Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[N:6]([CH2:13][CH2:14][CH2:15][N:16]3[CH2:47][CH2:46][C:19]4([N:23]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[CH2:22][N:21]([CH2:31][C:32]5[CH:33]=[C:34]([CH:42]=[CH:43][CH:44]=5)[C:35]([O:37]C(C)(C)C)=[O:36])[C:20]4=[O:45])[CH2:18][CH2:17]3)[C:5]2=[O:48])[CH2:3][CH2:2]1>Cl.O1CCOCC1>[CH:1]1([N:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[N:6]([CH2:13][CH2:14][CH2:15][N:16]3[CH2:47][CH2:46][C:19]4([N:23]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[CH2:22][N:21]([CH2:31][C:32]5[CH:33]=[C:34]([CH:42]=[CH:43][CH:44]=5)[C:35]([OH:37])=[O:36])[C:20]4=[O:45])[CH2:18][CH2:17]3)[C:5]2=[O:48])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccc(F)cc3)C3(CCN(CCCn4c(=O)n(C5CC5)c5ccccc54)CC3)C2=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cccc(CN2CN(c3ccc(F)cc3)C3(CCN(CCCn4c(=O)n(C5CC5)c5ccccc54)CC3)C2=O)c1
Yield: 36.2 %

Procedure:
A solution of tert-butyl 3-((8-(3-(3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (166 mg, 0.254 mmol, 1 equiv) in 4M hydrogen chloride solution in dioxane was stirred at ambient temperature for 5 h. The mixture was concentrated in vacuo and purified using preparative thin layer chromatography in 10% methanol in dichloromethane. The pure extract was treated with 4M hydrogen chloride solution in dioxane to afford the hydrogen chloride salt of the title compound as cream crystals (55 mg, 36.4%); 1H NMR (400 MHz, DMSO-d6): δ 0.86-0.90 (m, 2H); 1.01-1.06 (m, 2H); 1.93 (d, 2H, J=14 Hz); 2.06-2.11 (m, 2H); 2.58-2.73 (m, 2H); 2.88-2.89 (m, 1H); 3.19 (bs, 2H); 3.67-3.73 (m, 4H); 3.89 (t, 2H, J=6.8 Hz); 4.62 (s, 4H); 7.05-7.12 (m, 6H); 7.22-7.27 (m, 2H); 7.48-7.57 (m, 2H); 7.87-7.89 (m, 2H); 10.05 (bs, 1H); 13.03 (bs, 1H); MS for C34H36FN5O4 m/z 598.28 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[N:6][CH:7]=1.[NH2:12][C:13]1[C:17]([C:18](=[O:20])[NH2:19])=[CH:16][N:15]([C:21]2([CH2:35][C:36]#[N:37])[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[O:28])[CH2:23][CH2:22]2)[N:14]=1.C(P(C(C)(C)C)C1C(C)=C(C)C(C)=C(C)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:18]([C:17]1[C:13]([NH:12][C:2]2[CH:7]=[N:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=2)=[N:14][N:15]([C:21]2([CH2:35][C:36]#[N:37])[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[O:28])[CH2:23][CH2:22]2)[CH:16]=1)(=[O:20])[NH2:19]
Reactant: CC(C)(O)c1ccc(Br)cn1
Reactant: N#CCC1(n2cc(C(N)=O)c(N)n2)CCN(C(=O)OCC(F)(F)F)CC1
Agent: [Pd]
Agent: Cc1c(C)c(C)c(P(C(C)(C)C)C(C)(C)C)c(-c2c(C(C)C)cc(C(C)C)cc2C(C)C)c1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(O)c1ccc(Nc2nn(C3(CC#N)CCN(C(=O)OCC(F)(F)F)CC3)cc2C(N)=O)cn1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
