Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:13][CH:14]([OH:17])[CH2:15][OH:16].C(=O)([O-])[O-].[Na+].[Na+]>C(OC(O)C)C>[OH:17][CH:14]([CH2:15][OH:16])[CH2:13][C:3]1[C:2]([NH2:1])=[CH:7][CH:6]=[CH:5][C:4]=1[C:8]([F:9])([F:10])[F:11]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: OCC(O)CCl
Agent: CCOC(C)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Nc1cccc(C(F)(F)F)c1CC(O)CO

Procedure:
In a two liter three necked flask equipped with mechanical stirrer, refluxing condenser and thermometer was added 322.2 gms (2.0 moles) of 3-aminobenzotrifluoride, 500 ml of ethoxyethanol solvent and 442.0 gms (4 moles) 1-chloro-2,3-propanediol. While this mixture was cooling, 205 gms (2.36 moles) of sodium carbonate was added keeping the temperature below 35° C. The mixture was then heated to reflux for 24 hours. Afterwards, the crude reaction mixture was filtered from the salt by-product. The salt was then washed several times with chloroform and these washings were combined with the filtrate. The solvent and chloroform was then removed under low vacuum and high vacuum to give 450.5 gms of the crude bis-2,3-dihydroxypropyl-3-aminobenzotrifluoride as a viscous dark oil.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH:27]([CH3:29])[CH3:28])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[O:30]1[C:34]2[CH:35]=[CH:36][C:37](B(O)O)=[CH:38][C:33]=2[CH2:32][CH2:31]1.N1C=CC=CC=1.C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH2:1]([C:5]1[N:6]=[C:7]([CH:27]([CH3:28])[CH3:29])[N:8]([C:37]2[CH:36]=[CH:35][C:34]3[O:30][CH2:31][CH2:32][C:33]=3[CH:38]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: OB(O)c1ccc2c(c1)CCO2
Reactant: CCCCc1nc(C(C)C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1nc(C(C)C)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h
Yield: 84.2 %

Procedure:
A mixture of 4′-[(4-butyl-2-isopropyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), 2,3-dihydro-1-benzofuran-5-ylboronic acid (0.85 g), copper(II) acetate (0.94 g), pyridine (1.1 mL), triethylamine (1.8 mL), molecular sieves 4 A (2.0 g) and dichloromethane (12 mL) was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (1.1 g, 79%) as a pale-yellow liquid.
Reaction SMILES: NC1C=CC(F)=CC=1C(NC)=O.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[C:15]=1[O:23][CH3:24]>>[CH3:24][O:23][C:15]1[C:14]([F:13])=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:20]
Reactant: COc1c(F)cccc1[N+](=O)[O-]
Agent: CNC(=O)c1cc(F)ccc1N
Product: COc1c(N)cccc1F

Procedure:
The title compound was prepared according to the procedure for Compound 102A (2-Amino-5-fluoro-N-methylbenzamide) with 1-fluoro-2-methoxy-3-nitrobenzene (Compound 147J). 1H NMR (CDCl3, 400 MHz): δ=3.92 (d, J=1.52 Hz, 3H), 6.44-6.53 (m, 2H), 6.80 (td, J=8.15, 5.68 Hz, 1H). MS (ES+): m/z 142.07 [MH+] (TOF, polar).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[N:11]1([CH2:16][C:17]2[CH:18]=[CH:19][C:20](Br)=[N:21][CH:22]=2)[CH:15]=[CH:14][N:13]=[CH:12]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:20]1[CH:19]=[CH:18][C:17]([CH2:16][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:22][N:21]=1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Reactant: OB(O)c1ccccc1F
Product: Fc1ccccc1-c1ccc(Cn2ccnc2)cn1

