Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:4]([C:9]2(O)[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.CCN(S(F)(F)F)CC>C(Cl)Cl>[O:13]1[C:12]2([CH2:17][CH2:18][C:9]([C:4]3[C:3]([C:2]([F:20])([F:1])[F:21])=[CH:8][CH:7]=[CH:6][N:5]=3)=[CH:10][CH2:11]2)[O:16][CH2:15][CH2:14]1
Reactant: OC1(c2ncccc2C(F)(F)F)CCC2(CC1)OCCO2
Agent: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1cccnc1C1=CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 79.7 %

Procedure:
To a −78° C. solution of Example 36A (1.2 g, 3.96 mmol) in CH2Cl2 (25 mL) was added DAST (0.97 g, 0.76 mL, 5.75 mmol) and the reaction mixture was allowed to warm to ambient temperature. The mixture was quenched with water, diluted with EtOAc, and washed with water. Organic layer was separated, concentrated and chromatographed on silica gel (EtOAc-hexane, 0%-30%) to obtain the title compound (0.9 g, 80%). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.78 (m, 1H), 8.17 (dd, J=1.6, 8.2, 1H), 7.51 (m, 1H), 5.56 (m, 1H), 3.92 (s, 4H), 2.35 (m, 3H), 1.94 (dd, J=9.1, 16.3, 1H), 1.80 (t, J=6.5, 2H). MS (DCI) m/z 286 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:7][CH:6]([O:8][CH:9]([CH:49]2[CH:53]([OH:54])[CH:52]([OH:55])[CH:51]([N:56]3[CH:61]=[CH:60][C:59](=[O:62])[NH:58][C:57]3=[O:63])[O:50]2)[CH:10]([C:46]([OH:48])=[O:47])[NH:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:45])[CH:17]([CH:40]([OH:44])[CH:41]([CH3:43])[CH3:42])[NH:18][C:19](=[O:39])[CH:20]([CH:32]2[CH2:37][CH2:36][NH:35][C:34](=[NH:38])[NH:33]2)[NH:21][C:22](=[O:31])[NH:23][CH:24]([CH:28]([CH3:30])[CH3:29])[C:25]([OH:27])=[O:26])[CH:5]([O:64][CH3:65])[CH:4]1[OH:66].[CH2:67]([N:83]=[C:84]=[O:85])[CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH3:82]>CN(C)C=O>[O:63]=[C:57]1[NH:58][C:59](=[O:62])[CH:60]=[CH:61][N:56]1[C@@H:51]1[O:50][C@H:49]([C@H:9]([O:8][CH:6]2[C@H:5]([O:64][CH3:65])[C@@H:4]([OH:66])[C@@H:3]([CH2:2][NH:1][C:84]([NH:83][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH3:82])=[O:85])[O:7]2)[CH:10]([C:46]([OH:48])=[O:47])[NH:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:45])[CH:17]([CH:40]([OH:44])[CH:41]([CH3:42])[CH3:43])[NH:18][C:19](=[O:39])[CH:20]([CH:32]2[CH2:37][CH2:36][NH:35][C:34](=[NH:38])[NH:33]2)[NH:21][C:22](=[O:31])[NH:23][CH:24]([CH:28]([CH3:29])[CH3:30])[C:25]([OH:27])=[O:26])[C@@H:53]([OH:54])[C@H:52]1[OH:55]
Reactant: COC1C(OC(C(NCCCNC(=O)C(NC(=O)C(NC(=O)NC(C(=O)O)C(C)C)C2CCNC(=N)N2)C(O)C(C)C)C(=O)O)C2OC(n3ccc(=O)[nH]c3=O)C(O)C2O)OC(CN)C1O
Reactant: CCCCCCCCCCCCCCCCN=C=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCNC(=O)NC[C@H]1OC(O[C@H](C(NCCCNC(=O)C(NC(=O)C(NC(=O)NC(C(=O)O)C(C)C)C2CCNC(=N)N2)C(O)C(C)C)C(=O)O)[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)[C@H](OC)[C@H]1O
Yield: 4.8 %

