Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:16][C:17]1[C:22]([CH3:23])=[C:21](Cl)[N:20]=[C:19]([S:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:18]=1>C(O)C>[Cl:16][C:17]1[C:22]([CH3:23])=[C:21]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:20]=[C:19]([S:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:18]=1
Reactant: CCOC(=O)CSc1nc(Cl)c(C)c(Cl)n1
Reactant: NCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSc1nc(Cl)c(C)c(NCc2ccc(Cl)cc2)n1
Yield: 31.4 %

Procedure:
A stirred mixture of 4.2 g of p-chlorobenzylamine, 3.18 g of sodium carbonate and 8.4 g of (4,6-dichloro-5-methyl-2-pyrimidinylthio)acetic acid, ethyl ester in 100 ml of ethanol was heated under reflux for 4 hr. The reaction mixture was filtered and water was added to the filtrate to start precipitation. The collected solid was recrystallized from benzenepetroleum ether to give 3.6 g of product, mp. 114°-117°C.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2].[C:18]1([CH2:24][CH2:25][NH2:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCO>[CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([NH:26][CH2:25][CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2]
Reactant: NCCc1ccccc1
Reactant: CCN(CC)C(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CCO
Product: CCN(CC)C(=O)c1ccc(NCCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 85 °C
Yield: 95.6 %

Procedure:
Following general procedure 2B: A mixture of N,N-diethyl-4-fluoro-3-nitrobenzamide (0.125 g, 0.521 mmol), 2-phenylethanamine (0.065 mL, 0.521 mmol) in 80% aq. EtOH (3 mL) was heated at 85° C. for 4 hours. Usual work-up provided the title compound (0.170 g, 96%) which was used without further purification. MS (ESI) (M+H)+=342.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=O)[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C([O-])(=O)C.[NH4+:30].[OH-].[NH4+]>>[CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH2:30])=[O:23])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCC(=O)OCC
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [OH-]
Product: CCCc1nc2cnc3ccccc3c2n1CCCCC(N)=O
Temperature: 130 °C
Yield: 56.7 %

Procedure:
Ethyl 5-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentanoate (5.4 g, 15.9 mmol), prepared as described in Parts A through C of Example 34) and ammonium acetate (11.0 g, 143 mmol) were sealed in a high-pressure vessel and heated for two days at 130° C. and then allowed to cool to ambient temperature. Ammonium hydroxide was added to adjust the mixture to a neutral pH. The mixture was then extracted with dichloromethane, and the combined extracts were washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 2.8 g of 5-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentanamide, which was combined with material from another run.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:17]([OH:19])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28][C:29]1[S:30][CH:31]=[N:32][N:33]=1>ClCCl>[S:30]1[CH:31]=[N:32][N:33]=[C:29]1[NH:28][C:17](=[O:19])[C@@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: Nc1nncs1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)Nc1nncs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
To a solution of (2S)-6-benzyloxycarbonylamino-2-tert-butoxycarbonylaminohexanoic acid (1.09 g, 2.87 mmol) in dichloromethane (5 mL) is added 1,1-carbonyldiimidazole (0.47 g, 2.87 mmol). The resulting solution is stirred at 25° C. for 1 h and 2-amino-1,3,4-thiadiazole (0.29 g, 2.87 mmol) is added and the reaction is stirred for an additional 18 h. The mixture is diluted with dichloromethane (60 mL) and washed with 1 M aqueous sodium carbonate solution. The organic layer is dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by silica gel chromatography (elution with 1:1 EtOAc-hexanes) to provide (2S)-6-benzyloxycarbonylamino-2-tert-butoxycarbonylaminohexanoic acid 1,3,4-thiadiazol-2-ylamide as a foam (0.81 g, 61% yield).
Reaction SMILES: [C:1]([O:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:14]=1)=[O:8])([CH2:4][CH3:5])([CH3:3])[CH3:2].[Se](=O)=[O:22]>>[C:1]([O:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:14]=1)=[O:8])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cc1csc(NC(=O)OC(C)(C)CC)n1
Reactant: O=[Se]=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)OC(C)(C)CC)n1
Yield: 70.6 %

