Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH2:28][CH2:29][NH2:30])[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][CH:19]4[CH:18]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH:17]=[CH:16][C@@H:15]35)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.Cl.[N:49]1(C(N)=N)[CH:53]=CC=[N:50]1>CN(C)C=O>[O:1]([C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH2:28][CH2:29][NH:30][CH:53]=[N:49][NH2:50])[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][CH:19]4[CH:18]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:33])[CH3:34])[CH:17]=[CH:16][C@@H:15]35)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c3c1OC1C(O[Si](C)(C)C(C)(C)C)C=C[C@H]4[C@@H](C2)N(CCCN)CC[C@]314
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c3c1OC1C(O[Si](C)(C)C(C)(C)C)C=C[C@H]4[C@@H](C2)N(CCCNC=NN)CC[C@]314
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Anhydrous dimethylformamide (2 ml) was added to a mixture of 3,6-bis(t-butyldimethylsiloxy)-7,8-didehydro-4,5-epoxy-17-aminopropylmorphinan (0.2 g, 0.359 mmol), diisopropylethylamine (0.07 ml, 0.39 mmol), and 1H-pyrazole-1-carboxamidine hydrochloride (0.06g, 0.39 mmol) and the reaction mixture was stirred overnight at room temperature under nitrogen. The reaction mixture was evaporated to dryness under reduced pressure, and the crude product was chromatographed on silica gel (yield=0.155 g, 72%).
Reaction SMILES: Cl.[F:2][CH:3]([F:32])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25].Cl[C:34]([O:36][CH3:37])=[O:35]>>[CH3:37][O:36][C:34]([N:29]1[CH2:28][CH2:27][N:26]([C:24]([C:6]2[N:5]([CH2:4][CH:3]([F:2])[F:32])[C:13]3[C:8]([CH:7]=2)=[CH:9][C:10]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]2)=[CH:11][CH:12]=3)=[O:25])[CH2:31][CH2:30]1)=[O:35]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCNCC2)n3CC(F)F)CC1
Reactant: COC(=O)Cl
Agent: Cl
Product: COC(=O)N1CCN(C(=O)c2cc3cc(OC4CCN(C(C)C)CC4)ccc3n2CC(F)F)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [1-(2,2-difluoro-ethyl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone hydrochloride and methyl chloroformate. Light-yellow solid. MS (m/z): 493.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:10]([CH3:11])[C:9](=[O:12])[N:8]2[C:4](=[N:5][C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=32)[NH:3]1.[Cl:18][C:19]1[CH:20]=[C:21]([N:26]=[C:27]=[O:28])[CH:22]=[CH:23][C:24]=1[Cl:25]>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][C:27]([N:5]2[C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=3[N:8]3[C:9](=[O:12])[N:10]([CH3:11])[C:2]([CH3:17])([CH3:1])[N:3]=[C:4]23)=[O:28])[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CN1C(=O)n2c(nc3ccccc32)NC1(C)C
Product: CN1C(=O)N2C(=NC1(C)C)N(C(=O)Nc1ccc(Cl)c(Cl)c1)c1ccccc12

Procedure:
The procedure of Example 10 was employed to prepare the title compound from 1,2-dihydro-2,2,3-trimethyl-1,3,5-triazino[1,2-a]benzimidazol-4(3H)-one and 3,4-dichlorophenyl isocyanate. The confirmatory elemental analysis for the product, mp 198°-200° C., is shown in Table III.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([NH:17][CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[C:14]([CH:16]=3)[NH2:15])=[N:7][C:6]=2[CH:24]=1.[C:25]1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(OCC)(OCC)OCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]4[N:17]([CH2:18][CH2:19][C:20]([F:21])([F:23])[F:22])[CH:25]=[N:15][C:14]=4[CH:16]=3)=[N:7][C:6]=2[CH:24]=1
Reactant: Nc1cc(-c2nc3cc(Cl)ccc3o2)ccc1NCCC(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(OCC)OCC
Product: FC(F)(F)CCn1cnc2cc(-c3nc4cc(Cl)ccc4o3)ccc21
Temperature: 100 °C
Reaction time: 4 h
Yield: 598 %

