Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[C:8]([CH3:26])=[C:9]2[C:14](=[CH:15][C:16]=1F)[N:13]([C@@H:18]1[CH2:20][C@@H:19]1[F:21])[CH:12]=[C:11]([C:22]([OH:24])=[O:23])[C:10]2=[O:25].Cl.Cl.[N:29]12[CH2:36][CH:33]([CH2:34][CH2:35]1)[NH:32][CH2:31][CH2:30]2>C(N(CC)CC)C>[N:29]12[CH2:36][CH:33]([CH2:34][CH2:35]1)[N:32]([C:16]1[CH:15]=[C:14]3[C:9]([C:10](=[O:25])[C:11]([C:22]([OH:24])=[O:23])=[CH:12][N:13]3[C@@H:18]3[CH2:20][C@@H:19]3[F:21])=[C:8]([CH3:26])[C:7]=1[F:6])[CH2:31][CH2:30]2
Reactant: C1CN2CCC(C2)N1
Reactant: Cc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(F)c(N2CCN3CCC2C3)cc2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Temperature: 100 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To 6 ml of dried N,N-dimethylformamide were added 200 mg of 6,7-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 372 mg of 1,4-diazabicyclo[3.2.1]octane dihydrochloride, and 2 ml of triethylamine, and the mixture was stirred at 100° C. for 1 hour. After allowing to cool, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in a 1N sodium hydroxide aqueous solution under cooling with ice. The solution was neutralized with 1N hydrochloric acid and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting crude crystals were recrystallized from a mixed solvent of ethanol and 28% aqueous ammonia, and the crystals were collected by filtration, washed with diethyl ether, and dried at 60° C. under reduced pressure overnight to yield 131 mg of the titled compound as a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:30]=[C:31]=[O:32])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([NH:30][C:31](=[O:32])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: COc1ccc(N=C=O)cc1OC
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Product: COc1ccc(NC(=O)Nc2ccc(-c3c(C(N)=O)[nH]c4ncccc34)cc2)cc1OC

Procedure:
79 mg of solid beige-coloured 3-{4-[3-(3,4-dimethoxyphenyl)ureido]phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and 3,4-dimethoxyphenyl isocyanate.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH2:17]([C:21]1[C:30]([C:31]#[N:32])=[C:29]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26](/[CH:40]=[CH:41]/[CH:42]=O)[CH:27]=2)[N:22]=1)[CH:18]([CH3:20])[CH3:19]>O1CCCC1.C(OCC)(=O)C>[C:31]([C:30]1[C:21]([CH2:17][CH:18]([CH3:20])[CH3:19])=[N:22][C:23]2[C:28]([C:29]=1[C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)=[CH:27][C:26](/[CH:40]=[CH:41]/[CH:42]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:25][CH:24]=2)#[N:32]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cc1ccc(-c2c(C#N)c(CC(C)C)nc3ccc(/C=C/C=O)cc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/C=C/c1ccc2nc(CC(C)C)c(C#N)c(-c3ccc(C)cc3)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.4 %

