Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([C:10](=[CH:20][N:21]([CH3:23])[CH3:22])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[CH:16][CH:17]=1)([O-:3])=[O:2]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccccc1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 85.2 %

Procedure:
To a solution of ethyl 4-nitrobenzoylacetate (11.9 g) in benzene (100 ml) was dropwise added N,N-dimethylformamide dimethylacetal (9.5 g) dissolved in benzene (50 ml) during a period of 0.5 hour, under stirring at room temperature. The mixture was refluxed for 4 hours. The reaction mixture was evaporated under reduced pressure. The resulting oil was recrystallized from ether-hexane to give 12.5 g of ethyl 2-(4-nitrobenzoyl)-3-dimethylaminopropenoate.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([CH:11]=[C:12]([CH3:14])[N:13]=2)[CH:5]=[C:6]([C:8]([NH2:10])=[O:9])[CH:7]=1.[CH2:15]([C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:18]=1[CH2:19]Cl)[CH3:16].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O>[CH3:14][C:12]1[N:13]=[C:3]2[C:2]([NH:1][CH2:19][C:18]3[C:21]([CH3:25])=[CH:22][CH:23]=[CH:24][C:17]=3[CH2:15][CH3:16])=[CH:7][C:6]([C:8]([NH2:10])=[O:9])=[CH:5][N:4]2[CH:11]=1
Reactant: CCc1cccc(C)c1CCl
Reactant: Cc1cn2cc(C(N)=O)cc(N)c2n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cccc(C)c1CNc1cc(C(N)=O)cn2cc(C)nc12
Temperature: 50 °C
Reaction time: 48 h
Yield: 2.4 %

Procedure:
8-Amino-2-methylimidazo[1,2-a]pyridine-6-carboxamide (3.8 g, 20 mmol), 2-ethyl-6-methylbenzylchloride (2.8 g, 17 mmol), potassium carbonate (5.5 g, 40 mmol) and sodium iodide (0.1 g, 0.6 mmol) were added to dimethylformamide (75 ml) and the mixture was stirred at 50° C. for 4 h. and at room temperature for 48 h. The reaction mixture was filtred through silica gel and the gel was washed with methylene chloride. The solvents were evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using methylene chloride:methanol (9:1) as eluent. Crystallization from a mixture of methylene chloride and hexane gave 0.13 g (2%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][C:3]=1[C:15](=[O:17])[CH3:16].[H-].[Na+].[C:20](=O)([O:24]CC)[O:21][CH2:22][CH3:23]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[C:15](=[O:17])[CH2:16][C:20]([O:21][CH2:22][CH3:23])=[O:24]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1cc(CN2CCOCC2)ccc1F
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(=O)c1cc(CN2CCOCC2)ccc1F
Temperature: 0 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
A solution of 1-[2-fluoro-5-(4-morpholinylmethyl)phenyl]-1-ethanone (19.6 g) of Preparation No. 54 in diethyl carbonate (150 mL) is cooled to 0° C., and sodium hydride (60% dispersion, 6.6 g) is added slowly to the reaction mixture. The reaction is stirred at 0° C. for 3 hours, and then is allowed to warm to room temperature overnight. The reaction mixture is quenched with acetic acid (10 mL), diluted with water (200 mL) and then basified with sat. sodium carbonate. The solution is then extracted with ether (3×200 mL). The combined organic layers are washed with sat. sodium bicarbonate (100 mL) and brine (50 mL). The combined aqueous layers are back-extracted with ether (50 mL). The combined organic layers are then dried (Na2SO4) and concentrated in vacuo to an orange oil. The crude product is purified in 2 batches by column chromatography (heptane/IPA, 8/1; 4/1) to afford 20.2 g (79%) of the title compound as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH:2]=1.[Li+].CC([N-]C(C)C)C.Cl[C:22]([O:24][CH3:25])=[O:23]>C1COCC1>[O:12]=[C:8]1[CH:9]([C:22]([O:24][CH3:25])=[O:23])[CH2:10][CH2:11][N:7]1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)Cl
Reactant: O=C1CCCN1c1cccnc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1CCN(c2cccnc2)C1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 25.9 %

