Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[C:5]([C:13]([OH:15])=O)=[CH:4][C:3]=1[Cl:16].ClC(OCC)=O.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH:25]1[O:35][CH3:36]>ClC(Cl)Cl.C(N(CC)CC)C>[NH2:1][C:2]1[C:7]2[CH2:8][C:9]([CH3:11])([CH3:12])[O:10][C:6]=2[C:5]([C:13]([NH:23][C@H:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][C@H:25]2[O:35][CH3:36])=[O:15])=[CH:4][C:3]=1[Cl:16]
Reactant: CC1(C)Cc2c(N)c(Cl)cc(C(=O)O)c2O1
Reactant: CCOC(=O)N1CCC(N)C(OC)C1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CC[C@H](NC(=O)c2cc(Cl)c(N)c3c2OC(C)(C)C3)[C@H](OC)C1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
To a solution of 8.1 parts of 4-amino-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofurancarboxylic acid in 218 parts of trichloromethane and 3.43 parts of N,N-diethylethanamine were added dropwise 3.63 parts of ethyl chloroformate, keeping the temperature below 10° C. After stirring for 1/2 hour at 10° C., the whole was added to a solution of 6.26 parts of ethyl 4-amino-3-methoxy-1-piperidinecarboxylate in 145 parts of trichloromethane at 10° C. Stirring was continued for 1/2hour at room temperature. The reaction mixture was washed with water, NaOH 5% and water and was then dried, filtered and evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and dried, yielding 12.3 parts (93.2%) of ethyl cis-4-[(4-amino-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofuranyl)carbonylamino ]-3-methoxy-1-piperidinecarboxylate (interm. 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:14]([O:16][CH2:17][CH3:18])=[CH2:15])CCC.[F-].[K+].C(OCC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[CH2:15])[N:5]=[CH:4][N:3]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=C(OCC)c1cc(Cl)ncn1
Temperature: 80 °C
Yield: 45.5 %

Procedure:
4,6-Dichloropyrimidine (1.0 g, 6.71 mmol), bis(triphenylphosphine)palladium(II) chloride (0.094 g, 0.134 mmol) and tributyl[1-(ethyloxy)ethenyl]stannane (2.449 mL, 7.25 mmol) were added together in DMF (25 mL) and the resulting mixture was heated at 80° C. under argon for 18 hours. The reaction mixture was allowed to cool to room temperature and poured into an aqueous solution of potassium fluoride (5.7 g in 57 mL water). Diethyl ether (80 mL) was added and the solid was filtered, washed with diethyl ether (×2) and discarded. The filtrate was separated and the organic layer was washed with water, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Biotage SP4) eluting with a gradient of 0-20% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a white solid (564 mg);
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)=[C:2]=[O:3].[CH2:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:30]=1[NH:36][C:37]([NH2:39])=[S:38])[CH3:28]>>[CH2:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:30]=1[NH:36][C:37]([NH:39][C:2]([NH:1][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:25])([F:24])[F:26])=[CH:18][CH:17]=3)[N:12]=2)[CH:6]=1)=[O:3])=[S:38])[CH3:28]
Reactant: CCc1cccc(C)c1NC(N)=S
Reactant: O=C=NCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Product: CCc1cccc(C)c1NC(=S)NC(=O)NCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1