Procedure:
The title compound is prepared by the procedure of Example 11, using 50.0 mg (52 μmol) of 16-({[5-(aminomethyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}{5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11,15-pentaazaheptadecane-1,17-dioic acid (λmax nm in water=259) and 14.0 mg (52 μmol) hexadecyl isocyanate in 2.0 ml of N,N-dimethyl formamide to give 3.0 mg of the desired product.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][CH2:13][CH2:12]1>>[CH3:7][N:6]1[C:2]([N:11]2[CH2:17][CH2:16][C:15](=[O:18])[NH:14][CH2:13][CH2:12]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: O=C1CCNCCN1
Product: Cn1ncc([N+](=O)[O-])c1N1CCNC(=O)CC1
Yield: 58 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and 1,4-diazepan-5-one gave 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,4-diazepan-5-one as a yellow oil (173 mg, 58%). 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 6.35 (s, 1H), 3.82 (s, 3H), 3.53-3.47 (m, 2H), 3.38-3.31 (m, 4H), 2.83-2.78 (m, 2H)
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[CH:11]=[CH:12][C:13]4S[CH2:18][CH2:17][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:15][C:14]=4[CH:24]=3)=[CH:4][C:3]=2[O:2]1.ClC1C=CC=C(C(OO)=O)C=1.[S:36]([O-:40])([O-])(=[O:38])=S.[Na+].[Na+]>C1COCC1>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[CH:11]=[CH:12][C:13]4[S:36](=[O:40])(=[O:38])[CH2:18][CH2:17][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:15][C:14]=4[CH:24]=3)=[CH:4][C:3]=2[O:2]1
Reactant: O=S([O-])([O-])=S
Reactant: COC(=O)C1=Cc2cc(-c3ccc4c(c3)OCO4)ccc2SCC1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1=Cc2cc(-c3ccc4c(c3)OCO4)ccc2S(=O)(=O)CC1
Reaction time: 2 h

Procedure:
To a solution of methyl 7-(3,4-methylenedioxyphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylate (0.80 g) in THF (10 ml) was added at 0° C. 70% 3-chloroperbenzoic acid (1.22 g), and the mixture was stirred at 0° C. for 15 minutes and then at room temperature for 2 hours. To the mixture was added an aqueous solution of sodium thiosulfate, and the mixture was stirred for a few minutes and extracted with dichloromethane. The organic layer was washed with sodium bicarbonate solution and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give solid, which was recrystallized from THF/isopropanol to give colorless crystals of methyl 7-(3,4-methylenedioxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (763.3 mg).
Reaction SMILES: N1C=CC=CC=1.[OH:7][CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1>ClCCl.[O-2].[O-2].[O-2].[Cr+6]>[CH:8]([CH:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)C1
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(C=O)C1
Reaction time: 0.25 h

Procedure:
To a solution of pyridine (9.5 g, 0.12 mol) in dichloromethane (150 mL) was added chromium trioxide (6.0 g, 0.06 mol). The internal reaction temperature was not allowed to exceed 20° C. during the addition. After 15 minutes, the stirred mixture was charged with a solution of tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (2.0 g, 10 mmol) in dichloromethane (30 mL). After 15 minutes, the solution was decanted from the reaction vessel which was washed with dichloromethane (200 mL). The organics were combined, washed with 5% aqueous sodium hydroxide (3×100 mL), then washed with 5% hydrochloric acid (100 mL), then washed with 5% aqueous sodium bicarbonate (100 mL), and finally washed with 5% aqueous sodium chloride (100 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford tert-butyl 3-formylpyrrolidine-1-carboxylate that was used without additional purification.
Reaction SMILES: C(O[C:6](=O)[NH:7][C:8]1([CH3:20])[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)(C)(C)C.[OH-].[Na+].[CH:24](O)=O>>[CH2:13]([N:10]1[CH2:11][CH2:12][C:8]([N:7]([CH3:6])[CH3:24])([CH3:20])[CH2:9]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC1(NC(=O)OC(C)(C)C)CCN(Cc2ccccc2)C1
Reactant: O=CO
Agent: [Na+]
Agent: [OH-]
Product: CN(C)C1(C)CCN(Cc2ccccc2)C1

