Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5](OC)=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].Cl.C(C1C=CC(CC[NH2:24])=CC=1)C.N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1.O>[C:7]([NH2:24])(=[O:8])[C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:10]=1
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: CCc1ccc(CCN)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: NC(=O)c1ccccc1

Procedure:
A solution of 4.1 g of 5-chloro-2-methoxy-benzoyl chloride in 20 ml of toluene was added dropwise to a suspension of 4.65 g of 2-(4-ethylphenyl)-ethylamine hydrochloride in 100 ml of anhydrous toluene after addition of 5 ml of pyridine. The whole was heated under reflux, then shaken with water, dilute hydrochloric acid and a solution of sodium bicarbonate and dried over sodium sulfate. After concentration under reduced pressure, the residue, which solidified only slowly, was filtered off with suction after addition of petroleum ether (B.p. 30°-60° C.). The 5-chloro-2-methoxy-N-(2-<4-ethylphenyl>-ethyl)-benzamide so obtained was found to melt at 66°-68° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:5][C:6](=[O:9])[C:7]=1[CH3:8])=O.[CH2:10]([CH2:12][NH2:13])[OH:11]>>[OH:11][CH2:10][CH2:12][N:13]1[C:6](=[O:9])[C:7]([CH3:8])=[C:2]([CH3:1])[C:3]1=[O:5]
Reactant: NCCO
Reactant: CC1=C(C)C(=O)OC1=O
Product: CC1=C(C)C(=O)N(CCO)C1=O
Yield: 88.7 %

Procedure:
Analogously to Example 2, 126 g (1 l mol) of 2,3-dimethylmaleic anhydride and 61 g (1 mol) of ethanolamine are reacted to give 150 g of N(2-hydroxyethyl)-2,3-dimethylmaleimide (boiling point 110° C. under 13.3 Pa; yield 89% of theory). The N(2-hydroxyethyl)-2,3-dimethylmaleimide is mixed with 181.5 g (1.78 mols) of acetic anhydride and 3 drops of concentrated sulfuric acid and the mixture is refluxed for one hour in an oil bath heated to 160° C. The acetic acid formed and the acetic anhydride are then distilled off in vacuo. Fractionation of the residue under a high vacuum yields 179 g of N(2-acetoxyethyl)-2,3-dimethylmaleimide (boiling point 104° C./6.66 Pa; yield 95% of theory). The N(2-acetoxyethyl)-2,3-dimethylmaleimide is introduced dropwise, under nitrogen, in the course of 75 minutes into a glass column which is filled with Raschig rings and is heated to 550° C. The pyrolysis products are collected at the lower end of the glass column in a cooled receiver. The yellow oil obtained is taken up in diethyl ether and treated with aqueous sodium bicarbonate solution in order to remove the acetic acid. After drying the organic phase over sodium sulfate, the solvent is removed in vacuo and the product is distilled under a high vacuum. In addition to 39.3 g of unconverted starting material, 84.7 g of (N-vinyl)-2,3-dimethylmaleimide are obtained in the form of a yellowish oil; boiling point 58°-60° C./53.33 Pa; yield: 85% of theory, based on converted starting material.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:21]2[CH:20]=[N:19][C:18]([C:17]([F:28])([F:27])[F:16])=[CH:23][CH:22]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(C(F)(F)F)nc2)nc2cc(F)cc(F)c2c1Cl

