Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:19]([O:20]CC=C)=[CH:18][C:8]2[CH2:9][C:10]3([O:17][C:7]=2[CH:6]=1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)([CH3:4])([CH3:3])[CH3:2].CN(C)[C:26]1[CH:31]=CC=C[CH:27]=1>>[C:1]([C:5]1[C:19]([OH:20])=[C:18]([CH2:31][CH:26]=[CH2:27])[C:8]2[CH2:9][C:10]3([O:17][C:7]=2[CH:6]=1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1ccccc1
Reactant: C=CCOc1cc2c(cc1C(C)(C)C)OC1(CCCCCC1)C2
Product: C=CCc1c(O)c(C(C)(C)C)cc2c1CC1(CCCCCC1)O2
Yield: 67 %

Procedure:
Under a nitrogen stream, a solution of 0.76 g of 6-t-butyl-5-(2-propenyloxy)-2,3-dihydrobenzofuran-2-spiro-1′-cycloheptane was dissolved in 3 ml of dimethylaniline and the solution was refluxed overnight. The reaction mixture was allowed to attain room temperature and concentrated under reduced pressure, then extracted with ethyl acetate and 5% hydrochloric acid and the organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 1%-2% ethyl acetate) to give 0.51 g of 6-t-butyl-5-hydroxy-4-(2-propenyl)-2,3-dihydrobenzofuran-2-spiro-1′-cycloheptane as a colorless oil (yield 67%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.Cl[CH2:8][CH2:9][C:10]1[N:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1)[CH:14]=2>>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][CH2:9][C:10]1[N:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1)[CH:14]=2
Reactant: CC1CCCN1
Reactant: N#Cc1ccc(-c2ccc3cc(CCCl)nnc3c2)cc1
Product: CC1CCCN1CCc1cc2ccc(-c3ccc(C#N)cc3)cc2nn1
Temperature: 65 °C
Yield: 0.43 %

Procedure:
Racemic 2-methylpyrrolidine (0.5 mL, neat) was added to the product from Example 169D (0.01 g, 0.034 mmol) and heated to 65° C. in a sealed tube for 18 hours. After cooling, the reaction mixture was concentrated under reduced pressure and purified by column chromatography (100% dichloromethane to 95:5 dichloromethane/methanol) to afford the product in 0.43% yield as a brown-yellow semi-solid. 1H NMR (CD3OD, 300 MHz) δ 8.72 (m, 1H), 8.20 (dd, J=3, 9 Hz, 1H), 8.16 (s, 1H), 8.11 (d, J=9 Hz, 1H), 8.06 (d, J=9 Hz, 2H), 7.91 (d, J=9 Hz, 2H), 3.58-3.46 (m, 4H), 2.85-2.65 (m, 2H), 2.57-2.51 (m, 1H), 2.03-1.90 (m, 1H), 1.89-1.83 (m, 2H), 1.56-1.50 (m, 1H), 1.21 (d, J=6 Hz, 3H). MS (ESI) [M+H]+ at 343.
Reaction SMILES: [CH2:1]([O:17][C:18]1[O:22][C:21]([C:23]([OH:25])=O)=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH:12]=[CH:13][CH2:14][CH:15]=[CH2:16].[CH2:26](OC1OC(C(O)=O)=CC=1)CCCCCCCCCCCCC>>[CH2:1]([O:17][C:18]1[O:22][C:21]([C:23]([CH3:26])=[O:25])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH:12]=[CH:13][CH2:14][CH:15]=[CH2:16]
Reactant: C=CCC=CCC=CCCCCCCCCOc1ccc(C(=O)O)o1
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Product: C=CCC=CCC=CCCCCCCCCOc1ccc(C(C)=O)o1

