Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)=[CH:10][CH:9]=[C:8]([CH2:19][CH3:20])[N:7]=1)=[O:5])C.[OH-].[Li+]>C1COCC1.C(O)C>[CH2:19]([C:8]1[N:7]=[C:6]([C:4]([OH:5])=[O:3])[C:11]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)=[CH:10][CH:9]=1)[CH3:20]
Reactant: CCOC(=O)c1nc(CC)ccc1Nc1cncnc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1ccc(Nc2cncnc2)c(C(=O)O)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
6-Ethyl-3-(pyrimidin-5-ylamino)-pyridine-2-carboxylic acid ethyl ester (prepared according to US 2006/199960; 200 mg, 0.73 mmol) was dissolved in a THF/ethanol (12 ml/3 ml) mixture, cooled to 0° C. and treated with lithium hydroxide (2.2 ml, 1N aqueous solution). The reaction mixture was allowed to warm-up to ambient temperature and stirring was continued at that temperature for 2 hours. The pH value was subsequently adjusted to acidic and the reaction mixture was extracted with dichloromethane (3×40 ml). The combined organic phases were dried and evaporated to yield the product as light yellow solid (175 mg, 97%).
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[CH2:25]2.N1CCCCC1>C(O)C>[CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=[C:25]3[C:24]4[C:28](=[CH:29][CH:30]=[C:22]([F:21])[CH:23]=4)[NH:27][C:26]3=[O:31])=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2]
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4ccc(F)cc43)c(C)c2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
A stirred solution of 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (74 mg, 0.237 mmol), 5-fluoro-1,3-dihydro-indol-2-one (40 mg, 0.267 mmol, commercially available from Aldrich) in 0.66 ml of ethanol was added dropwise with anhydrous piperidine (0.1 ml). The mixture was stirred at room temperature overnight. The resulting solid was filtered under reduced pressure, washed with anhydrous ethanol (1 ml×3), purified by silica gel column chromatography with triethylamine:methanol:dichloromethane (1:20:500) as eluents to give 5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (60 mg, 54.8%) as a yellow solid
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][C:14]([O:30][CH2:31][CH3:32])=[C:15]([C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=2)[C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)=[CH:8][C:7]=1[CH3:33].[OH-].[Na+].Cl>C(O)C>[Br:29][C:26]1[CH:25]=[CH:24][C:23]([C:15]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)=[C:14]([O:30][CH2:31][CH3:32])[CH2:13][S:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:34])=[O:2])=[C:7]([CH3:33])[CH:8]=2)=[CH:28][CH:27]=1
Reactant: CCOC(CSc1ccc(OCC(=O)OC)c(C)c1)=C(c1ccc(Br)cc1)c1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(CSc1ccc(OCC(=O)O)c(C)c1)=C(c1ccc(Br)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
{4-[3,3-Bis-(4-bromo-phenyl)-2-ethoxy-allylsulfanyl]-2-methyl-phenoxy}-acetic acid methyl ester (170 mg, 0.3 mmol, example 25) was dissolved in ethanol (5 ml). 1N NaOH (3 ml, 3 mmol) was added at room temperature and the reaction mixture was stirred for 30 min at room temperature, after which it was treated with 1N HCl (15 ml) and extracted with ethyl acetate (2×20 ml). The combined organic phases were dried and evaporated to give the title compound in 150 mg (90%) yield.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][C:10]3[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=3[C:6]=2[N:5]2[N:17]=[C:18]([CH3:20])[CH:19]=[C:4]2[N:3]=1.[CH2:21]([NH2:25])[CH2:22][CH2:23][CH3:24]>>[CH2:21]([NH:25][C:2]1[C:7]2[CH:8]=[N:9][C:10]3[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=3[C:6]=2[N:5]2[N:17]=[C:18]([CH3:20])[CH:19]=[C:4]2[N:3]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCN
Reactant: CCn1ncc2c1ncc1c(Cl)nc3cc(C)nn3c12
Product: CCCCNc1nc2cc(C)nn2c2c1cnc1c2cnn1CC
Reaction time: 12 h