Procedure:
Ethyl 2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetate (0.3 g.) and selenium dioxide (0.11 g.) were treated according to a similar manner to that of Preparation 6-4) to give brown oil of ethyl 2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylate (0.22 g.).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]2[C:6](=[O:25])[N:7]=[C:8]([C:10]3[N:15]=[C:14]([CH2:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[CH:13]=[CH:12][CH:11]=3)[S:9][C:4]=2[CH:3]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:27]=[CH:26][C:5]2[C:6](=[O:25])[N:7]=[C:8]([C:10]3[N:15]=[C:14]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:13]=[CH:12][CH:11]=3)[S:9][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)CCc1cccc(-c2nc(=O)c3ccc(F)cc3s2)n1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCc1cccc(-c2nc(=O)c3ccc(F)cc3s2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
tert-Butyl 3-[6-(7-fluoro-4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propanoate (0.50 g, 1.3 mmol) was dissolved in trifluoroacetic acid (5 ml), and the mixture was stirred at 0° C. for 2 hrs. The solvent was evaporated, and the residue was crystallized from diethyl ether to give the titled compound (0.43 g, 99%) as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([OH:40])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:50][CH2:51][OH:52].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:38])([F:39])[F:37])[CH:27]=3)[C:22]([O:40][CH2:50][CH2:51][OH:52])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2]
Reactant: OCCBr
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(OCCO)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 60 °C
Reaction time: 8 h

Procedure:
(2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-hydroxypyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (150 mg) is dissolved in N,N-dimethylformamide (1 ml), then thereto are added potassium carbonate (200 mg) and 2-bromoethanol (162 μl), and the mixture is stirred at 60° C. overnight. To the reaction mixture is added 10% aqueous citric acid solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=2:1) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-hydroxyethoxy)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (95 mg). MS (m/z): 644 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:36]([F:39])([F:38])[F:37])[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][C:28](=[O:30])[NH:27][CH2:26]4)=[O:24])=[C:19]([CH2:31][C:32]([F:35])([F:34])[F:33])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CN(C)C=O.[F:45][C:46]([F:51])([F:50])[CH2:47][CH2:48]I.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:36]([F:37])([F:38])[F:39])[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][C:28](=[O:30])[N:27]([CH2:48][CH2:47][C:46]([F:51])([F:50])[F:45])[CH2:26]4)=[O:24])=[C:19]([CH2:31][C:32]([F:33])([F:35])[F:34])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=C1CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(C(F)(F)F)c4)(C(F)(F)F)C3)cc2CC(F)(F)F)CN1
Reactant: FC(F)(F)CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C1CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(C(F)(F)F)c4)(C(F)(F)F)C3)cc2CC(F)(F)F)CN1CCC(F)(F)F
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 25-mL round-bottom flask, was placed 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(2,2,2-trifluoroethyl)phenyl)carbonyl]imidazolidin-4-one (150 mg, 0.26 mmol, 1.00 equiv), N,N-dimethylformamide (10 mL), 1,1,1-trifluoro-3-iodopropane (114 mg, 0.51 mmol, 2.01 equiv), Cs2CO3 (166 mg, 0.51 mmol, 1.98 equiv). The resulting solution was stirred overnight at 50° C. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×10 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a TLCplate with ethyl acetate/petroleum ether (1:1). This resulted in 22.3 mg (12%) of 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(2,2,2-trifluoroethyl)phenyl)carbonyl]-3-(3,3,3-trifluoropropyl)imidazolidin-4-one as a light yellow solid. (ES, m/z): [M+CH3CN]− 726.0; 1H NMR (300 MHz, CDCl3): δ7.86-7.98 (m, 5H), 7.63 (d, J=8.1 Hz, 1H), 5.14 (s, 1H), 4.78 (s, 1H), 4.15-4.42 (m, 3H), 3.57-3.92 (m, 5H), 2.40-2.66 (m, 2H).
Reaction SMILES: [NH2:1][CH:2]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[C:8]2[C:3]1=[C:4]([OH:17])[C:5]([CH3:16])=[CH:6][C:7]=2[CH3:15].C(=O)([O-])[O-].[K+].[K+].CC(C)=O.Cl[CH2:29][CH2:30][CH2:31][C:32](Cl)=[O:33]>O>[OH:17][C:4]1[C:5]([CH3:16])=[CH:6][C:7]([CH3:15])=[C:8]2[C:3]=1[CH:2]([N:1]1[CH2:29][CH2:30][CH2:31][C:32]1=[O:33])[CH:14]1[CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: Cc1cc(C)c2c(c1O)C(N)C1CCCCC21
Reactant: O=C(Cl)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(C)c2c(c1O)C(N1CCCC1=O)C1CCCCC21