Procedure:
When in the procedure of Example 1(B) an appropriate amount of 5-(9,12,15-hexadecatrienyloxy)-2-furoic acid is substutited for 5-tetradecyloxy-2-furoic acid, methyl 5-(9,12,15-hexadecatrienyloxy)-2-furyl ketone is obtained.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:5]([F:21])=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:11]=3[CH2:10][C:9](=[O:19])[C:8]=2[CH:20]=1>O.[OH-].[Na+].O1CCOCC1>[Cl:3][C:4]1[C:5]([F:21])=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:11]=3[CH2:10][CH:9]([OH:19])[C:8]=2[CH:20]=1
Reactant: O=C1Cc2ccc(F)cc2Sc2cc(F)c(Cl)cc21
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: OC1Cc2ccc(F)cc2Sc2cc(F)c(Cl)cc21

Procedure:
A solution of sodium borohydride (1.0 g) in water (3 ml) containing 2 drops of 20% sodium hydroxide solution was added dropwise to a stirred solution of the ketone from the preceding experiment (7.9 g) in dioxane (100 ml). The mixture was refluxed for 6 hours, the dioxane evaporated in vacuo and the residue mixed with water and extracted with benzene. Evaporation of the extract and crystallization of the residue from an ether-cyclohexane mixture yielded 6.0 g of the pure 8-chloro-3,7-difluoro-10-hydroxy-10,11-dihydrodibenzo(b,f)thiepine, m.p. 84°-86° C.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=O)C.[ClH:23]>>[ClH:23].[CH3:21][S:18]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]([CH:7]2[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]2)=[O:22])=[CH:16][CH:15]=1)(=[O:19])=[O:20]
Reactant: CC(=O)N1CCC(C(=O)c2ccc(NS(C)(=O)=O)cc2)CC1
Agent: Cl
Product: CS(=O)(=O)Nc1ccc(C(=O)C2CCNCC2)cc1
Yield: 84 %

Procedure:
43.4 g (0.142 mol) of 1-acetyl-4-(4-methylsulfonylaminobenzoyl)piperidine was suspended in 1 l of 3N hydrochloric acid and the suspension was stirred under reflux for 3 h. After completion of the reaction, the liquid reaction mixture was cooled and white crystals thus formed were filtered, washed with water and dried to obtain 37.8 g (yield: 84%) of the intended compound.
Reaction SMILES: CO[C:3](=[O:23])[CH:4]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14]#[N:15])[N:13]=1)=[S:7].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:14]([C:12]1[N:13]=[C:9]([N:8]2[C:3](=[O:23])[CH:4]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:5][C:6]2=[S:7])[S:10][CH:11]=1)#[N:15]
Reactant: COC(=O)C(Cc1ccccc1)NC(=S)Nc1nc(C#N)cs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1csc(N2C(=O)C(Cc3ccccc3)NC2=S)n1
Temperature: 25 °C
Yield: 13.2 %

Procedure:
A solution of N-[[(4-cyano-2-thiazolyl)amino]thioxomethyl]-DL-phenylalanine methyl ester (1.42 g, 4.10 mmol) and p-toluene sulfonic acid hydrate (0.20 g 1.05 mmol) in toluene (80 mL) was refluxed with a Dean-Stark trap for 24 h. The reaction was cooled to room temperature, solvent removed under reduced pressure, residue taken up in ethyl acetate, washed with saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting product was recrystallized from ethyl ether-hexanes to provide 170.1 mg (10%) of the titled product: mp 214°-216° C.; IR (KBr, cm-1) 3294, 3092, 2246, 1781, 1505, 1381, 1325, 1244; 1H NMR (300 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.90 (s, 1H), 7.22-7.80 (m, 3H), 7.20-7.22 (m, 2H), 4.83 (t, 1H), 3.17 (d, 2H); MS (FD) m/e 314(M+); UV (EtOH) 259 nm (ε=15097), 205 nm (ε=26419). Anal. Calcd for C14H10N4OS2 : C, 53.49; H, 3.21; N,17.82. Found: C, 53.75; H, 3.43; N, 17.62.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([OH:19])=O)[CH2:12]2)[N:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][NH2:29])=[C:24]([C:30]([F:33])([F:32])[F:31])[CH:23]=1.C(N(C(C)C)CC)(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>CN(C)C=O>[CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([C:17]([NH:29][CH2:28][C:25]3[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][C:24]=3[C:30]([F:31])([F:32])[F:33])=[O:19])[CH2:12]2)[N:3]=1
Reactant: CNc1nc(C)nc(NC2CCCC(C(=O)O)C2)n1
Reactant: COc1ccc(CN)c(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nc(C)nc(N[C@@H]2CCC[C@H](C(=O)NCc3ccc(OC)cc3C(F)(F)F)C2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 15.9 %

