Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:18][C:17](=[O:19])[C:16]4[CH:20]=[C:21](I)[CH:22]=[C:23]([CH3:24])[C:15]=4[N:14]=3)=[CH:11][C:10]([C:26]([F:29])([F:28])[F:27])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:30]([NH2:33])([CH3:32])[CH3:31]>O1CCCC1>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([NH:14][C:15]3[C:16]([C:17]([NH:33][CH:30]([CH3:32])[CH3:31])=[O:19])=[CH:20][C:21]([C:17]([O:18][CH3:13])=[O:19])=[CH:22][C:23]=3[CH3:24])=[O:18])=[CH:11][C:10]([C:26]([F:28])([F:27])[F:29])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N
Reactant: Cc1cc(I)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c(NC(=O)c2cc(C(F)(F)F)nn2-c2ncccc2Cl)c(C(=O)NC(C)C)c1
Temperature: 60 °C
Yield: 160.7 %

Procedure:
The title compound of step B (3.07 g, 5.7 mmol) was dissolved in tetrahydrofuran (30 mL) and treated with isopropylamine (1.69 g, 28.7 mmol). The mixture was heated at 60° C. for 2 hours and concentrated to dryness under reduced pressure. The residue was subjected to chromatography on silica gel using ethyl acetate/hexanes (40:60) as eluent. Pooling appropriate fractions and evaporation of solvent provided the title compound of Step C (2.4 g): m.p.: 199-200° C. 1H NMR (CDCl3): δ 10.3 (NH), 8.42 (1H), 7.84 (1H), 7.61 (1H), 7.44 (2H), 7.42 (1H), 6.01 (1H), 4.21 (m, 1H), 2.13 (s, 3H), 1.2 (6H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[N+:12]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[C:18]2[CH:24]=[O:25])([O-:14])=[O:13].[O:26]1[CH:31]=[CH:30][CH2:29][CH2:28][CH2:27]1>C1COCC1.C(Cl)Cl>[N+:12]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][O:26]1)[N:19]=[C:18]2[CH:24]=[O:25])([O-:14])=[O:13]
Reactant: O=Cc1n[nH]c2ccc([N+](=O)[O-])cc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=Cc1nn(C2CCCCO2)c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 49.8 %

Procedure:
p-Toluenesulfonic acid (30 mg, 0.158 mmol) was added to a solution of 5-nitro-indazole-3-carbaldehyde (300 mg, 1.569 mmol) and 3,4-dihydro-2H-pyran (265 mg, 3.150 mmol) in a mixture of THF/CH2Cl2 (1:1, 8 mL). The reaction mixture was stirred for 12 h at room temperature and then the solvent was removed in vacuo. The residue was taken in CH2Cl2 (50 mL) and poured in water (20 mL). The organic layer was separated, the aqueous layer was extracted with CH2Cl2 (50 mL), the combined organic layers were washed with water (40 mL) and brine (40 mL), dried over Na2SO4, and concentrated. Purification by flash chromatography (CH2Cl2) afforded title compound 215 mg (50% yield) as a solid. 1H NMR (400 MHz, CDCl3): δ 10.23 (s, 1H), 9.23 (d, 1H, J=2.0 Hz), 8.35 (dd, 1H, J=2.0 and 9.2 Hz), 7.80 (d, 1H, J=9.2 Hz), 5.89 (dd, 1H, J=2.8 and 8.8 Hz), 3.98 (m, 1H), 3.80 (m, 1H), 2.53 (m, 1H), 2.19 (m, 2H), 1.76 (m, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]12[CH2:15][CH2:14][CH2:13][C:11]3[C:12]1=[C:7]([CH:8]=[CH:9][CH:10]=3)[NH:6][C:5]2=[O:16].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][C:4]23[CH2:15][CH2:14][CH2:13][C:11]4[C:12]2=[C:7]([CH:8]=[CH:9][CH:10]=4)[NH:6][C:5]3=[O:16])[CH2:27][CH2:26]1
Reactant: O=C1Nc2cccc3c2C1(CCBr)CCC3
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1N1CCN(CCC23CCCc4cccc(c42)NC3=O)CC1
Yield: 32.2 %

