Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]#[N:6])(=[O:3])[CH3:2].[Na].Cl[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Cl>CN(C)C=O>[C:1]([N:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:4]([C:5]#[N:6])[C:1](=[O:3])[CH3:2])[C:5]#[N:6])(=[O:3])[CH3:2]
Reactant: CC(=O)NC#N
Reactant: ClCCCCCCCl
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(=O)N(C#N)CCCCCCN(C#N)C(C)=O

Procedure:
106.1 g (1.0 mol) of sodium acetylcyanamide and 77.5 g (0.5 mol) of 1,6-dichlorohexane are reacted in 750 ml of dimethylformamide at 146°-147° C. for 8 hours, the mixture is then filtered with suction and the filtrate is concentrated on a rotary evaporator at 80° C. in vacuo. 125 g (99.9% of theory) of a crude product, which is recrystallised from a mixture of acetone/diisopropyl ether (3:5), are obtained. The yield of pure substance is 58.8 g (46.9% of theory) and the product has a melting point of 59°-61° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:26][CH2:25][C:5]2=[C:6]([C:13]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=3)=[O:14])[C:7]3[C:12]([N:4]2[CH2:3]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[OH-].[Na+].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CO.C1COCC1.O>[CH3:1][N:2]1[CH2:26][CH2:25][C:5]2=[C:6]([C:13]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)=[O:14])[C:7]3[C:12]([N:4]2[CH2:3]1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: COC(=O)c1ccc(C(=O)c2c3n(c4ccccc24)CN(C)CC3)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN1CCc2c(C(=O)c3ccc(C(=O)O)cc3)c3ccccc3n2C1
Reaction time: 0.5 h

Procedure:
To a solution of methyl 4-(2-methyl-1,2,3,4-tetrahydropyrimido[1,6-a]indole-5-carbonyl)benzoate (80 mg) in 1 mL of MeOH, 2 mL of THF and 1 mL of water was added 0.2 mL of 2N NaOH. After stirring for 0.5 h, the reaction mixture was treated with 5 mL of pH7 potassium phosphate buffer, extracted with 4×20 mL of EtOAc. The combined extracts were dried over Na2SO4, filtered, and concentrated to give the crude title compound which was used for the next step without further purification.
Reaction SMILES: C([O:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]3[O:16][CH2:15][O:14][C:11]=3[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])C.[C:22]1(C)C=CC=C[CH:23]=1>>[CH2:22]([N:7]1[C:8]2[C:13](=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[C:4](=[O:3])[C:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6]1)[CH3:23]
Reactant: CCOC(=O)c1cnc2cc3c(cc2c1OCC)OCO3
Reactant: Cc1ccccc1
Product: CCOC(=O)c1cn(CC)c2cc3c(cc2c1=O)OCO3

Procedure:
A melt of 5 g of ethyl 4-ethoxy-6,7-methylenedioxyquinoline-3-carboxylate was heated at 220°C for 7 hours and then cooled. The product was thinned with toluene, filtered and recrystallized from chloroform petroleum ether to provide 3.7 g of ethyl 1-ethyl-6,7-methylenedioxy-4-quinolone-3-carboxylate as needles, m.p. 177°-178°C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15](=[O:17])[CH3:16])[CH:8]=[C:9]([C:11]([OH:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br-:18].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.O.C(=O)([O-])O.[Na+]>C1COCC1>[Br:18][CH2:16][C:15]([C:7]1[CH:8]=[C:9]([C:11]([OH:14])([CH3:13])[CH3:12])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1)=[O:17]
Reactant: CC(=O)c1cc(C(C)(C)C)cc(C(C)(C)O)c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.7 %

