Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.[CH3:5][NH:6][CH2:7][CH2:8][CH3:9].[C:10]([C:12]1[C:17]2[N:18]=[C:19]([C:21]([O:23]CC)=O)[O:20][C:16]=2[C:15]([F:26])=[C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:13]=1[CH3:33])#[N:11].Cl>ClCCl.C1(C)C=CC=CC=1>[C:10]([C:12]1[C:17]2[N:18]=[C:19]([C:21]([N:6]([CH3:5])[CH2:7][CH2:8][CH3:9])=[O:23])[O:20][C:16]=2[C:15]([F:26])=[C:14]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:13]=1[CH3:33])#[N:11]
Reactant: CCCNC
Reactant: CCOC(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCN(C)C(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Reaction time: 0.67 h
Yield: 55.4 %

Procedure:
Under nitrogen atmosphere, trimethylaluminium (1.03 M n-hexane solution) (2.40 ml, 2.47 mmol) was dropwise added at room temperature to a toluene (6 ml) solution of N-methylpropylamine (127 μl, 1.23 mmol), followed by stirring for 40 minutes. Subsequently, a dichloromethane (2 ml) solution of ethyl 4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-2-carboxylate (I-111) (200 mg, 617 μmol) was dropwise added, followed by stirring for 48.5 hours. After the reaction, aqueous 1 N hydrochloric acid solution was added to the reaction liquid with cooling with ice, followed by stirring at room temperature, then the reaction liquid was extracted with chloroform. Next, the combined organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by middle-pressure liquid chromatography (eluent, n-hexane:ethyl acetate=2:1, v/v) to obtain the entitled compound (120 mg, 55%) as a pale yellow solid.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:14][CH:13]([C:15]([F:18])([F:17])[F:16])[C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][C:10]=2[CH:24]=1)=O.C([O-])(=O)C.[Na+].C(O)C>O.C(OCC)C>[OH:3][N:2]=[CH:4][C:6]1[CH:7]=[CH:8][C:9]2[O:14][CH:13]([C:15]([F:18])([F:17])[F:16])[C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][C:10]=2[CH:24]=1
Reactant: CCOC(=O)C1=Cc2cc(C=O)ccc2OC1C(F)(F)F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C1=Cc2cc(C=NO)ccc2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.9 %

Procedure:
A 50 mL round bottom flask was charged with hydroxylamine HCl (0.255 g, 3.67 mmol), ethyl 6-formyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 75, Step 1) (1.00 g, 3.34 mmol), sodium acetate (0.301 g, 3.67 mmol), ethanol (10 mL), and H2O (2 mL). The reaction was stirred at room temperature for 18 hours, then diluted with H2O and diethyl ether. The layers were separated and the organic phase washed with H2O, brine, dried over MgSO4, filtered, and concentrated in vacuo yielding an orange semi-crystalline mass. Recrystallization of this solid from hot ethyl acetate and isooctane yielded the oxime (0.578 g, 55%): mp 113.0–116.2° C. 1H NMR (acetone-d6/300 MHz) 10.46 (s, ca.1 exch.), 8.11 (s, 2H), 7.92 (s, 1H), 7.72 (d, 1H, J=2 Hz)), 7.68 (dd, 1H, J=8.5, 2.0 Hz), 7.07 (d, 1H, J=8.5 Hz), 5.89 (q, 1H, J=7.1 Hz), 4.43−4.22 (m, 2H), 1.34 9t, 3H, J=7.3 Hz). FABLRMS m/z 316 (M+H). EIHRMS m/z 315.0719 (M+, Calc'd 315.0733). Anal. Calc'd for C14H12F3N1O4: C, 53.34; H, 3.84; N 4.44. Found: C, 53.85; H, 3.90; N, 4.19.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([NH2:27])[CH2:25][CH3:26])=[CH:4][CH:3]=1.[F:28][CH:29]([F:33])[C:30](O)=[O:31].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([NH:27][C:30](=[O:31])[CH:29]([F:33])[F:28])[CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: O=C(O)C(F)F
Reactant: CCC(N)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCC(NC(=O)C(F)F)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.1 %