Procedure:
A solution of (1-benzyl-3-methyl-pyrrolidin-3-yl)-carbamic acid tert-butyl ester (682 mg) in aqueous formic acid/aqueous formaldehyde 1:2 (7 mL) was stirred at 90° C. for 4 h. The mixture was neutralized with sodium hydroxide solution, extracted with dichloromethane, dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC. In this way the product was obtained with molecular weight 218.34 (C14H22N2); MS (ESI): 219 (M+H+).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([C:14]#[N:15])[C:5]=1[N:16]1[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=[CH:17]1.O.O.O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:13])[F:12])[CH:7]=[C:6]([C:14]#[N:15])[C:5]=1[N:16]1[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[N:18]([Br:1])[CH2:17]1
Reactant: N#Cc1cc(C(F)(F)F)cc(Cl)c1-n1cnc(C(F)(F)F)cc1=O
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cc(C(F)(F)F)cc(Cl)c1N1CN(Br)C(C(F)(F)F)=CC1=O
Reaction time: 6 h

Procedure:
Bromine (35mg) was added to a stirred solution of 1-(2-chloro-6-cyano-4-trifluoromethylphenyl)-4-trifluoromethylpyrimidin-6-one (70mg) and sodium acetate trihydrate (77mg) in acetic acid (3.5ml). After stirring for 6 hours, the reaction mixture was allowed to stand overnight, whereupon the solvent was evaporated under reduced pressure. The residual solid was dissolved in ethyl acetate and washed with water, followed by aqueous sodium bicarbonate solution and finally brine. After drying over anhydrous magnesium sulphate the solvent was evaporated under reduced pressure to give 1-(2-chloro-6-cyano-4-trifluoromethylphenyl)-3-bromo-4-trifluoromethylpyrimidin-6-one as a colourless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[C:17]([C:19]1[CH:20]=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1)#[N:18]>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:25]([C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:17]#[N:18])[CH:20]=1)(=[O:27])=[O:26])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Product: N#Cc1cccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2)c1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-amino-5-chloro-phenyl)-phenyl-methanone and 3-Cyano-benzenesulfonyl chloride. 1H NMR (CDCl3): δ 7.39-7.45 (m, 6H), 7.53-7.62 (m, 3H), 7.43 (d, J=8.4 Hz, 1H), 7.91 (bs, 2H), 9.77 (s, 1H). MS: m/z 396.9 (M++1).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:27].C([O:41][C:42]([NH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)=O)(C)(C)C.O1CCOC[CH2:52]1.Cl>C(OCC)(=O)C>[C:42]([NH:44][CH:45]1[CH2:50][CH2:49][N:48]([C:16]2[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]3[C:8](=[O:27])[N:7]([CH2:6][C:5]4[CH:4]=[C:3]([C:2]([F:36])([F:35])[F:1])[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=4)[CH2:14][CH2:13][CH2:12][O:11][C:10]=3[N:15]=2)[CH2:47][CH2:46]1)(=[O:41])[CH3:52]
Reactant: Cc1ccccc1-c1cc(Cl)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCO2
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)NC1CCN(c2cc(-c3ccccc3C)c3c(n2)OCCCN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C3=O)CC1
Temperature: 150 °C
Reaction time: 3 h
Yield: 34 %