Procedure:
1-[3-tert-Butyl-5-(1-hydroxy-1-methylethyl)phenyl]ethanone (O2.100; 50 mg) was initially charged in THF (5 ml) while stirring at RT, and admixed with phenyltrimethylammonium tribromide (80 mg). After stirring at RT for 3 h, the mixture was left to stand overnight and admixed with water and saturated sodium hydrogencarbonate solution. Then it was extracted three times with EA, and the combined EA phases were dried over sodium sulfate, filtered and concentrated. The residue was purified using silica gel (10 g cartridge, n-heptane/EA gradient). 42 mg of the title compound were obtained. LC-MS rt: 1.10 min [M+H—H2O]+: 295.1 (met. b)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:22])=[C:12]([F:23])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4].IC.[C:26](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:22])=[C:12]([F:23])[C:8]2[N:9]=[CH:10][N:11]([CH3:26])[C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2c(ncn2C)c(F)c1Nc1ccc(Br)cc1Cl
Yield: 35.7 %

Procedure:
A solution of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester 8b (150 mg, 0.38 mmol), iodomethane (28 μL, 0.45 mmol) and potassium carbonate (78 mg, 0.56 mmol) in dimethylformamide (1.5 mL) is stirred at 75° C. for one hour. The reaction mixture is diluted with ethyl acetate, washed with saturated aqueous potassium carbonate (2×), brine, and dried (Na2SO4). Flash column chromatography (20:1 methylene chloride/ethyl acetate) provides 56 mg (36%) of the more mobile 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid methyl ester 9a as a white solid. 19F NMR (376 MHz, CD3OD)−133.5 (s). MS APCI (+) m/z 412, 414 (M+, Br pettern) detected. Also isolated in 54 mg (35%) of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-1-methyl-1H-benzoimidazole-5-carboxylic acid methyl ester as a white solid. 19 F NMR (376 MHz, CD3OD)−139.9 (s). MS APCI (+) m/z 412, 414 (M+, Br pattern) detected.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([O:6][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5]
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1c(Cl)ccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1c(Cl)ccnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
A mixture of 2,4-dichloronicotinic acid (5.0 g, 26 mmol), benzyl bromide (3.7 mL, 31 mmol) and K2CO3 (7.2 g, 52 mmol) in DMF (50 mL) was stirred at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate. The organic layers were combined and washed with water, brine, dried over sodium sulfate, evaporated and then purified by silica chromatography (0-7% ethyl acetate in hexanes) to give benzyl 2,4-dichloronicotinate (7.0 g, 96%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:28])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10](=[O:21])[C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:8]2)=[O:4].[Br:29]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:28])=[C:7]2[C:12](=[C:13]([Br:29])[N:14]=1)[N:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10](=[O:21])[C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2-c2ccccc2)c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2-c2ccccc2)c1O
Yield: 68.3 %

Procedure:
A mixture of 5-hydroxy-2-oxo-1,3-diphenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (138 mg, 0.37 mmol) and N-bromosuccinimide (73 mg, 0.41 mmol) in CH2Cl2 (1.5 mL) was refluxed for 3.5 h. Solvent was evaporated in vacuo, and the residue was purified twice by silica gel chromatography (0-100% EtOAc/hexanes+1% AcOH, then 30-100% CH2Cl2/hexanes) to give 114 mg of the title compound as a pale yellow solid. MS: (+) m/z 451.25, 453.01 (M+1, 79/81Br).
Reaction SMILES: [CH3:1][NH:2][C:3]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([O:26][CH3:27])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH3:15])=[CH:9][CH:8]=1)=O.CO.[ClH:30].C(OCC)C>O1CCCC1>[ClH:25].[ClH:30].[CH3:1][NH:2][CH2:3][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([O:26][CH3:27])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH3:15])=[CH:11][CH:12]=1
Reactant: CNC(=O)COc1ccc(CC(C)NCC(OC)c2cccc(Cl)c2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CO
Product: CNCCOc1ccc(CC(C)NCC(OC)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of N-[2-(4-methylaminocarbonylmethoxyphenyl)-1-methylethyl]-2-methoxy-2-(3-chlorophenyl)ethanamine (0.50 g; 85:15 mixture of diastereoisomers) in dry tetrahydrofuran (20 ml) was added borane-methyl sulphide complex (2 ml), under nitrogen. The solution was boiled under reflux for 3 hours, and after cooling to room temperature, methanol (6 ml) was added. This solution was allowed to stand overnight at room temperature, boiled under reflux for 1 hour, cooled, and hydrogen chloride gas passed through for 10 minutes. After dilution with diethyl ether, cooling to 0° C. and filtering, N-[2-(4-(2-methylaminoethoxy)phenyl)-1-methylethyl]-2-methoxy-2-(3-chlorophenyl)ethanamine dihydrochloride, mp 270°-273° C. (methanol-ethyl acetate), was obtained as a single diastereoisomer.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9](Cl)=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH3:16]>>[NH2:16][C:9]1[C:10](=[O:11])[N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[N:6]=[CH:7][C:8]=1[N+:13]([O-:15])=[O:14]
Reactant: CC(C)(C)n1ncc([N+](=O)[O-])c(Cl)c1=O
Reactant: N
Product: CC(C)(C)n1ncc([N+](=O)[O-])c(N)c1=O