Procedure:
A mixture of crude 1-[9-chloro-1-(2,4,6-trichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-amine (100 mg), difluoroacetic acid (0.0186 mL, 0.296 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (75.5 mg, 0.394 mmol), 1-hydroxybenzotriazole (53.2 mg, 0.394 mmol) and triethylamine (0.0824 mL, 0.591 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 3 h, and diluted with ethyl acetate. The resultant mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-30% ethyl acetate/n-hexane gradient mixture and NH silica gel eluting with a 30% ethyl acetate/n-hexane mixture to give the title compound as a colorless solid (42.4 mg, 0.0812 mmol).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][C:26]([O:28]C)=[O:27])[CH:13]=[CH:14][C:15]=1[CH2:16][NH:17]C(OC(C)(C)C)=O)=O)(C)(C)C.[OH-].[Na+].Cl>CO.C1COCC1>[NH2:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][C:26]([OH:28])=[O:27])[CH:13]=[CH:14][C:15]=1[CH2:16][NH2:17]
Reactant: COC(=O)Cc1ccc(CNC(=O)OC(C)(C)C)c(CNC(=O)OC(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: NCc1ccc(CC(=O)O)cc1CN
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
The methyl 2-(3,4-bis((tert-butoxycarbonylamino)methyl)phenyl)acetate (1.1 g) was dissolved in a mixture of MeOH/THF (50 mL, 2:1). 1N NaOH (10 mmol, 10 mL) was added and the reaction mixture was stirred at room temperature overnight. 1N HCl was added to adjust the pH of the reaction to ˜3. The aqueous was extracted with EtOAc. The organic phase was washed with 1N HCl, brine, dried and concentrated in vacuo to afford the product (0.38 g) as yellow solid.
Reaction SMILES: CC1NC(C)=C(C(OC)=O)C([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-])=O)[CH:23]=2)C=1C([O:10][CH2:11][CH2:12][N:13]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:14])=O.CC1NC(C)=C(C(OC)=O)C([C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([N+:53]([O-])=O)[CH:48]=2)C=1C(OC)=O.[CH3:61]OC(C1C(C2C=CC=C([N+]([O-])=O)C=2)C(C(O)=O)=C(C)NC=1C)=O>>[OH:10][CH2:11][CH2:12][N:13]([CH3:14])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH:49]1([N:53]=[C:61]=[N:28][CH:24]2[CH2:23][CH2:22][CH2:27][CH2:26][CH2:25]2)[CH2:48][CH2:47][CH2:52][CH2:51][CH2:50]1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)Cc2ccccc2)C1c1cccc([N+](=O)[O-])c1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Product: C(=NC1CCCCC1)=NC1CCCCC1
Product: CN(CCO)Cc1ccccc1

Procedure:
A new, technologically easily feasible process for the preparation of 2-(N-benzyl-N-methylamino)ethyl methyl 2,6-dimethyl-4(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, comprising a partrial hydrolysis of dimethyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate in an inert organic solvent at a temperature between room temperature and the reflux temperature of the reaction mixture with an aqueous solution of alkali hydroxide and the reaction of the obtained 3-methoxycarbonyl-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid either with N-(2-hydroxyethyl)-N-benzyl-methylamine in the presence or absence of an organic solvent in the presence of N,N'-dicyclohexylcarbodiimide at a temperature of between 25° and 120° C. or with N-(2-haloethyl)-N-benzyl-methylamine in the presence of an inert organic solvent and of a proton acceptor at a temperature of between 25° and 140° C., to yield the title compound, which can be, if desired, converted to its hydrochloride salt. The hydrochloride salt is known under the generic name "nicardipine hydrochloride" and is used as a valuable therapeutic in the therapy of cerebral insufficiency.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:25][C@@H:26]2[C@@H:31]3[CH2:32][C@@H:28]([CH:29]=[CH:30]3)[C@@H:27]2[C:33]([NH2:35])=[O:34])=[N:4][C:5]([NH:8][C:9]2[CH:22]=[CH:21][C:12]3[N:13]([CH2:19][CH3:20])[C:14](=[O:18])[CH2:15][CH2:16][CH2:17][C:11]=3[C:10]=2[O:23][CH3:24])=[N:6][CH:7]=1.[OH2:36].C[N+]1([O-])CCOCC1.[OH2:45]>CC(C)=O.C(Cl)Cl.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[C:3]([NH:25][C@@H:26]2[C@@H:31]3[CH2:32][C@@H:28]([C@@H:29]([OH:45])[C@H:30]3[OH:36])[C@@H:27]2[C:33]([NH2:35])=[O:34])=[N:4][C:5]([NH:8][C:9]2[CH:22]=[CH:21][C:12]3[N:13]([CH2:19][CH3:20])[C:14](=[O:18])[CH2:15][CH2:16][CH2:17][C:11]=3[C:10]=2[O:23][CH3:24])=[N:6][CH:7]=1
Reactant: O
Reactant: CCN1C(=O)CCCc2c1ccc(Nc1ncc(Cl)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n1)c2OC
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCN1C(=O)CCCc2c1ccc(Nc1ncc(Cl)c(N[C@@H]3[C@@H]4C[C@@H]([C@@H](O)[C@H]4O)[C@@H]3C(N)=O)n1)c2OC
Reaction time: 0.75 h
Yield: 67 %