Procedure:
2a-(2-Bromoethyl)-2a,3,4,5-tetrahydrobenz[cd]indole-2(1H)-one (140 mg, 0.5 mmol), 4-(2-methoxyphenyl)piperazine (148 mg, 0.77 mmol) and potassium carbonate (138 mg, 1 mmol) were stirred in anhydrous N,N-dimethylformamide (5 ml) at room temperature for 2 hours. The reaction solution was mixed with ethyl acetate (50 ml) and water (50 ml). The ethyl acetate layer was washed with water and dried with anhydrous sodium sulfate. Then the compound obtained by the evaporation of the solvent under a reduced pressure was separated and purified by a silica gel column chromatography to obtain 63 mg of the title compound (32% in yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:26][O:27][CH2:28][C:29](Cl)=[O:30].C(N(CC)CC)C.CN(C)C=O>O1CCCC1>[CH3:26][O:27][CH2:28][C:29]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:30]
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Reactant: COCC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCC(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(C(N)=O)cc23)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide in tetrahydrofuran (6 mL), was added 2-methoxyacetyl chloride (0.065 mL, 0.713 mmol) followed by triethyl amine (0.414 mL, 2.97 mmol). A small volume of dimethyl formamide was added to aid solubility (1 mL). The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and he crude was partitioned between ethyl acetate and water. The crude product was isolated as an oily yellow residue (yield not calculated): ES-MS (m/z) 409 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][C:11]([NH:13][NH2:14])=[O:12].Cl.[C:16](=N)(OCC)[CH3:17]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][C:11]1[O:12][C:16]([CH3:17])=[N:14][N:13]=1
Reactant: CCOC(C)=N
Reactant: Cc1cccc(C)c1NCC(=O)NN
Agent: Cl
Solvent: c1ccncc1
Product: Cc1nnc(CNc2c(C)cccc2C)o1
Yield: 34.1 %

Procedure:
A solution of 19.3 g (0.1 mol) alpha-(2,6-dimethylphenylamino)acethydrazide and 14 g (0.11 mol) ethyl actimidate hydrochloride (Aldrich Chemical Co.) in 150 ml pyridine was heated under reflux for 9 hours. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure to give an oil. The oil was placed on 400 g silica gel in a chromatography column and eluted the following solvent systems: (1) petroleum ether, (2) petroleum ether/ethyl ether, (3) ethyl ether, and (4) ethyl ether/methanol. The crude product (11.5 g) was eluted from the column with the ethyl ether/methanol solvent system. Crystallization of the crude product from dichloromethane/ethyl ether gave 7.4 g of crystalline product, m.p. 134°-135° C. The product is tabulated in Table I as Compound No. 1-A.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH2:11])[C:3]=1[N+:12]([O-:14])=[O:13].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.C(N(CC)CC)C.II>C(OCC)(=O)C.CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:21][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([F:15])=[CH:17][CH:18]=2)=[C:3]([N+:12]([O-:14])=[O:13])[C:4]=1[NH2:11])([O-:10])=[O:9]
Reactant: NCc1ccc(F)cc1
Reactant: Nc1c([N+](=O)[O-])ccc(F)c1[N+](=O)[O-]
Agent: II
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Nc1c([N+](=O)[O-])ccc(NCc2ccc(F)cc2)c1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A round bottom flask is charged with 8 (2.01 g, 10 mmol, 1 equiv), 4-fluorobenzylamine (3.79 g, 30 mmol, 3 equiv) and triethylamine (1.21 g, 12 mmol, 1.2 equiv). DMF (40 mL) is then added to the above mixture followed by iodine (catalytic, 1 mg). The reaction mixture is then heated to 120° C. and stirred at 120° C. for 16 hrs after which the flask is allowed to cool to room temperature. The reaction mixture is diluted with ethyl acetate and washed with water (5×80 mL) and dried with brine and then over MgSO4. The suspension is filtered and concentrated to give a residue, which is purified by silica gel flash chromatography (hexanes/ethyl acetate) to give the desired product (9).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10]
Reactant: Cc1ccccc1B(O)O
Reactant: N#CCc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1ccccc1CC#N
Temperature: 90 °C
Yield: 74.3 %

Procedure:
In a vial, 2-bromophenylacetonitrile (2 g, 10.2 mmol), 2-methylphenylboronic acid (1.53 g, 11.2 mmol) and potassium carbonate (2.82 g, 20.4 mmol, Eq: 2) were combined with toluene (15.0 ml), ethanol (15 ml) and water (5 ml) to give a light brown suspension. The mixture was degassed with argon and then tetrakis(triphenylphosphine)palladium(0) (354 mg, 306 μmol) was added. The reaction mixture was heated at 90° C. for 12 h, cooled and poured into water and extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4) and evaporated to dryness under reduced pressure. Chromatography (silica gel, 0% to 5% EtOAc in hexanes) provided the title product as a colourless oil (1.57 g; 74%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][CH2:11][C:12]1[N:13]([CH2:25][C:26]([NH:29][C:30](=[O:44])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH:36]C(=O)OC(C)(C)C)([CH3:28])[CH3:27])[C:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:24]=1)[CH3:9]>ClCCl.O.[OH-].[NH4+]>[NH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][C:30]([NH:29][C:26]([CH3:27])([CH3:28])[CH2:25][N:13]1[C:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:24]=[C:12]1[CH2:11][O:10][CH2:8][CH3:9])=[O:44]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC(C)(C)NC(=O)CCCCCNC(=O)OC(C)(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOCc1nc2cnc3ccccc3c2n1CC(C)(C)NC(=O)CCCCCN
Reaction time: 1.5 h
Yield: 105.6 %