Procedure:
6.95 g of 2-tert-butyl-4-chloro-5-nitropyridazin-3-(2H)-one and 50 ml of 28% aqueous ammonia were mixed, sealed and reacted for 5 hours in an oil bath of 110° C. After cooling, the precipitate was collected by filtration and washed a few times with water and then dried to obtain 5.97 g of 4-amino-2-tert-butyl-5-nitropyridazin-3-(2H)-one.
Reaction SMILES: Br[CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:3].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([OH:20])[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1>>[CH3:3][CH:2]([O:20][C:14]1[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=[C:12]([O:11][CH3:10])[CH:13]=1)[CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)CCCC(C)Br
Reactant: COc1cc(O)cc(OC)c1
Product: COc1cc(OC)cc(OC(C)CCCC(C)C)c1

Procedure:
2-bromo-6-methyl-heptane was reacted with 3,5-dimethoxy-phenol to obtain 1-[(1,5-dimethyl-hexyl)-oxy]-3,5-dimethoxy-benzene (boiling point = 135°C/0.4 mmHg);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([OH:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:19](OC=C)(=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([OH:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([O:18][C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C=COC(=O)CCCCC
Agent: CCOC(=O)CC(O)c1ccc(OC)c(OC)c1
Product: CCCCCC(=O)OC(CC(=O)OCC)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 288 h

Procedure:
The mixture of 5.0 g (20 mmol) of ethyl 3-(3,4-dimethoxyphenyl)-3-hydroxypropionate, 1.4 g (13 mmol) of vinyl caproate and 1.0 g of lipase PS was stirred at room temperature for 12 days. After the lipase was removed by filtration, the filtrate was eluted by column chromatography (eluting solution; 9/1 of toluene/ethyl acetate) to obtain 2 g (>50%ee) of (-)-ethyl 3-(3,4-dimethoxyphenyl)-3-hydroxypropionate and 4.3 g (about 43%ee) of (+)-ethyl 3-(3,4-dimethoxyphenyl)-3-hexanoyloxypropionate.
Reaction SMILES: CN1C=C(CN(C)C(C2N(C3C=CC(F)=CC=3)C(S)=NC=2)=O)C(C)=N1.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=1[S:34][CH2:35][C:36]1[N:37]([C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=2)[C:38]([C:41]([O:43]CC)=[O:42])=[CH:39][N:40]=1.[OH-].[Li+].C1COCC1>O.CO>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=1[S:34][CH2:35][C:36]1[N:37]([C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=2)[C:38]([C:41]([OH:43])=[O:42])=[CH:39][N:40]=1
Reactant: CCOC(=O)c1cnc(CSc2c(Cl)cccc2Cl)n1-c1ccc(F)cc1
Agent: Cc1nn(C)cc1CN(C)C(=O)c1cnc(S)n1-c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cnc(CSc2c(Cl)cccc2Cl)n1-c1ccc(F)cc1