Procedure:
To a stirred solution of 349 (1.48 g, 9.1 mmol) in anhydrous THF (25 ml) at −78° C. under nitrogen was slowly added a solution of LDA (mono THF, 13.4 mL, 20.1 mmol, 1.5 M in cyclohexane). After 45 min, methyl chloroformate (776 μL, 10.0 mmol) was added. The mixture was warmed to room temperature over 2 h, and then stirred overnight. Then, the reaction mixture was quenched by addition of sat. ammonium chloride and extracted with AcOEt. After separation, the organic layer was successively washed with sat. NH4Cl, water, and brine. The aqueous phase was extracted twice with AcOEt. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was purified by flash column chromatography (eluents MeOH/CH2Cl2: 2/98 to 5/95) to afford title compound 350 (520 mg, 26% yield) as a pale yellow sticky solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.86 (d, J=2.5 Hz, 1H), 8.38 (dd, J=4.7, 1.4 Hz, 1H), 8.12-8.06 (m, 1H), 7.44 (dd, J=8.4, 4.7 Hz, 1H), 3.99-3.84 (m, 2H), 3.81 (t, J=8.8 Hz, 1H), 3.70 (s, 3H), 2.48-2.29 (m, 2H). MS (m/z): 221.0 (M+H)+..
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH2:8][C@@H:7]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[C@@H:6]1[O:26][C:27](=[O:29])[CH3:28])(=[O:3])[CH3:2].[Br:30]N1C(=O)CCC1=O>O1CCOCC1>[C:1]([O:4][C@@H:5]1[C@@H:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2[Br:30])[CH2:8][C@@H:7]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[C@@H:6]1[O:26][C:27](=[O:29])[CH3:28])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@H]1C[C@H](n2cnc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: O=C1CCC(=O)N1Br
Solvent: C1COCCO1
Product: CC(=O)OC[C@@H]1C[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 62.6 %

Procedure:
(±)(1R*,2S*,3S*,5S*)-3-(Acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (4.20 g, 9.48 mmol) was refluxed in dry dioxane (25 mL) while freshly recrystallized N-bromosuccinimide (3.37 g, 18.9 mmol) was added all at once. After 5 minutes of reflux, volatiles were removed in vacuo. The residue was partitioned between water and chloroform. The chloroform layer was dried (sodium sulfate), and evaporated to an oil which was chromatographed on silica gel with elution by 1:1 hexanesoethyl acetate. Resolidification from ethanol-water gave title compound as white powder (3.10 g, 63%), m.p. 157°-158.5° C.; 1H-NMR(DMSO-d6) identical to that of the sample described in Example 3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[C:11]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:12]=[CH:13][C:14]=2[N+:15]([O-])=O)=[CH:4][CH:3]=1.[NH4+].[Cl-].O>CCO.[Fe]>[NH2:15][C:14]1[CH:13]=[CH:12][C:11]([S:18]([NH2:21])(=[O:19])=[O:20])=[CH:10][C:9]=1[S:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])c(Sc2ccc(Cl)cc2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(S(N)(=O)=O)cc1Sc1ccc(Cl)cc1