Procedure:
To a solution of 5-chloro-2-(2-(3,3,3-trifluoropropyl)aminoanilin-5-yl)benzoxazole (see Working Example 138-1) (200 mg, 0.562 mmol) in triethyl orthoformate (5 mL) was added p-toluenesulfonic acid (10 mg), and this was stirred at 100° C. for 4 hours. After the reaction was complete, saturated aqueous sodium hydrogen carbonate solution was added, and this was extracted with chloroform. The organic layer obtained was dried over anhydrous sodium sulfate, filtered, and concentrated to give crude crystals that were washed with diethyl ether and ethyl acetate to yield the title compound (127 mg, 62% yield) as light yellow crystals.
Reaction SMILES: [N:1]([CH2:4][C@H:5]([OH:18])[CH2:6][N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17])=[N+]=[N-].[ClH:19].[H][H]>[Pd].CCO>[ClH:19].[NH2:1][CH2:4][C@H:5]([OH:18])[CH2:6][N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17]
Reactant: [N-]=[N+]=NC[C@H](O)CN1C(=O)c2ccccc2C1=O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NC[C@H](O)CN1C(=O)c2ccccc2C1=O
Reaction time: 8 h

Procedure:
To EtOH solution (80 ml) of N-(3-azido-2(R)-hydroxypropyl)phthalimide 1.96 g (7.69 mmol), 10% Pd—C (200 mg) and concentrated hydrochloric acid solution 1.4 ml were added sequentially. To the reaction mixture, hydrogen was introduced at 2 kgf/cm2 atm. and then stirring was continued at room temperature overnight. After removal of catalyst by filtration, catalyst was washed with EtOH/DMF (1:1) solution (60 ml) and then combined filtrate was evaporated to dryness. Addition of EtOH to the residue gave crystal of desired product as a hydrogen chloride salt. Crystal was collected by filtration and dried under reduced pressure at 40° C. to afford 1.28 g of the product. The NMR spectra were consistent with the desired title intermediate.
Reaction SMILES: S(Cl)(Cl)=O.CC(CCC)C(O)=O.CC(CCC)C(Cl)=O.[CH3:21][CH:22]([CH2:28][CH2:29][CH3:30])[C:23]([N:25]=[C:26]=[S:27])=[O:24].[Cl:31][C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][C:38]=1[O:39][C:40]1[C:49]2[C:44](=[CH:45][C:46]([O:52][CH3:53])=[C:47]([O:50][CH3:51])[CH:48]=2)[N:43]=[CH:42][CH:41]=1)[NH2:35]>C(O)C.C1(C)C=CC=CC=1>[Cl:31][C:32]1[CH:33]=[C:34]([NH:35][C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH2:28][CH2:29][CH3:30])=[S:27])[CH:36]=[CH:37][C:38]=1[O:39][C:40]1[C:49]2[C:44](=[CH:45][C:46]([O:52][CH3:53])=[C:47]([O:50][CH3:51])[CH:48]=2)[N:43]=[CH:42][CH:41]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Reactant: CCCC(C)C(=O)N=C=S
Agent: CCCC(C)C(=O)Cl
Agent: CCCC(C)C(=O)O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: CCCC(C)C(=O)NC(=S)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(Cl)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 2-methylpentanoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 2-methylpentanoyl isothiocyanate was prepared using the resultant 2-methylpentanoyl chloride as a starting compound according to the description of the literature. The resultant 2-methylpentanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 16 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (69 mg, yield 94%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19][N:20]2[CH:25]3[CH2:26][NH:27][CH2:28][CH:21]2[CH2:22][O:23][CH2:24]3)[NH:12][C:11]([C:29]2[S:30][CH:31]=[CH:32][N:33]=2)=[N:10]1.[N:34]([Si](C)(C)C)=[C:35]=[O:36]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19][N:20]2[CH:25]3[CH2:26][N:27]([C:35](=[O:36])[NH2:34])[CH2:28][CH:21]2[CH2:22][O:23][CH2:24]3)[NH:12][C:11]([C:29]2[S:30][CH:31]=[CH:32][N:33]=2)=[N:10]1
Reactant: COC(=O)C1=C(CN2C3CNCC2COC3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Br
Reactant: C[Si](C)(C)N=C=O
Product: COC(=O)C1=C(CN2C3COCC2CN(C(N)=O)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Br
Yield: 70.9 %

