Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][N:23]=1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:14][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:25]1[CH:24]=[N:23][C:22]([Cl:21])=[CH:27][CH:26]=1)[C:11]([CH:12]=[O:13])=[CH:10]2
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: O=Cc1cc2cccc(Cl)c2nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1cc2cccc(Cl)c2nc1-c1ccc(Cl)nc1
Temperature: 90 °C
Yield: 123.3 %

Procedure:
A mixture of 2,8-dichloroquinoline-3-carbaldehyde (2.6 g, 11.5 mmol), Na2CO3 (1.83 g, 17.3 mmol) and 2-chloropyridin-5-ylboronic acid (1.81 g, 11.5 mmol) in 1,4-dioxane (40 mL) and water (20 mL) was degassed by bubbling nitrogen gas through it for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.115 mmol) was added and the mixture was heated at 90° C. for 16 h. The mixture was allowed to cool to room temperature. The resultant precipitate was filtered off and washed with water (5×50 mL) and diethyl ether (5×50 mL) to give the title compound (4.3 g, 70%) as a tan solid.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].C([O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:17]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:16]=1)C.[CH3:38][C:39]([C:41]1[CH:42]=[CH:43][C:44]([OH:48])=[CH:45][C:46]=1[OH:47])=[O:40]>O1CCCC1>[CH2:30]([O:29][C:17]1[CH:16]=[C:15]([C:14](=[O:13])[CH2:38][C:39]([C:41]2[CH:42]=[CH:43][C:44]([OH:48])=[CH:45][C:46]=2[OH:47])=[O:40])[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(=O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: CC(=O)c1ccc(O)cc1O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: O=C(CC(=O)c1ccc(O)cc1O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1

Procedure:
A solution of 20% lithiumhexamethyldisilazane in tetrahydrofuran (200.8 mL, 240 mmol), 2,4-dihydroxy acetophenone, 14 (9.12 g, 60 mmol) in tetrahydrofuran (150 mL) and ethyl-3,4-dibenzyloxy benzoate, 9 (21.7 g, 60 mmol) in tetrahydrofuran (100 mL) were reacted to afford 17, 1-(3,4-bis-benzyloxy-phenyl)-3-(2,4-dihydroxy-phenyl)-propane-1,3-dione (55 g), which was then cyclized with Dowex-H+ (12 g) in 2-propanol (400 mL) in a similar way as described for 22 to afford 23 (Frederique, A. A. A.; Hageman, J. A.; Guido, R. M. M. H.; Van Der Vijgh, W. J. F.; Bast, A.; Menge, W. M. P. B. J. Med. Chem. 2000, 43, 3752.). Yield 24 g (89%); mp 245-247° C. (lit. 244-245° C.); MS (FAB) 451 (M++1); IR (KBr) 3426, 1607; 1H NMR (200 MHz, DMSO-d6) δ 10.79 (s, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.68 (s, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.51-7.30 (m, 10H), 7.18 (d, J=8.5 Hz, 1H), 6.98 (s, 1H), 6.91 (d, J=8.8 Hz, 1H), 6.83 (s, 1H), 5.26 (s, 2H), 5.21 (s, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH:16][C:17]([CH:19]1[C:24](=O)[C@:23]2([CH3:29])[C:26]([CH3:28])([CH3:27])[C@H:20]1[CH2:21][CH2:22]2)=[O:18])=O)(C)(C)C>ClCCl>[CH2:30]([N:15]1[C:24]2[C@:23]3([CH3:29])[C:26]([CH3:28])([CH3:27])[C@@H:20]([CH2:21][CH2:22]3)[C:19]=2[C:17](=[O:18])[NH:16]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)NC(=O)C1C(=O)[C@@]2(C)CC[C@@H]1C2(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)[C@H]2CC[C@]1(C)c1c2c(=O)[nH]n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 7.2 %