Procedure:
4.0 Grams of 9-amino-8-hydroxy-5,7-dimethyl-1,2,3,4,4a,9a-hexahydrofluorene and 2.5 g of potassium carbonate were added to a mixture of 50 ml of acetone and 20 ml of water and thereto was added dropwise 2.5 ml of γ-chlorobutyryl chloride under ice-cooling and stirring. After stirring for 2 hours, the reaction mixture was concentrated and to the residue was added water and extraction was effected with chloroform. The choroform layer was dried with magnesium sulfate and concentrated. Then, the residue was dissolved in 30 ml of DMF and to the solution was added 2.0 g of sodium hydride (60% oiliness), followed by stirring to generate a gas with generation of heat. Then, the reaction mixture was stirred at room temperature overnight and thereafter concentrated. To the residue was added water and extraction was effected with chloroform. The chloroform layer was dried with magnesium sulfate and concentrated. To the residue was added ethyl acetate and the produced precipitate was collected by filtration and recrystallized from hydrous ethanol to obtain 2.0 g of 8-hydroxy-5,7-dimethyl-9-(2-oxo-1-pyrrolidinyl)-1,2,3,4,4a,9a-hexahydrofluorene having a melting point of 240°-213° C. (decomposed) and of light brown powdery crystal.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[N:3]1.[CH2:9]([NH2:11])[CH3:10]>C1COCC1>[CH2:9]([NH:11][CH2:7][C:4]1[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=1)[CH3:10]
Reactant: CCN
Reactant: Cn1ccc(C=O)n1
Solvent: C1CCOC1
Product: CCNCc1ccn(C)n1

Procedure:
prepared by reaction of 1-methyl-1H-pyrazole-3-carbaldehyde (prepared according to WO2004/058702) with 2M ethylamine in THF.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][NH:41][S:42]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])(=[O:44])=[O:43])[C@@:22]([OH:33])([CH2:30][CH2:31][CH3:32])[C:23]([O:25]C(C)(C)C)=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][NH:41][S:42]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])(=[O:44])=[O:43])[C@@:22]([OH:33])([CH2:30][CH2:31][CH3:32])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCNS(=O)(=O)CCCCCCCC)[C@@](O)(CCC)C(=O)OC(C)(C)C)C(=O)OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCNS(=O)(=O)CCCCCCCC)[C@@](O)(CCC)C(=O)O)C(=O)OC)cc1
Reaction time: 1.25 h
Yield: 89.9 %

