Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[Si](C)(C)C.[BH4-].[Li+].CS([O:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[O:24][CH2:23][C:22](=O)[N:21]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:20]2)=[CH:15][CH:14]=1)(=O)=O.[OH-].[K+]>O1CCCC1.C(O)C.O.CO>[CH2:26]([N:21]1[CH2:22][CH2:23][O:24][C@@H:19]([C:16]2[CH:15]=[CH:14][C:13]([OH:12])=[CH:18][CH:17]=2)[CH2:20]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CS(=O)(=O)Oc1ccc([C@H]2CN(Cc3ccccc3)C(=O)CO2)cc1
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc([C@H]2CN(Cc3ccccc3)CCO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
Chlorotrimethylsilane (96 g, 884 mmol) was added to a solution of lithium borohydride (9.6 g, 441 mmol) in tetrahydrofuran (500 ml) and the solution was stirred for one hour at room temperature. A solution of 4-((2S)-4-benzyl-5-oxo-morpholin-2-yl)phenyl methanesulfonate (79.8 g, 221 mmol) in tetrahydrofuran (200 ml) was added to the solution and stirred at room temperature for one hour. After careful addition of methanol (60 ml) under ice-cooling, the solvent was removed under reduced pressure. Potassium hydroxide (145 g, 2.2 mol) was added to a solution of the residue in ethanol (300 ml) and water (300 ml) and the solution was stirred at 80° C. for 2 hours. The solvents were removed under reduced pressure and the residue was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. Removal of the solvent yielded (2S)-4-benzyl-2-(4-hydroxyphenyl)morpholine (39.8 g, 67%) as white crystals.
Reaction SMILES: [CH3:1][NH:2][CH3:3].O.C(O)C.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17]>C(OCC)(=O)C>[CH3:1][N:2]([CH3:3])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17]
Reactant: CNC
Reactant: OCCCCCCCCBr
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)CCCCCCCCO
Reaction time: 75 h
Yield: 91 %

Procedure:
A solution of 40% dimethylamine/water (30 mL, 26.9 g, 239 mmol) and ethanol (50 mL) was treated with a solution of 8-bromo-1-octanol (15.13 g, 72.3 mmol) and ethanol (20 mL), added dropwise over 10 minutes. The reaction mixture was stirred for 75 hours, diluted with ethyl acetate (80 mL) and washed with saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate solution (50 mL) and brine (2×40 mL), dried over sodium sulfate, and concentrated. The 11.4 g of 8-dimethylamino-1-octanol, isolated as a yellow oil, was used as is.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:43]=[CH:42]C3[C:36](=[CH:37]C(CBr)=CC=3)[CH:35]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1[CH2:51][CH2:50][CH2:49][CH2:48][CH:47]1[O:52][CH2:53][CH2:54][OH:55].C(OCCCOC1C=CC(C2CCN(C(OC(C)(C)C)=O)CC2OCC2C=CC3C(=CC(CN(C)C)=CC=3)C=2)=CC=1)C1C=CC=CC=1>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:35]=[C:36]3[C:51]([CH:50]=[CH:49][C:48]([CH2:47][O:52][CH2:53][CH2:54][OH:55])=[CH:37]3)=[CH:42][CH:43]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3ccc(CBr)cc3c2)C1
Reactant: OCCOC1CCCCO1
Agent: CN(C)Cc1ccc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4)cc3)cc2c1
Product: OCCOCc1ccc2ccc(COC3CNCCC3c3ccc(OCCCOCc4ccccc4)cc3)cc2c1