Procedure:
Trifluoroacetic acid (25.5 mL) was added to a solution of N-benzyl-N′-((1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (˜30 mmol) in dichloromethane (25.5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min, at room temperature for 2 h, heated in a flak equipped with a reflux condenser at an oil-bath temperature of 80° C. for 6 h, and then at an oil-bath temperature of 100° C. overnight in the presence of molecular sieves. The molecular sieves were filtered off and washed with dichloromethane. The filtrate was washed with water until the washings were neutral. The organic layer was dried (sodium sulfate), filtered, evaporated, and purified using a Biotage system with a 330 g column, eluting with 2-5% methanol/dichloromethane, to give (4R,7S)-1-benzyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (610 mg, 7%) as a yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>>[F:20][C:21]([F:30])([F:31])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][S:16]([C:14]2[S:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])=[CH:24][CH:23]=1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: NCc1ccc(C(F)(F)F)cc1
Product: CCc1cc(-c2ccc(S(=O)(=O)NCc3ccc(C(F)(F)F)cc3)s2)c(C)[nH]c1=O
Yield: 44 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 4-trifluoromethylbenzylamine as described in Step 5, Example 24 to give the title compound as a solid (44% yield). LC/MS: RT 3.80 min; m/e 457 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]([C:11]2[CH:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=O)=[C:4](F)[CH:3]=1.[NH:19](C(OC(C)(C)C)=O)[NH2:20].C(O)(=O)C>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:9]([C:11]3[CH:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=3)=[N:19][NH:20]2)=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(c1ccc(Cl)nc1)c1cc(F)c(Br)cc1F
Solvent: CC(=O)O
Solvent: CO
Product: Fc1cc2c(-c3ccc(Cl)nc3)n[nH]c2cc1Br
Temperature: 150 °C
Yield: 23.2 %

Procedure:
Impure (4-bromo-2,5-difluorophenyl)(6-chloro-3-pyridinyl)methanone (0.548 g) in methanol (2 ml) was stirred with 1,1-dimethylethyl hydrazinecarboxylate (0.152 g) and acetic acid (100 μl) for 20 h. The crude mixture was partitioned between sodium bicarbonate and chloroform. The organic layer was separated using a hydrophobic filter tube and the solvent was removed under vacuum. The crude material in THF (1 ml) was treated with DBU (0.358 ml) and heated in a sealed tube in a microwave oven at 150° C. for 30 min. The reaction mixture was cooled and partitioned between ethyl acetate and 0.5M aqueous hydrochloric acid. The organic layer was washed with water then brine then separated using a hydrophobic filter tube. The organic phase was concentrated under vacuum and the residue was purifiedon a silica SPE cartridge (50 g) eluting with cyclohexane/ethyl acetate (100:0 to 0:100) to give the title compound (87 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[C:11]1[N:16]2[N:17]=[C:18]([S:21][CH3:22])[C:19]([NH2:20])=[C:15]2[CH:14]=[CH:13][CH:12]=1.CC(C)([O-])C.[Na+].O.Br[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[C:11]1[N:16]2[N:17]=[C:18]([S:21][CH3:22])[C:19]([NH:20][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)=[C:15]2[CH:14]=[CH:13][CH:12]=1
Reactant: Brc1ccccn1
Reactant: COc1cc(C)cc(C)c1-c1cccc2c(N)c(SC)nn12
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(C)cc(C)c1-c1cccc2c(Nc3ccccn3)c(SC)nn12
Temperature: 120 °C
Reaction time: 5 h

Procedure:
After dissolving [7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine (40 mg) in toluene (1 mL), 2-bromopyridine (0.013 mL), sodium t-butoxide (25 mg) and dichlorobis(tri-o-tolylphosphine)palladium complex (3 mg) were added and the mixture was heated and stirred at 120° C. for 5 hours. The mixture was cooled to room temperature, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and the title compound (12 mg) was obtained from the ethyl acetate:n-hexane (1:2) fraction as white crystals.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[C:7](Cl)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>N1C=CC=CC=1>[C:7]([O:1][CH2:2][CH:3]([OH:4])[CH2:5][O:6][C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCC(O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: OC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
Glycerol (5.0 g, 54.28 mmol) was dried by coevaporations with dry pyridine and dissolved in the same solvent (100 mL). Trityl chloride (45 g, 0.16 mol) was added portionwise, and the mixture was stirred overnight at RT. All volatiles were removed in vacuo. The residue was dissolved in dichloromethane, washed twice with sat NaHCO3 and dried over Na2SO4. Precipitation from diethyl ether gave the title compound (30 g). 1H NMR (CDCl3): 7.40-7.22 (30H) 3.94 (1H, m); 3.29 (4H, m); 2.29 (1H, d, J 5.9). ESI-TOF MS: required for C41H36NaO3+599.26 (M+Na+), found 599.21.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[CH2:24]([NH:31][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: OCCCSc1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: c1ccc(CNCCCSc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.1 %