Procedure:
tert-Butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy-10-(octane-1-sulfonylamino)-2-propyl-dec-4-enoate (35.0 mg, 0.0467 mmol) was dissolved in dichloromethane (1.0 mL), and trifluoroacetic acid (1.0 mL, 13.6 mmol) was then added at room temperature. The mixture was stirred for 75 minutes, and then concentrated under reduced pressure. The resulting crude product was purified by preparative HPLC to obtain 29.1 mg (0.0420 mmol, 90% yield) of the title compound.
Reaction SMILES: C[C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18]C2C=CC=CC=2)=[O:15])=[N:10][CH:9]=1)(C)[C:3]([OH:5])=[O:4].ClCC[C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:36].C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([N:16]([CH2:17][CH2:18][C:35](=[O:36])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:2][C:3]([OH:5])=[O:4])=[CH:9][N:10]=2)[CH2:26][CH2:27]1
Reactant: O=C(CCCl)c1ccccc1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCC(=O)c2ccccc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-propionic acid using 3-chloro-1-phenyl-propan-1-one and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:35]=[CH:34][C:13]3=[N:14][N:15]([C:17]4[CH:18]=[C:19]([CH:26]=[C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:28]=4[OH:29])[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[N:16]=[C:12]3[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:36][C:37]1([CH3:46])[CH2:42]C(O)[CH2:40][C:39]([CH3:45])([CH3:44])[NH:38]1.[NH2-].[Li+]>>[C:1]1([S:7]([C:10]2[CH:35]=[CH:34][C:13]3=[N:14][N:15]([C:17]4[CH:18]=[C:19]([CH:26]=[C:27]([C:30]([CH3:32])([CH3:31])[CH3:33])[C:28]=4[OH:29])[CH2:20][CH2:21][C:22]([O:24][CH:25]4[CH2:40][C:39]([CH3:45])([CH3:44])[NH:38][C:37]([CH3:46])([CH3:42])[CH2:36]4)=[O:23])[N:16]=[C:12]3[CH:11]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCc1cc(-n2nc3ccc(S(=O)(=O)c4ccccc4)cc3n2)c(O)c(C(C)(C)C)c1
Reactant: CC1(C)CC(O)CC(C)(C)N1
Agent: [Li+]
Agent: [NH2-]
Product: CC1(C)CC(OC(=O)CCc2cc(-n3nc4ccc(S(=O)(=O)c5ccccc5)cc4n3)c(O)c(C(C)(C)C)c2)CC(C)(C)N1
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 103.4 %

Procedure:
Methyl 3-(5-phenylsulfonylbenzotriazol-2-yl)-5-tert-butyl-4-hydroxyhydrocinnamate (10 g, 0.02 mol), xylenes (100 g, 0.93 mol) and 2,2,6,6-tetramethyl-4-hydroxypiperidine (4.0 g, 0.025 mol) are charged to a reactor. The contents are heated to reflux in order to dry the xylenes. The contents are cooled to 50° C. at which time lithium amide (0.4 g, 0.017 mol) is added. The reaction mass is then heated to reflux and held at that temperature for 3.5 hours. The reaction is monitored by thin layer chromatography. The reaction mass is cooled to 50° C. and washed thrice with 100 g of water. The xylene is removed by distillation under vacuum to give 12.8 g of an orange oil which is subjected to silica gel chromatography for purification using ethyl acetate as the eluent. The title compound is obtained in a yield of 9.6 g (77%) as a yellow semi-solid, melting at 85-125° C., whole structure is confirmed by mass spectrometry and 1Hnmr.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[C:14]#[N:15].[OH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1>CCO.N1CCCCC1>[OH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[N:1][C:2]2[NH:6][N:5]=[C:4]([NH:7][C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[C:3]=2[C:14]#[N:15])=[CH:19][CH:18]=1
Reactant: N#Cc1c(Nc2cccnc2)n[nH]c1N
Reactant: O=Cc1ccc(O)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: N#Cc1c(Nc2cccnc2)n[nH]c1N=Cc1ccc(O)cc1
Yield: 53 %

Procedure:
5-amino-3-(pyridin-3-ylamino)-1H-pyrazole-4-carbonitrile (100 mg) was then suspended in EtOH (4 mL) and 4-hydroxybenzaldehyde (31 mg, 1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 5-((4-hydroxybenzylidene)amino)-3-(pyridin-3-ylamino)-1H-pyrazole-4-carbonitrile as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr (40 mg, 53% yield).
Reaction SMILES: O.O1[CH:8]2[CH:3]1[CH2:4][CH:5]1[C:12](=O)N(CC=C)[C:9](=[O:10])[CH:6]1[CH2:7]2>C1(C)C=CC=CC=1>[CH2:5]([CH:6]([CH2:7][CH2:8][CH2:3][CH3:4])[CH2:9][OH:10])[CH3:12]
Reactant: C=CCN1C(=O)C2CC3OC3CC2C1=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCC(CC)CO
Yield: 0.3 %

