Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][N:16](COCC[Si](C)(C)C)[CH:17]=3)[N:10]3[CH:26]=[CH:27][N:28]=[C:9]3[CH:8]=2)=[CH:5][N:6]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:15]1[CH:14]=[C:13]([C:11]2[N:10]3[CH:26]=[CH:27][N:28]=[C:9]3[CH:8]=[C:7]([C:4]3[S:3][C:2]([CH3:1])=[N:6][CH:5]=3)[N:12]=2)[CH:17]=[N:16]1
Reactant: Cc1ncc(-c2cc3nccn3c(-c3cnn(COCC[Si](C)(C)C)c3)n2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncc(-c2cc3nccn3c(-c3cn[nH]c3)n2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
2-methyl-5-(5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-7-yl)thiazole (0.196 g, 0.475 mmol) was dissolved in 3 mL of DCM before TFA (2.0 mL, 26.0 mmol) was added slowly at room temperature. The reaction was allowed to stir at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure to afford the crude material. The crude material was purified via column chromatography, eluting with 5% MeOH in DCM with 1% NH4OH to afford the title compound (0.087 g, 64.9% yield). MS (apci) m/z=283.1 (M+H).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[CH2:15](O)CC>[Ti]>[CH2:7]([O:6][P:4]([CH2:9][C:10]([O:12][CH2:13][CH2:14][CH3:15])=[O:11])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCCO
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [Ti]
Product: CCCOC(=O)CP(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Titanium IV propoxide (12.1 g) was added to a stirred mixture of ethyl diethylphosphonoacetate (100.4 g) and n-propanol (610 cm3) under a nitrogen atmosphere. The mixture was stirred at the ambient temperature for a total of 18 hours, after which time analysis of the mixture showed that the reaction was complete. The volatile components were removed by distillation firstly at atmospheric pressure and then under reduced pressure on a rotary evaporator. 1.5 M aqueous hydrochloric acid (350cm3) was added to the crude product and the mixture extracted with diethyl ether. The organic layer was separated and washed with further 1.5 M aqueous hydrochloric acid solution. The aqueous phases were combined and extracted with more diethyl ether (2×100cm3). All of the organic layers were combined, washed with water and dried over anhydrous magnesium sulphate. Evaporation of the solvent under reduced pressure qave a yellow oil (85.4 g) which was used without further purification.
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].[CH:19](O)=O>O.CCOCC>[CH3:19][NH:6][C:5]1[CH:7]=[CH:8][C:9]2[O:10][CH2:1][O:2][C:3]=2[CH:4]=1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: O=CO
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CNc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3,4-methylenedioxyaniline (10 mmol) in formic acid (36 ml) is heated at reflux for 1 hour. After the removal of excess formic acid, the residue obtained is diluted with water and then extracted with dichloromethane. The combined organic phases are evaporated. The residue obtained is dissolved in ether, then lithium aluminium hydride (42 mmol) is added at 10° C., in small portions. After stirring the mixture at ambient temperature for 3 hours, water and 10% sodium hydroxide solution are added and the mixture is then filtered over Celite. The filtrate is dried and evaporated and the residue obtained is purified by chromatography on silica, using dichloromethane as eluant, to yield the expected product in the form of an oil.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.C([O-])(O)=O.[Na+].[C-:19]#[N:20].[K+]>CCO.O>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][C:19]#[N:20]
Reactant: ClCc1ccc2ccccc2n1
Reactant: [C-]#N
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a suspension of 2-Chloromethyl-quinoline hydrochloride(TCI, 4.28 g, 20 mmol) in 50 mL of EtOH was added a solution of NaHCO3 (EM, 3.36 g, 40 mmol) in 30 mL of H2O. The mixture was stirred for 15 min, then was added KI (Aldrich, 4.5 g, 30 mmol) and KCN (Acros, 1.95 g, 30 mmol) and the resulting mixture was refluxed for 4h. after cooled to room temperature, EtOH was removed under reduced pressure. The residue was extracted 3× with EtOAc (200 mL). The organic layers were combined and washed twice with a brine solution (200 mL), dried over Na2SO4, and concentrated under vacuum. The residue was chromatographed (30% EtOAc/hexanes) to yield 2.76 g (82%) of product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([CH:11]2[CH2:13][CH2:12]2)O)=[C:4]([F:14])[CH:3]=1.FC(F)(F)C(O)=O.[CH3:22][S:23]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:35]=1[NH:34][CH:33]=[CH:32]2)(=[O:25])=[O:24]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([CH:11]2[CH2:13][CH2:12]2)[C:32]2[C:31]3[C:35](=[C:27]([CH2:26][S:23]([CH3:22])(=[O:25])=[O:24])[CH:28]=[CH:29][CH:30]=3)[NH:34][CH:33]=2)=[C:4]([F:14])[CH:3]=1
Reactant: CS(=O)(=O)Cc1cccc2cc[nH]c12
Reactant: OC(c1c(F)cc(Cl)cc1F)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Cc1cccc2c(C(c3c(F)cc(Cl)cc3F)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
104 mg (0.48 mmol) of the compound from Example 156A and 0.04 ml (0.57 mmol) of trifluoroacetic acid were added to 100 mg (0.48 mmol) of the compound from Example 86A in 4 ml of dichloromethane. The reaction mixture was stirred at RT for 45 min, the solvent was removed in vacuo, and the crude product was then purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 100 mg (51% of theory) of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=O)[CH2:15][N:16]=1)=[CH:8]2.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1>O.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([N:54]3[CH2:59][CH2:58][O:57][CH2:56][CH2:55]3)=[O:20])[CH2:15][N:16]=1)=[CH:8]2
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)N4CCOCC4)S3)[nH]c12
Temperature: 25 °C
Reaction time: 72 h
Yield: 43.5 %