Procedure:
0.16 M of Osmium tetraoxide in Water (50 uL) was added to (1S,2S,3R,4R)-3-[5-Chloro-2-(1-ethyl-6-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (152 mg, 0.306 mmol) and 4-Methyl-morpholine 4-oxide hydrate (65 mg, 0.48 mmol) in Acetone (10 mL) and Water (1.0 mL), and the reaction was stirred under an atmosphere of Nitrogen for 45 min. The reaction was diluted with DCM (15 mL) washed with water (2×5 mL) and brine (10 mL), dried over sodium sulfate and conc. in vacuo. Chromatography of the residue (ISCO 12 g SiO2, 0-10% MeOH:DCM) afforded (1R,2S,3R,4S,5S,6R)-3-[5-Chloro-2-(1-ethyl-6-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-5,6-dihydroxy-bicyclo[2.2.1]heptane-2-carboxylic acid amide as brown solids (110 mg, 67%). MP: 164-170° C.; LCMS: 531 (M+H); 1H-NMR (CDCl3): 8.40 (d, 1H, J=8.8 Hz), 7.92 (s, 1H), 7.38 (s, 1H), 7.16 (d, 1H, J=7.8 Hz), 7.01 (d, 1H, J=9.0 Hz), 5.73 (s, 1H), 5.37 (s, 1H), 4.32 (t, 1H, J=8.0 Hz), 3.97 (m, 1H), 3.83 (m, 1H), 3.80 (s, 3H), 3.49 (d, 1H, J=5.3 Hz), 2.98 (m, 2H), 2.51 (m, 1H), 2.44 (m, 1H), 2.39 (m, 1H), 2.28 (m, 3H), 2.06 (m, 1H), 1.91 (m, 1H), 1.12 (t, 3H, J=7.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]1.[Cl:23][C:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[C:26]([Cl:39])[C:25]=1[OH:40]>>[ClH:1].[Cl:23][C:24]1[CH:29]=[C:28]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]2)[CH:27]=[C:26]([Cl:39])[C:25]=1[OH:40]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](O)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1N[C@H]1CC[C@H](O)CC1
Product: Cl

Procedure:
Following general procedure II, 1-[6-chloro-4-(trans-4-hydroxycyclohexylamino)-1,5-naphthyridin-3-yl]ethanone (160 mg, 0.50 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (165 mg, 0.60 mmol) followed by formation of the hydrochloride salt to afford the desired product (120 mg, 56%) as a pale yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.11 (s, 1H), 8.44 (d, J=9.0 Hz, 1H), 8.30 (d, J=9.0 Hz, 1H), 8.00 (t, J=1.9 Hz, 1H), 7.87 (dd, J=11.5, 2.3 Hz, 1H), 5.60 (tt, J=10.5, 4.2 Hz, 1H), 3.75 (tt, J=9.6, 4.2 Hz, 1H), 2.75 (s, 3H), 2.42-2.35 (m, 2H), 2.14-2.06 (m, 2H), 1.74-1.54 (m, 4H); ESI MS m/z 430 [M+H]+; HPLC>99% (AUC), tR=10.9 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9]([CH3:11])=[N:8][C:5]2=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.Cl[C:22]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:23]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([C:22]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:23])[C:9]([CH3:11])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)COC(=O)Cl
Reactant: Cc1nc2ncc(Br)cc2[nH]1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc2ncc(Br)cc2n1C(=O)OCC(C)C
Temperature: 25 °C
Yield: 46 %