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.50 g, 2.02 mmol), 2-(trifluoromethyl)-pyridine-5-boronic acid (0.385 g, 2.02 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 18 h to give 4-chloro-5,7-difluoro-3-methyl-2-(6-(trifluoromethyl)pyridin-3-yl)quinoline as a white solid. Mass Spectrum (ESI) m/e=359.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[N:9]/[OH:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].ClCCl.[Cl:18][C:19]1[CH:24]=[C:23]([C:25]([C:27]([F:30])([F:29])[F:28])=[CH2:26])[CH:22]=[C:21]([C:31]([F:34])([F:33])[F:32])[CH:20]=1.[O-]Cl.[Na+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:26][C:25]([C:23]3[CH:22]=[C:21]([C:31]([F:32])([F:33])[F:34])[CH:20]=[C:19]([Cl:18])[CH:24]=3)([C:27]([F:30])([F:29])[F:28])[O:10][N:9]=2)=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: C=C(c1cc(Cl)cc(C(F)(F)F)c1)C(F)(F)F
Reactant: O/N=C/c1ccc(Br)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: ClCCl
Product: FC(F)(F)c1cc(Cl)cc(C2(C(F)(F)F)CC(c3ccc(Br)c(C(F)(F)F)c3)=NO2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed (E)-N-[[4-bromo-3-(trifluoromethyl)phenyl]methylidene]hydroxylamine (1.5 g, 5.60 mmol, 1.00 equiv), dichloromethane (20 mL), 1-chloro-3-(trifluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (1.6 g, 5.83 mmol, 1.10 equiv), NaOCl (10 mL). The resulting solution was stirred for 2 h at room temperature. The resulting solution was diluted with 30 mL of H2O. The resulting solution was extracted with 3×50 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 3×50 mL of brine. The mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100). This resulted in 1.7 g (56%) of 3-[4-bromo-3-(trifluoromethyl)phenyl]-5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazole as a light yellow solid.
Reaction SMILES: [H-].[Na+].C1(C)C=CC=CC=1.C(OP([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])(OCC)=O)C.[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[C:31](=O)[CH2:30][CH2:29]2>O>[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)/[C:31](=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])/[CH2:30][CH2:29]2
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1ccc2c(c1)CCC2=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C1\CCc2cc(OC)ccc21
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed sodium hydride (1 g, 46.00 mmol, 2.50 equiv), toluene (150 mL), ethyl 2-(diethoxyphosphoryl)acetate (7 g, 31.22 mmol, 1.69 equiv). This was followed by the addition of 5-methoxy-2,3-dihydro-1H-inden-1-one (3 g, 18.50 mmol, 1.00 equiv) at 30° C. The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting solution was diluted with 10 mL of water. The resulting solution was extracted with 3×100 mL of toluene and the organic layers combined. The resulting mixture was washed with 2×20 mL of sodium chloride. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (30:70). This resulted in 2 g (47%) of ethyl 2-[(1E)-5-methoxy-2,3-dihydro-1H-inden-1-ylidene]acetate as yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]#[N:17])[CH2:15][C@@:9]1([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:10]([O:18][C@H:19]([C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=1)[CH2:20][OH:21])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[H-].[Na+].[CH2:46]1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]#[N:17])[CH2:15][C@@:9]1([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:10]([O:18][C@H:19]([C:22]1[CH:27]=[C:26]([C:28]([F:30])([F:31])[F:29])[CH:25]=[C:24]([C:32]([F:33])([F:34])[F:35])[CH:23]=1)[CH2:20][O:21][CH3:46])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: N#C[C@@H]1C[C@@]2(c3ccccc3)[C@H](O[C@@H](CO)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC[C@H](O[C@@H]1CC[C@H]2[C@H](C#N)C[C@]1(c1ccccc1)N2Cc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
(1R*,2R*,5S*,6R*)-8-Benzyl-2-{(1R*)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octane (Example 156; 0.3 g, 0.5 mmol), methyl iodide (0.04 g, 0.02 ml, 0.3 mmol), sodium hydride (0.04 g, 1.6 mmol) and 18-crown-6 (0.3 g, 1 mmol) in N,N-dimethylformamide (3 ml) was heated at 60° C. for 1 hour. The mixture was quenched with water and extracted with ethyl acetate. The organics were collected, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with 30% ethyl acetate/hexane. The title compound was isolated as a white crystalline solid (285 mg, 97%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:43](=[O:44])[N:13]3[C:14]([C:27]([O:29][CH:30]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[S:28])=[C:15]([C:18]4[S:19][CH:20]=[C:21]([CH2:23][C:24]([OH:26])=O)[N:22]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.[NH:67]1[CH2:72][CH2:71][O:70][CH2:69][CH2:68]1.C(=O)([O-])O.[Na+]>CN(C)C=O.C(OCC)(=O)C.O>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:43](=[O:44])[N:13]3[C:14]([C:27]([O:29][CH:30]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[S:28])=[C:15]([C:18]4[S:19][CH:20]=[C:21]([CH2:23][C:24]([N:67]5[CH2:72][CH2:71][O:70][CH2:69][CH2:68]5)=[O:26])[N:22]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1COCCN1
Reactant: O=C(O)Cc1csc(C2=C(C(=S)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)Cc4ccccc4)[C@H]3SC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(c3nc(CC(=O)N4CCOCC4)cs3)CS[C@H]12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 26.5 %