Procedure:
3-(4-Chlorophenylthio)-4-nitro-benzenesulphonamide (0.50 g, 1.45 mmol), NH4Cl (0.16 g; 2.90 mmol) and Fe powder (0.40 g; 7.25 mmol) were suspended in EtOH (10 ml)/water (5 ml) and refluxed for 30 minutes. The solution was filtered, evaporated down and the residue was taken up in CH2Cl2. It was washed with water, dried over MgSO4 and evaporated down. The residue was used again in its crude form. Yield: 0.43 g=94% 13C (100 MHz, CDCl3)d 152.17, 136.12, 133.59, 132.24, 130.75, 129.86, 129.38, 128.37, 114.69, 114.09
Reaction SMILES: C([O:5][C:6](=[O:32])[CH2:7][NH:8][C:9]([C:11]1[N:12]=[C:13]([CH3:31])[C:14]2[C:19]([C:20]=1[O:21][CH2:22][CH3:23])=[CH:18][CH:17]=[C:16]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:15]=2)=[O:10])(C)(C)C.FC(F)(F)C(O)=O>>[CH2:22]([O:21][C:20]1[C:19]2[C:14](=[CH:15][C:16]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:17][CH:18]=2)[C:13]([CH3:31])=[N:12][C:11]=1[C:9]([NH:8][CH2:7][C:6]([OH:32])=[O:5])=[O:10])[CH3:23]
Reactant: CCOc1c(C(=O)NCC(=O)OC(C)(C)C)nc(C)c2cc(Oc3ccccc3)ccc12
Solvent: O=C(O)C(F)(F)F
Product: CCOc1c(C(=O)NCC(=O)O)nc(C)c2cc(Oc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
A mixture of [(4-ethoxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid tert-butyl ester (14 mg, 0.032 mmol) and trifluoroacetic acid (2 ml) was stirred at ambient temperature for 3 h. Then the mixture was concentrated in vacuo and the residue dissolved in EtOH (5 ml). The mixture was evaporated in vacuo to give the title compound as a yellowish solid (12 mg); MS-(−)-ion: M−1=381.1.
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)#[N:2].[BH4-].[Na+]>CO>[C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(c2ccccc2)CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#CC1(c2ccccc2)CCC(O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A cold (0° C.) solution of 4-cyano-4-phenylcyclohexanone (5.0 g, 25.1 mmol) in 30 ml of MeOH was treated with sodium borohydride (1.14 g, 30.1 mmol). The reaction mixture was stirred for 2 hours at room temperature and then concentrated in vacuo.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][CH:12]([CH3:14])[CH3:13])[C:5]2[C:6](=[CH:8][S:9][CH:10]=2)[N:7]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>O>[CH:12]([NH:11][C:4]1[C:5]2[C:6](=[CH:8][S:9][CH:10]=2)[N:7]=[C:2]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1)([CH3:14])[CH3:13]
Reactant: C1COCCN1
Reactant: CC(C)Nc1nc(Cl)nc2cscc12
Solvent: O
Product: CC(C)Nc1nc(N2CCOCC2)nc2cscc12

Procedure:
6 g (0.26 moles) of 2-chloro-4-isopropylamino-thieno[3,4-d]pyrimidine and 25 mls. of morpholine are mixed and then heated under reflux for 4 hours. The mixture is cooled and poured into water with vigorous agitation; a brown solid appears, which is separated by filtration, washed with water and put to dry. The product is converted into the maleate, which is recrystallized from acetone. The free base is obtained again by treatment with alkali and is this way one obtains 3.4 g of pure product. M.P. 202°C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH:7]C(=O)OC(C)(C)C)=[CH:5][N:4]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[N:3]=1.FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>ClCCl>[Cl:1][C:2]1[C:6]([NH2:7])=[CH:5][N:4]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cn(-c2cccnc2)nc1Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
To tert-butyl (3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)carbamate (2 g, 6.79 mmol) in dichloromethane (6.79 ml) was added trifluoroacetic acid (6.79 ml) and the mixture was left stirring at room temperature for 2 hours. Toluene (12 mL) was added and the reaction was concentrated to near dryness. The mixture was poured into a separatory funnel containing saturated aqueous sodium bicarbonated and was extracted with dichloromethane. The combined organic layers were concentrated to give 3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-amine (0.954 g, 4.90 mmol, 72.2%) as a white solid: mp 137.9-139.9° C.; 1H NMR (400 MHz, CDCl3) δ 8.84 (d, J=2.4 Hz, 1H), 8.50 (dd, J=4.7, 1.4 Hz, 1H), 7.95 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.52 (s, 1H), 7.37 (ddd, J=8.4, 4.7, 0.7 Hz, 1H), 3.18 (s, 2H); ESIMS m/z 196 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:19][CH2:20][CH:21]=[C:22]([Cl:24])[Cl:23])[CH:5]=[C:6]([Cl:18])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH:16]=[CH2:17].S(=O)(=O)(O)[OH:26]>S([O-])([O-])(=O)=O.[Hg+2].O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([O:19][CH2:20][CH:21]=[C:22]([Cl:24])[Cl:23])[CH:5]=[C:6]([Cl:18])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][C:16](=[O:26])[CH3:17]
Reactant: C=CCOCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Hg+2]
Solvent: C1CCOC1
Product: CC(=O)COCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
A mixture of 4.12 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(5-(2-propenyloxy)pentyloxy)benzene, 0.36 g of mercury (II) sulfate, 5 ml of 1% aqueous sulfuric acid solution, and 50 ml of tetrahydrofuran was stirred at 60° C. for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with diluted hydrochloric acid and water in this order, dried over magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 4.05 g (yield, 94%) of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetone, nD25.5 1.5350.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:6]=1[CH3:14]>C(O)C.[Pd]>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[C:6]=1[CH3:14]
Reactant: Cc1c(OCCCl)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1c(N)cccc1OCCCl
Reaction time: 4 h
Yield: 98 %