Procedure:
The title compound was prepared in analogy to Example 18 starting from methyl (4R)-4-(2-bromo-4-fluoro-phenyl)-6-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-ylmethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate 53b (50 mg, 0.09 mmol) and isocyanato(trimethyl)silane (43 mg, 0.37 mmol). 37 mg of the title compound was isolated as a light yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[CH:3]=1.N1C=CN=C1.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20].O>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][Si:22]([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23])[CH:8]=2)[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
2-Bromo-6-hydroxynaphthalene (100.0 g, 0.45 mol) and imidazole (75.0 g, 1.10 mol) were dissolved in 300 mL of DMF. To this solution was added TBDMS-Cl (80.0 g, 0.53 mol). The reaction was stirred at room temperature under nitrogen overnight. The reaction was poured into water, and the precipitate was filtered, washed with water and cold ethanol. The crude product was recrystallized from ethanol to give 97.2 g of off-white crystals (64% yield). 1H NMR (CDCl3) δ ppm: 0.24 (s, 6 H), 1.01 (s, 9 H), 7.07 (dd, J1=8.8 Hz, J2=2.3 Hz, 1 H), 7.14 (s, 1 H), 7.45 (dd, J1=8.8 Hz, J2=2.3 Hz, 1 H), 7.53 (d, J=8.8 Hz, 1 H), 7.60 (d, J=8.8 Hz, 1 H), 7.90 (s, 1 H). 13C NMR (CDCl3) δ ppm: −4.34, 18.24, 25,68, 114.86, 117.26, 123.05, 128.29, 128.42, 129.39, 129.57, 130.24, 133.04. Mp 62-64° C. FD-MS: 337 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](N)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].S(=O)(=O)(O)[OH:12].N([O-])=O.[Na+].NC(N)=O>O>[Cl:1][C:2]1[CH:9]=[C:8]([OH:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(N)cc1Cl
Reactant: O=S(=O)(O)O
Agent: NC(N)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(O)cc1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
A mixture of 2-chloro-4-aminobenzonitrile (25 g, 0.187 m) in stirred concentrated sulfuric acid (58 g) and water (570 ml) was heated at between 49° and 61° C. for approximately thirty minutes. The suspension was cooled to approximately 0° C. and a cold solution of sodium nitrite (13.2 g, 0.187 m) in water (125 ml) was added dropwise at a solution temperature of between 0° and 6° C. Stirring continued thereafter for approximately three hours and then urea (1.5 g) was added to the mixture. The resulting insoluble impurity was filtered off. An aqueous solution of 50% sulfuric acid (600 ml) was added while the reaction mixture was heated at a temperature between 74° and 81° C. and stirred until the evolution of nitrogen gas ceased. The reaction product was separated by filtration and then recrystallized from water to yield 2-chloro-4-hydroxybenzonitrile (17.9 g, 62.5%, mp 160° C.).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[N+](C1C=CC=CC=1)([O-])=O.[F:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1.Cl>O.[Cu].C(Cl)(Cl)Cl>[F:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:29][CH:28]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=C(O)c1ccccc1I
Agent: [Cu]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(O)c1ccccc1Oc1ccc(F)cc1
Temperature: 160 °C
Reaction time: 0.67 h