Procedure:
To a solution of 3-{[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxylic acid (0.100 g, 0.377 mmol) in N,N-Dimethylformamide (DMF) (5 ml) was added ({[4-(methyloxy)-2-(trifluoromethyl)phenyl]methyl} amine (0.132 g, 0.415 mmol), followed by diisopropylethylamine (0.197 ml, 1.131 mmol) and 1H-1,2,3-benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent, 0.183 g, 0.415 mmol). The reaction was stirred at room temperature for 4 hours and then purified by preparative HPLC to provide (cis)-3-{[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]amino}-N-{[4-(methyloxy)-2-(trifluoromethyl)phenyl]methyl}cyclohexanecarboxamide (31 mg, 0.06 mmol, 16%). MS (ES+): m/e 453 [M+H]+.
Reaction SMILES: [C:1]1([S:7]([O-:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].F[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.O>CS(C)=O>[C:1]1([S:7]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1ccc(S(=O)(=O)c2ccccc2)cc1
Temperature: 120 °C
Yield: 79.6 %

Procedure:
Sodium phenylsulfinate (16.4 g, 0.1 mol) and 4-fluorobenzaldehyde (12.4 g, 0.1 mol) were combined in dimethylsulfoxide (100 mL) and heated at 120° C. for 4 days. The cooled reaction was poured into water. The resulting crystals were filtered off and washed with water, then dissolved in ethyl acetate/dichloromethane, dried and concentrated in vacuo until crystallisation ensued. The mixture was diluted with isohexane and the crystals filtered off and washed with further isohexane to yield 4-(phenylsulfonyl)benzaldehyde (19.6 g, 80%). δH (500 MHz, d6 DMSO): 10.06 (1H, s), 8.16 (2H, d, J=8.3 Hz), 8.09 (2H, d, J=8.3 Hz), 7.99 (2H, d, J=7.7 Hz), 7.71 (1H, t, J=6.9 Hz), 7.63 (2H, t, J=7.7 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[C:11](=[N:16][NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([OH:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[C:12]([O:14]C)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][NH2:37])=[CH:32][CH:31]=1.Cl>C(O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11](=[N:16][NH:17][C:18]3[CH:19]=[CH:20][C:21]([S:24]([OH:27])(=[O:25])=[O:26])=[CH:22][CH:23]=3)[C:12](=[O:14])[N:36]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)[N:37]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NNc1ccc(F)cc1
Reactant: COC(=O)C(=NNc1ccc(S(=O)(=O)O)cc1)C(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCO
Product: O=C1C(=NNc2ccc(S(=O)(=O)O)cc2)C(c2ccc([N+](=O)[O-])cc2)=NN1c1ccc(F)cc1