Procedure:
To a solution of benzhydryl 7β-(2-phenylacetamido)-3-(4-carboxymethylthiazol-2-yl)thio-3-cephem-4-carboxylate (500 mg) in N,N-dimethylformamide (10 ml) were added 1-hydroxybenzotriazole (123 mg), WSC.HCl (175 mg) and morpholine (79 mg) at room temperature. After stirring at room temperature for 2.5 hours, the solution was poured into a mixture of water and ethyl acetate, and adjusted to pH 7.0 with aqueous sodium hydrogen carbonate. The separated organic layer was washed with saturated sodium chloride solution (×3), dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (eluent: ethyl acetate/n-hexane) to give benzhydryl 7β-(2-phenylacetamido)-3-(4-morpholinocarbonylmethylthiazol-2-yl)thio-3-cephem-4-carboxylate (147 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.CCCCCC.Cl[C:16]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]=[C:18]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:17]=1>O1CCCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]2[N:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:19]=[C:18]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:17]=2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Brc1ccc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)cc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
1,4-Dibromobenzene 2.64 g (11.2 mmol) was dissolved in 30 mL of dried tetrahydrofuran and cooled down to −70° C. A hexane solution (1.6M) 7.4 mL (11.8 mmol) was dropwise added slowly to the above solution and stirred at −70° C. for 30 minutes. A tetrahydrofuran solution of 2-chloro-4,6-diphenyl-1,3,5-triazine 3.00 g (11.2 mmol) was dropwise added to the above mixture at −70° and stirred at −70° C. for 30 minutes, and then the solution was heated slowly up to room temperature and stirred further for 1.5 hour. The mixture thus obtained was extracted with ethyl acetate, and the organic layer was washed in order with water and a saturated saline solution and dried on anhydrous magnesium sulfate. Then, the solvent was removed by distillation, and the residue was refined by silica gel chromatography to thereby obtain 1.48 g (yield: 34%) of 2-(4-bromophenyl)-4,6-diphenyl-1,3,5-triazine.
Reaction SMILES: [O:1]1[CH:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:2]1[C:3]([O:5]C)=[O:4].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([NH:30][CH:2]([CH:7]([OH:1])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:3]([OH:5])=[O:4])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCCCCCCCCCCCCCCC1OC1C(=O)OC
Reactant: NCc1ccccc1
Product: CCCCCCCCCCCCCCCC(O)C(NCc1ccccc1)C(=O)O
Yield: 68 %