Procedure:
2-(((2,6-Dichlorophenyl)thio)methyl)-1-(4-fluorophenyl)-1H-imidazole-5-carboxylic acid (73) was prepared in a similar manner as that described for the synthesis of compound 7 using ethyl 2-(((2,6-dichlorophenyl)thio)methyl)-1-(4-fluorophenyl)-1H-imidazole-5-carboxylate (72) (1.5 g, 3.5 mmol), lithium hydroxide (1.6 g, 40 mmol), THF (50 mL), methanol (50 mL), and water (20 mL).
Reaction SMILES: C(N(C(C)C)C(C)C)C.[F:10][C:11]([F:20])([F:19])[C:12]1[CH:13]=[C:14]([SH:18])[CH:15]=[CH:16][CH:17]=1.Br[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[C:24]([F:30])[CH:23]=1.O>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[F:30][C:24]1[CH:23]=[C:22]([S:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:11]([F:10])([F:19])[F:20])[CH:13]=2)[CH:29]=[CH:28][C:25]=1[CH:26]=[O:27]
Reactant: FC(F)(F)c1cccc(S)c1
Reactant: O=Cc1ccc(Br)cc1F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=Cc1ccc(Sc2cccc(C(F)(F)F)c2)cc1F
Yield: 68 %

Procedure:
Under an argon atmosphere, ethyldiisopropylamine (7.0 mL), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (518 mg), xantphos (578 mg), and 3-trifluoromethylthiophenol (3.56 g) were added at room temperature into a solution of 4-bromo-2-fluorobenzaldehyde (4.06 g) in 1,4-dioxane (42 mL), and the resultant solution was heated to reflux for 5 hours. To the reaction solution added water, extracted with ethyl acetate, washed with water and saturated brine in that order, and then dried over anhydrous sodium sulfate. The solvent was evaporated, and the resultant residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to obtain the target product (4.08 g) as a colorless oil.
Reaction SMILES: Cl.NC[C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[C:7](O)[CH:8]=[CH:9][CH:10]=2)[N:5]=1.C(N(CC)CC)C>C(#N)C>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][CH:4]=1
Reactant: NCc1ccc2cccc(O)c2n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: c1ccc2ncccc2c1

Procedure:
A mixture of 2-aminomethyl-8-hydroxyquinoline hydrochloride (1.05 g, 5 mmol) N-succinimidyl S-tetrahydropyranylmercaptoacetate (1.37 g, 5 mmol), and triethylamine (0.51 g, 5 mmol) in acetonitrile (15 mL) was heated under reflux for 2 hours. The reaction mixture was poured onto water and extracted with methylene chloride (3×20 mL). The combined organic layers were washed with water and dried (MgSO4) to give the ligand of Formula 17 as an orange gum which was sufficiently pure for complexation purposes. 1H-NMR (CDCl3) δ8.42 (broad, 1H), 8.20 (d, 1H), 7.41 (d, 1H), 7.35 (m, 2H), 7.18 (d, 1H), 4.95 (dd, 1H), 4.82(dd, 1H), 4.73 (dd, 1H), 4.00 (m, 1H), 3.78 (m, 1H), 3.57 (d, 1H), 3.35 (d, 1H), 2.10-1.55 (m, 6H); 13C-NMR (CDCl3) δ169.6, 154.1, 152.1, 137.0, 136.9, 127.5, 127.4, 120.2, 117.8, 110.9, 83.7, 65.5, 44.7, 35.2, 30.8, 25.0, 21.6.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[C:5](=[CH:8][CH:9]=1)[CH:6]=[O:7].Br[CH2:12][C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][C:4]=1[O:10][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:7]
Reactant: Cc1ccc(C=O)c(O)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1cc(C)ccc1C=O
Yield: 91.8 %