Procedure:
A mixture of 1-(2-chloroethoxy)-2-methyl-3-nitrobenzene (10.7 g, 50 mmol) in ethanol (200 mL) containing 500 mg of 5% palladium on carbon was hydrogenated at 50 psi for 4 h. The catalyst was filter through Solka Floc and the solvent removed under vacuum to afford 9.1 g (98.8%) a yellow oil: 1H NMR (CDCl3) δ 2.76 (3H, s), 3.92 (2H, t, J=5.9 Hz), 4.40 (2H, t, J=5.9 Hz), 6.70 (1H, d, J=), 7.46 (1H, app t, J=), 8.04 (1H, d, J=), 8.24 (1H, s).
Reaction SMILES: C(C1C=CC(S(Cl)(=O)=O)=CC=1)(C)C.C1(C(C)C)C=CC=CC=1.Cl[C:24]1[C:29]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[C:28]([Cl:38])[N:27]=[CH:26][N:25]=1.[K].[CH:40]([C:43]1[CH:48]=[CH:47][C:46]([S:49]([NH2:52])(=[O:51])=[O:50])=[CH:45][CH:44]=1)([CH3:42])[CH3:41]>>[Cl:38][C:28]1[N:27]=[CH:26][N:25]=[C:24]([NH:52][S:49]([C:46]2[CH:47]=[CH:48][C:43]([CH:40]([CH3:42])[CH3:41])=[CH:44][CH:45]=2)(=[O:50])=[O:51])[C:29]=1[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1
Reactant: COc1ccc(-c2c(Cl)ncnc2Cl)cc1
Reactant: CC(C)c1ccc(S(N)(=O)=O)cc1
Agent: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: [K]
Solvent: CC(C)c1ccccc1
Product: COc1ccc(-c2c(Cl)ncnc2NS(=O)(=O)c2ccc(C(C)C)cc2)cc1
Yield: 57.5 %

Procedure:
p-Isopropylbenzenesulfonyl chloride, boiling point 105° C./0.25 Torr, was prepared from cumene and converted into the corresponding sulfonamide, melting point 104°-105° C. Reaction of 765 mg of 4,6-dichloro-5-(p-methoxyphenyl)-pyrimidine and 925 mg of p-isopropylbenzenesulfonamide potassium yielded 720 mg of N-[6-chloro-5-(p-methoxyphenyl)-4-pyrimidinyl]-p-isopropylbenzenesulfonamide, melting point 181°-182° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[C:10]=1[N+:18]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Ni]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[C:10]=1[NH2:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: Nc1cccc(OCc2ccccc2)c1N

