH2:21][CH2:22][C@H:23]([CH2:26][CH2:27][CH3:28])[CH2:24][CH2:25]4)=[CH:18][CH:19]=3)=[CH:12][N:13]=2)=[CH:4][C:3]=1[F:29])#[N:32]
Reactant: CCC[C@H]1CC[C@H](c2ccc(-c3cnc(-c4ccc(Br)c(F)c4)nc3)cc2)CC1
Reactant: N#C[Cu]
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: CCC[C@H]1CC[C@H](c2ccc(-c3cnc(-c4ccc(C#N)c(F)c4)nc3)cc2)CC1
Temperature: 60 °C

Procedure:
3.5 g (0.008 mol) of 2-(4'-bromo-3'-fluorophenyl)-5-[4'-(trans-4"-propylcyclohexyl)phenyl]pyrimidine and 1.1 g (0.012 mol) of copper (I) cyanide were added to 31 cm3 of NMP and the solution was refluxed for 2 hours using a mantle heater. The solution was cooled to 60° C. and added to a solution of 4.2 g of FeC13.6H2 o, 1.3 cm3 of concentrated hydrochloric acid and 6 cm3 of water. The resulting solution was maintained on a warm water bath at 60° C. for one hour. The crystals deposited were filtered, washed with water and treated through a silica gel column with chloroform as the solvent. The chloroform was distilled off and the residue was recrystallized from acetone to yield 1.9 g (0.005 mol) of 2-(4'-cyano-3'-fluorophenyl)-5-[4'-(trans-4"-propylcyclohexyl)phenyl]pyrimidine. The phase transition temperature of this compound measured by DSC, was: ##STR32##
Reaction SMILES: CC(C)([O-])C.[Na+].[CH3:7][C@H:8]([OH:11])[CH2:9][CH3:10].F[C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)=[C:15]([NH2:28])[N:14]=1>C(OCC)(=O)C>[CH3:7][C@H:8]([O:11][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)=[C:15]([NH2:28])[N:14]=1)[CH2:9][CH3:10]
Reactant: CC[C@H](C)O
Reactant: Nc1nc(F)nc2c1ncn2C1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC[C@H](C)Oc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 50 °C
Yield: 78.8 %

Procedure:
Sodium tert-butoxide (3.24 g, 33.7 mmol) was added portionwise with stirring to (2S)-2-butanol (10 g, 135 mmol). 2-Fluoro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (2 g, 8.43 mmol) was added to the resulting suspension and the mixture heated to 50° C. for 6 hours when LCMS showed complete reaction. After cooling the mixture was diluted with ethyl acetate (100 ml), and washed with water (50 ml) and the aqueous layer extracted again with ethyl acetate (50 ml). The combined organic extracts were washed with brine, dried using a hydrophobic frit and evaporated in vacuo (at 62° C. to remove the excess alcohol). The residue (2.52 g) was dissolved in dichloromethane and purified on an aminopropyl cartridge (110 g) using a Flashmasterll apparatus and eluting with a 0-100% ethyl acetate in cyclohexane gradient over 60 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid (1.935 g).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:19]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8]
Reactant: C=CCCCCCCCCCC
Reactant: Oc1ccccc1
Product: CCCCCCCCCCCCc1ccccc1O
Reaction time: 4 h
Yield: 59.9 %