Procedure:
Trifluoroacetic acid (30 mL) was added slowly to a solution of tert-butyl 6-({2-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}amino)-6-oxohexylcarbamate (3.99 g, 7.82 mmol) in dichloromethane (80 mL) at room temperature. After 1.5 hours, the solution was concentrated under reduced pressure to afford an oil. The oil was dissolved in a small amount of water and concentrated ammonium hydroxide. The resulting basic mixture was extracted with dichloromethane multiple times. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 3.4 g of 6-amino-N-{2-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}hexanamide, which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:3](S(C1C=CC(C)=CC=1)(=O)=O)=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[C:16]#[N:17])=[CH:7][CH:6]=1)#[N:2].C([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])#N.[N:36]12CCCN=C1CCCC[CH2:37]2>>[C:37]([C:3]1[C:4]([C:5]2[CH:6]=[CH:7][C:8]([C:11]3[S:12][CH:13]=[CH:14][C:15]=3[C:16]#[N:17])=[CH:9][CH:10]=2)=[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[NH:2][CH:1]=1)#[N:36]
Reactant: Cc1ccc(S(=O)(=O)C(C#N)=Cc2ccc(-c3sccc3C#N)cc2)cc1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCOC(=O)CC#N
Product: CCOC(=O)c1[nH]cc(C#N)c1-c1ccc(-c2sccc2C#N)cc1

Procedure:
In a manner analogous to the procedure set forth in example A-239, the title compound is prepared from 2-(4-{2-cyano-2-[(4-methylphenyl)sulfonyl]vinyl}phenyl)thiophene-3-carbonitrile, prepared directly above, ethyl cyanoacetate and 1,8-diazabicyclo[5.4.0]undec-7-ene.
Reaction SMILES: [CH3:1][N:2]([C@@H:10]([CH3:26])[C:11](=[O:25])[NH:12][C@H:13]1[CH2:19][O:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[NH:15][C:14]1=[O:24])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].N[C@H:28]1[C@@H](C)OC2C=CC=CC=2NC1=O>>[C:5]([O:4][C:3](=[O:9])[N:2]([CH3:1])[C@H:10]([C:11](=[O:25])[NH:12][C@@H:13]1[C:14](=[O:24])[NH:15][C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[O:18][C@@H:19]1[CH3:28])[CH3:26])([CH3:8])([CH3:6])[CH3:7]
Reactant: C[C@H]1Oc2ccccc2NC(=O)[C@H]1N
Reactant: C[C@@H](C(=O)N[C@H]1COc2ccccc2NC1=O)N(C)C(=O)OC(C)(C)C
Product: C[C@H]1Oc2ccccc2NC(=O)[C@H]1NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 61 %

Procedure:
In a similar manner to that described for the preparation of tert-butyl methyl((S)-1-oxo-1-((S)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)propan-2-yl)carbamate except the mixture was stirred 1.5 h and the crude product purified by silica gel chromatography, (2R,3S)-3-amino-2-methyl-2,3-dihydrobenzo[b][1,4]-oxazepin-4 (5H)-one (420 mg, 2.19 mmol) was converted to the title compound (505 mg, 61%) as a white foam.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)O1.C(=O)([O-])[O-].[K+].[K+].[Br:23][C:24]1[CH:25]=[C:26](I)[C:27]([NH2:30])=[N:28][CH:29]=1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:13][C:12]1[CH:11]=[CH:10][C:9]([C:26]2[C:27]([NH2:30])=[N:28][CH:29]=[C:24]([Br:23])[CH:25]=2)=[CH:15][CH:14]=1
Reactant: Nc1ncc(Br)cc1I
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(-c2cc(Br)cnc2N)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
Tetrakis(triphenylphosphine)palladium (1.16 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.48 g) and potassium carbonate (4.15 g) were added to a solution of 5-bromo-3-iodopyridin-2-amine (2.99 g) in 1,4-dioxane (40 ml) and water (10 ml) at room temperature. The reaction mixture was stirred at 100° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was then purified by silica gel chromatography [chloroform:methanol=9:1 (v/v)] to give 2.48 g of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].Br[CH:14]([CH2:20][CH2:21][Br:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[O:12][CH:14]([CH2:20][CH2:21][Br:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C(Br)CCBr
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCBr)Oc1cc([N+](=O)[O-])c(F)cc1Cl