2-(5-Bromopyridin-2-yl)propan-2-ol (Intermediate 5) (23 mg, 0.11 mmol), 2,2,2-trifluoroethyl 4-(3-amino-4-carbamoyl-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate (Intermediate 35-3) 40 mg, 0.11 mmol), Pd2(dba)3 (10 mg, 0.011 mmol), 2-di-t-butylphosphino-3,4,5,6-teramethyl-2′,4′,6′-triisopropylbiphenyl (15 mg, 0.032 mmol), potassium phosphate (45 mg, 0.21 mmol), and 1,4-dioxane (1.0 mL) were combined in a 4 mL vial. The vial was capped and flushed with argon. The mixture was heated to 90° C. and allowed to stir for 2 hours. The mixture was then cooled to ambient temperature, diluted with EtOAc, and washed sequentially with water and brine. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-10% MeOH/DCM) to afford the title compound, Example #10-1.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:8]([O:21][CH:22]3[CH2:25][N:24]([C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)[CH2:23]3)=[N:9][C:10]([N:13]3[CH2:18][CH2:17][CH:16]([CH2:19][OH:20])[CH2:15][CH2:14]3)=[N:11][CH:12]=2)[CH2:3][CH2:2]1>CO.[Pd]>[N:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[N:24]1[CH2:25][CH:22]([O:21][C:8]2[C:7]([CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:12][N:11]=[C:10]([N:13]3[CH2:18][CH2:17][CH:16]([CH2:19][OH:20])[CH2:15][CH2:14]3)[N:9]=2)[CH2:23]1
Reactant: OCC1CCN(c2ncc(C3=CCOCC3)c(OC3CN(c4ccc5ccccc5n4)C3)n2)CC1
Agent: [Pd]
Solvent: CO
Product: OCC1CCN(c2ncc(C3CCOCC3)c(OC3CN(c4ccc5ccccc5n4)C3)n2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 90.5 %

Procedure:
A mixture of (1-(5-(3,6-dihydro-2H-pyran-4-yl)-4-((1-(quinolin-2-yl)azetidin-3-yl)oxy)pyrimidin-2-yl)piperidin-4-yl)methanol (100 mg, 0.21 mmol) and wet Pd—C (50%, 50 mg) in MeOH (10 mL) was stirred under H2 (30 psi) at room temperature for 6 hours then the reaction mixture was filtered through CELITE® and washed with MeOH. The filtrate was concentrated in vacuo to give (1-(4-((1-(quinolin-2-yl)azetidin-3-yl)oxy)-5-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl)piperidin-4-yl)methanol (90 mg, 0.19 mmol, yield 90%). ESI-MS (M+1): 476 calc. for C27H33N5O3 475. PDE10 IC50 (uM): 0.0029 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.23 (d, J=9.2 Hz, 1H); 8.08-8.06 (m, 1H); 7.95-7.93 (m, 1H); 7.80-7.78 (m, 2H); 7.55-7.51 (m, 1H); 6.74-6.70 (m, 1H); 5.73-5.72 (m, 1H); 5.19-5.10 (m, 2H); 4.70-4.51 (m, 4H); 4.27 (d, J=6.4 Hz, 1H); 4.08-4.06 (m, 2H); 3.57-3.48 (m, 3H); 3.20-3.14 (m, 2H); 2.89-2.88 (m, 1H); 2.02-1.93 (m, 3H); 1.78-1.76 (m, 4H); 1.42-4.37 (m, 2H).