Procedure:
In a 300 ml four-necked flask equipped with a reflux condenser, Dean-Stark water separator, thermometer, stirrer, dropping funnel and oil bath there were charged 22.8 g of the 4,5-epoxy-N-allylcyclohexane-1,2-dicarboximide obtained in Reference Example 2, 180 g of toluene and 0.05 g of a 2-ethylhexanol solution containing 2 wt % platinic chloride, after which the oil bath kept at 140° C. was used for azeotropic dewatering while circulating for 1 hour, and after confirming lack of water runoff, a total of 36.3 g of the silicon compound represented by the following formula (X):
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[C:12]1([NH:18][C:19](=O)[CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[F:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]=[C:19]([CH3:20])[N:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:2]=2[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1Br
Reactant: CC(=O)Nc1ccccc1
Product: Cc1nc2ccc(F)cc2n1-c1ccccc1
Yield: 66 %

Procedure:
The title compound was prepared with the analogous procedure described in example 3 using 1-Bromo-5-fluoro-2-nitrobenzene and N-phenylacetamide (81 mg, 0.6 mmol) as starting materials to yield the title compound as brown solid (75 mg, 66%). 1H NMR (DMSO) δ 2.50 (s, 3 H), 7.11 (d, 1 H), 7.21-7.29 (m, 1H), 7.59-7.69 (m, 5 H), 7.79 (br s, 1 H).
Reaction SMILES: [C:1]([N:9]1[CH2:19][CH2:18][C:12]2[N:13]=[N:14][C:15](Cl)=[CH:16][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][NH:21][NH2:22]>>[C:1]([N:9]1[CH2:19][CH2:18][C:12]2[N:13]=[N:14][C:15]([N:21]([CH3:20])[NH2:22])=[CH:16][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCc2nnc(Cl)cc2C1
Reactant: CNN
Product: CN(N)c1cc2c(nn1)CCN(C(=O)c1ccccc1)C2

Procedure:
13.7 g of 6-benzoyl-3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine in 40 cc of methyl hydrazine are stirred at a bath temperature of 50° for 61/2 hours. The oil resulting after concentrating the reaction solution is dissolved in 200 cc of chloroform, the solution is dried with sodium sulphate and again concentrated to an oil. This is boiled for a short time with 12.0 g of gentisic acid in 100 cc of methanol on a water bath. After concentrating the solution to approximately 2/3 of its volume, and cooling with ice, the bisgentisinate of the title compound precipitates. M.P. 166°-168° (decomp., from absolute ethanol).
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1.[OH:30][CH2:31][CH2:32][NH:33][CH2:34][CH2:35][OH:36]>CN(C)C(=O)C>[OH:30][CH2:31][CH2:32][N:33]([CH2:34][CH2:35][OH:36])[CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1
Reactant: CN(C[C@H]1CC[C@H](COC/C=C/CBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: OCCNCCO
Solvent: CC(=O)N(C)C
Product: CN(C[C@H]1CC[C@H](COC/C=C/CN(CCO)CCO)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the method described in example 12.1, trans-N-[4-(4-bromo-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with bis-(2-hydroxy-ethyl)-amine in N,N-dimethylacetamide at room temperature to yield trans-N-(4-{4-[bis-(2-hydroxy-ethyl)-amino]-(E)-but-2-enyloxymethyl}-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide as light yellow solid, MS: 523 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][CH:10]([C:14]([O:16][CH3:17])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:24](I)[CH3:25]>CN(C)C=O>[CH2:24]([O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[CH2:11][CH:10]([C:14]([O:16][CH3:17])=[O:15])[CH2:9]2)=[CH:6][CH:7]=1)[CH3:25]
Reactant: COC(=O)C1CC(=O)N(c2ccc(O)cc2)C1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(N2CC(C(=O)OC)CC2=O)cc1
Temperature: 80 °C
Reaction time: 22 h

Procedure:
Methyl 1-(4-hydroxyphenyl)-5-oxo-3-pyrrolidinecarboxylate (3.00 g) is dissolved in dimethylformamide (30 ml) and thereto are added potassium carbonate (4.40 g) and ethyl iodide (2.56 ml). The mixture is heated with stirring at 80° C. for 22 hours. The reaction solution is concentrated under reduced pressure and the resulting residue is neutralized by adding thereto water and 1N hydrochloric acid. The precipitated crystal is collected by filtration and washed with water to give the desired product (3.07 g), m.p. 67°-69° C.