Procedure:
By the method of Example 1, Step F, 8,27 g (0.060 mole) of 4-methyl-salicylaldehyde and 11.15 g (0.073 mole) of methyl bromoacetate were reacted in the presence of 10.1 g (0.073 mole) of anhydrous potassium carbonate in 150 mL of acetone, yielding 11.47 g of methyl (2-formyl-5-methylphenoxy)acetate as a white solid, m. p. 63°-64° C. The NMR was consistent with the proposed structure.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[NH:25]1[CH:29]=[CH:28][N:27]=[CH:26]1>>[N:25]1([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=4)=[CH:13][C:11]=3[CH:12]=2)[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Reactant: c1c[nH]cn1
Product: N#Cc1ccc(-c2ccc3oc(CCn4ccnc4)cc3c2)cc1

Procedure:
The product from Example 1C and imidazole were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 8.88 (s, 1H), 7.88 (m, 1H), 7.80 (m, 5H), 7.60 (m, 4H), 6.75 (s, 1H), 4.7 (t, J=6.3 Hz, 2H), 3.5 (t, J=6.3 Hz, 2H); MS (DCI) m/z 314 (M+H)+;
Reaction SMILES: [N:1]1[N:12]2[C:4]([N:5]=[C:6]3[C:10](=[C:11]2[C:13]2[CH:14]=[CH:15][C:16]4[O:20][C:19]([CH2:21][CH2:22]OS(C)(=O)=O)=[CH:18][C:17]=4[CH:28]=2)[CH2:9][CH2:8][CH2:7]3)=[CH:3][CH:2]=1.[CH3:29][O:30][CH2:31][C@H:32]1[CH2:36][CH2:35][CH2:34][NH:33]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:29][O:30][CH2:31][C@H:32]1[CH2:36][CH2:35][CH2:34][N:33]1[CH2:22][CH2:21][C:19]1[O:20][C:16]2[CH:15]=[CH:14][C:13]([C:11]3[N:12]4[C:4](=[CH:3][CH:2]=[N:1]4)[N:5]=[C:6]4[C:10]=3[CH2:9][CH2:8][CH2:7]4)=[CH:28][C:17]=2[CH:18]=1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3c4c(nc5ccnn35)CCC4)ccc2o1
Reactant: COC[C@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC[C@H]1CCCN1CCc1cc2cc(-c3c4c(nc5ccnn35)CCC4)ccc2o1
Temperature: 70 °C

Procedure:
Methanesulfonic acid 2-[5-(6,7-dihydro-5H-1,4,8a-triaza-s-indacen-8-yl)-benzo-furan-2-yl]-ethyl ester (0.085 mmol) described above was dissolved in acetonitrile (2 ml) followed by addition of 2-(R)-methoxymethylpyrrolidine (0.85 mmol) and potassium carbonate (0.425 mmol) and heated to 70° C. for 24 hours. The reaction was cooled, filtered and concentrated. The residue was purified via preparative HPLC to give the desired 8-{2-[2-(2-(R)-Methoxymethyl-pyrrol idin-1-yl)-ethyl]-benzofuran-5-yl}-6,7-dihydro-5H-1,4,8a-triaza-s-indacene.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.[CH3:50][O:51][C:52]1[CH:57]=[CH:56][C:55]([CH2:58][CH2:59][NH2:60])=[CH:54][CH:53]=1>C(Cl)Cl.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([NH:60][CH2:59][CH2:58][C:55]3[CH:56]=[CH:57][C:52]([O:51][CH3:50])=[CH:53][CH:54]=3)=[O:26])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1
Reactant: COc1ccc(CCN)cc1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CCNC(=O)C2CCN(C(=O)c3cc4ccccc4n3Cc3ccc(Cl)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (100 mg, 0.252 mmol), EDCI (72.5 mg, 0.378 mmol), and 1-hydroxybenzotriazole (51.1 mg, 0.378 mmol) were dissolved in DCM (Volume: 3.0 ml). The reaction was stirred at room temperature for 10 minutes before Hunig'sBase (0.066 ml, 0.378 mmol) and 2-(4-methoxyphenyl)ethanamine (0.055 ml, 0.378 mmol) were added. The reaction was allowed to stir overnight at room temperature. The reaction was diluted with water and ethyl acetate. The organic phase was washed with 1N HCl, saturated sodium bicarbonate, and brine. The organic phase was dried over magnesium sulfate, filtered, and concentrated. The crude material was triturated with ethyl acetate to obtain product as a white solid. (Yield: 84 mg, white solid) 1H-NMR (400 MHz, DMSO-d6) 7.80, 7.59, 7.51, 7.34-7.27, 7.23-7.14, 7.12-7.02, 6.84-6.78, 6.68, 5.45, 4.48-3.82, 3.67, 3.18, 2.89, 2.60, 2.34-2.26, 1.59, 1.31
Reaction SMILES: [CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:22]=[CH:21][C:20](OS(C(F)(F)F)(=O)=O)=[C:19]([F:31])[C:18]=2[F:32])=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[Na+].OO>O1CCCC1>[CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:22]=[CH:21][C:20](/[CH:11]=[CH:1]/[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[C:19]([F:31])[C:18]=2[F:32])=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1cnc(-c2ccc(OS(=O)(=O)C(F)(F)F)c(F)c2F)nc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCC/C=C/c1ccc(-c2ncc(CCCCCCCCCC)cn2)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 159.3 %