Procedure:
by reaction of tert-butyl (3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-(7-bromomethyl-naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with rac-2-[(tetrahydro-2H-pyran-2-yl)oxy]-1-ethanol, a mixture of (3RS,4RS)- and (3SR,4SR)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-{7-[2-[(RS)-tetrahydro-pyran-2-yloxy]-ethoxymethyl]-naphthalen-2-ylmethoxy}-piperidine-1-carboxylate [colourless oil, MS: 740 (M+H)+ ] and tert-butyl (3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-(7-dimethylaminomethyl-naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [byproduct, colourless oil, MS: 639 (M)+ ]. Simultaneous cleavage of the BOC and tetrahydropyranyl groups from the main product gave 2-(7-{(3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-piperidin-3-yloxymethyl}-naphthalen-2-ylmethoxy)-ethanol as a colourless oil; MS: 556 (M+H)+. Cleavage of the BOC group from the byproduct gave (7-{(3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-piperidin-3-yloxymethyl}-naphthalen-2-ylmethyl)-dimethyl-amine as a colourless oil; MS: 539 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[C:8]([CH3:14])([CH3:13])[C:7](=[O:15])[C:6]([C:16]([NH:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[O:17])=[C:5]2[OH:27]>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[C:8]([CH3:14])([CH3:13])[C:7](=[O:15])[C:6]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:5]2[OH:27]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(F)c(F)cc2C(C)(C)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2cc(F)c(F)cc21
Yield: 85.7 %

Procedure:
1,1-Dimethylethyl N-((6,7-difluoro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (312 mg, 818 μmol) was dissolved in TFA (2 mL) at ambient temperature and reacted for 30 minutes. The mixture was then concentrated, precipitated with hexanes, filtered, and dried in a vacuum oven to give the title compound (228 mg, 85.7% yield) as a white solid. MS (m/z)=326 (M+H)+. Calculated for C15H13F2NO5 325.08.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][C@H:4]1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1.C(N(CC)CC)C.Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:34].O>C1COCC1>[Cl:24][C:19]1[CH:18]=[C:17]([C@H:4]2[C@@H:3]([CH2:2][NH:1][C:33]([O:35][C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)=[O:34])[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]2)[CH:22]=[CH:21][C:20]=1[Cl:23]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CN)[C@H](c2ccc(Cl)c(Cl)c2)C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@H](CNC(=O)Oc2ccc([N+](=O)[O-])cc2)[C@H](c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 34.4 %

Procedure:
To a solution of tert-butyl (6R,7S)-7-(aminomethyl)-6-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (200 mg) and triethylamine (0.149 mL) in THF (4.0 mL) was added 4-nitrophenyl chloroformate (129 mg) under ice-cooling, and the mixture was stirred at room temperature for 5 hr. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (99 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:14][C@H:13]2[CH2:25][CH2:26][OH:27])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1.C(OCC)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([O:17][Si:18]([C:21]([CH3:23])([CH3:24])[CH3:22])([CH3:20])[CH3:19])[CH2:14][C@H:13]2[CH2:25][CH2:26][O:27][C:30](=[O:32])[CH3:31])=[O:11])=[CH:28][CH:29]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CCO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)OCC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
(2R,4R)-1-p-Nitrobenzyloxycarbonyl-2-(2-hydroxyethyl)-4-t-butyldimethylsilyloxypyrrolidine (900 mg) was dissolved in 2.25 ml of dry pyridine, and 2.25 ml of acetic anhydride was added to the solution at room temperature, followed by stirring for 1 hour. The reaction mixture was diluted with diethyl ether, washed successively with brine, a diluted aqueous hydrochloric acid, brine, a diluted aqueous sodium hydroxide solution and brine, dired over anhydrous sodium sulfate to give (2R,4R)-1-p-nitrobenzyloxycarbonyl-2-(2-acetoxyethyl)-4-t-butyldimethylsilyloxypyrrolidine.
Reaction SMILES: [CH:1]([CH:5]([N:34]([CH3:51])[C:35]([CH:37]([NH:41][C:42](=[O:50])[CH:43]([N:47]([CH3:49])[CH3:48])[CH:44]([CH3:46])[CH3:45])[CH:38]([CH3:40])[CH3:39])=[O:36])[CH:6]([O:32][CH3:33])[CH2:7][C:8]([N:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[CH:15]([S:30][CH3:31])[CH:16]([C:18](=[O:29])[NH:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=1)[CH3:17])=[O:9])([CH2:3][CH3:4])[CH3:2].[CH2:52]([N:54]=[C:55]=[O:56])[CH3:53].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:49][N:47]([CH3:48])[CH:43]([CH:44]([CH3:46])[CH3:45])[C:42]([NH:41][CH:37]([CH:38]([CH3:39])[CH3:40])[C:35]([N:34]([CH3:51])[CH:5]([CH:1]([CH3:2])[CH2:3][CH3:4])[CH:6]([O:32][CH3:33])[CH2:7][C:8]([N:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[CH:15]([S:30][CH3:31])[CH:16]([CH3:17])[C:18]([NH:19][CH2:20][CH2:21][C:22]1[CH:23]=[C:24]([O:28][C:55](=[O:56])[NH:54][CH2:52][CH3:53])[CH:25]=[CH:26][CH:27]=1)=[O:29])=[O:9])=[O:36])=[O:50]
Reactant: CCC(C)C(C(CC(=O)N1CCCC1C(SC)C(C)C(=O)NCCc1cccc(O)c1)OC)N(C)C(=O)C(NC(=O)C(C(C)C)N(C)C)C(C)C
Reactant: CCN=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNC(=O)Oc1cccc(CCNC(=O)C(C)C(SC)C2CCCN2C(=O)CC(OC)C(C(C)CC)N(C)C(=O)C(NC(=O)C(C(C)C)N(C)C)C(C)C)c1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a stirred solution of N-(1-{[1-sec-butyl-4-(2-{2-[2-(3-hydroxy-phenyl)-ethylcarbamoyl]-1-methylsulfanyl-propyl}-pyrrolidin-1-yl)-2-methoxy-4-oxo-butyl]-methyl-carbamoyl}-2-methyl-propyl)-2-dimethylamino-3-methyl-butyramide (30 mg, 0.035 mmol) in CH2Cl2 (0.5 mL) were added ethyl isocyanate (0.042 mL, 0.53 mmol) and diisopropylethylamine (0.062 mL, 0.35 mmol) at room temperature. After being stirred at room temperature for 13hr, the mixture was concentrated in vacuo to give a crude oil (58 mg), which was purified by preparative HPLC (column:ODS-8OTs, eluent: 35/35 H2O:CH3CN/0.05% TFA). The appropriate fractions were lyophilized to give the title compound as a white amorphous powder (13 mg, 39%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[CH2:14]Cl)[CH2:2][CH2:3][CH3:4].[P:16]([O:23]CC)([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19]>>[CH2:18]([O:17][P:16]([CH2:14][C:7]1[CH:8]=[C:9]([CH:10]=[O:11])[CH:12]=[CH:13][C:6]=1[O:5][CH2:1][CH2:2][CH2:3][CH3:4])(=[O:23])[O:20][CH2:21][CH3:22])[CH3:19]
Reactant: CCCCOc1ccc(C=O)cc1CCl
Reactant: CCOP(OCC)OCC
Product: CCCCOc1ccc(C=O)cc1CP(=O)(OCC)OCC