Procedure:
To a solution of ethyl diethylphosphonoacetate (1.90 g, 10.2 mmol) in tetrahydrofuran (50 ml) was added sodium hydride (60% in oil, 408 mg, 10.2 mmol) at 0° C. and the mixture was stirred for 10 min. To the reaction mixture was added 2-isobutyl-4-(4-methylphenyl)-6-[(1E)-3-oxoprop-1-en-1-yl]quinoline-3-carbonitrile (3.00 g, 8.47 mmol). The temperature of the mixture was raised to room temperature and the mixture was stirred for 10 min. The reaction mixture was diluted with a mixture of tetrahydrofuran and ethyl acetate, washed successively with 2N aqueous sodium hydroxide solution, 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give yellow crystals. The crystals were washed with diisopropyl ether to give ethyl (2E,4E)-5-[3-cyano-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]penta-2,4-dienoate (2.71 g, yield 75%) as yellow crystals. The solvent of the mother liquor was removed under reduced pressure and the residue was purified by silica gel column chromatography to give ethyl (2E,4E)-5-[3-cyano-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]penta-2,4-dienoate (320 mg, yield 9%) as yellow crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][C:10]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH:22]=[CH2:23])(=[O:15])=[O:14])=[O:11])[N:3]=1.[CH3:24][O-:25].[Na+].[CH3:27][OH:28]>>[CH3:24][O:25][C:2]1[N:7]=[C:6]([O:28][CH3:27])[N:5]=[C:4]([NH:9][C:10]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH:22]=[CH2:23])(=[O:15])=[O:14])=[O:11])[N:3]=1
Reactant: C[O-]
Reactant: C=Cc1ccccc1S(=O)(=O)NC(=O)Nc1nc(Cl)nc(Cl)n1
Reactant: CO
Agent: [Na+]
Product: C=Cc1ccccc1S(=O)(=O)NC(=O)Nc1nc(OC)nc(OC)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The crude 2-ethenyl-N-[(4,6-dichloro-1,3,5-triazin-2-yl)aminocarbonyl]benzenesulfonamide of Example 6 is contacted with methanol (10 ml) and then with a solution of sodium methoxide (14 mmol) in methanol. The mixture is then stirred at room temperature for 1.5 hours and evaporated to dryness. Subsequently, the residue is taken up in water, filtered to remove unwanted solids, and acidified to precipitate the product. The crystalline product obtained can be purified by chromatography on silica gel or recrystallization to yield the title compound.
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])/[CH:2]=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].C([O:13][C:14]1O[C:17]([CH:19]=[CH2:20])=[N:16][C:15]=1[CH3:21])C.Cl.C(=O)(O)[O-].[Na+]>CO.O.CCOCC>[CH3:21][C:15]1[C:14]([OH:13])=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:2]([C:1]([O:9][CH3:10])=[O:8])=[C:17]([CH:19]=[CH2:20])[N:16]=1
Reactant: COC(=O)/C=C\C(=O)OC
Reactant: C=Cc1nc(C)c(OCC)o1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: C=Cc1nc(C)c(O)c(C(=O)OC)c1C(=O)OC

Procedure:
A mixture of 0.2 mole of dimethyl maleate and 0.1 mole of 5-ethoxy-4-methyl-2-vinyloxazole are heated at 110°-115° C. for 4 hours. The reaction mixture is cooled and 20 ml. of a 25% solution of hydrogen chloride (dry) in absolute methanol added. Addition of ether to the cooled reaction mixture precipitates the hydrochloride salt of the product. The free base is obtained by dissolving the hydrochloride salt in a minimum volume of water, adding solid sodium bicarbonate to pH 6.5 to 7.0 and extracting with chloroform. The combined chloroform extracts are dried over sodium sulfate and concentrated in vacuo to give dimethyl 2-methyl-3-hydroxy-6-vinyl-pyridine 4,5-dicarboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[C:18]([Cu])#[N:19].C(N)CN.O>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:18]#[N:19])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: N#C[Cu]
Reactant: Cc1ccc2nc(-c3ccc(Br)cc3)cn2c1
Solvent: O
Solvent: NCCN
Solvent: CN(C)C=O
Product: Cc1ccc2nc(-c3ccc(C#N)cc3)cn2c1

Procedure:
6-Methyl-2-(4'-bromophenyl)imidazo[1,2-a]pyridine (6.0 g) was mixed with 3.0 g of CuCN and 50 ml DMF. The mixture was refluxed for 24 hrs. The hot solution was then poured into a (1:4) ethylenediamine-water mixture (200 ml). Using chloroform, the compound was extracted. The chloroform layer was washed with water, dried and evaporated. The residue was crystallized and recrystallized from ethanol; yield; 3.4 g (69%); mp 225°-226° C.
Reaction SMILES: [N:1]1([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.BrCCCCCN1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32].N1C2C=CC=CC=2N=C1>>[C:23]1(=[O:32])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[CH:2]2)[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]12
Reactant: NCCCCCn1cnc2ccccc21
Reactant: O=C1c2ccccc2C(=O)N1CCCCCBr
Agent: c1ccc2[nH]cnc2c1
Product: O=C1c2ccccc2C(=O)N1CCCCCn1cnc2ccccc21