Procedure:
First, dodecyl phenol was prepared. Specifically, to a 2-liter four-necked flask, 325 g of phenol and 30 g of dried activated clay (manufactured by MIZUSAWA INDUSTRIAL CHEMICALS, LTD.: product name, Galeonite #136) were added. 575 g of 1-dodecene was dropped in this mixture with agitation at 135 degrees C. for 4 hours. The activated clay was filtered, and then 537 g of dodecyl phenol was obtained by vacuum distillation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:13]#[N:14])([CH3:12])[C:7](=[O:15])[C:6]([C:16](OCC)=[O:17])=[C:5]2[OH:21].Cl.[C:23]([O:27][C:28](=[O:31])[CH2:29][NH2:30])([CH3:26])([CH3:25])[CH3:24].NCC(O)=O>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:13]#[N:14])([CH3:12])[C:7](=[O:15])[C:6]([C:16]([NH:30][CH2:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:31])=[O:17])=[C:5]2[OH:21]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C#N)C1=O
Agent: Cl
Agent: NCC(=O)O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C#N)C1=O
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Ethyl 6-chloro-1-cyano-4-hydroxy-1-methyl-2-oxo-naphthalene-3-carboxylate (0.165 g, 0.54 mmol) was dissolved in 1,4-dioxane (30 mL), and glycine tert-butyl ester hydrochloride (0.090 g, 0.54 mmol) and TEA (TEA) (0.11 mL, 0.81 mmol) were added. The reaction was stirred overnight at 70° C. The reaction was stirred for 18 hours. Another 0.5 equivalents of glycine and one equivalent of TEA were added, and the reaction was stirred at 105° C. for 1 hour. The solvent was then removed, and the crude residue was dissolved in EtOAc and washed with water (3×25 mL), dried with MgSO4, and concentrated. The crude product was purified by silica flash chromatography using the 10-50% EtOAc/hexanes. MS m/e=392 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:7][C:8]2=O.C[Si]([C:24]#[N:25])(C)C.[Cl-].[Al+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:24]([C:8]1[C:9]2[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=2)[CH2:5][CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1)#[N:25]
Reactant: COc1cccc2c1CC(c1ccccc1)CC2=O
Reactant: C[Si](C)(C)C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2c1CC(c1ccccc1)C=C2C#N
Temperature: 60 °C

Procedure:
To a suspension of 8.8 g (35 mmol) of 5-methoxy-3-phenyl-1,2,3,4-tetrahydro-1-naphthalenone, the product of Example 1, is added 7.5 g (75.6 mmol) of trimethylsilyl cyanide (commercially available from Aldrich Chemical Company) and approximately 50 mg of anhydrous aluminum chloride (AlCl3). The reaction mixture is heated at 60° C. for 3 h then cooled to ambient temperature and diluted with 150 mL of toluene. The volume of the reaction mixture is reduced in vacuo to approximately 50 mL. The resultant trimethylsilyl adduct is dehydrated by treatment with 15 mL of trifluroacetic acid and 100 mg of p-toluenesulfonic acid in 200 mL of toluene at reflux temperature for 1 h. The reaction mixture is cooled to ambient temperature, the layers separated and the organic layer washed with water, aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound.
Reaction SMILES: [CH3:1][C:2]12[CH:9](O)[C:6]([CH3:11])([CH2:7][CH2:8]1)[CH2:5][CH2:4][CH2:3]2.[BrH:12]>>[CH3:1][C:2]12[CH:9]([Br:12])[C:6]([CH3:11])([CH2:7][CH2:8]1)[CH2:5][CH2:4][CH2:3]2
Reactant: CC12CCCC(C)(CC1)C2O
Reactant: Br
Product: CC12CCCC(C)(CC1)C2Br
Yield: 85.1 %

Procedure:
1,5-dimethyl-8-hydroxy bicyclo[3,2,1]octane (13.6 g (0.1 mol)) was boiled with 50 ml 48% hydrogen bromide for 4 hours under stirring in the presence of 1 g AMBERLYST A15 ion-exchange resin. The reaction product was extracted after cooling with pentane. The pentane layer was washed with water and a diluted sodium bicarbonate solution. After drying over anhydrous sodium sulfate and boiling down pentane the residue was subjected to fractional distillation under reduced pressure. 18.5 g 1,5-dimethyl-8-bromobicyclo[3,2,1]octane was obtained in 85.1% yield (b.p. 93° C./10 mm Hg). The product obtained was identical with the compound according to the process described in Example 2a.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[NH:12][CH:11]=[N:10][C:9]=3[N:8]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[C:6]2=[O:7])[CH2:3][CH2:2]1.Cl[CH2:21][CH2:22][CH3:23]>>[CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[N:12]([CH2:21][CH2:22][CH3:23])[CH:11]=[N:10][C:9]=3[N:8]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[C:6]2=[O:7])[CH2:3][CH2:2]1
Reactant: CCCCl
Reactant: O=c1c2[nH]cnc2n(CC2CC2)c(=O)n1CC1CC1
Product: CCCn1cnc2c1c(=O)n(CC1CC1)c(=O)n2CC1CC1