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]2[CH:9]3[CH2:13][CH:12]([C:2]1=2)[CH2:11][CH2:10]3.[NH2:14][C:15]1[C:16]([CH3:45])=[C:17]([C:21]2[N:22]=[C:23]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([CH:36]4[C:41](=[O:42])[N:40]([CH3:43])[CH2:39][CH2:38][N:37]4[CH3:44])=[CH:32][CH:31]=3)[C:24](=[O:28])[N:25]([CH3:27])[CH:26]=2)[CH:18]=[CH:19][CH:20]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O.CN(C=O)C>[CH3:44][N:37]1[CH2:38][CH2:39][N:40]([CH3:43])[C:41](=[O:42])[CH:36]1[C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:23]2[C:24](=[O:28])[N:25]([CH3:27])[CH:26]=[C:21]([C:17]3[C:16]([CH3:45])=[C:15]([NH:14][C:6]([C:5]4[S:1][C:2]5[CH:12]6[CH2:13][CH:9]([C:3]=5[CH:4]=4)[CH2:10][CH2:11]6)=[O:8])[CH:20]=[CH:19][CH:18]=3)[N:22]=2)=[CH:31][CH:32]=1
Reactant: O=C(O)c1cc2c(s1)C1CCC2C1
Reactant: Cc1c(N)cccc1-c1cn(C)c(=O)c(Nc2ccc(C3C(=O)N(C)CCN3C)cc2)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(NC(=O)c2cc3c(s2)C2CCC3C2)cccc1-c1cn(C)c(=O)c(Nc2ccc(C3C(=O)N(C)CCN3C)cc2)n1
Temperature: 60 °C
Yield: 44.5 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 1e (100 mg, 0.515 mmol), 1p (203 mg, 0.469 mmol), N,N-diisopropylethylamine (242 mg, 1.88 mmol) and anhydrous DMF (2 mL). Benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP, 249 mg, 0.563 mmol) was added, and the reaction was heated at 60° C. for 16 h. After this time, the reaction was diluted with water (10 mL), and the resulting suspension was filtered. The filter cake was dissolved in methylene chloride (20 mL), and the solution was washed with 10% aqueous citric acid (10 mL), saturated aqueous sodium bicarbonate (10 mL), and water (10 mL), and dried over sodium sulfate. The drying agent was removed by filtration, and the solvent was evaporated under reduced pressure. The resulting residue was eluted with a gradient from 0% to 20% of methanol in ethyl acetate, and the fractions containing 1q were collected to afford, after concentrating under reduced pressure, a 44% yield (127 mg) of 1q as an off-white solid: mp 178-179° C.; 1H NMR (500 MHz, CD2Cl2) δ 8.35 (s, 1H), 7.85 (d, 1H, J=8.0 Hz), 7.77 (d, 2H, J=8.5 Hz), 7.59 (s, 1H), 7.42 (s, 1H), 7.29-7.22 (m, 4H), 6.76 (s, 1H), 3.68 (td, 1H, J=11.5, 4.5 Hz), 3.62-3.60 (m, 2H), 3.58 (s, 3H), 3.47 (m, 1H), 3.18 (m, 1H), 2.97 (m, 1H), 2.91 (s, 3H), 2.64 (m, 1H), 2.39 (s, 3H), 2.13 (s, 3H), 1.98-1.90 (m, 3H), 1.67 (dt, 1H, J=9.0, 2.5 Hz), 1.10 (dd, 2H, J=12.5, 3.5 Hz); MS (ESI+) m/z 609.3 (M+H).
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[N:9]=[C:8]([C:10]([CH3:14])([CH3:13])[C:11]#[N:12])[CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-:17].[K+].[K+].OO>CS(C)=O>[F:15][CH:2]([F:1])[O:3][C:4]1[N:9]=[C:8]([C:10]([CH3:13])([CH3:14])[C:11]([NH2:12])=[O:17])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C#N)c1cccc(OC(F)F)n1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C(N)=O)c1cccc(OC(F)F)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a 1 L round bottom flask was added 2-(6-(difluoromethoxy)pyridin-2-yl)-2-methylpropanenitrile (19.2 g, 91 mmol, 1 equiv), potassium carbonate (37.0 g, 270 mmol, 3 equiv), and DMSO (150 mL). The reaction was cooled to 0° C. and 30% hydrogen peroxide (25 mL) was added slowly in 2 mL portions over ten minutes. The reaction was then warmed to room temperature and stirred for 1 h. After consumption of starting material, the reaction was poured into ethyl acetate (600 mL), washed with brine (3×300 mL), dried over Na2SO4, and concentrated to give 2-(6-(difluoromethoxy)pyridin-2-yl)-2-methylpropanamide (20 g, 97%) as a clear oil.