Procedure:
A mixture of 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (47.6 mg), 4-(t-butoxycarbonylamino)piperidine (45.1 mg), and 1,4-dioxane (1 mL) was stirred at 150° C. for 3 hours. The solvent was then removed to obtain a residue. To this residue, a 3 mol/L ethyl acetate solution of hydrogen chloride (1 mL) was added and the mixture was stirred at room temperature for 1 hour. The solvent was removed and the resulting residue was dissolved in tetrahydrofuran (1 ml). While the solution was chilled on an ice bath, triethylamine (60 μl) and acetylchloride (30 μl) were added, and the mixture was stirred at room temperature for 30 min. This was followed by the addition of ethyl acetate, and the mixture was washed with water and was then dried on anhydrous sodium sulfate. Subsequently, the solvent was removed and the resulting residue was purified on a silica gel column chromatography (ethyl acetate) to obtain 9-[4-(acetylamino)piperidine-1-yl]-5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (19.2 mg, 34%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH3:12])[CH:3]=1.[NH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]#[N:28])=[CH:17][CH:16]=1>C(O)C>[C:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[CH:17]=[CH:16][C:15]([CH2:14][NH:13][C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([CH2:11][CH3:12])[CH:3]=2)=[CH:20][CH:19]=1)#[N:28]
Reactant: N#Cc1ccccc1-c1ccc(CN)cc1
Reactant: CCc1cc(Cl)n2nccc2n1
Solvent: CCO
Product: CCc1cc(NCc2ccc(-c3ccccc3C#N)cc2)n2nccc2n1

Procedure:
5.5 g (30.3 mmol) of the chloride from Example 1, Step B and 6.3 g (30.3 mmol) of 4-aminomethyl-2'-cyanobiphenyl (prepared according to EP 459 136) were heated in 150 ml dry ethanol for 10 h. After removal of the solvent in vacuo yellow crystals formed. These were purified by suspension in acetone and dissolved, in ethyl acetate. The solution was washed with 10% sodium carbonate solution, the organic layer dried over sodium sulfate, and evaporated to dryness to give colorless crystals of the title compound, m.p. 230°-233° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9]C(C)C)=[CH:4][C:3]=1[N:13]1[C:18](=[O:19])[C:17]([CH3:20])=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=[N:14]1.O>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:13]1[C:18](=[O:19])[C:17]([CH3:20])=[C:16]([C:21]([F:23])([F:24])[F:22])[CH:15]=[N:14]1
Reactant: Cc1c(C(F)(F)F)cnn(-c2cc(OC(C)C)c(Cl)cc2F)c1=O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(C(F)(F)F)cnn(-c2cc(O)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 102.1 %

Procedure:
Then, 3.5 g (9.7 mmol) of 2-[2-fluoro-4-chloro-5-isopropoxyphenyl]-4-methyl-5-trifluoromethylpyridazin-3-one was dissolved in about 10 ml of concentrated sulfuric acid under ice cooling, and the solution was warmed to room temperature. After 10 minutes, about 100 ml of water was added to the reaction mixture. The precipitated crystals were collected by filtration and washed twice with 20 ml of water and then once with 10 ml of hexane. The resulting crystals were recrystallized from isopropanol to give 3.2 g (9.9 mmol) of 2-[2-fluoro-4-chloro-5-hydroxyphenyl]-4-methyl-5-trifluoromethylpyridazin-3-one.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1.[OH:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][NH:31]1.O>CN(C=O)C>[OH:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][N:31]1[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CCl)cc3)c2)cc1
Reactant: OCCC1CCCCN1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CN4CCCCC4CCO)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.4 %

Procedure:
In DMF (3 ml) was dissolved (E)-N-[4-(chloromethyl)phenyl]-3-(4-methylphenyl)cinnamamide (200 mg), and to the mixture was added 2-(2-hydroxyethyl)piperidine (214 mg). The mixture was stirred at room temperature for 18 hours, and to the mixture was added water (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give (E)-N-[4-[2-(2-hydroxyethyl)piperidinomethyl]phenyl]-3-(4-methylphenyl)cinnamamide (Compound 69) (202 mg) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[P:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[O:9]CC.Br[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]=1[C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[CH2:41]Br.[CH2:43](Br)[CH3:44]>CC1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[P:8]([CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]=1[C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[CH2:41][P:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:9])([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:43]=1[CH3:44])=[O:9]
Reactant: CCOP(c1ccccc1C)c1ccccc1C
Reactant: BrCc1ccc2ccccc2c1-c1c(CBr)ccc2ccccc12
Reactant: CCBr
Solvent: Cc1ccccc1C
Product: Cc1ccccc1P(=O)(Cc1ccc2ccccc2c1-c1c(CP(=O)(c2ccccc2C)c2ccccc2C)ccc2ccccc12)c1ccccc1C
Temperature: 0 °C