Procedure:
To 147 g of iodobenzoic acid and 45.5 g of potassium carbonate are added 57 ml of nitrobenzene. The mixture is heated with stirring at 160° C. for 40 minutes. To the heated mixture is added an additional 46.5 g of potassium carbonate and then successively 73.1 g of 4-fluorophenol, another 46.5 g of potassium carbonate and 0.3 g of copper powder. After these additions, the mixture is stirred at 160° C. for 45 minutes and the resulting solid is cooled to 0° C. The cooled solid is mixed with 100 ml of water and 220 ml of 6N hydrochloric acid. The acidic mixture is diluted with water to a volume of one liter and then mixed with 450 ml of chloroform. The white solid is filtered off and washed with chloroform and water. The solid is dissolved in hot acetone, cooled and filtered to leave a white crystalline product, mp 146°-147° C. of 2-(4-fluorophenoxy)benzoic acid.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:45])[CH:5]([NH:15][C:16]([C:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[C:27]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([NH:36][C:37]([C:39]4[O:40][CH:41]=[CH:42][C:43]=4[CH3:44])=[O:38])[CH:31]=3)[CH:26]=[CH:25][N:24]=2)[NH:20][CH:19]=1)=[O:17])[CH2:6][CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([NH:3][C:4](=[O:45])[CH:5]([NH:15][C:16]([C:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[C:27]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([NH:36][C:37]([C:39]4[O:40][CH:41]=[CH:42][C:43]=4[CH3:44])=[O:38])[CH:31]=3)[CH:26]=[CH:25][N:24]=2)[NH:20][CH:19]=1)=[O:17])[CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH3:2]
Reactant: CCNC(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c1c[nH]c(-c2cc(Oc3cccc(NC(=O)c4occc4C)c3)ccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)C(CCC(=O)O)NC(=O)c1c[nH]c(-c2cc(Oc3cccc(NC(=O)c4occc4C)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl 5-(ethylamino)-4-({[5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3-yl]carbonyl}amino)-5-oxopentanoate (34 mg, 0.055 mmol) in 5 ml of methylene chloride was added 2 ml of TFA. The mixture was stirred at room temperature for 1 hour, and evaporated to dryness under reduced pressure. The residue was re-dissolved in 5 ml of methanol and poured into 100 ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give 5-(ethylamino)-4-({[5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3-yl]carbonyl}amino)-5-oxopentanoic acid as white solid. Yield: 26 mg, 84%.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:10]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C[O:25][C:26](=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Br)[CH:28]=1>>[N:1]1([CH2:7][CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:23][CH2:22][N:21]([CH2:33][C:29]4[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=4)[C:26]([OH:35])=[O:25])[CH2:20][CH2:19]3)=[CH:10]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)c(C1CCNCC1)cn2CCN1CCOCC1
Reactant: COC(=O)c1cccc(CBr)c1
Product: O=C(O)c1cccc(CN2CCC(c3cn(CCN4CCOCC4)c4ccccc34)CC2)c1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 2.4 g (7.5 mmol) of 1-(2-morpholin-4-yl-ethyl)-3-piperidin-4-yl-1H-indole and 1.8 g (7.8 mmol) of 3-bromomethyl-benzoic acid methyl ester. After standard work-up and purification, 0.75 g (22% of yield) of the expected acid were obtained.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].CC(C)[O-].[Ti+4:13].CC(C)[O-].CC(C)[O-].CC(C)[O-]>C1(C)C=CC=CC=1>[C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O-:4])[O-:2].[Ti+4:13].[C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O-:4])[O-:2]
Reactant: Oc1ccccc1O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Product: [O-]c1ccccc1[O-]
Temperature: 100 °C