Procedure:
In this case, the 1H-benzimidazole-1-pentanamine used as the starting material was obtained by first reacting N-(5-bromopentyl)phthalimide with 1H-benzimidazole to give 1-(5-phthalimidopentyl)-1H-benzimidazole which was then treated with hydrazine to give the amine, all according to general procedures known in the art (Houben-Weyl, Vol. XI/1, page 82, George Thieme Verlag, Stuttgart, 1957).
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[N+:6]([C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=1)[C:12]([NH:14][CH2:15][C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)=[O:13])([O-:8])=[O:7].[OH-].[CH2:25]([N+:29]([CH2:38][CH2:39][CH2:40][CH3:41])([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH3:28]>C(Cl)Cl>[N+:6]([C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=1)[C:12]([NH:14][CH2:15][C:16]1[S:17][C:18]([S:2]([O-:5])(=[O:4])=[O:3])=[CH:19][CH:20]=1)=[O:13])([O-:8])=[O:7].[CH2:38]([N+:29]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:34][CH2:35][CH2:36][CH3:37])[CH2:39][CH2:40][CH3:41]
Reactant: O=C(NCc1cccs1)c1cccc([N+](=O)[O-])c1
Reactant: O=S(=O)(O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCc1ccc(S(=O)(=O)[O-])s1)c1cccc([N+](=O)[O-])c1
Reaction time: 3 h
Yield: 97.9 %

Procedure:
Chlorosulfonic acid (5.62 mL, 84 mmol) was dissolved in 20 mL CH2Cl2 and added to a solution of 3-Nitro-N-(thien-2-ylmethyl)benzamide (11.0 g, 42 mmol) in 100 mL CH2Cl2 under vigorous stirring. A gummy solid was formed and the reaction mixture was stirred for 3 h. The reaction was quenched with ice, and ice cold NaHCO3 solution was added to reach pH8.5. The aqueous layer was washed twice with CH2Cl2. Tetrabutylammoniumhydroxide (40% in water) (32 mL, 50 mmol) was added to the aqueous layer, while a solid was formed. The precipitate was extracted into CH2Cl2 and the aqueous layer was washed 3× with CH2Cl2. The combined organic layers were dried over MgSO4 and evaporated to dryness to afford a slightly colored foam of Tetrabutylammonium 5-{[(3-Nitrobenzoyl)amino]methyl}thiophene-2-sulfonate (24 g, 97%). NMR spectra indicated pure compound, which was used for the following chlorination step.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8](=[CH:14]N(C)C)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[C:4]([Cl:20])[CH:3]=1.[NH2:21][C:22]([CH3:26])([CH3:25])[CH2:23][OH:24].C(N(CC)CC)C.[C:34]([Si:38]([CH3:41])([CH3:40])Cl)([CH3:37])([CH3:36])[CH3:35]>ClCCCl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8](=[CH:14][NH:21][C:22]([CH3:26])([CH3:25])[CH2:23][O:24][Si:38]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:41])[CH3:40])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[C:4]([Cl:20])[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccc(Br)cc1Cl
Reactant: CC(C)(N)CO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCOC(=O)C(=CNC(C)(C)CO[Si](C)(C)C(C)(C)C)C(=O)c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
3.6 g of ethyl 2-(4-bromo-2-chloro-benzoyl)-3-dimethylaminoacrylate (Example 13bk)) and 2-amino-2-methyl-1-propanol in 40 ml of 1,2-dichloroethane were stirred at room temperature for 1 hr. with the direct introduction of argon. Then, 0.74 ml of triethylamine, 1.66 g of tert.-butyldimethylchlorosilane and 1.22 mg of 4-dimethylaminopyridine were added and the mixture was stirred at room temperature for 24 hrs. The reaction mixture was chromatographed directly on silica gel in dichloromethane. 4.64 g (92%) of ethyl 2-(4-bromo-2-chloro-benzoyl)-3-[2-(tert.-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethylamino]-acrylate were obtained as a colourless oil. Mass spectrum (ISP): peaks inter alia at 520 (M+H, 100%), 518 (75%).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH:8]([OH:10])[C:7]2[CH:11]=[CH:12][S:13][C:6]=2[S:5]1(=[O:15])=[O:14])[CH:2]=[CH2:3].[CH2:16]([O:18][CH:19]=[CH2:20])[CH3:17]>O1CCCC1.C(OCC)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([N:4]1[CH2:9][CH:8]([O:10][CH2:17][CH2:16][O:18][CH2:19][CH3:20])[C:7]2[CH:11]=[CH:12][S:13][C:6]=2[S:5]1(=[O:15])=[O:14])[CH:2]=[CH2:3]
Reactant: C=COCC
Reactant: C=CCN1CC(O)c2ccsc2S1(=O)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCN1CC(OCCOCC)c2ccsc2S1(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
The product from Step A (4.2 g, 17.1 mmol) was dissolved in tetrahydrofuran (75 mL) and cooled to 0° C. at which point p-toluenesulfonic acid (163 mg, 0.6 mmol) was added followed by ethylvinyl ether (3.3 mL, 34.3 mmol). This mixture was stirred at 0° C. for 2 h, diluted with cold ethyl acetate (100 mL) and washed with saturated sodium bicarbonate (70 mL) and brine (70 mL). The organic layer was dried (MgSO4) and evaporated to provide 5.2 g of crude product which was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O)[CH3:22]>>[CH2:19]([O:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[CH:2]1[N:1]([CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([O:23][CH2:21][CH3:22])[CH:25]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1)[CH3:20]
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OCC
Reactant: CCOc1cccc(C=O)c1
Product: CCOc1cccc(CN2C(=O)C(C)CC2c2c(F)cccc2OCC)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate with commercially available 3-ethoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.92 min.; [M+H]+: 372.03 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:10][C:9](O[Si](C)(C)C)=[C:8](O[Si](C)(C)C)[CH2:7][C:6]=1[C:21]([O:23][CH3:24])=[O:22])=[O:4].[CH:25]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:4])[C:5]1[C:6](=[CH:7][C:8]([NH:31][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:9]([NH:31][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:10]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)C1=C(C(=O)OC)CC(O[Si](C)(C)C)=C(O[Si](C)(C)C)C1
Reactant: NC1CCCCC1
Solvent: CC(=O)O
Product: COC(=O)c1cc(NC2CCCCC2)c(NC2CCCCC2)cc1C(=O)OC