Procedure:
A solution of O-benzyl-2,3-dinitrophenol (Description 12) (4.5 g) in ethanol (300 ml) was hydrogenated at atmospheric pressure over Raney nickel (2 g) until uptake of hydrogen ceased. The solution was filtered and evaporated to dryness in vacuo to afford unstable O-benzyl-2,3-diaminophenol which was immediately heated with phenylacetic acid (20 g) at 140°-150° C. for 3 h. The product was heated under reflux with 5N-hydrochloric acid (70 ml) for 3 h and neutralised with 10% sodium carbonate. The mixture was extracted with chloroform, and the organic layer washed with 10% sodium carbonate, water and dried (Na2SO4). The recovered product was chromatographed on Silica Gel 60 (250 g) eluting with ethylacetate-chloroform (1:19) to afford the title compound (1.6 g), m.p. 172°-174° C. (ethanol/ether).
Reaction SMILES: [CH:1]([C:4]1[S:8][C:7]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15](I)[CH:14]=2)=[O:11])=[N:6][CH:5]=1)([CH3:3])[CH3:2].CN(C)C(=N)N(C)C.[I-].[OH2:29]>CN(C)C=O>[OH:29][CH:4]([CH3:5])[C:1]#[C:2][C:15]1[CH:14]=[C:13]([NH:12][C:10]([NH:9][C:7]2[S:8][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][N:6]=2)=[O:11])[CH:18]=[CH:17][CH:16]=1
Reactant: O
Reactant: CC(C)c1cnc(NC(=O)Nc2cccc(I)c2)s1
Agent: CN(C)C(=N)N(C)C
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(O)C#Cc1cccc(NC(=O)Nc2ncc(C(C)C)s2)c1

Procedure:
To a solution of 0.2 g (0.56 mmol) of N-(5-isopropyl-1,3-thiazol-2-yl)-N′-(3-iodophenyl)urea in 3 ml of anhydrous N,N-dimethylformamide 0.6 ml of tetramethylguanidine, 0.088 ml (1.126 mmol) of D,L-1-butyn-3-ol, 19 mg (0.027 mmol) of bis(triphenylphosphine)palladium(II)dihydrochloride and 5.8 mg (0.03 mmol) of rameous iodide under argon were added successively. After 5 hours water was added and the mixture extracted with ethylacetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated, giving 0.116 g of the title compound as a yellowish solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:24][CH:25]=[CH2:26])[C:5]1[N:10]=[C:9]([NH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N+:8]([O-])=[C:7]([NH:18][C:19]([O:21]CC)=[O:20])[N:6]=1)[CH:2]=[CH2:3]>CN(C)C=O>[CH2:1]([N:4]([CH2:24][CH:25]=[CH2:26])[C:5]1[N:10]=[C:9]([NH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:8]2[O:20][C:19](=[O:21])[N:18]=[C:7]2[N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCN(CC=C)c1nc(NC(=O)OCC)[n+]([O-])c(NC(=O)OCC)n1
Solvent: CN(C)C=O
Product: C=CCN(CC=C)c1nc(NC(=O)OCC)n2oc(=O)nc2n1

Procedure:
6 g. of diethyl 6-diallylamino-s-triazine-2,4-dicarbamate-3-oxide are suspended in 120 ml. of dimethylformamide and warmed to 140° C. for 20 minutes under an argon atmosphere and while stirring. The solvent is then evaporated off under reduced pressure and the residue is recrystallized from methylene chloride/ethanol/diethyl ether, there being obtained pure ethyl 5-diallylamino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazine-7-carbamate, having a melting point of 172°-174° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]([OH:14])=[O:13])[NH:7][CH2:6][CH2:5]2.[C:15](Cl)(=O)C>CO>[CH3:15][O:13][C:12]([CH:8]1[C:9]2[C:4](=[CH:3][C:2]([OH:1])=[CH:11][CH:10]=2)[CH2:5][CH2:6][NH:7]1)=[O:14]
Reactant: O=C(O)C1NCCc2cc(O)ccc21
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)C1NCCc2cc(O)ccc21
Temperature: 25 °C
Yield: 75 %