Procedure:
For preparation of racemic dihydrosphingosines, K. Sisido, et al., report in J. Org. Chem., Vol. 29, No. 9, pp. 2783-2784 (1964) a process comprising, for example, reacting methyl trans-2-octadecenoate with perbenzoic acid in chloroform to obtain methyl 2,3-epoxyoctadecanoate having formula (V'): ##STR3## whose planar structure is the same as that of the compound represented by formula (V) hereinafter described, hydrolyzing the ester (V'), cyclizing the resulting acid by reaction with benzylamine to obtain 2-benzylamino-3-hydroxyoctadecanoic acid (cyclization yield: 68%), converting the acid to a methyl ester, and reducing the ester in an ether solvent with lithium aluminum hydride (LiAlH4) (reduction yield: 71%). Reduction of such a carboxylic acid as 2-benzylamino-3-hydroxyoctadecanoic acid to an alcohol has generally been carried out by once esterifying the carboxylic acid and using LiAlH4 as a reducing agent as in the above report. However, LiAlH4 is a reagent unsuitable to industrial use because it is not only expensive but difficult to handle on account of reactivity with moisture in air.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH:8]=O)=[CH:3][CH:2]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:18]23[CH2:27][CH2:26][CH2:25][CH2:24][C:23]2([CH3:28])[CH2:22][NH:21][CH2:20][CH2:19]3)[CH:15]=[CH:16][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:8]([N:21]1[CH2:20][CH2:19][C:18]2([C:14]3[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH3:10])[CH:13]=3)[C:23]([CH3:28])([CH2:24][CH2:25][CH2:26][CH2:27]2)[CH2:22]1)[CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: COc1cccc(C23CCCCC2(C)CNCC3)c1
Reactant: O=CCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1cccc(C23CCCCC2(C)CN(CCc2ccccc2)CC3)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
Phenacetaldehyde 87 mg (0.72 mmol) and 190 mg (0.72 mmol) of 10 were mixed in 1,2-dichloroethane (15 mL) and then treated with sodium triacetoxyborohydride 230 mg (1.08 mmol). The reaction mixture remained cloudy throughout the reaction. The mixture was stirred at room temperature under N2 atmosphere for 2 h. The reaction mixture was quenched by adding saturated NaHCO3, and the product was extracted with EtOAc. The EtOAc extract was dried (MgSO4), and the solvent was evaporated to give 0.25 g (95%) of a light yellow oil. Purification by chromatography on alumina using 10% ethyl acetate/hexane gave 0.23 g (89%) of desired product 11 as colorless clear viscous oil: 13C NMR (300 MHz, CDCl3) δ 158.9, 129.1, 128.6, 128.1, 126.2, 122.5, 117.1, 109.9, 63.2, 61.1, 55.5, 43.1, 37.4, 36.3, 34.0, 30.7, 22.4, 22.1.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[CH2:10]([O:12][C:13](=[O:25])[C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[O:15])[CH3:11].C([O-])([O-])=O.[K+].[K+]>>[CH2:10]([O:12][C:13](=[O:25])[C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:17]=1)=[O:15])[CH3:11]
Reactant: CCOC(=O)C(=O)c1c[nH]c2ccccc12
Reactant: ClCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(=O)c1cn(CCN2CCCCC2)c2ccccc12
Yield: 65.7 %

Procedure:
The general procedure 1 was then followed using 1-(2-chloroethyl)piperidine (10 mmol, 1.5 g), ethyl-2-(1H-indol-3-yl)-2-oxoacetate (7 mmol, 1.5 g) and K2CO3 (10.9 mmol, 1.5 g). The purification was achieved by column chromatography (petrol-ether:ethylacetate:diethylamine 8:1:1) to yield ethyl-2-{1-[2-(piperidin-1-yl)ethyl]-1H-indol-3-yl}2-oxoacetate (4.6 mmol, 66%) as an pale yellow oil. IR {tilde over (ν)} [cm−1]=2936; 2857; 1730; 1638. EI-MS m/z (rel. int.)=328 (18.99%; M+•.). 1H NMR (300 MHz, CDCl3) 8.43 (m; 2H; indole-H); 7.35 (m; 3H; indole-H); 4.40 (q; 3J=7.1 Hz; 2H; OCH2CH3); 4.25 (t; 3J=6.8 Hz; 2H; indole-CH2CH2N); 2.72 (t; 3J=6.8 Hz; 2H; indole-CH2CH2N); 2.43 (m; 4H; piperidin-CH2(C-2+6)); 1.57 (m; 4H; piperidin-CH2(C-3+5)); 1.43 (m; 5H; piperidin-CH2(C-4)+OCH2CH3).
Reaction SMILES: [OH:1][CH:2]([CH2:11][OH:12])[CH2:3][N:4]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Cl[C:14]1[N:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>O1CCOCC1>[OH:1][CH:2]([CH2:11][OH:12])[CH2:3][N:4]1[CH2:10][CH2:9][CH2:8][N:7]([C:14]2[N:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])[CH2:6][CH2:5]1
Reactant: OCC(O)CN1CCCNCC1
Reactant: O=C(O)c1cccnc1Cl
Solvent: C1COCCO1
Product: O=C(O)c1cccnc1N1CCCN(CC(O)CO)CC1