Procedure:
A solution of catechol (22.0 g, 200 mmol) and toluene (220 ml) was dehydrated by distilling 20 mL of the solution. Thereafter, 28.4 g (100 mmol) of titanium(IV) isopropoxide (TTIP) was added to the solution while stirring. The mixed solution was refluxed for 1 hour, and then, while the distillation temperature was 100° C. or higher, distilled until the amount of the solution became half. After the distillation, solid content of the product was isolated by suction filtering using a membrane suction filter. The residual solid content was heated to 100° C. under vacuum using a vacuum dryer so that remaining volatile components were completely removed. The solid content (catechol-titanium complex) was brown in color. The yield amount was 26.0 g (98.5 mmol), and the yield percentage was 98%. 2.64 g of catechol-titanium complex was dissolved into 100 mL of 1:4 acetylacetone/toluene to produce a coating liquid.
Reaction SMILES: [C:1]([S:4][C@@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O=C(Cl)OC(Cl)(Cl)Cl.[Cl:50][CH2:51][C:52]([NH:54][C:55]1[S:56][CH:57]=[C:58]([C:60](=[N:64][O:65][CH3:66])[C:61]([OH:63])=O)[N:59]=1)=[O:53].C1OC1C>C(N(CC)CC)C.CN(C=O)C.N1C=CC=CC=1>[C:1]([S:4][C@@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:61](=[O:63])[C:60]([C:58]1[N:59]=[C:55]([NH:54][C:52](=[O:53])[CH2:51][Cl:50])[S:56][CH:57]=1)=[N:64][O:65][CH3:66])(=[O:3])[CH3:2]
Reactant: CON=C(C(=O)O)c1csc(NC(=O)CCl)n1
Reactant: CC(=O)S[C@@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC1CO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CON=C(C(=O)N[C@@H]1C(=O)N[C@H]1SC(C)=O)c1csc(NC(=O)CCl)n1
Yield: 65.3 %

Procedure:
By employing 0.805 g of (3R,4S)-4-acetylthio-3-tritylamino-2-oxoazetidine, 0.437 g of p-toluenesulfonic acid monohydrate, 0.19 g of pyridine, and, 0.175 g of DMF, 0.144 ml of diphosgene, 0.61 g of 2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetic acid, 0.243 g of triethylamine and 2 ml of propylene oxide, a procedure similar to Reference Example 38B is taken to give 0.548 g of (3R,4S)-4-acetylthio-3-[2-(2-chloroacetoamidothiazole-4-yl)-2-methoxyiminoacetoamido]-2-oxoazetidine.
Reaction SMILES: C1(OC(=O)[N:9]([CH2:13][CH2:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)(=[O:17])=[O:16])[CH:10]([CH3:12])[CH3:11])C=CC=CC=1>Br>[Cl:25][C:20]1[CH:19]=[C:18]([S:15]([CH2:14][CH2:13][NH:9][CH:10]([CH3:12])[CH3:11])(=[O:16])=[O:17])[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: CC(C)N(CCS(=O)(=O)c1ccc(Cl)c(Cl)c1)C(=O)Oc1ccccc1
Agent: Br
Product: CC(C)NCCS(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 32.4 %

Procedure:
A solution of 44.27 g (0.107 mole of N-[2-[(3,4-dichlorophenyl)sulfonyl]ethyl]-N-(1-methylethyl)carbamic acid phenyl ester in 300 ml of 48% HBr was heated at reflux for 12 hr. The reaction mixture was cooled to room temperature, made alkaline with 50% sodium hydroxide-ice and extracted with chloroform. The chloroform layer was extracted with 1N sulfuric acid. The sulfuric acid layer was extracted with chloroform and the chloroform layers combined and evaporated to an oil, the free base of the title compound. A portion of the oil was reacted with ethereal hydrogen chloride to give an overall yield of 32.4% white crystalline product, m.p. 219°-221° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[C:8]2[C:20]3[N:19]4[CH:21]=[CH:22][N:23]=[C:18]4[C:17](=[O:24])[NH:16][C:15]=3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=3)[CH:2]=1.CN(C)C=O>[Pd].C(O)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]2[C:20]3[N:19]4[CH:21]=[CH:22][N:23]=[C:18]4[C:17](=[O:24])[NH:16][C:15]=3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=3)[CH:2]=1
Reactant: O=c1[nH]c2c3ccccc3c(=Cc3cccnc3)c2n2ccnc12
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=c1[nH]c2c(n3ccnc13)C(Cc1cccnc1)c1ccccc1-2
Yield: 37.8 %