Procedure:
A mixture of [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (500 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (330 mg), 1-hydroxybenzotriazole (230 mg), morpholine (190 mg) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 3 days. Water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol=100:0 to 95:5, volume ratio) to give pale yellow crystals. The crystals were recrystallized from acetone-hexane and then recrystallized from acetone-methanol to give the title compound (250 mg, 43%) as colorless prisms. MS 531 (MH+). mp 148-149° C.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)=[O:4].O1CCC[CH2:19]1.[Li+].CCC[CH2-].IC>CCCCCC.O>[CH3:1][C:2]([CH3:17])([CH3:16])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][C:7]=1[CH3:19])=[O:4]
Reactant: CC(C)(C)C(=O)Nc1ccc(C(F)(F)F)cc1
Reactant: C1CCOC1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: O
Solvent: CI
Solvent: CCCCCC
Product: Cc1cc(C(F)(F)F)ccc1NC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a chilled (28° C.) solution of 4.91 g of 2,2-dimethyl-N-(4-trifluoromethylphenyl)propanamide and 80 ml tetrahydrofuran, was added over two mins, 18.5 ml of a 2.5M solution of N-butyllithium in hexane, with stirring. The reaction mixture was stirred for two hours at 0° C. and added, dropwise over eight minutes, to a solution of 3.19 g of iodomethane and 7 ml of hexane, keeping the temperature between -2° C.+1° C. The solution was stirred for 45 mins (internal temperature reached 18° C.). Water (20 ml) was added and the mixture was extracted with dichloromethane. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was separated by preparative HPLC (Waters Associates Prep LC/System 500, silica gel, sample applied in and eluted with methylenechloride, 200 ml/min flow rate). The appropriate fractions were combined, concentrated, and the residue was recrystallized from toluene to give 2.23 g of product, mp 111°-114° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]3[O:24][CH2:23][CH2:22][NH:21][CH2:20]3)=[CH:15][CH:14]=2)[CH2:9]O)=[CH:4][CH:3]=1.C(N(S(F)(F)F)CC)C.[OH-].[NH4+].CCCCCCC.C(OC(=O)C)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:9][O:25][C:12]([C:13]3[CH:18]=[CH:17][C:16]([C@@H:19]4[O:24][CH2:23][CH2:22][NH:21][CH2:20]4)=[CH:15][CH:14]=3)=[N:11]2)=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](CO)c1ccc(F)cc1)c1ccc([C@H]2CNCCO2)cc1
Agent: CCN(CC)S(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Fc1ccc([C@@H]2COC(c3ccc([C@H]4CNCCO4)cc3)=N2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 37.2 %