Procedure:
5.7 g of 5-chloro-8-ethyl-2-methyl-8H-pyrazolo[1,5-a]-pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine (0.02 mol) are dissolved in 50 ml of dry alcohol. After addition of 1.5 g of n-butylamine, the mixture is heated at reflux temperature with stirring for 12 hours. The solvent is removed and the crystalline residue is treated with water. The N-butyl-8-ethyl-2-methyl-8H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido-[4,3-e]pyrimidin-5-amine is filtered off and recrystallized from ethyl acetate, yield 5 g (77%); m.p. 160°-162°.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1>C1COCC1>[O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[CH2:10][OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1Oc1ccccc1
Agent: B
Solvent: C1CCOC1
Product: OCc1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of o-phenoxybenzoic acid (19.0 g, 88.7 mmol) in THF (100 mL) at 0° C. under N2 was added BH3.THF (133 mL, 1.0M in THF) over a period of 1 h, keeping the temperature below 5° C. The reaction mixture was then stirred at room temperature for 2 h. It was quenched with H2O, then 1N aqueous HCl. The two layers were separated. The aqueous layer was extracted with EtOAc. The combined organic mixture was washed with brine, dried over MgSO, and concentrated to a light yellow oil (16.9 g). The crude product was used in the next step without further purification. MS m/e 183.1, [M+H-H2O]+ ; 1H NMR (300 MHz, CDCl3): δ 2.08 (t, 1H, OH), 4.76 (d, 2H, CH2Ar), 6.82-7.48 (m, 9H, ArH). ##STR64##
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[CH:31]2.CC#N>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:29]=[C:30]5[C:34](=[CH:35][CH:36]=4)[NH:33][CH:32]=[CH:31]5)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: ClCCCOc1ccc2[nH]ccc2c1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Fc1ccc2c(C3CCN(CCCOc4ccc5[nH]ccc5c4)CC3)noc2c1
Yield: 123.4 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.6 g, 11.8 mmol), K2CO3 (1.6 g, 11.6 mmol), KI (200 mg), 5-(3-chloropropoxy)indole (2.2 g, 10.5 mmol) and CH3CN (100 ml) was stirred at reflux under N2 for 18 hours. The cooled reaction was poured into H2O and the aqueous mixture was extracted with EtOAc. The EtOAc extract was washed 2 times with H2O, 2 times with brine and after drying with MgSO4 the solvent was removed in vacuo to yield 5.1 g of a dark oil. The oil was purified by preparative HPLC (Water's Associates Prep LC/System 500, using 2 silica gel columns and 4% MeOH--CH2Cl2 as eluent) to afford 2.65 g (65%) of a beige solid. Recrystallization from ethanol gave 2.2 g (54%) of a beige powder, m.p.=118°-121° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].CO.[N+]([C:9]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12])([O-])=O>O>[CH3:1][O:2][C:9]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12]
Reactant: C[O-]
Reactant: N#Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(C(F)(F)F)ccc1C#N
Reaction time: 1 h

Procedure:
Twenty-five percent sodium methoxide in methanol (24.3 g, 11 mol) was added dropwise to a stirred mixture of 19 g (0.091 mol) 2-nitro-4-(trifluoromethyl)benzonitrile and 100 mL of methanol at 20°-30° C. After 1 hour at 25° C., 100 mL of water was added. The solids were collected on a filter and washed with water. The solids were dried to yield 12.5 g of product melting at 59°-61° C. 1H NMR (CDCl3) δ4.00 (s, 3H), 7.2-7.7 (3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([C:9]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)([CH2:13][NH:14][CH3:15])[CH2:10][CH:11]=[CH2:12])[CH3:8])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.ClC(F)(F)C([O:35][C:36](=O)[C:37]([F:40])([F:39])[Cl:38])=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:24])[N:7]([C:9]([CH2:13][N:14]([C:36](=[O:35])[C:37]([Cl:38])([F:40])[F:39])[CH3:15])([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)[CH2:10][CH:11]=[CH2:12])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(OC(=O)C(F)(F)Cl)C(F)(F)Cl
Reactant: C=CCC(CNC)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCC(CN(C)C(=O)C(F)(F)Cl)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Reaction time: 0.83 h
Yield: 46 %