Procedure:
To a solution of 6-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (3.40 g, 16.0 mmol) and diisopropylethylamine (6.5 mL, 65 mmol) in N,N-dimethylformamide (20 mL) cooled in an ice bath was added dropwise isobutyl chloroformate (2.51 mL, 19.2 mmol) and the mixture was warmed to room temperature. After 1 hour the reaction was diluted with ethyl acetate (80 mL) and washed with water (60 mL), 10% aqueous citric acid (40 mL) and brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to a slurry. The residue was triturated diethyl ether (100 mL) and the solid isolated by filtration to give isobutyl 6-bromo-2-methyl-1H-imidazo[4,5-b]pyridine-1-carboxylate (2.3 g, 46% yield). MS (EI) for C12H14BrN3O2: 313 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=O)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:20]([O:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([N+:32]([O-:34])=[O:33])[C:30]=1[OH:31])[CH:26]=O)[CH3:21].[NH2:35][C:36]([NH2:38])=[O:37].Cl>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:38][C:36](=[O:37])[NH:35][CH:26]([C:25]3[CH:28]=[C:29]([N+:32]([O-:34])=[O:33])[C:30]([OH:31])=[C:23]([O:22][CH2:20][CH3:21])[CH:24]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: NC(N)=O
Reactant: COc1ccc(C(=O)Cc2ccccc2)cc1OC
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccc(OC)c(OC)c3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 34.5 %

Procedure:
A mixture of 1-(3,4-dimethoxyphenyl)-2-phenylethanone (180 mg, 0.7 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (124 mg, 0.59 mmol), urea (105 mg, 1.8 mmol), and concentrated HCl solution (0.05 mL, 0.59 mmol) in EtOH (5 mL) was refluxed overnight. The mixture was evaporated in vacuo, and the residue was purified by preparative HPLC to give Compound 38 (100 mg, yield 35%) as a yellow solid. 1H NMR (CD3OD 400 MHz): δ 7.63 (d, J=1.2 Hz, 1H), 7.19 (s, 1H), 7.13-7.06 (m, 3H), 6.93-6.85 (m, 4H), 6.73 (s, 1H), 5.34 (s, 1H), 4.11-4.02 (m, 2H), 3.80 (s, 3H), 3.57 (s, 3H), 1.41 (t, J=6.8 Hz, 3H); MS (ESI): m/z 492.0 [M+1]+.
Reaction SMILES: [Na].Cl.[NH:3]=[C:4]([NH:14][CH:15]1[CH2:17][CH2:16]1)[NH:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[NH:7].[CH3:18][C:19]1([C:22](OCC)=O)[CH2:21][CH2:20]1>C(O)C>[CH:15]1([NH:14][C:4]2[N:3]=[C:18]([C:19]3([CH3:22])[CH2:21][CH2:20]3)[N:7]=[C:6]([N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[N:5]=2)[CH2:17][CH2:16]1
Reactant: CCOC(=O)C1(C)CC1
Reactant: N=C(NC(=N)N1CCOCC1)NC1CC1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CC1(c2nc(NC3CC3)nc(N3CCOCC3)n2)CC1
Yield: 17.8 %