Procedure:
A solution of 2.4 g (6 mmol) of 4,5-bis(trimethylsilyloxy)cyclohexa-1,4-diene-1,2-dicarboxylic acid dimethyl ester (Example 1a) in 21.5 ml (188 mmol) of cyclohexylamine and 4.5 ml of glacial acetic acid is boiled under reflux for 3.5 hours. The reaction mixture is cooled, the solvent is evaporated off and the dark-brown residue is dissolved in dichloromethane and the solution is washed in succession with 100 ml of 2N HCl, 50 ml of saturated NaHCO3and twice with 20 ml of water, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed on silica gel with ethyl acetate/hexane 5:12 and the product fractions are concentrated by evaporation and again chromatographed with ethyl acetate/hexane 1:4, yielding the title compound in the form of a yellow oil, FAB-MS: 388 [M+ ].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:28])[C:9](=[O:27])[C:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)([CH3:12])[CH3:11])=[C:4]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH:3]=1.C[Si](C)(C)Cl.[C:41](Cl)(=[O:47])[CH2:42][CH2:43][C:44](Cl)=[O:45]>N1C=CC=CC=1>[F:22][C:19]([F:20])([F:21])[C:17]1[CH:18]=[C:13]([C:10]([CH3:12])([CH3:11])[C:9]([N:8]([C:5]2[CH:6]=[N:7][C:2]([N:1]3[C:44](=[O:45])[CH2:43][CH2:42][C:41]3=[O:47])=[CH:3][C:4]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH3:28])=[O:27])[CH:14]=[C:15]([C:23]([F:26])([F:24])[F:25])[CH:16]=1
Reactant: O=C(Cl)CCC(=O)Cl
Reactant: Cc1ccccc1-c1cc(N)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Product: Cc1ccccc1-c1cc(N2C(=O)CCC2=O)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.25 h
Yield: 25.1 %