Procedure:
Synthesized using 2-fluorophenylboronic acid (176 mg, 1.26 mmol) and 1a (150 mg, 0.63 mmol) according to Method C. Yellow solid. Yield: 112 mg, 0.44 mmol, 70%. 1H NMR (500 MHz, CDCl3): δH (ppm): 5.18 (s, 2H), 6.93 (t, J=1.3 Hz, 1H), 7.12 (bs, 1H), 7.15 (ddd, J=11.7, 8.2, 1.3 Hz, 1H), 7.26 (dt, J=7.9, 1.3 Hz, 1H), 7.36-7.40 (m, 1H), 7.48 (dd, J=8.2, 2.5 Hz, 1H), 7.59 (s, 1H), 7.78 (ddd, J=8.2, 2.2, 0.9 Hz, 1H), 7.97 (dt, J=7.9, 1.9 Hz, 1H), 8.60 (dd, J=2.5, 0.6 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.1, 116.2 (d, J=23.0 Hz), 119.0, 124.5 (d, J=9.1 Hz), 124.6, 126.6, 126.7, 130.0 (d, J=9.1 Hz), 130.7 (d, J=9.1 Hz), 130.9 (d, J=2.7 Hz), 135.3, 137.3, 148.5, 153.6 (d, J=2.7 Hz), 160.4 (d, J=250.2 Hz); MS (ESI): m/z=254.18 [M+H]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[N:13]=[C:14]2[C:19]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:17]=[CH:16][N:15]2[CH:28]=1)=O)C.O.[OH-].[Na+]>O1CCCC1>[CH2:21]([O:20][C:19]1[C:14]2[N:15]([CH:28]=[C:12]([CH2:10][OH:9])[N:13]=2)[CH:16]=[CH:17][CH:18]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1cn2cccc(OCc3ccccc3)c2n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cn2cccc(OCc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cooled suspension of 1.5 g lithium aluminium hydride in 150 ml tetrahydrofuran there was added 15.0 g 8-benzyloxyimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (obtained according to Example 5) in portions so that the temperature remains below 10° C. After stirring at 0°-5° C. for an additional 1hr., 1.5 ml water was added dropwise at 0°-10° C., followed by 1.5 ml 15% aqueous sodium hyroxide and then 4.5 ml water. The mixture was allowed to warm to room temperature with stirring, and was then suction-filtered in a sintered glass funnel. The solids left in the funnelwere thoroughly washed with 4×200 ml hot chloroform.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C@H:13]2[CH2:19][C:20]2[N:21]=[N:22][N:23]([C@@H:25]([C:27]3[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=3)[CH3:26])[CH:24]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C@H:13]2[CH2:19][C:20]2[N:21]=[N:22][N:23]([C@@H:25]([C:27]3[CH:34]=[CH:33][C:30]([CH2:31][N:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:29][CH:28]=3)[CH3:26])[CH:24]=2)(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[C@H](c1ccc(C=O)cc1)n1cc(C[C@@H]2C(=O)NC=CN2S(=O)(=O)c2ccc(Cl)c(Cl)c2)nn1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: C[C@H](c1ccc(CN2CCCCC2)cc1)n1cc(C[C@@H]2C(=O)NC=CN2S(=O)(=O)c2ccc(Cl)c(Cl)c2)nn1
Reaction time: 18 h