Procedure:
The crude product methyl 3-(4-nitrophenyl)-3-oxo-2-(2-(4-sulfophenyl)hydrazono)-propanoate (200 mg, 0.49 mmol) (synthesized as described for 11-1) was dissolved in ethanol (10 ml), and 4-fluorophenylhydrazine (96 mg, 0.59 mmol) and hydrochloric acid (37%, 0.2 ml) were added. The product 4-((1,5-dihydro-3-(4-nitrophenyl)-5-oxo-1-(4-fluorophenyl)-4H-pyrazol-4-ylidene)-hydrazino)-benzenesulfonic acid was isolated by filtration as a brown solid (yield 82%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@H:11]3[CH2:15][C@H:14]([OH:16])[C@H:13]([CH2:17][OH:18])[CH2:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:19][C@@H:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1.C(N(C(C)C)CC)(C)C>CC(O)CC>[C@@H:20]1([NH:19][C:2]2[C:3]3[CH:10]=[CH:9][N:8]([C@H:11]4[CH2:15][C@H:14]([OH:16])[C@H:13]([CH2:17][OH:18])[CH2:12]4)[C:4]=3[N:5]=[CH:6][N:7]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1
Reactant: OC[C@@H]1C[C@@H](n2ccc3c(Cl)ncnc32)C[C@@H]1O
Reactant: N[C@H]1CCc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC(C)O
Product: OC[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@@H]1O
Temperature: 55 °C
Yield: 77.3 %

Procedure:
A jacketed reactor was charged with (1S,2S,4R)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)cyclopentanol (30.8 Kg, 115.05 mol), 2-butanol (198.5 Kg), (S)-(+)-1-aminoindane (16.95 Kg, 127.26 mol) and diisopropylethylamine (19.45 Kg, 150.50 mol). The mixture was heated to 55±5° C. and then moved to a mobile vessel. The reactor was then rinsed with 2-butanol (15.6 Kg) at 55±5° C. which was moved to the mobile vessel. The mobile vessel contents were then transferred to a pressure reactor and 2-butanol (51 L) was used to rinse the mobile vessel. The reaction mixture was then heated to 135±5° C. and adjusted to a pressure of 8 bar. The mixture was then stirred until reaction was complete by HPLC analysis. The mixture was cooled to 30±10° C. and transferred to a mobile vessel via a plate filter. The pressure reactor was rinsed with 2-butanol (43.1 L). The contents of the mobile vessel were then charged to a jacketed reactor via an in-line filter and the vessel rinsed with 2-butanol (39.2 Kg). The mixture was heated to 50±5° C. and concentrated under reduced pressure to about 50 L. The mixture was cooled to 20±5° C. and then dichloromethane (256 Kg) added over a period of about 3 hours. The mixture was stirred for a further 9.5 hours and then further cooled to 0±5° C. and stirred for about 4 hours. The solid product was isolated by filtration and washed with dichloromethane (82 Kg) at 0±5° C. The solids were then dried under reduced pressure at 40±5° C. to constant weight. A reactor was charged with water (371 Kg) and the dried solids and the mixture stirred at 20±5° C. for about 14.5 hours. The solid product was isolated by filtration and washed with water (371 Kg). The solids were then dried under reduced pressure at 50±5° C. to afford the title compound (32.4 Kg) as a white solid. 1H NMR (300 MHz, DMSO, 6): 8.15 (s, 1H), 7.71 (d, 1H), 7.07-7.29 (m, 5H), 6.61 (d, 1H), 5.88 (dd, 1H), 5.24-5.38 (m, 1H), 4.60 (d, 1H), 4.26-4.37 (m, 2H), 3.53-3.65 (m, 1H), 3.35-3.46 (m, 1H), 2.90-3.04 (m, 1H), 2.75-2.90 (m, 1H), 2.33-2.56 (m, 2H), 2.04-2.14 (m, 2H), 1.88-2.03 (m, 2H), 1.74-1.87 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][C:11]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:10][C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])(O)=O.[Na+]>C1COCC1.O>[C:2]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH2:13][CH2:12][C:11]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:10][C:9]2=[O:21])[CH:3]=1
Reactant: CC1(c2ccccc2)CCN(c2cccc(Br)c2)C(=O)O1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(c2ccccc2)CCN(c2cccc(-c3ccccc3)c2)C(=O)O1
Yield: 20.8 %