Procedure:
To a solution of 100 mg (0.20 mmol) N-(6-amino-4-o-tolyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide in 3 ml pyridine were added 54 mg (0.50 mmol) trimethylchlorosilane at room temperature. After stirring for 15 min, this mixture was added slowly under stirring to 155 mg (1.0 mmol) succinyl chloride and stirring was continued overnight. The solvent was removed in vacuo and the residue was purified by flash-chromatography to give 29 mg (25%) of the title compound as white solid.
Reaction SMILES: [Cl:1][CH:2]1[CH:12]=[CH:11][CH:5]2[C:6]([O:8][C:9](=[O:10])[CH:4]2[CH2:3]1)=O.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:13]1[C:9](=[O:10])[CH:4]2[CH2:3][CH:2]([Cl:1])[CH:12]=[CH:11][CH:5]2[C:6]1=[O:8]
Reactant: O=C1OC(=O)C2CC(Cl)C=CC12
Reactant: Nc1ccccn1
Product: O=C1C2C=CC(Cl)CC2C(=O)N1c1ccccn1
Temperature: 130 °C
Yield: 97 %

Procedure:
119.5 grams (0.64 moles) of 4-chlorotetrahydrophthalic anhydride and 94.1 grams (0.64 moles) of 2-aminopyridine were added to a 500-mL, 3-necked, round-bottomed flask equipped with a Dean-Stark trap topped with a condenser, a nitrogen outlet, means for maintaining a mild sweep of nitrogen over the reaction mixture, and a magnetic stir. The material was heated to 130° C. with an externally heated oil bath to provide an easily stirred melt. The reaction was heated to 175° C. for a 45 minute period. The water of imidization collected in the Dean-Stark trap. The reaction was then heated to 220 to 225° C. for 2.5 hours and the resulting amber material was transferred into a clean glass jar. The crude material was recovered in 97% yield. HPLC analysis of the crude material indicated >98% purity of the desired compound.
Reaction SMILES: O=[C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=2[CH2:4][CH2:3]1.Cl.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22]N)=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:21]=[CH:20][C:19]2[NH:22][C:2]3[C:10]4[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=4[CH2:4][C:3]=3[C:18]=2[CH:17]=1
Reactant: NNc1ccc(Br)cc1
Reactant: O=C(O)c1cccc2c1CCC2=O
Agent: Cl
Product: O=C(O)c1cccc2c1Cc1c-2[nH]c2ccc(Br)cc12

Procedure:
In a manner similar to Example 17, 1-oxo-indan4-carboxylic acid and 4-bromophenylhydrazine hydrochloride were reacted to form 8-bromo-5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acid which was converted to the ethyl ester in a manner similar to that described in Example 22 to afford the title compound as a tan solid: mp 198-200° C.; 1H NMR (DMSO-d6): δ 1.39 (t, 3H), 4.00 (s, 2H), 4.37 (q, 2H), 7.22 (d, 1H), 7.42 (d, 1H), 7.52 (t, 1H), 7.79-7.84 (m, 3H), 11.86 (s, 1H); MS [EI, m/z]: 355 [M]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:5][CH:6]([N:8]1[C:21]2[CH:20]=[C:19]([C:22]#[N:23])[CH:18]=[CH:17][C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:7])[CH3:4])[CH3:2].C(N(CC)CC)C.[SH2:31]>N1C=CC=CC=1>[CH2:1]([N:3]([CH2:5][CH:6]([N:8]1[C:21]2[CH:20]=[C:19]([C:22](=[S:31])[NH2:23])[CH:18]=[CH:17][C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:7])[CH3:4])[CH3:2]
Reactant: CCN(C)CC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCN(C)CC(C)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Reaction time: 16 h

Procedure:
A solution of 10-[(2RS)-1-(N-ethyl-N-methylamino)-2-propyl]-2-phenothiazinecarbonitrile (3 g) and triethylamine (1.3 cc) in anhydrous pyridine (60 cc) is treated with excess hydrogen sulphide, and stirring is then continued for 16 hours at a temperature in the region of 20° C. The solution obtained is purged with a stream of nitrogen for 1 hour, poured into ethyl acetate (100 cc), washed with distilled water (3×200 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual brown oil is purified by chromatography on a column (height: 40 cm; diameter: 3 cm) of silica gel (0.2-0.06 mm), eluting successively with methylene chloride (1 liter), a mixture (95:5 by volume) (1 liter) of methylene chloride and methanol and a mixture (80:20 by volume) (3 liters) of methylene chloride and methanol and collecting 150-cc fractions. Fractions 26 to 30 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 10-[(2RS)-1-(N-Ethyl-N-methylamino)-2-propyl]-2-phenothiazinecarbothioamide (2.15 g) is thereby obtained in the form of an orange oil.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]#[N:9].N1(/[C:15](/[CH3:25])=[CH:16]\[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=O)CCCC1>C(O)(=O)C>[CH3:7][C:4]1[C:3]([C:8]#[N:9])=[C:2]2[N:1]=[C:15]([CH3:25])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:6]2[N:5]=1
Reactant: Cc1n[nH]c(N)c1C#N
Reactant: C/C(=C/C(=O)c1ccccc1)N1CCCC1
Solvent: CC(=O)O
Product: Cc1cc(-c2ccccc2)n2nc(C)c(C#N)c2n1
Yield: 78.3 %