Procedure:
N—((R)-1-(4-Fluorophenyl)-2-hydroxyethyl)-4-((S)-morpholin-2-yl)benzamide (14.4 mg, 0.042 mmol) was dissolved in dichloromethane (0.4 ml) and diethylaminosulfur trifluoride (DAST) (6.74 mg, 0.042 mmol) was added. The reaction mixture was allowed to stir at room temperature for 5 hours. The reaction mixture was poured over crushed ice mixed with 25% ammonium hydroxide solution (10 ml) and the solution was extracted twice with dichloromethane (2×10 ml). The combined organic layer was dried over MgSO4 and evaporated to give a sticky solid. Addition of heptane/ethy lacetate 4:1 and some drops of dichloromethane gave a white solid which was isolated by filtration and dried in vacuo to afford the product as a white solid (5.1 mg, 37%): MS (ISP): 327.2 ([M+H]+).
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.[CH3:14][C:15]1([CH3:22])[NH:19][C:18](=[O:20])[NH:17][C:16]1=[O:21].[N+:23]([C:26]1[CH:31]=[CH:30][C:29](Cl)=[CH:28][C:27]=1[C:33]([F:36])([F:35])[F:34])([O-:25])=[O:24]>>[F:34][C:33]([F:35])([F:36])[C:27]1[CH:28]=[C:29]([N:17]2[C:16](=[O:21])[C:15]([CH3:22])([CH3:14])[NH:19][C:18]2=[O:20])[CH:30]=[CH:31][C:26]=1[N+:23]([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1C(F)(F)F
Reactant: CC1(C)NC(=O)NC1=O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC1(C)NC(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C1=O
Temperature: 190 °C

Procedure:
The following were introduced into 288 ml of phenyl oxide: 96.10 grams of 5,5-dimethyl-hydantoin, 170.86 grams of 2-nitro-5-chloro trifluoromethylbenzene and 89.40 grams of cupric oxide. The mixture was heated to 190° C. for about 23 hours, then cooled to 20° C. and filtered. The residue was characterized in the phenyl oxide filtrate by thin layer chromatography.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][C:7](=[O:9])[CH2:6][C:5](=[O:10])[CH2:4]1)[CH3:2].[C:11]1([CH3:23])[CH:16]=[CH:15][C:14]([S:17]([N:20]=[C:21]=[O:22])(=[O:19])=[O:18])=[CH:13][CH:12]=1>C1C=CC=CC=1>[CH2:1]([CH:3]1[CH2:8][C:7](=[O:9])[CH:6]([C:21](=[O:22])[NH:20][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:23])=[CH:12][CH:13]=2)(=[O:18])=[O:19])[C:5](=[O:10])[CH2:4]1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: CCC1CC(=O)CC(=O)C1
Solvent: c1ccccc1
Product: CCC1CC(=O)C(C(=O)NS(=O)(=O)c2ccc(C)cc2)C(=O)C1

Procedure:
Reaction of 5-ethyl-1,3-cyclohexanedione with p-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5-ETHYL-2-(N-p-TOLUENESULFONYLCARBAMOYL)-1,3-CYCLOHEXANEDIONE, m.p. 86°-87° C. (corr.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:19]=[C:18]([C:20](O)=[O:21])[CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][NH:24][CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1.C(N=C=NCCCN(C)C)C.O>ClCCl.CN(C)C1C=CN=CC=1>[CH3:23][N:24]([CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)[C:20]([C:18]1[N:19]=[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[CH:15]=[CH:16][CH:17]=1)=[O:21]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(C(=O)O)n2)CC1
Reactant: CNC1CCCc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CN(C(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)n1)C1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-[1-(tert-butoxycarbonyl)piperidin-4-yl]pyridine-2-carboxylic acid (247 mg) in dichloromethane (5 ml) are added, at room temperature, N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine (130 mg), 4-dimethylaminopyridine (10 mg) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (162 mg). The mixture is stirred at room temperature overnight, and then water is added. The aqueous phase is removed and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography. This gives tert-butyl 4-{6-[methyl(1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl]pyridin-2-yl}piperidine-1-carboxylate (219 mg).
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]([CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:8]2)=[CH:4][CH:3]=1.Cl.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34]Cl.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(O)C.O1CCCC1.O.CN(C)C=O>[C:12]1([C:10]2[C:9]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:8][N:7]([CH2:6][C:5]3[CH:25]=[CH:26][C:2]([O:1][CH2:34][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=4)=[CH:3][CH:4]=3)[CH:11]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: ClCc1ccccn1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1cn(Cc2ccc(OCc3ccccn3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
A mixture of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (1.31 g), 2-picolyl chloride hydrochloride (0.73 g), potassium carbonate (0.69 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and an oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). A mixture of the oily substance obtained, 1N aqueous sodium hydroxide solution (8 ml), tetrahydrofuran (8 ml) and ethanol (8 ml) was stirred at room temperature for 3 hours and the organic solvent was removed under reduced pressure. After adding water, the residue was neutralized by adding 1N hydrochloric acid. The colorless crystals obtained were collected by filtration to yield 3-[4-phenyl-1-[4-(2-pyridylmethoxy)benzyl]-3-pyrrolyl]propionic acid (1.06 g, yield: 69%). This was recrystallized from ethanol-water. Melting point: 109–110° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([OH:13])=O)=[CH:7][CH:8]=2)[NH:3]1.[NH2:14][C:15]1[CH:16]=[C:17]([NH:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:19][CH:20]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:22]([NH:21][C:17]1[CH:16]=[C:15]([NH:14][C:11]([C:6]2[CH:5]=[C:4]3[C:9]([CH2:10][C:2](=[O:1])[NH:3]3)=[CH:8][CH:7]=2)=[O:13])[CH:20]=[CH:19][CH:18]=1)(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C1Cc2ccc(C(=O)O)cc2N1
Reactant: Nc1cccc(NC(=O)c2ccccc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Cc2ccc(C(=O)Nc3cccc(NC(=O)c4ccccc4)c3)cc2N1
Reaction time: 20 h