Procedure:
To a solution of 3-(3-bromophenyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one (50 mg, 0.14 mmol) and phenylboronic acid (35 mg, 0.29 mmol) in THF (2 mL) was added a solution of NaHCO3 (31 mg, 0.29 mmol) in H2O (2 mL) followed by Pd(PPh3)Cl2 (9 mg, 0.01 mmol). The mixture was refluxed overnight. The mixture was concentrated to give the crude product, which was purified by column chromatography, followed by preparative HPLC to afford 3-(biphenyl-3-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one (10 mg, 20%). 1H NMR: (400 MHz, CDCl3): δ 1.71 (s, 3H), 2.40 (m, 1H), 2.48 (m, 1H), 3.31 (m, 1H), 3.54 (m, 1H), 7.08 (m, 1H), 7.30 (m, 3H), 7.7.32-7.42 (m, 8H), 7.46 (m, 2H). LC-MS Method 3, tR=1.362 min, m/z=344. 1H NMR (CDCl3) 1.75 (s, 3H), 2.32-2.43 (m, 1H), 2.50 (m, 1H), 3.20 (m, 1H), 3.52 (m, 1H), 7.10 (d, 1H), 7.25-7.45 (m, 11H), 7.50 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:23]([NH2:24])=[C:22](I)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[CH2:26]([OH:31])[CH2:27][CH2:28][C:29]#[CH:30]>C(#N)C.C(N(CC)CC)C.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.[Cu]I>[NH2:24][C:23]1[C:22]([C:30]#[C:29][CH2:28][CH2:27][CH2:26][OH:31])=[N:21][CH:20]=[N:19][C:18]=1[NH:17][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[C:2]([Cl:1])[CH:3]=1
Reactant: C#CCCCO
Reactant: Nc1c(I)ncnc1Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1c(C#CCCCO)ncnc1Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.8 %

Procedure:
To a solution of N4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodopyrimidine-4,5-diamine (300 mg) and 4-pentyn-1-ol (65 mg) in acetonitrile-triethylamine (6.0 mL-4.5 mL) were added bis(triphenylphosphine)palladium(II) dichloride (22.5 mg) and copper(I) iodide (7.3 mg) at room temperature, and the mixture was stirred at room temperature under an argon atmosphere for 24 hrs. 4-Pentyn-1-ol (65 mg), bis(triphenylphosphine)palladium(II) dichloride (22.5 mg) and copper(I) iodide (7.3 mg) were added to the reaction system and the mixture was stirred at 60° C. for 2 hrs. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, eluent, ethyl acetate→methanol:ethyl acetate=1:19) to give the title compound (157.2 mg) as a yellow solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[CH2:19]1[C:22]2([CH2:25][NH:24][CH2:23]2)[CH2:21][O:20]1>CN(C)C=O.O>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([N:24]2[CH2:25][C:22]3([CH2:19][O:20][CH2:21]3)[CH2:23]2)=[C:3]([CH:6]=1)[C:4]#[N:5])([O-:12])=[O:11]
Reactant: C1NCC12COC2
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc([N+](=O)[O-])ccc1N1CC2(COC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.7 %

Procedure:
2-Fluoro-5-nitrobenzonitrile (1.0 g, 6.02 mmol, purchased from Combi-Blocks AN1040) was dissolved in dimethylformamide (25 mL) under nitrogen. Potassium carbonate (3.50 g, 25.3 mmol) and 2-oxa-6-azaspiro[3.3]heptane (1.05 g, 7.22 mmol, purchased from Ryan Scientific EN300-89755) were added to the mixture. The resulting mixture was stirred at room temperature overnight. The reaction was then diluted with water (75 mL) and extracted with ethyl acetate (4×75 mL). The organic layer was washed with water (5×75 mL) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by Combiflash, eluting with hexane and ethyl acetate to provide the desired product as a bright yellow solid (350 mg, 24% yield).
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][CH2:26][C:27](OCC)=O)[CH2:22][CH:23]=2)=[CH:14][CH:13]=1>>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][C:27]3[O:9][N:8]=[C:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:20][CH:19]=2)=[CH:16][CH:17]=1
Reactant: ON=C1CCCCCC1
Reactant: CCOC(=O)CCCN1CC=C(c2ccc(OC)cc2)CC1
Product: COc1ccc(C2=CCN(CCCc3onc4c3CCCCC4)CC2)cc1