Procedure:
4-Butoxy-3-chloromethylbenzaldehyde and triethyl phosphite in a 1:1 ratio were heated until no more gas evolved and the reaction mixture had turned light orange. The reaction mixture was then vacuum distilled to give the desired product. bp 188° C. at 1.4 mm Hg.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@@H:13]([CH3:17])[CH2:14][O:15][CH3:16])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:16][O:15][CH2:14][C@H:13]([CH3:17])[O:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([O:1][C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)OC)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(F)cc2)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A suspension of methyl 3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]benzoate (3.53 g, 14.7 mmol), p-fluoro-phenyl-boronic acid (16.2 mmol), copper(II) acetate (2.94 g, 16.2 mmol), triethylamine (10.3 ml, 73.5 mmol) and freshly activated 4A molecular sieves (17.7 g) in dichloromethane was stirred at ambient temperature and under ambient atmosphere for 2 days. The reaction mixture was filtered, and the dichloromethane was removed in vacuo. The residual oil was partitioned between ethyl acetate and 2 mol/l hydrochloric acid. The ethyl acetate layer was separated, washed with aqueous sodium hydrogen carbonate and brine, dried over Na2SO4 and evaporated to give a residue, which was purified by column chromatograph on silica gel (20-60% ethyl acetate in iso-hexane, gradient) to give the desired ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([N+:13]([O-])=O)=[CH:5][CH:4]=1.O.O.[Sn](Cl)Cl.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[C:6]([NH2:13])=[CH:5][CH:4]=1
Reactant: COc1ccc([N+](=O)[O-])c(C(F)(F)F)n1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: COc1ccc(N)c(C(F)(F)F)n1
Temperature: 70 °C
Yield: 70.5 %