Procedure:
The title compound was prepared as described in Example 75 using 3-(3-(isocyanatomethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (CB34) and 1-(2-ethyl-6-methylphenyl)thiourea (CA39) and isolated as an off-white solid (0.212 g, 50%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][C@H:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH:20]([CH3:22])[CH3:21])[N:12]=2)=[O:10])[CH2:5][N:4]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].[H-].[Na+].C1OCCOCCOCCOCCOCCOC1.Br[CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53]>O1CCCC1>[CH2:55]([O:54][C:52](=[O:53])[CH2:51][O:1][CH2:2][C@@H:3]1[CH2:7][C@H:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH:20]([CH3:21])[CH3:22])[N:12]=2)=[O:10])[CH2:5][N:4]1[C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH3:56]
Reactant: CCOC(=O)CBr
Reactant: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](CO)N(C(=O)OC(C)(C)C)C2)c2ccccc21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COC[C@@H]1C[C@H](NC(=O)c2nn(C(C)C)c3ccccc23)CN1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
To a stirred solution of tert-butyl (2S,4S)-2-(hydroxymethyl)-4-{[(1-isopropyl-1H-indazol-3-yl) carbonyl]amino}pyrrolidine-1-carboxylate (358 mg, 0.89 mmol, step 2 of Example 7) in tetrahydrofuran (7 mL) was added sodium hydride (60% dispersion in mineral oil, 90 mg, 2.2 mmol) at 0° C. Then to the solution was added 18-crown-6 (164 mg, 0.45 mmol) and a solution of ethyl bromoacetate (446 mg, 2.67 mmol) in tetrahydrofuran (5 mL) at 0° C. It was stirred overnight rising to room temperature. The resulting mixture was quenched by addition of water and it was extracted with ethyl acetate (10 mL×3). The organic layer was washed with brine, dried over sodium sulfate and concentrated. The resulting residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (2:1 to 1:1) to give 310 mg (71%) of the title compound as a colorless oil.
Reaction SMILES: [Br-:1].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[C:30](=[O:44])[CH2:31][C:32]1[CH:33]=[CH:34][C:35]2[N:36]([C:38]([CH:41]([CH3:43])[CH3:42])=[N:39][N:40]=2)[N:37]=1>C1COCC1.C(Cl)Cl>[Br:1][CH:31]([C:32]1[CH:33]=[CH:34][C:35]2[N:36]([C:38]([CH:41]([CH3:42])[CH3:43])=[N:39][N:40]=2)[N:37]=1)[C:30]([C:24]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=1[F:22])=[O:44]
Reactant: CC(C)c1nnc2ccc(CC(=O)c3ccc(F)cc3F)nn12
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)c1nnc2ccc(C(Br)C(=O)c3ccc(F)cc3F)nn12
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
Pyridinium tribromide (0.567 g, 1.77 mmol) was added to a solution of 1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (0.488 g, 1.54 mmol; Preparation #K.1) in THF (6 mL) and the resulting reaction mixture was stirred at ambient temperature for about 4 h. The crude mixture was diluted with DCM (20 mL) and washed with water. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude title compound (0.61 g, 100%): LC/MS (Table 1, Method a) Rt=3.28 min; MS m/z: 396.9 (M+H)+.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[CH3:26][NH:27][CH2:28][CH2:29][OH:30]>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[N:27]([CH2:28][CH2:29][OH:30])[CH3:26])=[O:13])[CH2:8]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Reactant: CNCCO
Product: CN(CCO)c1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccccc1

Procedure:
5-[(2-Hydroxy-ethyl)-methyl-amino]-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and 2-(methylamino)ethanol. Mass spectrum (ES) MH+=396.
Reaction SMILES: CO.[N+:3]([C:6]1[CH:21]=[CH:20][C:9]([O:10][CH2:11][C:12]([CH3:19])=[CH:13][CH2:14]CC([O-])=O)=[CH:8][CH:7]=1)([O-:5])=[O:4].C(=O)([O-])[O-:23].[K+].[K+]>O>[N+:3]([C:6]1[CH:21]=[CH:20][C:9]([O:10][CH2:11][C:12]([CH3:19])=[CH:13][CH2:14][OH:23])=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: CC(=CCCC(=O)[O-])COc1ccc([N+](=O)[O-])cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(=CCO)COc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 176.5 %

Procedure:
Into methanol (1,200 ml) and water (400 ml) were dissolved 120 g (0.25 mol) of [4-(p-nitrophenoxy)-3-methyl-2-butenyl]acetate. With stirring at room temperatures, 40 g (0.29 mol) of potassium carbonate were added therein, and stirred for one hour. The reaction liquid was added into water and extracted with ethyl acetate. After the organic layer was washed with water and dried, the solvent was distilled off, whereby 98.5 g of the title compound were obtained. (Yield: 98.5%)
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:11]([C:19]1[CH:31]=[C:30]2[C:22]([C:23]3[CH:24]=[CH:25][C:26]([C:32](Cl)=[O:33])=[CH:27][C:28]=3[CH2:29]2)=[CH:21][CH:20]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N1C=CC=CC=1>O1CCOCC1>[C:1]([NH:9][NH:10][C:32]([C:26]1[CH:25]=[CH:24][C:23]2[C:22]3[C:30](=[CH:31][C:19]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:20][CH:21]=3)[CH2:29][C:28]=2[CH:27]=1)=[O:33])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC(=O)NN
Reactant: CCCCCCCCc1ccc2c(c1)Cc1cc(C(=O)Cl)ccc1-2
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CCCCCCCCc1ccc2c(c1)Cc1cc(C(=O)NNC(=O)CCCCCC)ccc1-2
Temperature: 0 °C
Yield: 69.8 %