Procedure:
To a solution of 2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid (0.20 g, 1.1 mmol) in DMF (1 ml) is added N-(3-amino-phenyl)-benzamide (0.26 g, 1.2 mmol), N,N-diisopropylethylamine (0.44 g, 3.4 mmol) and HATU (0.47 g, 1.24 mmol). The reaction is stirred for 20 hours and concentrated. The residue is purified by HPLC (C18 column, eluted with CH3CN—H2O containing 0.05% TFA) to give 2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid (3-benzoylamino-phenyl)-amide as off-white solid. This amide (15 mg, 0.04 mmol) is then heated with 1H-pyrrole-2-carbaldehyde (6.0 mg, 0.06 mmol) in ethanol (2 ml) in the presence of 2 drops of piperidine at 80° C. for 20 hours. The mixture is concentrated and the desired compound is obtained after HPLC purification: 1H NMR (DMSO-d6) δ 6.41 (s, 1H), 6.93 (s, 1H), 7.31 (t, 1H, J=7.8 Hz), 7.44 (s, 1H), 7.48-7.51 (m, 3H), 7.54 (t, 2H, J=7.2 Hz), 7.59 (d, 1H, J=6.6 Hz), 7.70 (d, 1H, J=8.4 Hz), 7.78 (d, 1H, J=8.4 Hz), 7.92 (s, 1H), 7.98 (d, 2H, J=7.2 Hz), 8.33 (s, 1H), 10.27 (s, 1H), 10.31 (s, 1H), 11.13 (s, 1H), 13.38 (s, 1H); LC-MS: 449.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(N(CC)CC)C.Cl[C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1COCC1.C(OCC)(=O)C>[NH2:6][C:4]([C:3]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:2]=1[NH:1][C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:5]
Reactant: NC(=O)c1cc(F)ccc1N
Reactant: CCOC(=O)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)Nc1ccc(F)cc1C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.1 %

Procedure:
To a solution of 2-amino-5-fluorobenzamide (2.00 g, 13.0 mmol) and triethylamine (1.45 g, 14.3 mmol) in THF (40 mL) was added dropwise ethyl chloroglyoxylate (1.95 g, 14.3 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was washed with ethanol to give ethyl ((2-(aminocarbonyl)-4-fluorophenyl)amino)(oxo)acetate as a white powder (2.88 g, 87%).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:7]1[C:8]([Cl:18])=[C:9]([CH:13]=[C:14]([F:17])[C:15]=1[Cl:16])[C:10](O)=[O:11])#[N:6].[ClH:19].S(=O)=O>N1C=CC=CC=1>[C:5]([C:7]1[C:8]([Cl:18])=[C:9]([CH:13]=[C:14]([F:17])[C:15]=1[Cl:16])[C:10]([Cl:19])=[O:11])#[N:6]
Reactant: N#Cc1c(Cl)c(F)cc(C(=O)O)c1Cl
Reactant: Cl
Agent: O=S=O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: N#Cc1c(Cl)c(F)cc(C(=O)Cl)c1Cl
Yield: 95.7 %