Procedure:
To a solution of 6-methoxy-3-nitro-2-(trifluoromethyl)pyridine (3.61 g) in 95% Ethyl alcohol (162 ml) was added tin(II) chloride dihydrate. It was heated to 70° C. for 3 hr. After it was cooled to room temperature, it was poured over ice water and adjusted to pH 11 with 2N NaOH. It was stirred well with ethyl acetate and filtered through celite. The organic phase was separated, washed with brine, dried (MgSO4), filtered and concentrated. The flash column chromatography (SiO2, 3˜8% EtOAc in heptane) gave the title compounds (2.20 g, 71%). 1H NMR (CDCl3) δ 3.81, 6.70, 7.05; 19F NMR (CDCl3) δ 65.73; IR (liq.) 2434 (w), 2389, 2272, 2229, 2174, 1488 (s), 1436 (s), 1426 (s), 1276 (s), 1170 (s), 1102 (s, b), 1050 (s), 1024 (s), 740 (s), 658 (s) cm−1 HRMS (ESI) calcd for C7H7N2OF3+H1 193.0589. found 193.0581. Anal. Calcd for C7H7F3N2O: C, 43.76; H, 3.67; N, 14.58; F, 29.66. Found: C, 43.61; H, 3.49; N, 14.49.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:13]([NH2:17])[CH2:14][CH2:15][CH3:16]>CN(C=O)C>[CH2:13]([NH:17][C:4]1[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCN
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Solvent: CN(C)C=O
Product: CCCCNc1nc(Cl)nc2c(C)csc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
In DMF was dissolved 700 mg (3.2 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine, and then an aqueous solution of 548 mg (7.5 mmol) of butylamine was added dropwise to the resulting solution under ice cooling over 5 minutes. The reaction mixture was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for one hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/10) to give 698 mg (yield: 85.4%) of the title compound.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]#[N:13])(OCC)=O)C.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>O1CCCC1>[C:12](#[N:13])[CH:11]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC=Cc1ccccc1
Reaction time: 1 h
Yield: 69 %

Procedure:
Four grams of 60% sodium hydride was suspended in 100 ml tetrahydrofuran, and 17.1 g of diethylphosphonoacetonitrile was added with ice cooling. To the resulting solution, was added dropwise a solution of 10.6 g benzaldehyde in 80 ml tetrahydrofuran, and the mixture was stirred for one hour. After admixing 50 ml water, the organic layer was collected, dried over anhydrous sodium sulfate and concentrated. Distillation of the concentrate under reduced pressure (102°-106° C./6 mmHg) gave 8.9 g yield: 69.0%) of cinnamonitrile.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[C:13]1([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)C(C)C)C>>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([N:22]2[CH2:23][CH2:24][CH:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:20][CH2:21]2)[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CSc1nc(Cl)c(C#N)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc(Cl)c(C#N)c(N2CCC(c3ccccc3)CC2)n1

Procedure:
In analogy to the procedure described in example 57a, the 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbonitrile (J. Heterocycl. Chem. 1971, 8, 445-453) was treated with 4-phenyl-piperidine in the presence of N-ethyl-diisopropylamine at room temperature during 18 hours to yield the 4-chloro-2-methylsulfanyl-6-(4-phenyl-piperidin-1-yl)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=345.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=2[CH3:15])=[CH:6][CH:7]=1.NC(N)=[S:18].C([O-])([O-])=O.[Na+].[Na+]>CCO>[CH3:15][C:9]1[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2](=[S:18])[NH:3][N:4]=1
Reactant: NC(N)=S
Reactant: Cc1ccc(-c2ccc(Cl)nn2)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(-c2ccc(=S)[nH]n2)c(C)c1
Yield: 83.5 %