Procedure:
Then, in a 50 ml-three-necked flask, 0.32 g (2.22 mM) of heptanohydrazide and 15 ml of dioxane were placed. To the mixture, a solution of the above-prepared 7-octyl-2-fluorenecarbonyl chloride in 5 ml of dioxane was added, followed by addition of 0.84 ml of pyridine at about 85° C. under stirring and further stirring for 30 minutes at 85°-88° C. After the reaction, the reaction mixture was cooled and poured into 200 ml of ice water to precipitate a crystal. The crystal was recrystallized from a mixture solvent of toluene-acetone to obtain 0.68 g of N-heptanoyl-N'-(7-octyl-2-fluorenecarbonyl) hydrazine (Yield: 69.8%).
Reaction SMILES: [C:1]1(=[O:17])[N:5]([N:6]2[CH:10]=[CH:9][CH:8]=[C:7]2[CH3:11])[C:4](=[O:12])[C:3]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]12.[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].[Sn](Cl)(Cl)(Cl)Cl>ClCCl>[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([C:10]1[N:6]([N:5]2[C:4](=[O:12])[C:3]3=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]3[C:1]2=[O:17])[C:7]([CH3:11])=[CH:8][CH:9]=1)=[O:22]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Cc1cccn1N1C(=O)c2ccccc2C1=O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2ccccc2Cl)n1N1C(=O)c2ccccc2C1=O
Yield: 75.1 %

Procedure:
To a suspension of 1-phthalimido-2-methylpyrrole (105 g, 0.46 mol) and o-chlorobenzoyl chloride (162.5 g, 0.93 mol) in 1.5 liters of dichloromethane at 0° was added tin (IV) chloride (243 g, 0.94 mol) over 15 minutes. The resultant mixture was warmed to room temperature over 30 minutes and then quenched with 2 liters of H2O. The organic layer was washed with H2O and brine, dried (MgSO4), charcoaled and filtered. Evaporation of the volatiles left an oil which was purified by flash chromatography (silica, dichloromethane) to give 126 g of powder. This powder was recrystallized from ether-petroleum ether to give 82 g (48%) of powder, m.p. 260°-262°.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9]([C:12]1[C:13](=[O:23])[O:14][C:15]([OH:22])=[C:16]([C:19](=O)[CH3:20])[C:17]=1[OH:18])(=[O:11])[CH3:10]>CO>[C:9]([C:12]1[C:13](=[O:23])[O:14][C:15](=[O:22])[C:16](=[C:19]([NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH2:8])[CH3:20])[C:17]=1[OH:18])(=[O:11])[CH3:10]
Reactant: Nc1ccccc1N
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Solvent: CO
Product: CC(=O)C1=C(O)C(=C(C)Nc2ccccc2N)C(=O)OC1=O

Procedure:
o-Phenylenediamine (2.1 g., 0.02 m.) is added to a hot solution of 4.2 g. (0.02 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in methanol and the resulting mixture is refluxed for two hours. The reaction mixture is cooled and filtered to yield 5-acetyl-3-[1-(o-aminophenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 179°-181° C.
Reaction SMILES: [C:1]1([S:7][CH2:8][N:9]=[C:10]=[S:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH-:12].[K+:13]>CC(C)=O.C(O)(C)(C)C>[C:1]1([S:7][CH2:8][NH:9][C:10](=[S:12])[S-:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K+:13]
Reactant: S=C=NCSc1ccccc1
Reactant: [SH-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CC(C)(C)O
Product: S=C([S-])NCSc1ccccc1

Procedure:
Potassium phenylthiomethyldithiocarbamate was prepared by the reaction of phenylthiomethyl isothiocyanate and potassium hydrosulfide in a t-butyl alcohol acetone mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:20])[CH2:10][N:9]=1.[OH-].[Na+].CO.Cl.Cl[CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>O>[N:29]1([CH2:28][CH2:27][S:20][C:11]2[CH2:10][N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:14]3[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=3[N:12]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: ClCCN1CCCC1
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCC(SCCN1CCCC1)=N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 9.6 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-1,4-benzodiazepine-2-thione in a solvent mixture comprising 40 ml of a 10% aqueous sodium hydroxide solution and 40 ml of methanol is added at room temperature 4.4 g of 1-chloro-2-(1-pyrrolidinyl)ethane hydrochloride, and the resulting mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate and, thereafter, the solvent is distilled off under reduced pressure to obtain an oily 2-[2-(1-pyrrolidinyl)ethylthio]-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine. The oily product thus obtained is treated, according to usual procedure, with fumaric acid and recrystallized from isopropyl alcohol to obtain 6.9 g of 2-[2-(1-pyrrolidinyl)ethylthio]-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine fumarate, m.p. 184°-188° C.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([CH2:20]O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS([Cl:33])(=O)=O>ClCCl>[CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([CH2:20][Cl:33])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=c1c(CO)nn(Cc2ccccc2)c2cccc(Cl)c12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1c(CCl)nn(Cc2ccccc2)c2cccc(Cl)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 58.2 %