Reaction SMILES: [C:1]([C:3]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH:11]=2)[C:6]([C:18]2[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=2)=[N:5][C:4]=1SC)#[N:2].[CH3:28][NH2:29]>C(O)C>[C:1]([C:3]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH:11]=2)[C:6]([C:18]2[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=2)=[N:5][C:4]=1[NH:29][CH3:28])#[N:2]
Reactant: CSc1ccc(-c2nc(SC)c(C#N)c(=O)n2-c2ccc(C)c(C)c2)cc1
Reactant: CN
Solvent: CCO
Product: CNc1nc(-c2ccc(SC)cc2)n(-c2ccc(C)c(C)c2)c(=O)c1C#N
Yield: 38.2 %

Procedure:
A suspension of 5-cyano-1-(3,4-dimethylphenyl)-4-(methylthio)-2-[4-(methylthio)phenyl]-6-oxo-1,6-dihydropyrimidine (1 g, 2.5 mmol) (prepared according to example 10) in ethanol (10 ml) with methylamine (0.16 g, 5 mmol) was refluxed for 3 hr. Then the reaction mass poured on to ice and the resulted solid filtered, washed thoroughly with water. The solid thus obtained was purified by column chromatography using ethyl acetate and hexane mixture as eluent to yield title compound (0.36 g, yield 38%, mp 199-205° C., purity 98.72% by HPLC). 1H-NMR (CDCl3):δ 2.19 (s, 3H), 2.22 (s, 3H), 2.44 (s, 3H), 3.17-3.18 (d, 3H), 5.73 (s, 1H, D2O exchangeable) 6.75-6.77 (d, 2H), 6.90 (s, 1H), 7.02-7.06 (m, 3H), 7.24-7.26 (d, 1H). IR (KBr) cm−1: 3280, 2920, 2207 (—CN), 1661 (—C═O). MS m/z:377.2 (M+).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[C:6]([CH:17]=O)[C:7]3[C:12]([C:13]=2[CH:15]=O)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[NH2:19][NH:20][C:21]([NH2:23])=[S:22].C(O)C>C(O)(=O)C>[N:19](=[CH:15][C:13]1[C:14]2[C:5]([C:6]([CH:17]=[N:19][NH:20][C:21]([NH2:23])=[S:22])=[C:7]3[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]3)=[CH:4][CH:3]=[CH:2][CH:1]=2)[NH:20][C:21]([NH2:23])=[S:22]
Reactant: NNC(N)=S
Reactant: O=Cc1c2ccccc2c(C=O)c2ccccc12
Solvent: CCO
Solvent: CC(=O)O
Product: NC(=S)NN=Cc1c2ccccc2c(C=NNC(N)=S)c2ccccc12
Reaction time: 8 h

Procedure:
A mixture of 2.34 g. of 9,10-anthracenedicarboxaldehyde and 3.65 g. of thiosemicarbazide in 250 ml. of absolute ethanol containing 2.0 ml. of glacial acetic acid is heated on a steam bath for 24 hours, allowed to cool and then let stand overnight. The solid is collected, washed with absolute ethanol, dried and recrystallized from aqueous dimethylformamide giving the desired product as orange crystals, m.p. 275°-277° C.