Procedure:
3-chloro-6-(2,4-dimethylphenyl)pyridazine (example 13b) (1.36 g) was refluxed with thiourea (473 mg, 6.2 mmol) in EtOH (25 mL) for 5 hrs. The mixture was evaporated, and water (45 mL) was added to the residue, followed by Na2CO3 (318 mg, 3 mmol). The precipitate that formed was collected by filtration, washed with diethylether and dried to give 6-(2,4-Dimethylphenyl)pyridazine-3(2H)-thione (1.12 g, 52%). 1H NMR (300 MHz, dMSO): δ 2.29 (s, 3H), 2.32 (s, 3H), 7.12-7.30 (m, 2H), 7.29-7.31 (d, 1H), 7.46-7.49 (d, 1H), 7.65-7.68 (dd, 1H); MS (M+H, 217).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[N:17]=[C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:19][C:20]=3[CH3:21])=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.F[C:29]1[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[CH:31][N:30]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH3:21][C:20]1[O:19][C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:17][C:16]=1[C:14]([NH:13][C:10]1[CH:9]=[CH:8][C:7]([CH:4]2[CH2:5][CH2:6][N:1]([C:29]3[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[CH:31][N:30]=3)[CH2:2][CH2:3]2)=[CH:12][CH:11]=1)=[O:15]
Reactant: O=C(O)c1ccc(F)nc1
Reactant: Cc1oc(-c2ccccc2)nc1C(=O)Nc1ccc(C2CCNCC2)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1oc(-c2ccccc2)nc1C(=O)Nc1ccc(C2CCN(c3ccc(C(=O)O)cn3)CC2)cc1
Temperature: 175 °C
Yield: 50.8 %

Procedure:
A mixture of 5-methyl-2-phenyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide (181 mg, 0.5 mmol) and 6-fluoronicotinic acid (113 mg, 0.8 mmol) in dioxane (2 mL) containing diisopropylethylamine (0.5 mL, 2.7 mmol) was heated in a microwave at 175° C. for 30 minutes. The mixture was evaporated and extracted with ethyl acetate and aqueous citric acid solution. The organic layer was dried over sodium sulfate and solvents were evaporated. The residue was triturated with ethyl acetate and filtered to give a pale pink solid as 4-{4-[(5-methyl-2-phenyl-oxazole-4-carbonyl)-amino]-phenyl}-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (122.5 mg). LC-MS for C28H26N4O4 (m/e) calcd 482, obsd 483 (M+H). 1H-NMR is consistent with the desired structure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=O)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)=[C:6]([OH:22])[CH:5]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=3)[O:22][C:6]=2[CH:5]=1)=[O:23]
Reactant: COC(=O)c1ccc(NC(=O)c2cccc([N+](=O)[O-])c2)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3cccc([N+](=O)[O-])c3)oc2c1

Procedure:
Prepared from the method of Example 15c), from 4-(3-nitrobenzamido)-3-hydroxybenzoic acid methyl ester (20 g, 63.0 mmol) and p-toluenesulfonic acid monohydrate (26.3 g, 138 mmol) the subtitle compound was obtained (3.05 g, 16%). 1H NMR (CDCl3) δ 9.13(t, 1H), 8.62(d, 1H), 8.44(dd, 1H), 8.33(s, 1H), 8.15(dd, 1H), 7.85(d, 1H), 7.77(t, 1H), 4.00(s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[C:23]1[C:27]([C:28](Cl)=[O:29])=[C:26]([CH3:31])[O:25][N:24]=1>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:28]([C:27]1[C:23]([C:17]2[C:18]([F:22])=[CH:19][CH:20]=[CH:21][C:16]=2[Cl:15])=[N:24][O:25][C:26]=1[CH3:31])=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCCCN
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Product: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)NCCCCCNC(=O)OC(C)(C)C
Yield: 94.6 %

Procedure:
N-t-butyloxycarbonyl-1,5-diaminopentane (1.04 g, 5.14 mmol) and 3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-oyl chloride (1.41 g, 5.14 mmol) were converted to 2.14 g of the title compound by the procedure of Preparation 1. (95%). MS(IS) m/z 412 (M+). IR(CHCl3) 3496, 3012, 2936, 1708, 1663, 1611, 1510 cm−1.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([O:10][CH3:11])=[O:9])=[O:20])=[CH:22][CH:23]=1)([O-:14])=[O:13]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1ccccc1N
Product: COC(=O)c1ccccc1NC(=O)c1ccc([N+](=O)[O-])cc1
Yield: 69.9 %

Procedure:
Using methyl anthranilate (3.02 g, 20.0 mmol) and 4-nitrobenzoic acid (3.67 g, 22.0 mmol), the procedure of Reference Example 16 was repeated to obtain 4.20 g (72.9%) of the title compound in the form of light yellow prism crystals.