Procedure:
Grams 5 of 1-(2,3-dihydroxypropyl)homopiperazine and 2.25 g of 2-chloronicotinic acid in 50 ml dioxane were refluxed for 24 hours. The reaction mixture was evaporated to dryness and the residue was purified on column eluting with ethanol:ammonium hydroxyde (95:5). The fractions containing the product were dried and the residue, triturated with acetonitrile, gave 1.3 g of 2-[4-(2,3-dihydroxypropyl)homopiperazin-1-yl]nicotinic acid, melting at 70°-77° C. (with decomposition).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12]2[NH:13][C:14]3[C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.S(O)(O)(=O)=O.[NH2:53][C:54]1[NH:55][CH:56]=[CH:57][N:58]=1>>[NH:55]1[CH:56]=[CH:57][N:58]=[C:54]1[NH:53][C:21]([C:20]1[C:14]2[NH:13][C:12]([NH:11][C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[N:16][C:15]=2[CH:17]=[CH:18][CH:19]=1)=[O:22]
Reactant: O=C(O)c1cccc2nc(Nc3cc4ccccc4cn3)[nH]c12
Reactant: Nc1ncc[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Product: O=C(Nc1ncc[nH]1)c1cccc2nc(Nc3cc4ccccc4cn3)[nH]c12
Yield: 16.4 %

Procedure:
100 mg (0.33 mmol) of the above carboxylic acid was reacted with 200 mg (0.53 mmol) of HBTU and 200 mg (1.2 mmol) of 2-aminoimidazole sulfate according to the general procedure A. The crude product was purified by flash column chromatography (EtOAc then EtOAc/MeOH=10:1) to give 2-(isoquinolin-3-ylamino)-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide (20 mg, 15%). LCMS: 370 (M+1)+. 1H NMR (DMSO-d6, 400 MHz): δ 6.82 (s, 1H), 6.89 (s, 1H), 7.20 (dd, 1H), 7.47 (dd, 1H), 7.71 (m, 2H), 7.84 (dd, 1H), 8.04 (s, 1H), 8.08 (d, 1H), 8.18 (d, 1H), 9.21 (s, 1H), 11.14 (s, 1H), 11.84 (s, 1H), 12.11 (s, 1H), 12.60 (s, 1H) ppm.
Reaction SMILES: [CH2:1]=[C:2]([CH3:4])[CH3:3].[Br:5][C:6]([CH3:11])([CH3:10])[C:7]([OH:9])=[O:8].FC(F)(F)C(O)=O>C(Cl)Cl>[Br:5][C:6]([CH3:11])([CH3:10])[C:7]([O:9][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:8]
Reactant: CC(C)(Br)C(=O)O
Reactant: C=C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)C(C)(C)Br

Procedure:
Isobutene is condensed into a solution of 2-bromo-2-methylpropanoic acid (10 mmol) and trifluoroacetic acid (1 mmol) in 100 mL of CH2Cl2 until the starting material is consumed, as observed by TLC. The volatile components are evaporated in vacuo, and the residue is filtered through a pad of neutral alumina using 50% ether/hexane. The filtrate is concentrated in vacuo and used without further purification.
Reaction SMILES: FC1[C:11]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=CC2NC=C3C(=O)N(C4C=CC=CC=4)N=C3C=2C=1.F[C:29]1[C:30]([F:48])=[CH:31][C:32]2[C:33]3[C:34]([C:39](=[O:47])[N:40]([C:42]4[CH:46]=[CH:45][S:44][CH:43]=4)[N:41]=3)=[CH:35][NH:36][C:37]=2[CH:38]=1.CN1CCNCC1>>[F:48][C:30]1[C:29]([N:15]2[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)=[CH:38][C:37]2[NH:36][CH:35]=[C:34]3[C:39](=[O:47])[N:40]([C:42]4[CH:46]=[CH:45][S:44][CH:43]=4)[N:41]=[C:33]3[C:32]=2[CH:31]=1
Reactant: O=c1c2c[nH]c3cc(F)c(F)cc3c-2nn1-c1ccsc1
Reactant: O=c1c2c[nH]c3cc(N4CCNCC4)c(F)cc3c-2nn1-c1ccccc1
Agent: CN1CCNCC1
Product: CN1CCN(c2cc3[nH]cc4c(=O)n(-c5ccsc5)nc-4c3cc2F)CC1