Procedure:
tert-Butyl[1-(3,4-dichlorophenyl)-1-methylaminomethyl-3-butenyl]methylcarbamate (500 mg) produced in Example 4 was dissolved in methylene chloride (10 mL). Under cooling with ice, pyridine (163 μL) and chlorodifluoroacetic acid anhydride (350 μL) were added thereto. Under cooling with ice, the mixture was stirred for 50 minutes. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the resultant mixture was extracted with methylene chloride. The organic layer was washed with saturated brine, dried over sodium sulfate anhydrate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (n-hexane:ethyl acetate=4:1), to thereby give the title compound (300 mg, 46%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1[CH3:20])[C:13](=O)[CH2:14]Br.C([O-])(O)=O.[Na+]>C(O)C>[Cl:8][C:6]1[CH:5]=[CH:4][N:3]2[CH:14]=[C:13]([C:12]3[CH:17]=[CH:18][C:19]([CH3:20])=[C:10]([CH3:9])[CH:11]=3)[N:1]=[C:2]2[CH:7]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: Cc1ccc(C(=O)CBr)cc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(-c2cn3ccc(Cl)cc3n2)cc1C
Reaction time: 16 h
Yield: 69.4 %

Procedure:
To a stirred solution of 2-amino-4-chloro-pyridine (0.39 g, 3.03 mmol) in ethanol (25 ml) was added 3,4-dimethyl-phenacylbromide (0.69 g, 3.03 mmol). The reaction mixture was stirred under reflux conditions for 16 h, poured into sat. NaHCO3 solution (70 ml) and extracted with dichloromethane (70 ml). The combined organic layers were washed with brine (70 ml), dried (MgSO4) and evaporated to give the crude product as a brown solid (0.84 g). Further purification by column chromatography on silica gel (ethyl acetate/toluene 1:9) and crystallization from ethyl acetate/hexane yielded the title compound (0.54 g, 69%) as a pale yellow solid, m.p. 144° C. and MS: m/e=256.2 (M+).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[N:18]([C:20]([CH3:25])=[C:21]([CH2:23]O)[N:22]=4)[CH:19]=3)[C:10](=[O:26])[CH:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:31])=O>C(Cl)Cl>[Cl:31][CH2:23][C:21]1[N:22]=[C:17]2[CH:16]=[CH:15][C:14]([N:11]3[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]4[CH:27]=[CH:28][C:2]([F:1])=[CH:3][CH:4]=4)=[CH:9][C:10]3=[O:26])=[CH:19][N:18]2[C:20]=1[CH3:25]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(CO)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cn12
Solvent: ClCCl
Product: Cc1c(CCl)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cn12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 4-((4-fluorobenzyl)oxy)-1-(2-(hydroxymethyl)-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (120 mg) in DCM (1 ml) was added thionyl chloride (1 ml), and the mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo, diluted with DCM and quenched with aqueous NaHCO3 under ice-cold condition. The organic layer was separated, washed successively with water and brine, dried over Na2SO4 and concentrated in vacuo to give the title compound (120 mg) as an off-white solid.
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([CH3:19])=[C:13]1[C:12]1[C:7](=[C:8]([Cl:23])[C:9]([O:21]C)=[C:10]([F:20])[CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].Cl.N1C=CC=CC=1>>[CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([CH3:19])=[C:13]1[C:12]1[C:7](=[C:8]([Cl:23])[C:9]([OH:21])=[C:10]([F:20])[CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12CCC(=O)C(C)=C1c1cc(F)c(OC)c(Cl)c1C2
Agent: Cl
Solvent: c1ccncc1
Product: CCCCC12CCC(=O)C(C)=C1c1cc(F)c(O)c(Cl)c1C2
Temperature: 200 °C