Procedure:
To a solution of 4-((R)-1-(4-(((R)-1-(3,4-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetra-hydropyrazin-2-yl)methyl)-1H-1,2,3-triazol-1-yl)ethyl)benzaldehyde (0.150 g, 0.288 mmol) and piperidine (0.10 mL, 1.01 mmol) in 1,2-dichloroethane (10 mL) was added NaBH(OAc)3 (0.126 g, 0.594 mmol). After 18 h, the solution was diluted with 60 mL EtOAc and washed with 5% NaHCO3 (60 mL×2), brine (60 mL×2), dried over Na2SO4 and concentrated under reduced pressure. The crude product was chromatographed on SiO2 (100% CH2Cl2 to 5% 2N methanolic NH3 in CH2Cl2) to yield the title compound.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].CO.[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=O)[CH2:12][CH3:13]>O>[C:15]1([C:11](=[N:2][OH:3])[CH2:12][CH3:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCC(=O)c1ccccc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCC(=NO)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
Hydroxylamine hydrochloride (17.1 g, 246 mmol) and sodium acetate (20.2 g, 246 mmol) were added to 110 mL of methanol and the resulting white slurry was stirred at room temperature for 30 min. Propiophenone (30 g, 224 mmol) was added and the mixture was stirred at room temperature for 20 hours. Water (100 mL) was added and the mixture was stirred for 10 min. The product was extracted with EtOAc and the organic layer was washed with saturated NaHCO3 solution and dried over MgSO4. The solvent was evaporated in vacuo to give 32.4 g of the title compound. 1H NMR (CDCl3, 200 MHz): δ=9.21 (s, 1H), 7.60-7.72 (m, 2H), 7.38-7.50 (m, 3H), 2.91 (q, 2H, J=7.8 Hz), 1.23 (t, 3H, J=7.4 Hz).
Reaction SMILES: CC1C=[C:10]([C:12]([OH:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.N1C2C(=CC=CC=2)C(=O)C1=O.CC(C)=O.[F:30][C:31]([F:36])([F:35])[C:32]([CH3:34])=O>[OH-].[K+]>[F:30][C:31]([F:36])([F:35])[C:32]1[CH:34]=[C:10]([C:12]([OH:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(C(=O)O)c2ccccc2n1
Reactant: CC(=O)C(F)(F)F
Agent: O=C1Nc2ccccc2C1=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(O)c1cc(C(F)(F)F)nc2ccccc12

Procedure:
2-Methylcinchoninic acid has been prepared, as disclosed in Bull. Soc. Chem., France, 1956, 1294, by the reaction of isatin and acetone in 30 percent aqueous potassium hydroxide solution. However, it has been found that when isatin is reacted with 1,1,1-trifluoroacetone in an attempt to produce 2-trifluoromethyl cinchoninic acid in an analogous manner, the desired product cannot be obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[CH:9][CH:8]=1.[C:22]1([CH:28]2[O:33][CH2:32][CH2:31][NH:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Na+].Cl>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.[Pd].[Pd].O1CCCC1.CO.C1(C)C=CC=CC=1>[C:22]1([CH:28]2[O:33][CH2:32][CH2:31][N:30]([C:2]3[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=3)[CH2:5][O:6][C:7]3[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:9][CH:8]=3)[CH2:29]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(C2CNCCO2)cc1
Reactant: COC(=O)CCc1ccc(OCc2cccc(Br)c2)cc1
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CO
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(OCc2cccc(N3CCOC(c4ccccc4)C3)c2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 50.1 %

Procedure:
A mixture of methyl 3-{4-[(3-bromobenzyl)oxy]phenyl}propanoate (0.3 g, 0.86 mmol), 2-phenylmorpholine (0.21 g, 1.29 mmol), tris(dibenzylideneacetone)dipalladium(0) (31 mg, 34 μmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (32 mg, 52 μmol), cesium carbonate (0.39 g, 1.2 mmol) and toluene (6.0 mL) was stirred under a nitrogen atmosphere at 80° C. for 16 hr. After cooling, the reaction mixture washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give an oil. Then, to a mixture of the obtained oil, methanol (4.0 mL) and tetrahydrofuran (6.0 mL) was added 1N aqueous sodium hydroxide solution (2.0 mL) with stirring at room temperature, and the mixture was stirred at the same temperature for 2 hr. The reaction mixture was adjusted to pH 7 with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1-hexane/ethyl acetate=1/2) to give the title compound (0.18 g, yield 36%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([N+:11]([O-])=O)[CH:5]=[CH:4][CH:3]=1.[ClH:14]>CO.[Pd]>[ClH:14].[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1c(F)cccc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1cccc(F)c1C(=O)O