Procedure:
0.48 g (20 mmoles) of sodium is dissolved in 20 ml of anhydrous ethanol. This solution is added to an ethanol solution containing 2.48 g (10 mmoles) of N-[imino(cyclopropylamino)methyl]-4-morpholinecarboximidamide hydrochloride, and 2.82 g (22 mmoles) of ethyl 1-methylcyclopropane-carboxylate are then also added to the mixture. The mixture is then heated under reflux under nitrogen for 88 hours. It is cooled, the alcohol is evaporated under reduced pressure and the residue is redissolved in 50 ml of water and 200 ml of dichloromethane. The aqueous phase is separated off and the organic phase is washed twice with 50 ml of water and dried over magnesium sulfate. The solvent is evaporated under reduced pressure and the residue is recrystallized from a 1:1 (v/v) mixture of petroleum ether-dichloromethane. 0.49 g of 2-cyclopropylamino-4-(1-methylcyclopropyl)-6-morpholino-1,3,5-triazine is obtained. Yield: 17%. M.P.: 94°-95°% C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13]C)=O)=[CH:4][CH:3]=1.O.[NH2:16][NH2:17]>CO>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH:16][NH2:17])=[O:13])=[CH:4][CH:3]=1
Reactant: COC(=O)CCCc1ccc(O)cc1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)CCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
A mixture of methyl 4-(4-hydroxyphenyl)butyrate (4.93 g, 0.025 mol) and hydrazine hydrate (25.4 g, 0.254 mol) in methanol (64 mL) was heated under reflux for an hour. It was then cooled down to room temperature and stirred overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was dried over Na2SO4, filtered and concentrated to dryness to give the titled compound as a white crystal (3.30 g, 67%). 400 MHz 1H NMR (DMSO-d6) δ 9.10 (s, 1H), 8.89 (s, 1H), 6.93 (d, J=8.8 Hz, 2H), 6.63 (d, J=8.8 Hz, 2H), 3.32 (s, 2H), 2.40 (t, J=7.6 Hz, 2H), 1.97 (t, J=7.2 Hz, 2H), 1.71−1.67 (m, 2H); Mass (M−H−)=193.27.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH:19]=[C:18](I)[N:17]=[CH:16]3)[N:9]=2)=[CH:4][C:3]=1[CH3:21].[NH2:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH:19]=[C:18]([C:26]4[CH:27]=[CH:28][C:23]([NH2:22])=[N:24][CH:25]=4)[N:17]=[CH:16]3)[N:9]=2)=[CH:4][C:3]=1[CH3:21]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-n2cnc(I)c2)n1
Product: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-n2cnc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 4-(4-chloro-3-methyl-phenyl)-2-(4-iodo-imidazol-1-yl)-6-methyl-pyrimidine (example E.76) (0.41 g, 1.0 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.26 g, 1.2 mmol) according to the general procedure VI. Obtained as a yellow solid (0.14 g, 37%). MS (ISP) 377.3 [(M+H)+]; mp 202° C. (dec.).
Reaction SMILES: [CH3:1][S:2]([Cl:5])(=[O:4])=[O:3].[NH:6]1[C:14]2[C:9](=[CH:10][C:11]([CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][C:20]4([CH2:27][C:26](=[O:28])[C:25]5[CH:29]=[C:30]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:31]=[CH:32][C:24]=5[O:23]4)[CH2:19][CH2:18]3)=[CH:12][CH:13]=2)[CH2:8][CH2:7]1.Cl.[N:39]1C=CC=CC=1>C(O)C>[ClH:5].[CH3:1][S:2]([NH:39][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH2:15][CH2:16][N:17]3[CH2:18][CH2:19][C:20]4([CH2:27][C:26](=[O:28])[C:25]5[CH:29]=[C:30]([NH:33][S:34]([CH3:37])(=[O:35])=[O:36])[CH:31]=[CH:32][C:24]=5[O:23]4)[CH2:21][CH2:22]3)=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)(=[O:4])=[O:3]
Reactant: c1ccncc1
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(=O)CC1(CCN(CCc3ccc4c(c3)CCN4)CC1)O2
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=O)CC1(CCN(CCc3ccc4c(c3)CCN4NS(C)(=O)=O)CC1)O2
Reaction time: 22 h
Yield: 40 %