Procedure:
To 0.42 g (1.4 mmol) of 1-benzyl-5-chloro-3-hydroxymethylcinnolin-4(1H)-one in 25 mL of dichloromethane at 0° C. was added 0.97 mL (7.0 mmol) of triethylamine and 0.33 mL (4.2 mmol) of methanesulfonyl chloride. The reaction was allowed to warm to room temperature and stirred for 5 h. The reaction was concentrated by rotary evaporation and was subsequently dissolved in dichloromethane and concentrated onto silica gel. The crude material was purified by flash chromatography eluting with a 33-50% ethyl acetate/hexanes gradient mixture to give 0.26 g (59%) of the title compound as an off-white solid.
Reaction SMILES: [CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4].[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24].C[Si](Cl)(C)C.O>ClCCl>[CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:25]([CH2:26][CH3:27])[CH2:23][CH3:24])=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCNCC
Reactant: CCCCN(CCCC)CCCOc1ccc(C(=O)Cl)cc1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: O
Product: CCCCN(CCCC)CCCOc1ccc(C(=O)N(CC)CC)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 77 %

Procedure:
6.5 g of 4-(3-dibutylaminopropoxyl)benzoyl chloride (V) (0.02 mol) is dissolved in 60 mL of dichloromethane. 1.46 g of diethylamine (0.02 mol, 1 eq) is added and the reaction mixture is cooled to 0° C. 0.43 g TMSCl (0.004 mol, 0.2 eq) is added in 5 min. The reaction mixture is heated to room temperature and stirred for 5 hours. 50 mL of water is added to the mixture, it is stirred for 15 min and the phases are separated. The organic phase is washed with 30 mL of water then it is concentrated. The residue is purified by column chromatography (spheric silica; eluent: toluene:MTBE:methanol=5:4:1) to give 5.58 g of the title compound (VId) (77%) as a yellowish solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH:20]1([NH2:27])[CH2:25][CH2:24][CH2:23][CH:22]([NH2:26])[CH2:21]1>>[NH2:26][CH:22]1[CH2:23][CH2:24][CH2:25][CH:20]([NH:27][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:21]1
Reactant: O=C(Nc1nc2cccc(Cl)n2n1)c1ccccc1
Reactant: NC1CCCC(N)C1
Product: NC1CCCC(Nc2cccc3nc(NC(=O)c4ccccc4)nn23)C1
Reaction time: 0.08 h

Procedure:
The title compound was prepared following procedure described for example 30 but starting from N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B3), 52 mg; 0.19 mmol; 1.0 eq) and 1,3-cyclohexanediamine (1.0 mL). The crude was directly purified by preparative HPLC (Starting with 45% ACN in water for 5 min, then up to 60% in 10 min.). The title compound was isolated after lyophilisation as a white powder (63 mg, 94%). HPLC, Rt: 1.84 min. (purity 98.2%). LC/MS, M+(ESI): 351.4, M−(ESI): 349.4.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:15][NH:16][CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([N:16]([CH3:17])[CH3:15])=[O:5]
Reactant: CNC
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.5 %

Procedure:
To a 50 mL round bottom flask, 2-fluoro-4-nitrobenzoic acid (3.0 g, 0.0162 mol) and DMF (10 mL) was added. To the same flask, TEA (4.6 mL, 0.0324 mol), dimethylamine hydrochloride (2.65 g, 0.0324 mol), HOBt (3.28 g, 0.0243 mol) and EDCI.HCl(4.62 g, 0.0243 mol) was added. The reaction mixture was stirred at room temperature for 12 h. The reaction mass was quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to get the title compound [2.8 g, 81%]. 1H NMR (300 MHz, CDCl3): δ 8.12 (d, J=8.4 Hz, 1H), 8.02 (d, J=8.7 Hz, 1H), 7.62 (dd, J′=8.1 Hz, J″=6.6 Hz, 1H), 3.16 (s, 3H), 2.93 (s, 3H); LC-MS (ESI): Calculated mass: 212.1; Observed mass: 213.1 (RT: 0.37 min).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH3:5])[O-:3].[Al+3:6].[CH3:7][CH:8]([CH2:10][CH3:11])[O-:9].[CH3:12][CH:13]([CH2:15][CH3:16])[O-:14].[OH2:17].[N+]([O-])(O)=[O:19]>C(O)(CC)C>[CH3:1][CH:2]([CH2:4][CH3:5])[O-:3].[Al+3:6].[CH3:7][CH:8]([CH2:10][CH3:11])[O-:9].[CH3:12][CH:13]([CH2:15][CH3:16])[O-:14].[OH2:19].[OH2:17].[OH2:3].[OH2:3].[Al:6]
Reactant: O=[N+]([O-])O
Agent: CCC(C)[O-]
Agent: [Al+3]
Solvent: O
Solvent: CCC(C)O
Product: [Al]
Reaction time: 3 h