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridin-1-yl)-n-butyrate, 3-(3-(4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].C(=O)([O-])[O-].[K+].[K+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C(#N)C>[CH2:14]([N:1]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@H:2]([CH2:3][OH:4])[C:5]([O:7][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:6])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: N[C@H](CO)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(OCc1ccccc1)[C@@H](CO)N(Cc1ccccc1)Cc1ccccc1
Yield: 88.9 %

Procedure:
D-serine (10.5 g, 0.1 mol) was stirred with potassium carbonate (69 g, 0.5 mol), benzyl bromide (64.8 g, 0.375 mol) and water (10 mL) in acetonitrile (250 mL) at 55° C. for 24 hours. The reaction mixture was filtered and washed with ethyl acetate. The filtrate was concentrated with silica gel. The product was purified by column chromatography, eluting with 5-20% ethyl acetate in hexanes to give benzyl (2R)-2-(dibenzylamino)-3-hydroxypropanoate (33.36 g, 88%) as a pale-yellow sticky oil. 1H NMR (300 MHz, CDCl3): (ppm) 7.20-7.44 (m, 15H), 5.27 (q, 2H), 3.91 (d, 2H), 3.80 (m, 2H), 3.67 (d, 2H), 3.63 (m, 1H) and 2.52 (dd, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[C:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)#[N:18]>>[C:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=2)[C:5]([CH:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]2)=[O:6])=[O:24])=[CH:21][CH:20]=1)#[N:18]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccc(C#N)cc3)c2)CC1
Yield: 121.1 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 4-cyanobenzoyl chloride (38 mg, 0.229 mmol), 48.4 mg (>100%) of the title compound were recovered.
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.F[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>O>[F:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 80 °C
Reaction time: 21 h
Yield: 94.8 %

Procedure:
To an N,N-dimethylformamide (40.0 mL) solution of 4fluorophenol (5.00 g, 44.6 mmol) and 4-fluorobenzaldehyde (4.00 mg, 32.2 mmol) was added potassium carbonate (13.4 g, 96.6 mmol), which was stirred for 21 hours at 80° C. The reaction solution was then cooled to room temperature, water was added thereto, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:15→1:10) to obtain the title compound (6.60 g, 90.1%).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]([O:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH:35]=O)([CH3:31])[CH3:30]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:34]3[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=3[O:32][CH:29]([CH3:31])[CH3:30])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: CC(C)Oc1ccccc1C=O
Product: CC(C)Oc1ccccc1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2-isopropoxy-benzaldehyde. MS (ESI) m/z 527.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][C@H:3]1[C:23]([O:25][CH3:26])=[O:24].[O:27]1[C:36]2[CH:35]=[C:34]([CH:37]=O)[N:33]=[CH:32][C:31]=2[O:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[C:19]2[C:14]=1[CH:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][C@@H:2]([NH:1][CH2:37][C:34]2[N:33]=[CH:32][C:31]3[O:30][CH2:29][CH2:28][O:27][C:36]=3[CH:35]=2)[C@H:3]([C:23]([O:25][CH3:26])=[O:24])[CH2:4]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: COC(=O)[C@@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COC(=O)[C@@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1NCc1cc2c(cn1)OCCO2
Yield: 79.2 %

Procedure:
Methyl(3R,4R)-4-amino-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidine-3-carboxylate (Intermediate 38) (195 mg, 0.53 mmol), 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (88 mg, 0.53 mmol) and sodium triacetoxy borohydride (339 mg, 1.6 mmol) were reacted as described for Example 14 to give 216 mg (79%) of product as a colorless hard foam.