Procedure:
To a solution containing 2-chloro-4-fluoro-5-nitrophenol (1 equivalent) and ethyl 2,4-dibromobutanoate (1 equivalent) in DMF is added potassium carbonate (1 equivalent) at room temperature and the mixture is stirred. After completion of the reaction, to the reaction mixture is added aqueous diluted hydrochloric acid and the mixture is extracted with ethyl acetate. After concentrating the organic layer, the residue is subjected to chromatography to give ethyl 2-(2-chloro-4-fluoro-5-nitrophenoxy)-4-bromobutanoate.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[C:18]1([CH2:24][OH:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:24]([O:25][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCc1ccccc1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: c1ccc(COc2nc(Nc3cc[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and phenyl methanol to give (1-benzyloxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 317(MH+).
Reaction SMILES: C(Cl)(=O)C.[CH2:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]([N:17]3[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18]3)=[O:16])=[CH:11][CH:12]=2)[CH2:7][NH:6]1.NC1C=C2C(=CC=1)CN(C(N[C:39]1[CH:44]=[CH:43][C:42]([C:45](=[O:50])NCCC)=[CH:41][CH:40]=1)=O)C2>>[C:45]([N:6]1[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[C:10]([NH:14][C:15]([N:17]3[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18]3)=[O:16])[CH:9]=2)[CH2:5]1)(=[O:50])[C:42]1[CH:43]=[CH:44][CH:39]=[CH:40][CH:41]=1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Reactant: O=C(Nc1ccc2c(c1)CNC2)N1Cc2ccccc2C1
Solvent: CC(=O)Cl
Product: O=C(Nc1ccc2c(c1)CN(C(=O)c1ccccc1)C2)N1Cc2ccccc2C1

Procedure:
The title compound was prepared as described in Example 278, substituting benzoyl chloride for acetyl chloride and N-(isoindolin-5-yl)isoindoline-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.40 (d, J=8.8 Hz, 1H), 7.59-7.67 (m, 3H), 7.11-7.52 (m, 9H), 4.68-4.84 (m, 8H); MS (ESI(+)) m/e 384 (M+H)+.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2ccc(OC)cc2c1O
Product: CCOC(=O)c1cnc2ccc(OC)cc2c1Cl
Temperature: 25 °C
Yield: 97 %

Procedure:
A solution of ethyl 4-hydroxy-6-methoxyquinoline-3-carboxylate (Example 1c, 1.24 g, 5.0 mmol) in POCl3 was refluxed under nitrogen for 3 hrs. The solution was cooled to room temperature and evaporated under reduced pressure. The residue was carefully quenched with ice, and neutralized with 2.0 N NaOH to pH 7. The precipitate was collected by filtration, washed with cold water, and dried under vacuum to give the title compound as a pale-yellow solid (1.29 g, 97%). 1H NMR (400 MHz, DMSO-d6) δ 1.36 (t, J=7.0 Hz, 3H), 3.96 (s, 3H), 4.41 (q, J=7.0 Hz, 2H), 7.57 (d, J=2.8 Hz, 1H), 7.61 (dd, J=2.8, 8.8 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 8.97 (s, 1H). MS 266, 268 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[OH-].[NH4+:22]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][C:12]([NH2:22])=[O:14])=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: Cc1ccc(CCOCC(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1ccc(CCOCC(N)=O)cc1

Procedure:
The subtitle compound (0.77 g) was prepared according to the procedure in example 1 part b using 2-[2-(4-methylphenyl)ethoxy]acetic acid (1.1 g). oxalyl chloride (1.44 g), concentrated ammonium hydroxide (20 ml), and toluene (40 ml).
Reaction SMILES: C([Mg]Br)C.Br[CH2:6][C:7]1([CH2:10][C:11]#[N:12])[CH2:9][CH2:8]1.[Br:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:22]=1[NH:21][C:20]([CH3:23])=[CH:19]2>C1(C)C=CC=CC=1>[Br:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:22]=1[NH:21][C:20]([CH3:23])=[C:19]2[CH2:6][C:7]1([CH2:10][C:11]#[N:12])[CH2:9][CH2:8]1
Reactant: N#CCC1(CBr)CC1
Reactant: Cc1cc2cccc(Br)c2[nH]1
Agent: CC[Mg]Br
Solvent: Cc1ccccc1
Product: Cc1[nH]c2c(Br)cccc2c1CC1(CC#N)CC1
Temperature: 100 °C
Reaction time: 1.33 h
Yield: 53.6 %