Procedure:
A mixture of 4.88 g of 5-amino-3-methyl-4-pyrazolecarbonitrile and 8.61 g of 3-(1-pyrrolidinyl)crotonophenone in 50 ml of glacial acetic acid is stirred and heated at reflux for 6 hours. The reaction mixture is cooled and the procedure described in Example 2 is then followed to obtain 7.77 g of the desired product, mp 175°-177° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([CH2:22][O:23][CH2:24][CH3:25])([OH:21])[CH:6]([N+:18]([O-])=O)[CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)[CH3:2]>[Ni].C(O)(C)C>[CH2:24]([O:23][CH2:22][C:5]([CH2:4][O:3][CH2:1][CH3:2])([OH:21])[CH:6]([NH2:18])[CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)[CH3:25]
Reactant: CCOCC(O)(COCC)C(Cc1ccc2ccccc2c1)[N+](=O)[O-]
Agent: [Ni]
Solvent: CC(C)O
Product: CCOCC(O)(COCC)C(N)Cc1ccc2ccccc2c1
Yield: 85.9 %

Procedure:
A mixture of α,α-diethoxymethyl-β-nitro-2-naphthalenepropanol (4.7 g) and Raney nickel in isopropanol (80 ml) was stirred under hydrogen at atmospheric pressure. When absorption of hydrogen was complete the mixture was degased in vacuo for 15 minutes and filtered through celite. Evaporation of the solvent in vacuo yielded α,α-diethoxymethyl-β-amino-2-naphthalenepropanol (3.69 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:13])[N:4]([CH2:10][CH2:11][CH3:12])[C:5](=[O:9])[NH:6][C:7]=1[NH2:8].[F:14][C:15]([F:32])([F:31])[C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][CH:30]=1)[CH2:19][N:20]1[CH:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[N:21]1.CCN=C=NCCCN(C)C.Cl>CO>[NH2:8][C:7]1[NH:6][C:5](=[O:9])[N:4]([CH2:10][CH2:11][CH3:12])[C:3](=[O:13])[C:2]=1[NH:1][C:25]([C:23]1[CH:22]=[N:21][N:20]([CH2:19][C:18]2[CH:28]=[CH:29][CH:30]=[C:16]([C:15]([F:32])([F:14])[F:31])[CH:17]=2)[CH:24]=1)=[O:26]
Reactant: O=C(O)c1cnn(Cc2cccc(C(F)(F)F)c2)c1
Reactant: CCCn1c(=O)[nH]c(N)c(N)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Product: CCCn1c(=O)[nH]c(N)c(NC(=O)c2cnn(Cc3cccc(C(F)(F)F)c3)c2)c1=O
Temperature: 0 °C
Reaction time: 6 h
Yield: 71.7 %

Procedure:
A mixture of 5,6-diamino-3-propyl-1H-pyrimidine-2,4-dione (4.25 g, 0.023 mol), 1-(3-Trifluoromethyl-benzyl)-1H-pyrazole-4-carboxylic acid (6.23 g, 0.023 mol), prepared by conventional methods starting from pyrazole-4-carboxylic ester, in methanol (50 ml) were cooled to 0° C. and added EDCI.HCl (8.82 g, 0.046 mol). The reaction mixture was stirred at 25° C. for 6 h and the organic volatiles were evaporated. To this residue water (50 ml) was added and the precipitate was filtered off, and washed with cold water (50 ml) to obtain 1-(3-Trifluoromethyl-benzyl)-1H-pyrazole-4-carboxylic acid (6-amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-amide (7.2 g, 72%) as a pale yellow solid.