Procedure:
The title compound was prepared following the procedure described in the synthesis of 28a using 27d and 1-methylpiperazine. 1H-NMR (DMSO-d6) δ (ppm): 2.28 (3H, s), 2.64 (4H, brm), 3.22 (4H, brm), 7.21 (1H, m), 7.58 (1H, m), 7.79 (3H, m), 8.67 (1H, m). m/z 384.2
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:20][CH3:21])=[C:8]([C:10]2[CH:18]=[C:17]3[C:13]([CH2:14][C:15](=[O:19])[NH:16]3)=[CH:12][CH:11]=2)[CH:9]=1)([CH3:3])[CH3:2].[N:22]1([CH2:27][CH2:28][NH:29][C:30]([C:32]2[C:36]([CH3:37])=[C:35]([CH:38]=O)[NH:34][C:33]=2[CH3:40])=[O:31])[CH2:26][CH2:25][CH2:24][CH2:23]1>>[N:22]1([CH2:27][CH2:28][NH:29][C:30]([C:32]2[C:36]([CH3:37])=[C:35]([CH:38]=[C:14]3[C:13]4[C:17](=[CH:18][C:10]([C:8]5[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[CH:6][C:7]=5[O:20][CH3:21])=[CH:11][CH:12]=4)[NH:16][C:15]3=[O:19])[NH:34][C:33]=2[CH3:40])=[O:31])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Reactant: COc1ccc(C(C)C)cc1-c1ccc2c(c1)NC(=O)C2
Product: COc1ccc(C(C)C)cc1-c1ccc2c(c1)NC(=O)C2=Cc1[nH]c(C)c(C(=O)NCCN2CCCC2)c1C
Yield: 74.8 %

Procedure:
6-(5-Isopropyl-2-methoxyphenyl)-1,3-dihydroindol-2-one (50 mg, 0.17 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)amide (45 mg) to give 67 mg (75%) of the title compound as an orange solid.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:35])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[CH3:35][C:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:29]5[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=5)=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: Cn1nccc1-c1ccc(C2(c3nnc4n3CCSC(C)(CO[Si](C)(C)C(C)(C)C)C4)CC2)cc1
Agent: Cl
Solvent: CO
Product: Cn1nccc1-c1ccc(C2(c3nnc4n3CCSC(C)(CO)C4)CC2)cc1
Yield: 104.4 %

Procedure:
A solution of the compound (159 mg, 0.31 mmol) obtained in Example 56-1) and 4 M hydrochloric acid (1,4-dioxane solution, 1 mL) in methanol (4 mL) was stirred at room temperature for 15 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (128 mg, quant.) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2Cl)[N:7]=[C:8]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[NH:9][C:10]=1[CH3:11])=[O:4].[F:25]C1C=C(C=CC=1F)C=O>>[CH3:1][O:2][C:3]([C:5]1[CH:6]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:25])[CH:18]=2)[N:7]=[C:8]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[NH:9][C:10]=1[CH3:11])=[O:4]
Reactant: COC(=O)C1=C(C)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Reactant: O=Cc1ccc(F)c(F)c1
Product: COC(=O)C1=C(C)NC(c2nccs2)=NC1c1ccc(F)c(F)c1

Procedure:
Compound D was prepared in analogy to Compound B with the procedure shown in Scheme 3 by using 3,4-difluoro-benzaldehye instead of 2-chloro-5-fluorobenzaldehyde.