Procedure:
1,3-Di-cyclopropylmethyl-7-n-propyl xanthine was prepared from 1,3-di-cyclopropylmethyl xanthine and 1-chloropropane using an analogous procedure to that described in Example 5. The title compound was isolated as a crystalline solid, m.p. 67° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]([OH:18])([C@H:15]([OH:17])[CH3:16])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(OCC)(=O)C>[CH3:26][S:27]([O:17][C@H:15]([CH3:16])[C@:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([OH:18])[CH2:9][N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)(=[O:29])=[O:28]
Reactant: C[C@@H](O)[C@](O)(Cn1cncn1)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@@H](OS(C)(=O)=O)[C@](O)(Cn1cncn1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of (2R,3R)-2-(4-chlorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol (12.4 g) and triethylamine (7.6 ml) in ethyl acetate (200 ml) was added dropwise methanesulfonyl chloride (6.25 g) under ice-cooling. After stirring for 45 minutes at room temperature, the reaction mixture was washed with water and saturated saline, dried over magnesium sulfate and distilled under reduced pressure to give (2R,3R)-2-(4-chlorophenyl)-2-hydroxy-1-(1H-1,2,4-triazol-1-yl)-3-butyl methanesulfonate.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:11][CH:10]([CH3:18])[N:9]2[CH:19]=1)([O:3][CH2:4][CH3:5])=[O:2].Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22].[OH-].[Na+]>CC(C)=O.O>[C:1]([C:6]1[CH:7]=[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:10]([CH3:18])[N:9]2[CH:19]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1cc2n(c1)C(C)Nc1ccccc1-2
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)c1cc2n(c1)C(C)N(C(=O)OCC)c1ccccc1-2

Procedure:
A solution of the product of Example XXXVIII (3.0 g, 0.0117 m) and ethyl chloroformate (12.6 g, 0.117 m) in acetone (50 ml) and H2O (50 ml) was treated with NaOH (0.21 ml aq. 30%) and the mixture refluxed for 1 hr. The acetone was removed in vacuo and the aqueous residue cooled in ice-bath. A solid formed and this was filtered, washed with water, and dried in vacuo. The crude product (3.4 g) was crystallized from methanol (25 ml) to afford the desired product; m.p. 125°-127°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]=[CH2:10])=[CH:4][C:3]=1[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C1C=CC(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC1(C)C(C)(C)OB[O:52]1.B(O[O-])=O.[Na+]>C1COCC1>[Cl:8][C:7]1[CH:6]=[C:5]([CH2:9][CH2:10][OH:52])[CH:4]=[C:3]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15])[C:2]=1[Cl:1]
Reactant: CC1(C)OBOC1(C)C
Reactant: C=Cc1cc(Cl)c(Cl)c(CO[Si](C)(C)C(C)(C)C)c1
Agent: O=BO[O-]
Agent: [Na+]
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cc(CCO)cc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
{[(2,3-Dichloro-5-ethenylphenyl)methyl]oxy}(1,1-dimethylethyl)dimethylsilane (1 eq.) from the previous step, [Ir(COD)Cl]2 (0.025 eq.) and DPPB (0.05 eq.) were combined in THF (0.11 M). To this solution was then added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.3 eq.) and the resulting red solution was stirred at RT for 16 h. Finally, sodium perborate (0.1 M aqueous solution, 1 eq.) was added and the now black biphasic solution was vigorously stirred at RT for another 8 h. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were then washed further with 1 N aq. NaOH, water and brine. This was then dried over Na2SO4, filtered and the filtrate concentrated in vacuo to afford a black oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→1:1 (v/v) EtOAc:Hex) afforded the title compound as a pale yellow oil.