Procedure:
In 150 ml of methylene chloride were dissolved 5.22 g (30.8 mmol) of 4-(3-hydroxypropylthio)pyridine and 5.16 ml (37.0 mmol) of triethylamine, methanesulfonyl chloride [2.86 ml (37.0 mmol)] was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried. Then the solvent was distilled off. 2.62 ml (24.0 mmol) of benzylamine was added to the residue, and the mixture was heated at 80° C. for 3 hours. After cooling, the mixture was purified by column chromatography (eluent: chloroform/methanol=25:1) to obtain 1.0 g of the desired compound (yield: 16.1% yellow oil)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[C:10](=[O:22])[NH:11][C:12]2([CH2:19][CH2:18][N:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[C:13]=1[OH:14].C(N(C(C)C)C(C)C)C.Cl[C:33]([O:35][CH3:36])=[O:34]>ClC1C=CC=CC=1>[CH3:36][O:35][C:33](=[O:34])[O:14][C:13]1[C:12]2([CH2:19][CH2:18][N:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[NH:11][C:10](=[O:22])[C:9]=1[C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: CON1CCC2(CC1)NC(=O)C(c1cc(C)ccc1C)=C2O
Reactant: COC(=O)Cl
Solvent: Clc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)OC1=C(c2cc(C)ccc2C)C(=O)NC12CCN(OC)CC2
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 200 mg of 3-(2,5-dimethyl-phenyl)-4-hydroxy-8-methoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one and 0.14 ml of ethyl diisopropyl amine in 2 ml of chlorobenzene is added a solution of 66 mg of methyl chloroformate in 0.5 ml of chlorobenzene at 50° C. After stirring for 1 hour at 50° C., the reaction mixture is cooled to room temperature, diluted with 5 ml of chlorobenzene and washed with cold 5% aqueous sodium hydroxide and water. The organic phase is separated, dried over sodium sulfate, filtered and evaporated. The residue is purified by flash chromatography on silica gel. Yield: 120 mg of carbonic acid 3-(2,5-dimethyl-phenyl)-8-methoxy-2-oxo-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester methyl ester. This material is triturated with ethyl acetate/hexane, filtered and dried to afford a solid, mp: 186-188° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][CH2:8][C:9](Cl)=[O:10].[C:12]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[CH:17]2)#[N:13]>ClCCl>[Cl:5][CH2:6][CH2:7][CH2:8][C:9]([C:17]1[C:16]2[C:20](=[CH:21][CH:22]=[C:14]([C:12]#[N:13])[CH:15]=2)[NH:19][CH:18]=1)=[O:10]
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: O=C(Cl)CCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: N#Cc1ccc2[nH]cc(C(=O)CCCCl)c2c1
Temperature: 2.5 °C
Reaction time: 0.08 h
Yield: 74.9 %

Procedure:
Aluminium chloride (82.44 g) was added to dichloromethane (350 ml) under stifling at 25-30° C. The resulting mass was cooled to 0-5° C., followed by drop-wise addition of 4-chlorobutyryl chloride (87.5 g) for 30-45 minutes at 0° C. and then stirring for 5 minutes at the same temperature. A solution of 5-cyanoindole (50 g) in dichloromethane (350 ml) was added drop-wise to the resulting mass at 0-5° C. within 1-2 hours, followed by stirring for 30 minutes at the same temperature. The temperature of the reaction mass was gradually increased to 25-30° C., followed by stirring for 12-16 hours at the same temperature. The reaction mass was slowly poured into crushed ice (420 g) with slow stirring, the resulting mixture was cooled to 0-5° C. and then stirred for 1 hour at the same temperature. The separated solid was filtered, washed the material subsequently with dichloromethane (2×85 ml) and water (2×85 ml) and then dried at 25-30° C. to produce a solid material (Dry weight: 93 g). The resulting solid was dissolved in ethyl acetate (4000 ml) at 50-55° C., followed by the addition of activated carbon (5 g) and then stifling the mixture for 5 minutes at the same temperature. The resulting mass was filtered through celite bed and washed the bed with hot ethyl acetate (100 ml). The resulting filtrate was initially cooled to 25-30° C. and further cooled to 0-5° C., followed by stirring the mass for 1 hour at the same temperature. The separated solid was filtered, washed with chilled ethyl acetate (100 ml) and then dried the material at 50-55° C. until constant weight to produce 65 g of 3-(4-chlorobutyryl)-1H-indole-5-carbonitrile (Purity by HPLC: 99.2%; Yield: 74.8%).
Reaction SMILES: [K+].[N:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[C:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.Cl[CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][C:24]1=[O:28]>C1COCC1>[O:28]=[C:24]1[CH2:25][CH2:26][CH2:27][N:23]1[CH2:22][O:19][C:18]([C:10]1[NH:11][C:12]2[C:17]([C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:20]
Reactant: O=C([O-])c1[nH]c2ccccc2c1Nc1ccncc1
Reactant: O=C1CCCN1CCl
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(OCN1CCCC1=O)c1[nH]c2ccccc2c1Nc1ccncc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 8.5 %