Procedure:
4100 ml of thionyl chloride and 41 ml of pyridine were introduced into a stirred apparatus fitted with metering device and gas outlet leading to a scrubber via a reflux condenser, and, at 20° C., 2050 g of 3-cyano-2,4-dichloro-5-fluorobenzoic acid (99.5% strength) were introduced at the rate of hydrogen chloride/sulphur dioxide evolution. At the end of the addition, the mixture was heated to reflux until the evolution of gas ceased. The mixture was then distilled. In the boiling range from 142 to 145° C./10 mbar, 2150 g (95.7% of theory) of 3-cyano-2,4-dichloro-5-fluorobenzoyl chloride were obtained (content according to GC: 98.0%).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:10]([N:17]=[C:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(O)C>[CH2:10]([N:17]1[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:2][C:19]2[CH2:20][CH2:21][CH2:22][C:18]1=2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: c1ccc(CN=C2CCCC2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2c(n1Cc1ccccc1)CCC2
Reaction time: 2 h

Procedure:
Add dropwise 3.9 gm of ethyl bromopyruvate in 50 ml of ethanol to a flask containing 3.46 gm of benzyliminocyclopentane and 2.0 g of triethylamine in 50 ml of ethanol at 0° C., stir for 2 hours, then heat to reflux for 2 hours. Concentrate the reaction mixture and partition between 1N HCl and ether. Dry the ether extract over magnesium sulfate, filter, ooncentrate under high vacuum to obtain a brown oil and distill in a kugelrohr at 190°-210°/0.1 mm to obtain the title compound of Part A as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([C:13](=[O:17])[CH2:14][CH2:15][CH3:16])=[C:9]([CH2:11][CH3:12])[N:10]=2)[CH:5]=[CH:6][N:7]=1.[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[C:22](B(O)O)=[C:21]([O:29][CH3:30])[CH:20]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>COCCOC.O>[CH2:11]([C:9]1[N:10]=[C:3]2[C:2]([C:20]3[C:19]([CH3:18])=[CH:24][C:23]([CH3:25])=[CH:22][C:21]=3[O:29][CH3:30])=[N:7][CH:6]=[CH:5][N:4]2[C:8]=1[C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[CH3:12]
Reactant: CCCC(=O)c1c(CC)nc2c(Cl)nccn12
Reactant: COc1cc(C)cc(C)c1B(O)O
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: CCCC(=O)c1c(CC)nc2c(-c3c(C)cc(C)cc3OC)nccn12
Yield: 77.5 %

Procedure:
1-(8-Chloro-2-ethylimidazo[1,2-a]pyrazin-3-yl)-1-butanone (226 mg, 0.90 mmol) and 4,6-dimethyl-2-methoxybenzeneboronic acid (198 mg, 1.1 mmol) were dissolved in a mixed solvent of 1,2-dimethoxyethane (4.5 mL) and water (0.75 mL). Barium hydroxide octahydrate (347 mg, 1.1 mmol) and tetrakis(triphenylphosphine)palladium complex (79 mg, 0.068 mmol) were added thereto, and the mixture was heated under reflux for 4 hours under nitrogen atmosphere. After being allowed to cool, the reaction mixture was filtered and washed with ethyl acetate. Then, the filtrates were combined and washed with a 1N aqueous sodium hydroxide solution. It was extracted with ethyl acetate and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3) to give 1-[2-ethyl-8-(2-methoxy-4,6-dimethylphenyl)imidazo[1,2-a]pyrazin-3-yl]-1-butanone (245 mg) as a white amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH:18]([NH2:20])[CH3:19])[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:7]2.Br[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[NH:24][CH:25]=[N:26]2.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH:18]([NH:20][C:22]1[N:30]=[CH:29][N:28]=[C:27]3[C:23]=1[N:24]=[CH:25][NH:26]3)[CH3:19])[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:7]2
Reactant: CC(N)c1cc2c(Cl)cccc2nc1-c1ccccn1
Reactant: Brc1ncnc2nc[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Nc1ncnc2[nH]cnc12)c1cc2c(Cl)cccc2nc1-c1ccccn1
Temperature: 110 °C
Yield: 68.6 %

Procedure:
Added 1-(5-chloro-2-(pyridin-2-yl)quinolin-3-yl)ethanamine (103 mg, 363 μmol), 6-bromopurine (72 mg, 363 μmol), n-butanol (2 mL) and DIPEA (190 μl, 1089 μmol) to a 10 mL flask. Submerged in an oil bath and heated at 110° C. for 40 h. The reaction mixture was concentrated on the rotavap to ˜0.5 mL of solvent, diluted with DCM, and chromatographed with 0-15% MeOH:DCM on 12 g silica gel column. The desired fractions were combined and concentrated to an oil which was dissolved in ACN:H2O and lyophilized to obtained 100 mg (69%) of a light tan solid. LC-MS (+esi, M+H4=402.1).