Procedure:
Aluminum sec-butoxide was prepared in accordance with the process described in U.S. Pat. No. 4,242,271. A 75% mixed solution of this aluminum sec-butoxide in sec-butyl alcohol was hydrolyzed at 85° C. with a mixed solution of sec-butyl alcohol containing 30% of water to obtain an alumina slurry. After the alumina slurry was aged at 125° C. for 3 hours in an electromagnetically stirring autoclave, water was immediately added to the alumina slurry until a solids content was 20%, and the thus-treated alumina slurry was cooled. The pH of the alumina slurry was adjusted with a 3.8% aqueous solution of nitric acid to obtain Alumina Hydrate 6A. Alumina hydrate A obtained by drying colloidal sol of this alumina hydrate was determined by X-ray diffractometry and found to have a pseudoboehmite structure. At this time, the BET specific surface area was 175 m2/g, and the pore volume was 0.65 ml/g. Incidentally, the specific surface area and pore volume were determined by the following respective methods.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](/[CH:19]=C/C)=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:22]=[O+][O-].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:18]([CH:19]=[O:22])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[O+][O-]
Reactant: C/C=C/c1ccc2ncccc2c1OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=Cc1ccc2ncccc2c1OCc1ccccc1

Procedure:
Treatment of 5-(benzyloxy)-6-[(1E)-prop-1-enyl]quinoline in methylene chloride with excess ozone at −78° C. followed by addition of diisopropylethylamine, aqueous work-up, and subsequent purification by flash column chromatography provides 5-(benzyloxy)quinoline-6-carbaldehyde.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[NH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1>>[N:14]1([S:2]([C:5]2[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=2)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Product: O=C(O)c1cccc(S(=O)(=O)N2CCCc3ccccc32)c1

Procedure:
3-(chlorosulfonyl)benzoic acid (0.5 g, 2.27 mmol) was treated with 1,2,3,4-tetrahydroquinoline (906 mg, 6.80 mmol) using method A to give 3-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid as an off white solid. Yield: 318 mg (44%). 1H-NMR: 8.17 (d, J=8.0 Hz, 1H), 8.06-8.04 (m, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.68 (t, J=8.0 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.24-7.18 (m, 1H), 7.15-7.05 (m, 2H), 3.80-3.76 (m, 2H), 2.40 (t, J=6.5 Hz, 2H), 1.61-1.54 (m, 2H).
Reaction SMILES: Br[CH2:2][CH:3]([C:12]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:30])[NH:17]2)[O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][NH2:40])=[CH:34][CH:33]=1>CS(C)=O.C(OCC)(=O)C>[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][NH:40][CH2:2][C@@H:3]([C:12]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:18]3[C:13]=2[CH:14]=[CH:15][C:16](=[O:30])[NH:17]3)[O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6])=[CH:34][CH:33]=1
Reactant: NCCc1ccc(N)cc1
Reactant: CC(C)(C)[Si](C)(C)OC(CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCc1ccc(N)cc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 100 °C
Yield: 91.6 %

Procedure:
A mixture of 5-(2-bromo-1-(tert-butyl-dimethyl-silanyloxy)-ethyl)-8-benzyloxy-1H-quinolin-2-one (5.0 g, 1.0 equiv) and 2-(4-aminophenyl)ethylamine (2.8 g, 2.0 equiv) in dimethylsulfoxide (10 mL) was heated at 100° C. for 12 h. The reaction mixture was cooled to 20° C., and the resulting red oil was diluted with ethyl acetate (200 mL) and extracted with two portions water (200 mL). The organic layer was washed with two portions of (1:1 10% aqueous acetic acid and saturated aqueous sodium chloride (200 mL). The organic layer was basified by carefully extracting with two portions of saturated sodium bicarbonate (200 mL), followed by saturated sodium chloride (200 mL). The resulting organic solution was treated with anhydrous sodium sulfate, and the solvent was removed under reduced pressure to afford the title intermediate (5.1 g) which was used without further purification.