Procedure:
Heated at 50° C. a suspension of 3-(4-pyridinylamino)-1H-indole-2-carboxylic acid potassium salt (2.0 g, 6.86 mmol) in anhydrous THF (100 mL) was oil bath for 20 min. Add to it a solution of N-(chloromethyl)-2-pyrrolidinone (1.10 g, 8.23 mmol) in anhydrous THF (5 mL) dropwise. After 3 hrs, cool the reaction to ambient temperature. Add water (100 mL) and extract with ethyl acetate (3×100 mL). Combine the organic layers and wash with NaHCO3 (sat), water, brine, dry with MgSO4 and then concentrate. Purify the residue on an ISCO RediSep 10-gram silicagel cartridge, eluting with ethyl acetate and then 5% methanol in ethyl acetate. Combine product containing fractions and concentrate to give the title compound as an off-yellow solid (205 mg): MS 313(M+H), TLC (silica gel, MeOH/EtOAc 1:1). Rf=0.33, 1H NMR (DMSO-d6) δ 11.78 (1H, s), 8.47 (1H, s), 8.09 (2H, d, J=6.2 Hz), 7.49 (3H, m), 7.09 (1H, m), 6.59 (2H), 5.76 (residual CH2Cl2), 5.44 (2H, s), 3.37 (2H, m), 2.22 (2H, m), 1.87 (2H, m).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)#[N:3]>CO.[Pd]>[C:2]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[CH2:13][CH2:12][CH2:11]2)=[CH:8][CH:9]=1)#[N:3]
Reactant: N#Cc1ccc(-c2cccc3cncn23)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: N#Cc1ccc(C2CCCc3cncn32)cc1

Procedure:
A solution of 54 mg of 5-(p-cyanophenyl)imidazo[1,5-a]-pyridine hydrochloride in 5.0 ml methanol is hydrogenated at room temperature and atmospheric pressure for 30 min with 0.1 g of 10% palladium on charcoal. The catalyst is filtered and 0.21 ml of 1N sodium hydroxide is added. The filtrate is evaporated, taken up in 10 ml of methylene chloride and filtered through Celite®. Evaporation yields an oil which is chromatographed on silica gel with ethyl acetate to yield the title compound, m.p. 117°-118°.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:18][OH:19])[CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][NH:5]1.[C:20]1([N:26]=[C:27]=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[C:20]1([NH:26][C:27]([O:1][CH2:2][CH:3]([CH2:18][O:19][C:27](=[O:28])[NH:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:4]2[C:13]3[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=3)[CH2:7][CH2:6][N:5]2[C:27](=[O:28])[NH:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1cc2c(cc1OC)C(C(CO)CO)NCC2
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)C(C(COC(=O)Nc1ccccc1)COC(=O)Nc1ccccc1)N(C(=O)Nc1ccccc1)CC2

Procedure:
0.01 mole of 1-[bis(hydroxymethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline is reacted with 0.03 mole of phenylisocyanate in toluene, as described in Example 22. The aimed compound is obtained, which has the same physical and analytical characteristics as the product of Example 26 (Table 2).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[CH3:18][NH:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1.C(N(CC)CC)C>ClCCl>[CH:1]1([CH2:4][NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:19]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[CH3:18])=[O:14])=[CH:15][CH:16]=2)[CH2:2][CH2:3]1
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)c1ccc(NC(=O)NCC2CC2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 47.9 %

Procedure:
Propanephosphonic acid cyclic anhydride (3.74 mL, 6.40 mmol) was added to a solution of 4-(3-(cyclopropylmethyl)ureido)benzoic acid (500 mg, 2.134 mmol), tert-butyl 4-(methylamino)piperidine-1-carboxylate (457 mg, 2.134 mmol) and triethylamine (1.19 mL, 8.54 mmol) in dichloromethane (20 mL). The mixture was stirred at ambient temp for 3.5 hours and then concentrated under reduced pressure. The crude material was purified by silica chromatography (eluting with a solvent gradient from 2.5% methanol/97.5% dichloromethane to 5% methanol/95% dichloromethane) to afford the title compound (440 mg). MS (ESI) m/z 431.5 [M+H]+
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[CH:11][C:5]2=[N:4][C:3]=1[CH3:12].Cl.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20]Cl.[OH-].[Na+]>C(O)C>[CH3:12][C:3]1[N:4]=[C:5]2[CH:11]=[CH:10][CH:9]=[N:8][C:6]2=[N:7][C:2]=1[S:1][CH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=1
Reactant: Cc1nc2cccnc2nc1S
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2cccnc2nc1SCc1ccccn1
Yield: 79.7 %