Procedure:
The procedure is performed as in Example 21, but starting with 1 g of 10-(3-pyridylmethylene)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 150 ml of dimethylformamide, 5 ml of acetic acid and 0.1 g of 10% palladium on charcoal. 0.38 g of 10-(3-pyridylmethyl)-5H,10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-4-one is obtained, in the form of an off-white solid melting above 260° C. (Analysis % calculated C: 72.60, H: 4.49, N: 17.82, O: 5.09, % found C: 72.3, H: 4.8, N: 17.8, O: 5.4).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].[CH3:12][CH2:13][CH2:14][CH:15]([NH2:19])[CH2:16][CH2:17][CH3:18]>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:19][CH:15]([CH2:16][CH2:17][CH3:18])[CH2:14][CH2:13][CH3:12])=[O:8])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1O
Reactant: CCCC(N)CCC
Product: CCCC(CCC)NC(=O)c1ccc(O)c(C)c1

Procedure:
Prepared in a similar manner as described in example 4 using 4-hydroxy-3-methyl benzoic acid and 4-heptylamine. MS (M+H, 250.2).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.N1CCC(OC2C=CC(C#N)=CC=2)C[CH2:24]1>C(OC(=O)C)(=O)C.N1C=CC=CC=1>[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)(=[O:5])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C#N)cc2)CC1
Reactant: N#Cc1ccc(OC2CCNCC2)cc1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCC(Oc2ccc(C#N)cc2)CC1

Procedure:
Synthesized from 4-(4-cyanophenoxy)piperidine-1-carboxylic acid tert-butyl ester (1.5 g) according to an analogous synthetic method to Example 215 described below, the total amount of 4-(piperidin-4-yloxy)benzonitrile crude product was dissolved in acetic anhydride (20 ml) and pyridine (20 ml), and the solution was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, extracted with ethyl acetate, then sequentially washed with a saturated aqueous solution of sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (1.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[C:5]2[CH:6]=[CH:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:9]=2[CH:10]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:16])([CH3:18])[CH3:17])=[C:4]([NH:19][S:28]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=2)(=[O:30])=[O:29])[CH:3]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[Si](C)(C)CCOCn1ccc2c(N)cc(Cl)cc21
Product: COc1ccc(S(=O)(=O)Nc2cc(Cl)cc3c2ccn3COCC[Si](C)(C)C)cc1
Yield: 0.1 %

Procedure:
6-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-4-amine (880 mg, 2.52 mmol) was treated with 4-methoxybenzene-1-sulfonyl chloride (572 mg, 2.77 mmol) according to the method described in Preparation 15b to give 1.48 mg (97% yield) of the title compound. Purity 85%.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][N:5]=1)[CH3:2].S(=O)(=O)(O)O.[N+:19]([O-])([OH:21])=[O:20].C(=O)([O-])O.[Na+]>>[CH2:1]([NH:3][C:4]1[C:9]([N+:19]([O-:21])=[O:20])=[CH:8][C:7]([C:10]([F:13])([F:11])[F:12])=[CH:6][N:5]=1)[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCNc1ccc(C(F)(F)F)cn1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCNc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 95 °C

Procedure:
A mixture of N-ethyl-(5-trifluoromethylpyridin-2-yl)-amine (1.0 g) and sulfuric acid (7 ml) was stirred with heating at 95° C., and then a mixture of fuming nitric acid (0.45 ml) and sulfuric acid (3 ml) were added thereto, and stirred with heating for 1 hour. The reaction mixture cooling to room temperature was poured into ice, and then saturated aqueous sodium hydrogen carbonate solution was poured, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to give 600 mg of N-ethyl-(3-nitro-5-trifluoromethylpyridin-2-yl)-amine.