Reaction SMILES: [Cl-].[Cl-].C([Al+2])C.[CH3:6][C:7]([CH3:15])=[CH:8][CH2:9][CH2:10][C:11]([CH:13]=[CH2:14])=[CH2:12].[CH3:16][C:17](=[CH:20][CH3:21])[CH:18]=[O:19].O>C1C=CC=CC=1.[Cl-].[Cl-].C([Al+2])C>[CH3:16][C:17]1([CH:18]=[O:19])[CH:20]([CH3:21])[CH2:12][C:11]([CH2:10][CH2:9][CH:8]=[C:7]([CH3:15])[CH3:6])=[CH:13][CH2:14]1
Reactant: CC=C(C)C=O
Reactant: C=CC(=C)CCC=C(C)C
Agent: CC[Al+2]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: O
Product: CC(C)=CCCC1=CCC(C)(C=O)C(C)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
A 3-neck reaction vessel is charged with 100 ml benzene and 50 grams of 25% ethyl aluminum dichloride in benzene. A solution containing 320 grams myrcene (85% pure), 170 grams 2-methyl-2-butenal, and 200 ml benzene is fed in at 40°-50° C. over a 1 hour period. The temperature is then raised to 60° C. and held there for 1/2 hour. An additional 10 grams ethyl aluminum dichloride solution mixed with 20 ml benzene is added and heating is continued for an additional 1/2 hour. The mixture is then cooled, water is added and the layers are separated. The organic layer is washed with water and distilled without fractionation to free the material of residue. Redistillation through an 18" Goodloe packed column provides 199 grams of 1,6-dimethyl-4-(4-methyl-3-pentenyl)-3-cyclohexene-1-carboxaldehyde (b.p. 105° C., 0.9 mm).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]2[C:16]3[CH:17]=[C:18]([C:21]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)([OH:28])[C:22]4[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=4)[CH:19]=[CH:20][C:15]=3[NH:14][C:13](=[O:36])[CH2:12][S:11]2)[CH:7]=[CH:8][CH:9]=1.Br[CH2:38][CH:39]1[CH2:41][CH2:40]1>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]2[C:16]3[CH:17]=[C:18]([C:21]([C:29]4[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=4)([OH:28])[C:22]4[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=4)[CH:19]=[CH:20][C:15]=3[N:14]([CH2:38][CH:39]3[CH2:41][CH2:40]3)[C:13](=[O:36])[CH2:12][S:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)SCC(=O)N2
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)SCC(=O)N2CC1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 17.7 %

Procedure:
Sodium hydride (0.0016 mol, 60% in oil) was added portionwise at 10° C. to a mixture of 5-(3-chlorophenyl)-7-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1,5-dihydro-4,1-benzothiazepin-2(3H)-one (0.0013 mol), obtained in Example B2, in DMF (7 ml). The mixture was stirred for 30 minutes. (Bromomethyl)-cyclopropane (0.0016 mol) was added. The mixture was brought to room temperature, then stirred for 3 hours, poured out into ice water and stirred again for 30 minutes. The precipitate was filtered and taken up in DCM. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (0.6 g) was purified by column chromatography over kromasil (eluent: CH2Cl2/CH3OH/NEt3 97/3/0.1; 10 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.16 g) was crystallized from acetonitrile. The precipitate was filtered off and dried, yielding 0.13 g (17%) of 5-(3-chlorophenyl)-7-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-(cyclopropylmethyl)-1,5-dihydro-4,1-benzothiazepin-2(3H)-one, mp. 245° C.
Reaction SMILES: O1CCCCC1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C@@H:14]([OH:18])[C:15]([OH:17])=O.[C:19]([C:21]1[CH:35]=[CH:34][C:24]([CH2:25][NH:26][C:27](=[O:33])[C@@H:28]2[CH2:32][CH2:31][CH2:30][NH:29]2)=[CH:23][CH:22]=1)#[N:20].ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[C:19]([C:21]1[CH:22]=[CH:23][C:24]([CH2:25][NH:26][C:27](=[O:33])[C@@H:28]2[CH2:32][CH2:31][CH2:30][N:29]2[C:15](=[O:17])[C@@H:14]([CH2:13][C:8]2[CH:7]=[CH:12][CH:11]=[CH:10][CH:9]=2)[OH:18])=[CH:34][CH:35]=1)#[N:20]
Reactant: O=C(O)[C@H](O)Cc1ccccc1C1CCCCO1