Procedure:
The product mixture from step 3 and pyridine hydrochloride (5.3 g) were combined and heated in an oil bath at 200° C. for 90 minutes. After cooling, the mixture was partitioned between EtOAc (50 mL) and water (50 ml). The organic phase was washed with brine (50 mL), dried over MgSO4, filtered, and evaporated under vacuum to a blue oil. The oil was purified by preparative layer chromatography on four 0.05×20×20 silica gel GF plates, developing with 5% EtOAc in CH2Cl2. One of the plates was discarded due to excessive streaking. The combined product bands were eluted with EtOAc, the eluent evaporated under vacuum, and the residue lyophilized from benzene (3 mL) containing EtOH (2 drops) to afford 9a-butyl-8-chloro-6-fluoro-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one as an amorphous solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[C:10]([O:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br)=[O:16])([CH3:13])([CH3:12])[CH3:11].O>CN(C)C=O>[C:10]([O:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)NCCCCCCBr
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCCCCOc1cccnc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
3-Hydroxypyridine (262 mg) was added to a suspension of 60% sodium hydride (128 mg) in N,N-dimethylformamide (5 ml) and the mixture was stirred at 60° C. for 30 minutes. After cooling in ice a solution of N-(tert-butoxycarbonyl)-6-bromo-hexylamine (770 mg) (Helv. Chim. Acta 76 891 (1993) in N,N-dimethylformamide (3 ml) was added dropwise and stirring was continued overnight at room temperature. Ice and water were added and the mixture was extracted three times with diethyl ether. The organic phases were washed with saturated sodium chloride, dried and evaporated to leave a yellow oil which after purification by chromatography on silica gel with diethyl ether as eluent gave the desired compound as a colourless oil.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].CC(C)([O-])C.[K+].Br[C:13]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:18])[C:14]([O:16][CH3:17])=[O:15].C(=O)=O.CO>C1COCC1>[C:3]([CH:2]([C:1]#[N:5])[C:13]([CH3:18])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])#[N:4]
Reactant: COC(=O)C(C)(Br)c1ccccc1
Reactant: N#CCC#N
Agent: CC(C)(C)[O-]
Agent: O=C=O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C(C)(c1ccccc1)C(C#N)C#N
Temperature: 25 °C

Procedure:
Malononitrile (4.29 g, 65 mmol) and potassium t-butoxide (7.29 g, 65 mmol) were added to a THF (100 mL) solution containing the intermediate from Step B (15.8 g, 65 mmol). The reaction solution was then placed in an 85° C. oil bath for 4 hours. The solution was then cooled to room temperature and partitioned between saturated aqueous ammonium chloride and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated racemic product. 1H NMR (500 MHz, CHCl3-d): δ 7.44-7.42 (m, 3H); 7.38-7.36 (m, 2H); 4.50 (s, 1H); 3.80 (s, 3H); 2.00 (s 3H). The racemic material was resolved on a Berger SFC II preparative instrument using a ChiralPak AD-H, 250×30 mm I.D. column and a SFC CO2/Methanol eluent.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:17][CH:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20]>ClCCl.C(Cl)(Cl)Cl>[Cl:17][CH:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19]([NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1)=[O:20]
Reactant: O=C(Cl)C(Cl)c1ccccc1
Reactant: N#Cc1ccc(N)cn1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(NC(=O)C(Cl)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 5-amino-2-cyanopyridine (0.500 g, 4.2 mmol) in dry dichloromethane (20 mL) was added triethylamine (0.637 g, 6.3 mmol) and the mixture was stirred at 0° C. α-Chloro phenylacetyl chloride (0.952 g, 5.04 mmol) was added dropwise to the mixture, and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with chloroform (100 mL) and washed with water (150 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel and ethyl acetate (20%) in petroleum ether as an eluent) to obtain the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[N:3]=[CH:2]1.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:13]1([C:10]([C:7]2[CH:8]=[C:9]3[NH:1][CH:2]=[N:3][C:4]3=[N:5][CH:6]=2)=[O:12])[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1cnc2nc[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1cnc2nc[nH]c2c1)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 71 %

Procedure:
The title compound is prepared from 1H-imidazo[4,5-b]pyridine-6-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 71% of theory; LC (method 4): tR=1.79 min; Mass spectrum (ESI+): m/z=319 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([C:22]5[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=5)[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1.C(OO)(=[O:32])C>C(Cl)Cl>[CH3:1][C:2]1([CH3:29])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([C:22]5[CH:23]=[N+:24]([O-:32])[C:25]([CH3:28])=[CH:26][CH:27]=5)[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1
Reactant: CC(=O)OO
Reactant: Cc1ccc(-c2ccc3c(c2)N(c2nc4c(s2)C(=O)NC(C)(C)C4)CCO3)cn1
Solvent: ClCCl
Product: Cc1ccc(-c2ccc3c(c2)N(c2nc4c(s2)C(=O)NC(C)(C)C4)CCO3)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.4 %