Procedure:
2.7 g of 10 percent palladium/carbon are added to a solution of 20.0 g (0.108 mol) of 6-fluoro-nitrobenzoic acid in a mixture of 200 ml of methanol and 27 ml of concentrated hydrochloric acid and the resulting mixture is hydrogenated at 35°-40° C. under a slight over-pressure. After filtration of the catalyst and concentration of the filtrate, the crude product is recrystallised from methanol/ether. There is obtained 6-fluoroanthranilic acid hydrochloride of melting point 176°-178° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C1C(C(OO)=O)=CC=CC=1.BrN1C(=O)CCC1=O.Cl.[CH2:31]([O:33][C:34](=[O:37])[CH2:35][NH2:36])[CH3:32].C(=O)([O-])O.[Na+]>C1C=CC=CC=1.C(O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:36][CH2:35][C:34]([O:33][CH2:31][CH3:32])=[O:37])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: CCOC(=O)CN
Reactant: Cc1ccc(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C(OO)c1ccccc1
Agent: O=C([O-])O
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCOC(=O)CNCc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4.84 g (28.3 mmol) of 4-chloro-2-nitrotoluene was dissolved in 50 ml of benzene. 50 mg of perbenzoic acid and 6.0 g (34 mmol) of N-bromosuccinimide were added to the obtained solution, and the obtained solution was stirred at 80° C. overnight. The reaction solution was treated with ethyl acetate as the extracting solvent by an ordinary method to obtain the crude product. The crude product was dissolved in 100 ml of ethanol. 11.9 g (84.9 mmol) of glycine ethyl ester hydrochloride and 8.9 g (106 mmol) of sodium hydrogencarbonate were added to the obtained solution, and they were stirred at 80° C. for 4 hours. The insoluble matter was removed by the filtration, and the solvent was evaporated. After the extraction with ethyl acetate followed by washing with 1 N hydrochloric acid, the obtained aqueous layer was made basic with 1 N sodium hydroxide. After the extraction with ethyl acetate, the obtained organic layer was washed with saturated aqueous sodium chloride solution and then dried. The solvent was evaporated to obtain the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:13][O-:14].[Na+].[Na]>CO>[CH3:13][O:14][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COCc1cccc(C(=O)OC)c1
Temperature: 65 °C
Yield: 66 %

Procedure:
To a solution of 15 g (65.5 mmol) of methyl 3-(bromomethyl)benzoate in 20 mL of anhydrous MeOH is added dropwise, at room temperature, a solution of sodium methoxide in MeOH, prepared beforehand from 2.25 g (98.2 mmol) of sodium in 65 mL of MeOH. The reaction medium is then heated for 4 hours at 65° C. and then concentrated under reduced pressure, taken up in 500 mL of DCM, washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. 7.8 g of methyl 3-(methoxymethyl)benzoate are obtained in the form of an oil, which is used without further purification in the following step.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[C:11](=[O:23])[C:12]4[N:21]([CH3:22])[N:20]=[CH:19][C:13]=4[NH:14][C:15]=3[CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:7][CH:8]=1.COC1C=CC(C2C3C(=O)C4N(C)N=CC=4NC=3C=CC=2)=CC=1>>[OH:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[C:11](=[O:23])[C:12]4[N:21]([CH3:22])[N:20]=[CH:19][C:13]=4[NH:14][C:15]=3[CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2cccc3[nH]c4cnn(C)c4c(=O)c23)c1
Agent: COc1ccc(-c2cccc3[nH]c4cnn(C)c4c(=O)c23)cc1
Product: Cn1ncc2[nH]c3cccc(-c4cccc(O)c4)c3c(=O)c21