Procedure:
While stirring under nitrogen, 21.5 g (83 mmol) of ethyl bis(2-methylphenyl)phosphinite are slowly added dropwise to a solution of 18.4 g (42 mmol) of 2,2'-bis(bromo-methyl)-1,1'-binaphthyl in 100 ml of o-xylene, which solution has been heated to 120° C., with ethyl bromide distilling off. After the end of the addition, the mixture is heated under reflux for a further two hours and is then cooled to 0° C. The solid is filtered off, washed with cold o-xylene and dried in vacuo. This gives 25.1 g (81%) of colorless crystals having a melting point of 231°-234° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[N:10]=1)[C:5]([OH:7])=[O:6].[NH3:12].[S-2].[Na+].[Na+]>O>[NH2:12][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[N:10]=1)[C:5]([OH:7])=[O:6]
Reactant: N
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Agent: [Na+]
Agent: [S-2]
Solvent: O
Product: Cc1cc(C(=O)O)cc(N)n1
Temperature: 155 °C

Procedure:
2-chloro-6-methylisonicotinic acid (9 g), of aq ammonia (44 ml), of Cu(II)SO4 (0.9 g) and of sodium sulphide (0.32 g) are added to an autoclave and heated to 155° C. overnight. The crude product is suspended in water to yield 2-amino-6-methylisonicotinic acid (3.6 g). HPLC: Rt=0.37 min (method D)
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[O:22]=[C:11]1[CH:12]=[CH:13][C:14]2[C:19](=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)[N:10]1[CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][CH:2]([NH:1][CH2:34][C:32]2[CH:31]=[CH:30][C:27]3[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=3[N:33]=2)[CH2:3][CH2:4]1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: N#Cc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: N#Cc1ccc2ccc(=O)n(CCN3CCC(NCc4ccc5c(n4)NC(=O)CO5)CC3)c2c1

Procedure:
1-[2-(4-Aminopiperidin-1-yl)ethyl]-2-oxo-1,2-dihydroquinoline-7-carbonitrile (Intermediate 14, 70 mg, 0.24 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (42 mg, 0.24 mmol)and sodium triacetoxy borohydride (150 mg, 0.75 mmol) were reacted as described for Example 5. Chromatography on silica gel with dichloromethane/methanol (6:1) and crystallization from ethyl acetate/hexanes gave the product as a colorless solid, 73 mg (67%), mp 212° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[CH2:16][OH:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C>CS(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[CH:16]=[O:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCCC2CO)cc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N2CCCC2C=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To a mixture of 8.64 g of 1-[(4-methylphenyl)sulfonyl] 2-pyrrolidinemethanol and 14.2 ml of triethylamine in 100 ml of dry methyl sulfoxide is added slowly a solution of 16.16 g of sulfur trioxide pyridine complex in 100 ml of dry methyl sulfoxide. The solution is stirred at room temperature for one hour, then poured onto 1 l of ice water. The mixture is extracted with ethyl acetate. The combined organic extracts are washed with 1N citric acid (twice), water (twice), a saturated sodium bicarbonate solution then a saturated brine solution. After drying over magnesium sulfate, the solvent is removed under reduced pressure and the residue crystallized from chloroform/hexane. The solid is dried in vacuo at 40° giving 5.75 g of a solid, mp 136°-136.5° dec, [α]D23 -121.0° (c 2, methanol).
Reaction SMILES: C(OC([C@H]1[C@H:13](O)[CH2:12][C@H:11]2[C@@H]1C[C:9]1([O:18][CH2:17][CH2:16][O:15]1)[CH2:10]2)=O)C.[O:19]1C=C[CH2:22][CH2:21][CH2:20]1>C(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[O:19]1[CH2:20][CH2:21][CH2:22][CH2:16][CH:17]1[O:18][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][O:15]1
Reactant: C1=COCCC1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC3(C[C@H]2C[C@H]1O)OCCO3
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C1CCC(OC2CCCCO2)OC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 192.1 %