Procedure:
To a stirred solution of Example 48 (0.08 g, 0.19 mmol) in DCM (10 ml) was added peracetic acid (0.14 mL, 32 wt % in AcOH, 0.59 mmol). The reaction mixture was stirred at r.t. for 16 h, then concentrated in vacuo. Purification by preparative HPLC (Method 6) gave the title compound (0.014 g, 22%) as a white solid. δH (CD3OD) 8.53 (1H, d, J 1.5 Hz), 8.40 (1H, d, J 2.1 Hz), 7.69 (1H, dd, J 8.1 and 1.7 Hz), 7.55 (1H, d, J 8.3 Hz), 7.34 (1H, dd, J 8.7 and 2.3 Hz), 7.10 (1H, d, J 8.5 Hz), 4.46-4.37 (2H, m), 4.19-4.13 (2H, m), 2.92 (2H, s), 2.58 (3H, s), 1.41 (6H, s,). LCMS (ES+) 423.0 (M+H)+, RT 2.48 minutes (Method 1).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:17]([NH:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O.O>[C:17]([NH:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:31])=[CH:33][CH:34]=1)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2)cc1
Reactant: c1ccc2c(c1)CCCN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(Nc1ccc(C(=O)N2CCCc3ccccc32)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
To a solution of 1,2,3,4-tetrahydroquinoline (28.7 g) in acetone (400 ml) and water (200 ml) is added potassium carbonate (38.8 g) and further thereto is added 4-benzoylaminobenzoyl chloride (56 g) under ice-cooling. The mixture is stirred at room temperature overnight. Water is added to the reaction mixture, and the mixture is extracted with dichloromethane. The extract is dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue is purified by silica gel column chromatography and recrystallized from methanol to give 1-[4-(benzoylamino)benzoyl-]-1,2,3,4-tetrahydroquinoline (57 g) as white powder, m.p. 202.5-203.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=3)[C:6]=2[N:7]=1.Cl[C:23]1[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([N:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][OH:38])[CH2:32][CH2:31]2)[CH:24]=1>>[OH:38][CH2:37][CH2:36][N:33]1[CH2:32][CH2:31][N:30]([C:25]2[N:26]=[C:27]([CH3:29])[N:28]=[C:23]([NH:1][C:2]3[N:3]=[CH:4][C:5]4[S:10][CH:9]=[C:8]([C:11]5[CH:12]=[C:13]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=5)[C:6]=4[N:7]=3)[CH:24]=2)[CH2:35][CH2:34]1
Reactant: CS(=O)(=O)Nc1cccc(-c2csc3cnc(N)nc23)c1
Reactant: Cc1nc(Cl)cc(N2CCN(CCO)CC2)n1
Product: Cc1nc(Nc2ncc3scc(-c4cccc(NS(C)(=O)=O)c4)c3n2)cc(N2CCN(CCO)CC2)n1
Yield: 53.7 %

Procedure:
N-(3-(2-(6-(4-(2-Hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl)methanesulfonamide (18 mg, 53% yield) was prepared in the same manner as Step 10 of Example 1 using N-(3-(2-aminothieno[3,2-d]pyrimidin-7-yl)phenyl)methanesulfonamide (20 mg, 0.062 mmol) and 2-(4-(6-chloro-2-methylpyrimidin-4-yl)piperazin-1-yl)ethanol (16 mg, 0.062 mmol).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH3:16])=[CH:8]1.[OH-].[Na+].CN([CH:22]=[O:23])C>O>[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH3:16])=[C:8]1[CH:22]=[O:23]
Reactant: Cc1cn(C)c2ccccc12
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(C=O)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a stirred solution of phosphorus oxychloride (7.0 mL, 75 mmole) in DMF (25 mL) was added dropwise a solution of 1,3-dimethylindole (12.0 g, 83 mmole) in dry DMF (6.0 mL). The reaction was stirred at RT for 2 hr then was poured onto ice. The mixture was basified with a solution of NaOH (13.2 g, 330 mmole) in H2O (44 mL), then was extracted with Et2O (2×50 mL). The combined organic layers were washed with brine, dried (MgSO4), and concentrated under vacuum. Flash chromatography on silica gel (10% ethyl acetate/hexanes) gave the tide compound (13.03 g, 91%) as an off-white solid: LCMS (ES) m/e 174.2 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 10.16 (s, 1 H), 7.68 (d, J=8.1 Hz, 1 H), 7.42 (t, 1 H), 7.32 (d, J=8.5 Hz, 1 H), 7.15 (t, 1 H), 4.04 (s, 3 H), 2.63 (s, 3 H).