Procedure:
The title compound was prepared according to the procedure of step 4 in EXAMPLE 38 using 8-(3-methoxyphenyl)-1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one (EXAMPLE 39, step 2), instead of 8-(4-methoxyphenyl)-1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one.
Reaction SMILES: [C:1]([C:3](=[CH:9][NH:10][C:11]1[C:16]([CH2:17][CH2:18][CH2:19][CH3:20])=[CH:15][CH:14]=[CH:13][N:12]=1)[C:4](OCC)=[O:5])#[N:2].[NH:21]1C(C2C(=O)N3C=CC=CC3=NC=2)=N[N:23]=[N:22]1>>[CH2:17]([C:16]1[C:11]2=[N:10][CH:9]=[C:3]([C:1]3[NH:2][N:23]=[N:22][N:21]=3)[C:4](=[O:5])[N:12]2[CH:13]=[CH:14][CH:15]=1)[CH2:18][CH2:19][CH3:20]
Reactant: O=c1c(-c2nnn[nH]2)cnc2ccccn12
Reactant: CCCCc1cccnc1NC=C(C#N)C(=O)OCC
Product: CCCCc1cccn2c(=O)c(-c3nnn[nH]3)cnc12
Yield: 30 %

Procedure:
The title compound (m.p. 255.5°-257.5° with decomposition, 30% yield) was prepared from ethyl 2-cyano-3-(3-n-butyl-2-pyridylamino)acrylate in a manner similar to that described for the preparation of 3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one in Example 2 of U.S. Pat. No. 4,122,274.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Br:11][C:12]1[CH:13]=[C:14]([C:20]2[NH:24][C@@H:23]3[CH2:25][CH2:26][CH2:27][CH2:28][C@H:22]3[N:21]=2)[C:15]([O:18][CH3:19])=[N:16][CH:17]=1.C(N(CC)CC)C>ClCCl>[Br:11][C:12]1[CH:13]=[C:14]([C:20]2[NH:21][C:22]3[CH2:28][CH2:27][CH2:26][CH2:25][C:23]=3[N:24]=2)[C:15]([O:18][CH3:19])=[N:16][CH:17]=1
Reactant: COc1ncc(Br)cc1C1=N[C@@H]2CCCC[C@H]2N1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1ncc(Br)cc1-c1nc2c([nH]1)CCCC2
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 76.7 %

Procedure:
To a solution of Oxalyl dichloride (10 ml) in dichloromethane (10 mL), was treated with DMSO (2 mL) in dichloromethane (10 mL) by dropwise at −78° C., the solution was stirred at −78° C. for another 10 min, then trans-2-(5-bromo-2-methoxypyridin-3-yl)-3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazole (1 g, 3.3 mmol) was added in one portion under N2 protection. The react solution was stirred at −60° C. for 30 min, triethylamine is added over 5 min and the mixture was stirred at R.T. overnight. The resulting solution was treated with ice-cold 1 M hydrochloric acid solution (10 mL), the two phases are separated, the aqueous phase was extracted with dichloromethane (2*30 mL), and the combined organic phases was washed with pH 7 aqueous phosphate buffer (2*20 mL), then dried with anhydrous sodium sulfate and concentrated under reduced pressure to provide 2-(5-bromo-2-methoxypyridin-3-yl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazole (0.78 g, yield 78.8%) as a solid. 1HNMR (400 MHz, DMSO) δ 14.5 (br, 1H), 8.78 (d, J=2 Hz, 1H), 8.50 (d, J=2 Hz, 1H), 4.04 (s, 3H), 3.15 (s, 4H), 2.66 (s, 4H). MS (M+H)+: 310/312. MS (M+H)+: 308/310.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:17][CH3:18])=[C:4]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:19][S:20]([N:23]([CH3:47])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[N:38]2[C:33]([CH:34]=[N:35][C:36](OS(C(F)(F)F)(=O)=O)=[N:37]2)=[CH:32][CH:31]=1)(=[O:22])=[O:21].C(N(CC)C(C)C)(C)C.COCC(O)C>>[CH3:18][O:17][C:3]1[C:4]([C:8]([N:10]2[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]2)=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:36]1[N:35]=[CH:34][C:33]2=[CH:32][CH:31]=[C:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[N:23]([CH3:47])[S:20]([CH3:19])(=[O:22])=[O:21])[N:38]2[N:37]=1
Reactant: CN(c1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12)S(C)(=O)=O
Reactant: COc1c(N)cccc1C(=O)N1CCN(C)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1c(Nc2ncc3ccc(-c4ccccc4N(C)S(C)(=O)=O)n3n2)cccc1C(=O)N1CCN(C)CC1
Temperature: 120 °C