Procedure:
Apart from the above, inner atmosphere of a four-necked flask equipped with a stirring device, a reflux condenser and a thermometer was replaced with nitrogen gas, and then the flask was charged with 1.6 g (3.3 mmol) of 5-decyl-2-(2,3-difluoro-4-trifluoromethylsulfonyloxyphenyl)-pyrimidine, 0.06 g (0.05 mmol) of tetrakis-triphenylphosphine-palladium, 0.6 g (15 mmol) of sodium hydroxide and 15 of tetrahydrofuran. Subsequently, 13 ml of a solution prepared by dissolving 5 mmol of the above-obtained E-1-nonenylcatecholborane in tetrahydrofuran was dropwise added thereto at room temperature. Then, the whole mixture was heated under reflux with stirring for 3 hours. After cooling the reaction mixture to room temperature, 3 ml of 10% aqueous solution of sodium hydroxide and 1 ml of 30% aqueous solution of hydrogen peroxide were added, and the resulting mixture was stirred for one hour. The mixture was extracted with ether, and the organic layer was twice washed with each 10 ml portion of saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 1.2 g (yield 79%) of 5-decyl-2-{2,3-difluoro-4-(1-trans-nonenyl)-phenyl}-pyrimidine. ##STR19##
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[H-].[Na+].F[C:21]1[C:26]([CH:27]2[CH2:32][CH2:31][N:30]([C:33](=[O:35])[CH3:34])[CH2:29][CH2:28]2)=[CH:25][CH:24]=[CH:23][N:22]=1>CN1CCCC1=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:21]2[C:26]([CH:27]3[CH2:28][CH2:29][N:30]([C:33](=[O:35])[CH3:34])[CH2:31][CH2:32]3)=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:13][CH:12]=1
Reactant: CC(=O)N1CCC(c2cccnc2F)CC1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(=O)N1CCC(c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.3 %

Procedure:
To 4-(benzo[d]thiazol-2-ylamino)phenol (0.327 g, 1.35 mmol) dissolved in N-Methyl-2-pyrrolidinone (3 mL) was added sodium hydride, 60% dispersion in mineral oil (54 mg, 1.4 mmol). After stirring at RT for 10 min, 1-(4-(2-fluoropyridin-3-yl)piperidin-1-yl)ethanone (0.15 g, 0.68 mmol) was added and the reaction mixture was stirred at 140° C. for 16 h. After cooling to RT, the reaction mixture was partitioned between EtOAc and brine. The aqueous layer was back extracted with EtOAc (3×) and the combined organics were dried (Na2SO4) and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 10% to 100% EtOAc in hexane, followed by trituration with Et2O and hexane to provide 1-(4-(2-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyridin-3-yl)piperidin-1-yl)ethanone (0.137 g, 0.308 mmol, 45.7% yield) as off-white solid. MS (ESI, pos. ion) m/z: 445.0 (M+1). IC50 (uM) +++++.