Procedure:
Methanesulfonyl chloride (55 mg, 0.48 mmol) was added to a suspension of 3,4-dihydro-1'-[2-(2,3-dihydro-1H-indol-5-yl)ethyl]-6-methanesulfonamidospiro[(2H)-benzopyran-2,4'-piperidine]-4-one (crude, 84% pure, 217 mg, 0.4 mmol) in pyridine (5 ml). The mixture was stirred for 22 hours, then the solvent was evaporated under reduced pressure. Aqueous sodium hydrogen carbonate (saturated, 20 ml) and water (5 ml) were added and the mixture was extracted with dichloromethane (3×25 ml). The combined organic fractions were dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2 /MeOH/NH3 (Aq.) (96:4:0.4) to give a yellow glass which was suspended in ethanol (5 ml) and treated with ethanolic HCl (6N, 0.5 ml). The mixture was stirred for 1 hr, cooled and the precipitate was collected and dried in vacuo to give the hydrochloride as a white solid (91 mg, 40%), m.p.>285° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br.Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)=O>>[N+:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:6]1[C:5]([C:3]([OH:2])=[O:4])=[CH:10][C:9]([C:11]2[S:13][CH:25]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[N:12]=2)=[CH:8][CH:7]=1)([O-:22])=[O:21]
Reactant: O=C(CBr)c1ccccn1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Agent: Br
Product: O=C(O)c1cc(-c2nc(-c3ccccn3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 79 %

Procedure:
2′-Nitro-4-(4-pyridin-2-yl-thiazol-2-yl)-biphenyl-2-carboxylic acid (200 mg, 79%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-(bromoacetyl)pyridine hydrobromide (available from Oakwood Products, Inc.) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 8.67 (d, J=4.9 Hz, 1H), 8.60 (d, J=1.9 Hz, 1H), 8.50 (s, 1H), 8.26-8.30 (m, 2H), 8.15 (d, J=7.5 Hz, 2H), 8.00-8.05 (m, 1H), 7.76-7.81 (m, 1H), 7.62-7.68 (m, 1H), 7.41-7.49 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH:13]([C:15]2[C:16]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:17]=3[S:18][CH:19]=2)[OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O=[Mn]=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])([C:13]([C:15]2[C:16]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:17]=3[S:18][CH:19]=2)=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)CCC1(C(O)c2csc3ccc(F)cc23)CCN(C(=O)OC(C)(C)C)C1
Agent: O=[Mn]=O
Product: CC(C)(C)CCC1(C(=O)c2csc3ccc(F)cc23)CCN(C(=O)OC(C)(C)C)C1

Procedure:
3-(3,3-Dimethyl-butyl)-3-(5-fluoro-benzo[b]thiophene-3-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared from 3-(3,3-dimethyl-butyl)-3-[(5-fluoro-benzo[b]thiophen-3-yl)-hydroxy-methyl]-pyrrolidine-1-carboxylic acid tert butyl ester by oxidation with MnO2 using the procedure of step 3 of Example 18.
Reaction SMILES: [ClH:1].[CH:2](=[C:9]1[C:14](=O)[C:13](=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][NH:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:23][C:24]([F:29])([F:28])[CH2:25][NH:26][NH2:27]>CO>[ClH:1].[C:3]1([CH:2]2[CH:9]3[CH2:10][NH:11][CH2:12][C:13](=[CH:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:14]3=[N:27][N:26]2[CH2:25][C:24]([F:29])([F:28])[F:23])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1C(=Cc2ccccc2)CNCC1=Cc1ccccc1
Reactant: NNCC(F)(F)F
Agent: Cl
Solvent: CO
Product: FC(F)(F)CN1N=C2C(=Cc3ccccc3)CNCC2C1c1ccccc1
Yield: 107 %

Procedure:
3,5-Dibenzylidene-4-piperidone, hydrochloride (10.0g) is reacted with 5.8 g of 70% aqueous 2,2,2-trifluoroethylhydrazine in 220 ml of methanol at reflux for 4 hours. Evaporation of the methanol on a rotary evaporator leaves 14 g of a foamy residue which crystallizes when triturated with 50 ml of boiling acetonitrile to yield (after cooling for about 16 hours) 10.3 g of material, melting point 206°-209° C (sintering at 195° C). Crystallization from 80 ml of ethanol yields 6.7 g of product, melting point 207°-209° C, sintering at 196° C.