Procedure:
Into a 8-dram vial, (3-Amino-2-methoxy-phenyl)-(4-methyl-piperazin-1-yl)-methanone (107 mg, 0.430 mmol), Trifluoro-methanesulfonic acid 7-[2-(methanesulfonyl-methyl-amino)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (88.0 mg, 0.195 mmol), N,N-Diisopropylethylamine (0.0749 mL, 0.430 mmol), and 1-Methoxy-2-propanol (0.70 mL, 7.2 mmol) were added. The reaction mixture was heated at 120° C. for 6 hours. The solvent was removed under vacuum. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give N-(2-{2-[2-Methoxy-3-(4-methyl-piperazine-1-carbonyl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-phenyl)-N-methyl-methanesulfonamide a yellow solid (42 mg, 32%). LCMS (E/I+) 550.16 (M+H). NMR 1H (DMSO-d6)-9.79 (bs, 1H), 9.02 (s, 1H), 8.13 (bs, 1H), 8.06 (s, 1H), 7.90-7.96 (m, 1H), 7.45-7.65 (m, 3H), 7.09 (t, 1H, J=7.80 Hz), 7.05 (d, 1H, J=4.63 Hz), 7.00 (d, 1H, J=4.63 Hz), 6.92 (bs, 1H), 2.70-4.50 (m, 20H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17](F)(F)F)[CH:15]=3)[N:10]([CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][NH:31][C:30]4=[O:34])[CH2:23][CH2:22]3)[CH:9]=2)=[CH:4][CH:3]=1.N1(CCN2CCC(N3C4C(=CC=CC=4)C(C4C=CC=CC=4)=C3C)CC2)CCN[C:36]1=O>>[CH3:36][C:9]1[N:10]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][NH:31][C:30]3=[O:34])[CH2:23][CH2:22]2)[C:11]2[C:16]([C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2
Reactant: Cc1c(-c2ccccc2)c2ccccc2n1C1CCN(CCN2CCNC2=O)CC1
Reactant: O=C1NCCN1CCN1CCC(n2cc(-c3ccc(F)cc3)c3cc(C(F)(F)F)ccc32)CC1
Product: Cc1ccc2c(c1)c(-c1ccc(F)cc1)c(C)n2C1CCN(CCN2CCNC2=O)CC1

Procedure:
In a corresponding manner the following indole derivatives were prepared: 3-(4-Fluorophenyl)-1-[1-[2-(imidazolidin-2-on-1-yl)ethyl]-4-piperidyl]-5-trifluoromethyl-1H-indole 7b, mp 182°-186° C 1-[1-[2-(Imidazolidin-2-on-1-yl)ethyl]-4-piperidyl]-2-methyl-3-phenyl-1H-indole 7c, mp 179°-183° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([Cl:24])[CH:23]=3)[N:16]=[C:15]([C:25](O)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=O)C=2)C=C(F)C=1.Cl.N1C=CNC1=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([Cl:24])[CH:23]=3)[N:16]=[C:15]([C:25]([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:11])([F:10])[F:12])[CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2cncc(Cl)c2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Agent: Cl
Agent: O=c1[nH]cc[nH]1
Product: O=C1CN(C(=O)c2cc(-c3cc(Br)cc(OC(F)(F)F)c3)n(-c3cncc(Cl)c3)n2)CN1

Procedure:
75 mg (0.16 mmol) of the compound of Example 43A is reacted analogously to the synthesis of the compound of Example 1 with 22 mg (0.18 mmol) of 4-imidazolinone-hydrochloride. 72 mg (83% of theory) of the title compound is obtained.