Procedure:
To 1.67 g of 3-mercapto-2-methylpyrido[2,3-b]pyrazine were added 10 ml of ethanol and a solution of 1.15 g of 2-picolyl chloride hydrochloride and 0.67 g of sodium hydroxide. The obtained mixture was heated under refluxing for 1.5 hrs, and then the solvent was removed under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride solution, and dried over sodium sulfate. The sodium sulfate was removed by filtration. and the filtrate was placed under reduced pressure to remove the solvent. The residue was dissolved in 20 ml of acetonitrile, and the insolubles were removed by filtration. The filtrate was concentrated to give 1.5 g of 2-methyl-3-(2-pyridylmethylthio)pyrido[2,3-b]pyrazine as a brown oil.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:21]1[CH:26]=[CH:25][C:24](F)=[C:23]([F:28])[CH:22]=1.BrC1C=CC([O:36]C)=C(F)C=1>>[F:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:21]1[CH:26]=[CH:25][C:24]([OH:36])=[C:23]([F:28])[CH:22]=1
Reactant: CCC[C@H]1CC[C@H](c2ccc3c(F)c(-c4ccc(F)c(F)c4)ccc3c2)CC1
Reactant: COc1ccc(Br)cc1F
Product: CCC[C@H]1CC[C@H](c2ccc3c(F)c(-c4ccc(O)c(F)c4)ccc3c2)CC1

Procedure:
20 g of 1-fluoro-2-(3-fluoro-4-hydroxyphenyl)-6-(trans-4-propylcyclohexyl)naphthalene (obtained in the same manner as in (5-f) except that 1-bromo-3-fluoro-4-methoxybenzene was used instead of 3,4-difluoro-1-bromobenzene to obtain 1-fluoro-2-(3-fluoro-4-methoxyphenyl)-6-(trans-4-propylcyclohexyl)naphthalene which was then demethylated with hydrobromic acid) was dissolved in 80 ml of dichloromethane. To the solution was then added dropwise 15.8 g of trifluoromethanesulfonic anhydride under cooling with ice. To the reaction mixture was then added dropwise 10 ml of pyridine in such a manner that the temperature thereof didn't exceed 5° C. After the termination of dropwise addition, the reaction mixture was stirred at the same temperature for 1 hour. To the reaction mixture was then added 20 ml of water to terminate the reaction. The resulting organic phase was washed twice with 20 ml of water, and then dehydrated and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled off. The residue was then purified through silica gel column chromatography (hexane) to obtain 24.3 g of 1-fluoro-2-(3-fluoro-4-trifluoromethanesulfonyloxyphenyl)-6-(trans-4-propylcyclohexyl)naphthalene.
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[CH2:14][S:15][C:16]1[O:17][CH:18]=[CH:19][N:20]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>ClCCl>[F:21][CH:2]([F:1])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:12])([F:13])[F:11])[C:5]=1[CH2:14][S:15]([C:16]1[O:17][CH:18]=[CH:19][N:20]=1)=[O:30]
Reactant: Cn1nc(C(F)(F)F)c(CSc2ncco2)c1OC(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1nc(C(F)(F)F)c(CS(=O)c2ncco2)c1OC(F)F

Procedure:
Under an atmosphere of argon, 2-({[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}sulfanyl)-1,3-oxazole (2.00 g, 6 mmol) is initially charged in 333 ml of dichloromethane. With stirring and ice-cooling, 3-chloroperbenzoic acid (1.362 g, 6 mmol, 77% pure) is then added a little at a time, and the mixture is stirred at 0° C. for a further 6 hours. For work-up, the reaction mixture is extracted twice with 2-molar sodium hydroxide solution and then washed with water and finally with saturated NaCl solution. The combined organic phases are dried over magnesium sulfate, filtered off and concentrated. The crude product is purified chromatographically (heptane:ethyl acetate, gradient 10:0 to 6:4). This gives 1.98 g of product (89.7% of theory).