Reactant: N#Cc1ccc(CNC(=O)[C@@H]2CCCN2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(CNC(=O)[C@@H]2CCCN2C(=O)[C@H](O)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5.5 g (20.4 mmol) of o-tetrahydropyranyl-3-phenyl-D-lactic acid (WO 93/18060) were dissolved in 30 ml of DMF and, successively, 5.4 g (20.4 mmol), N-(p-cyanobenzyl)prolin-amide, 3.3 g (20.4 nmol) of N-hydroxybenzotriazole, 3.0 g DIPEA and 4.33 g (20.6 mmol) of dicyclohexylcarbodiimide were added. The mixture was left to stir at room temperature for 48 h. The precipitated urea was filtered off with suction and then the solvent was substantially removed under reduced pressure, and the residue was mixed with 50 ml of water and extracted with ethyl acetate. After washing with water, NaHCO3 solution and drying over Na2SO4, the ethyl acetate was distilled off, the remaining oily residue was dissolved in methanol, and the pH was. adjusted to 2 with p-toluenesulfonic acid. This solution was left to stand at room temperature for 6 h. The methanol was then distilled off, and the residue was taken up in ethyl acetate and washed with water, 5% strength citric acid and NaBCO3 solutions. The residue obtained after drying over Na2SO4 and removal of the solvent by distillation was purified by column chromatography (eluent: methylene chloride/acetone/methanol, 45/5/2). 2.5 g of white crystals were obtained, and these melted at 108° C.-110° C. after crystallization from an ether/hexane mixture.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[CH2:9][C:10]#[N:11])[CH2:2][CH2:3][CH3:4].[H][H]>[Ni].CO>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH2:9][CH2:10][NH2:11])[CH:12]=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cccc(CC#N)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CCCCOc1cccc(CCN)c1
Temperature: 25 °C
Yield: 106.9 %

Procedure:
Raney nickel catalyst (approx 5 g) was added to a solution of 3-butyloxybenzyl cyanide (38.64 g, prepared according to example 1 D) in saturated ammoniacal methanol (700 cm3). The resulting mixture was heated at 70° C. in the presence of hydrogen (45 Atmospheres) for two hours and was then allowed to cool to room temperature overnight. The cooled mixture was filtered to remove the catalyst and was then evaporated down to give a green oil (42.2 g).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][C:6]=2[N:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>CCOCC>[CH3:1][N:2]([CH3:14])[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([CH2:12][NH2:13])=[CH:8][C:6]=2[N:7]=1
Reactant: CN(C)c1nc2cc(C#N)ccc2o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CN(C)c1nc2cc(CN)ccc2o1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 2-(Dimethylamino)-1,3-benzoxazole-5-carbonitrile (1.5 g, 8.0 mmol) in 150 mL of dry ether, 640 mg (16.0 mmol) of LiAlH4 were slowly added. The mixture was stirred at room temperature for 1.5 h and the excess of reagent was decomposed by careful addition of the minimum amount of water and filtered. The solids were washed with hot EtOAc (3×100 mL) giving a residue after evaporation. The purification by column chromatography yield 622 mg (41%) of the title compound as a white solid. Rf (CH2Cl2/MeOH 9:1+0.25% NH3) 0.2; 1H NMR (CD3OD) δ 7.23 (s, 1H, H-4), 7.15 (d, 1H, J=8.1 Hz, H-7), 6.89 (d, 1H, J=8.1 Hz, H-6), 3.83 (s, 2H, CH2), 3.14 (s, 6H, CH3×2); 13C NMR (CD3OD) δ 163.7 (C-2), 148.4 (C-7a), 144.2 (C-3a), 139.8 (C-5), 119.6 (C-6), 114.9 (C-4), 108.7 (C-7), 47.1 (CH2), 38.0 (CH3); mass spectrum (ES+): m/e 192.0 (M++1).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:10](=[O:30])[NH:11][C:12]([C:15]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[CH:24][CH:23]=2)=[CH:16][C@H:17]2[CH2:21][CH2:20][CH2:19][NH:18]2)=[CH:13][CH:14]=1.[C:31](Cl)(=[O:33])[CH3:32].O>C(Cl)Cl>[C:31]([N:18]1[CH2:19][CH2:20][CH2:21][C@@H:17]1/[CH:16]=[C:15](/[C:12]1[NH:11][C:10](=[O:30])[C:9]([Cl:8])=[CH:14][CH:13]=1)\[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[CH:24][CH:23]=1)(=[O:33])[CH3:32]
Reactant: CCc1ccc(C(=C[C@H]2CCCN2)c2ccc(Cl)c(=O)[nH]2)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCc1ccc(/C(=C\[C@H]2CCCN2C(C)=O)c2ccc(Cl)c(=O)[nH]2)cc1
Yield: 23 %

Procedure:
Triethylamine (15.3 μL) was added to a solution of 3-chloro-6-{1-(4-ethylphenyl)-2-[(2R)-pyrrolidin-2-yl]ethenyl}pyridin-2(1H)-one (E:Z=1:3 mixture) (32.9 mg) in methylene chloride (1 mL) at room temperature, and acetyl chloride (7.8 μL) was added under ice-cooling, after which the mixture was stirred under ice-cooling for 30 minutes. Triethylamine (15.3 μL) and acetyl chloride (7.8 μL) were added under ice-cooling and the mixture was stirred under ice-cooling for further 30 minutes. Water was added to the reaction solution, followed by extraction with methylene chloride. The organic layer was filtered through diatomaceous earth, and then the solvent was concentrated under reduced pressure. Acetonitrile (329 μL) and 48% hydrobromic acid (329 μL) were added to the resulting residue, and the mixture was stirred at 50° C. for one hour. Separately, triethylamine (121 μL) and acetyl chloride (61.6 μL) were added to a solution of 3-chloro-6-{1-(4-ethylphenyl)-2-[(2R)-pyrrolidin-2-yl]ethenyl}pyridin-2(1H)-one (E:Z=1:3 mixture) (190 mg) in methylene chloride (2 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes. Water was added to the reaction solution, followed by extraction with methylene chloride. The organic layer was filtered through diatomaceous earth, and then the solvent was concentrated under reduced pressure. Acetonitrile (1.9 mL) and 48% hydrobromic acid (1.9 mL) were added to the resulting residue, and the mixture was stirred at room temperature for 30 minutes. The reaction solutions were neutralized respectively with saturated aqueous sodium bicarbonate at room temperature, combined and extracted with ethyl acetate. The organic layer was filtered through diatomaceous earth, and then the solvent was concentrated under reduced pressure. The resulting residue was purified by NH-silica gel column chromatography (hexane:ethyl acetate=1:1→ethyl acetate:methanol=4:1) to give a yellow oil. This was powdered with acetonitrile, and filtration operation gave the title compound as a colorless solid (49 mg, 23%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C@@H:21](O)[CH2:20]2.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH:10]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)[C:11]([O:13][C@@H:21]2[CH:22]3[CH2:25][CH2:26][N:19]([CH2:24][CH2:23]3)[CH2:20]2)=[O:12])=[CH:7][CH:8]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: COc1ccc(NC(C(=O)O)c2ccsc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COc1ccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccsc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.3 %

Procedure:
A mixture of 2-(4-methoxyphenylamino)-2-(thiophen-3-yl)acetic acid (I56) (544 mg, 2.01 mmol), (R)-quinuclidin-3-ol (614 mg, 4.83 mmol), DCC (511 mg, 2.47 mmol), and HOBT (380 mg, 2.48 mmol) in dry THF (160 ml) was stirred at room temperature overnight. The solvent was evaporated, and the residue was partitioned between EtOAc and 2M NaHCO3. The organic phase was further washed with 2M NaHCO3 and brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (DCM/MeOH=95/5 to 7/3) to obtain (R)-quinuclidin-3-yl 2-(4-methoxyphenylamino)-2-(thiophen-3-yl)acetate (40 mg, 5% yield).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(=O)([O-])O.[Na+].[Br-].[Na+].C1C(=O)N(Cl)C(=O)C1>CC1(C)N([O])C(C)(C)CC(OC)C1.ClCCCl>[CH:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCO
Agent: COC1CC(C)(C)N([O])C(C)(C)C1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCCl
Product: CCCCCCCC=O
Yield: 84.6 %

Procedure:
1-Octanol (2.0 g, 15.4 mmol), sodium hydrogencarbonate (1.6 g, 18.5 mmol), 4-methoxy TEMPO (29 mg, 0.15 mmol), sodium bromide (0.16 g, 1.54 mmol) and 1,2-dichloroethane (15 ml) were put in a 50-ml egg plant type flask. The suspension was cooled to less than 10° C. in an ice bath and thereto was added NCS (2.3 g, 16.9 mmol) divided in two portions. The insoluble materials were filtered off and the filtrate was washed with 5% aqueous sodium bicarbonate solution. The crude product was purified by distillation to give 1-octanal (1.67 g, yield 85%).