Procedure:
A mixture of 2.65 g of (1R,5S,6R,7R)-6- ethoxycarbonyl-3,3-ethylenedioxy-7-hydroxybicyclo[3.3.0]octane (IX), 1.34 g of dihydropyrane, 0.26 g of pyridinium p-toluenesulfonate in 30 ml of anhydrous methylene chloride was stirred at room temperature for 3 hours. Then, the reaction mixture was successively washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over sodium sulfate, and concentrated to obtain as the residue 3.70 g of oily tetrahydropyranyl ether. A solution of the resulted crude tetrahydropyranyl ether in 15 ml of anhydrous diethyl ether was added dropwise over 1 hour to a stired and ice-cooled suspension of 0.59 g of lithium aluminum hydride in 50 ml of anhydrous diethyl ether. The mixture was further stirred at room temperature for 30 minutes. After ice-cooling, to the reaction mixture was added successively 0.6 ml of water, 1.8 ml of 10% aqueous sodium hydroxide solution and 0.6 ml of water, and the mixture was further stirred for 1 hour. The mixture was filtered through Celite, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (eluting solution: 25% (v/v) ethyl acetate/hexane) to obtain 3.04 g of the oily title compound.
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].[H-].[Na+].Cl[C:8]1[N:13]=[C:12]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:17]=3[CH:18]=2)[CH:11]=[CH:10][N:9]=1.O>O1CCCC1>[F:1][CH2:2][CH2:3][O:4][C:8]1[N:13]=[C:12]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:17]=3[CH:18]=2)[CH:11]=[CH:10][N:9]=1
Reactant: OCCF
Reactant: COc1ccc2cc(-c3ccnc(Cl)n3)sc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2cc(-c3ccnc(OCCF)n3)sc2c1
Temperature: 60 °C
Yield: 72.1 %

Procedure:
2-Fluoroethanol (32 μL, 0.54 mmol) and sodium hydride (NaH, 22 mg, 0.54 mmol) were dissolved in a solvent of anhydrous tetrahydrofuran (4 mL) under nitrogen, and the mixture was added to a solution of anhydrous tetrahydrofuran (3 mL) containing 2-(2-chloropyrimidine-4-yl)-6-methoxybenzothiophene (105a, 100 mg, 0.36 mmol) obtained in Preparation Example 19 dissolved therein at room temperature, heated at 60° C. for 10 hours, cooled to room temperature, followed by adding water. Organic compounds were extracted with ethyl acetate and evaporated after a treatment with sodium sulfate. Column chromatography was performed to give the target compound 2-[2-(2-fluoroethoxy)pyrimidine-4-yl]-6-methoxybenzothiophene (1-31, 79 mg, 72%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Cl[C:7]1[S:8][CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:1]([N:3]([CH2:4][CH3:5])[C:7]1[S:8][CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=1)[CH3:2]
Reactant: CCNCC
Reactant: CCOC(=O)c1csc(Cl)n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1csc(N(CC)CC)n1

Procedure:
The reaction described in Preparation 26 was repeated, but using 2.3 g of diethylamine, 4 g of ethyl 2-chlorothiazole-4-carboxylate, 4.2 g of triethylamine, and 15 ml of dimethylformamide, giving ethyl 2-diethylaminothiazole-4-carboxylate as a pale yellow oil.