Procedure:
A suspension of 1,2,3,4-tetrahydro-6-hydroxy-1-isoquinolinecarboxylic acid (5.0 g, 25.9 mmol, prepared according to W. K. Anderson, H. L. McPherson, J. S. New and A. C. Rick, Journal of Medicinal Chemistry, Vol. 27, p. 1321, 1984) in methanol (150 mL) was treated with acetyl chloride (3 mL) (reaction mixture became homogenous) and heated under reflux for 24 hours. The reaction mixture was then cooled to room temperature and concentrated in vacuo. It was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution and water. After drying over anhydrous magnesium sulfate, the solvent was removed in vacuo to yield the title compound (4.0 g, 75%) as a colorless solid, mp 214-216° C.
Reaction SMILES: [CH:1]1([CH:6]=[C:7]2[CH2:16][CH2:15][C:14]3[CH:13]=[C:12]([C:17]([O:19]C)=[O:18])[CH:11]=[CH:10][C:9]=3[C:8]2=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH:23]([C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([CH3:33])[CH:26]=1)[NH2:24].C(O)C>>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([N:23]2[CH:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:7]3[C:8]([C:9]4[CH:10]=[CH:11][C:12]([C:17]([OH:19])=[O:18])=[CH:13][C:14]=4[CH2:15][CH2:16]3)=[N:24]2)=[CH:26][C:27]=1[CH3:33])#[N:30]
Reactant: Cc1cc(NN)ccc1C#N
Reactant: COC(=O)c1ccc2c(c1)CCC(=CC1CCCC1)C2=O
Agent: Cl
Solvent: CCO
Product: Cc1cc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)ccc1C#N
Yield: 64 %

Procedure:
The title compound was prepared from Methyl 6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate; Preparation 18 (310.5 mg, 1.09 mmol) and 4-hydrazinyl-2-methylbenzonitrile hydrochloride; Preparation 2 (265 mg, 1.45 mmol) according to Method B and Method C (hydrolysis conducted at 60° C.). The crude precipitate was purified by reverse phase chromatography with 60-95% acetonitrile/water to give the title compound (yellow solid, 280 mg, 0.563 mmol, 64% yield). The title compound was largely present as (±)-(3SR,3aRS)-2-(4-cyano-3-methylphenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.56 (m, 7H), 1.64-1.74 (m, 1H), 1.76-1.92 (m, J=12.89, 4.30 Hz, 1H), 2.01-2.14 (m, 1H), 2.18-2.29 (m, 1H), 2.41 (s, 3H), 2.81-2.96 (m, 1H), 3.04-3.14 (m, 1H), 3.51-3.63 (m, 1H), 4.89 (dd, J=9.67, 5.37 Hz, 1H), 7.09 (dd, J=8.59, 2.15 Hz, 1H), 7.22 (d, J=1.88 Hz, 1H), 7.52 (d, J=8.59 Hz, 1H), 7.82 (dd, J=8.19, 1.48 Hz, 1H), 7.85 (s, 1H), 8.07 (d, J=8.06 Hz, 1H), 13.01 (s, 1H). ES-MS m/z 400 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:32])=[CH:26][CH:25]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(Cl)cc4)cc3)c2cc1OC
Yield: 55 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (52 mg) was dissolved in toluene (5 ml) with heat, 4-chlorophenyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 1 hour. The separated crystals were filtered and washed with toluene to obtain 43 mg of the title compound (yield: 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH:10]=[CH:9][C:8]2=[O:20])=[C:4]([F:23])[CH:3]=1.O[CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:8](=[O:20])[CH:9]=[CH:10][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:15][CH:14]=3)=[CH:12]2)=[C:4]([F:23])[CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: O=c1ccc(-c2ccc(O)cc2)cn1Cc1ccc(Cl)cc1F
Product: CC(C)(C)OC(=O)NCCOc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3F)c2)cc1
Yield: 66.7 %

Procedure:
The title compound was prepared from 1-(4-chloro-2-fluorobenzyl)-5-(4-hydroxyphenyl)pyridin-2(1H)-one (1 eq, 0.60 mmol, 0.20 g, Example 20 Step 2) and tert-butyl 2-hydroxyethylcarbamate (1.5 eq, 0.90 mmol, 0.10 g) according to the procedure described for Example 25 Step 2. The crude product was purified by crystallization in pentane/Et2O followed by silica gel chromatography (AIT Flashsmart prepacked column 25 g SiO2, CH2Cl2/AcOEt 80/20) to afford tert-butyl 2-(4-(1-(4-chloro-2-fluorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)phenoxy)ethylcarbamate (0.40 mmol, 0.19 g, 66%) as a yellow oil.