Procedure:
Ethyl magnesium bromide (3.0M diethyl ether solution, 72 mL) was slowly added dropwise under an argon atmosphere and ice-cooling to a solution of [1-(bromomethyl)cyclopropyl]acetonitrile (15 g) and 7-bromo-2-methyl-1H-indole (45 g) in toluene (250 mL), followed by stirring at 100° C. for 80 minutes. The reaction mixture was cooled to room temperature; quenched with a saturated aqueous ammonium chloride solution, diluted with water; and extracted with ethyl acetate. The organic layer was washed sequentially with water and brine. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by a purification system CombiFlash CompanionXL (manufactured by Isco, Co., Ltd., column: RediSep 350 g; hexane:ethyl acetate=95:5->70:30) to obtain title compound (14 g) having the following physical properties.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[NH:5][C:4](=[O:11])[C:3]=1[N+:12]([O-:14])=[O:13].[NH3:15]>CO>[NH2:15][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[NH:5][C:4](=[O:11])[C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CC(C)c1cc(Cl)c([N+](=O)[O-])c(=O)[nH]1
Reactant: N
Solvent: CO
Product: CC(C)c1cc(N)c([N+](=O)[O-])c(=O)[nH]1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of 4-chloro-6-isopropyl-3-nitro-1H-pyridin-2-one (700 mg, 3.23 mmol) in 6-7 mL of 7 N NH3 in MeOH is stirred at 100° C. in a sealed tube for 1.5 h. After cooling, the reaction mixture is concentrated in vacuo. The residue is suspended in H2O, filtered, washed with H2O, and dried, yielding 4-amino-6-isopropyl-3-nitro-1H-pyridin-2-one. 1H NMR (DMSO-d6, 300 MHz) δ 10.96 (br s, 1H), 8.15 (br s, 2H), 5.70 (d, J=0.9 Hz, 1H), 2.58 (sept, J=6.9 Hz, 1H), 1.11 (d, J=6.9 Hz, 6H) ppm.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].C([CH:14]1[N:26]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]3[NH:44][N:43]=[N:42][N:41]=3)=[CH:30][CH:29]=2)[C:17]2=[N:18][C:19](=S(=O)=O)[CH:20]=[C:21]([CH3:22])[C:16]2=[N:15]1)C.Cl>O.CN(C=O)C>[CH2:1]([O:5][C:14]1[N:26]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]3[NH:44][N:43]=[N:42][N:41]=3)=[CH:32][CH:33]=2)[C:17]2=[N:18][CH:19]=[CH:20][C:21]([CH3:22])=[C:16]2[N:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCC1N=C2C(C)=CC(=S(=O)=O)N=C2N1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: CCCCO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 49 %

Procedure:
A mixture of 100 mg (1.3 mmol) of n-butanol, 400 mg (3.6 retool) of potassium tert.-butoxide and DMF was heated at 80 degree C for 5 minutes. 300 mg (0.65 mmol) of 2-ethyl-sulfonyl-7-methyl-3[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazo[4.5-b]pyridine was added to the mixture. The resultant was heated for 2 hours. The reaction product mixture was mixed with water, neutralized with 2n HCl and extracted with dichloromethane. The dichloromethane phase was washed with a saturated saline and dried with anhydrous magnesium sulfate. The solvent was distilled out at a reduced pressure and the residue was treated with ether-hexane-dichloromethane or re-crystallization to obtained 140 mg of the intended compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([OH:14])[CH3:13])[CH2:11][O:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34](O)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12]([O:14][C:34](=[O:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH3:13])[CH2:11][O:10]1
Reactant: O=C(O)c1ccccc1
Reactant: C[C@@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@H](OC(=O)c1ccccc1)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 78.5 %

Procedure:
To a solution of 16.1 g of (1R)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol in 320 ml of tetrahydrofuran were added, under ice-cooling, 63.3 of triphenylphosphine, 29.5 g of benzoic acid and 42.0 g of diethyl azodicarboxylate, and the mixture was stirred in an argon atmosphere at room temperature for 6 hours. To the reaction mixture were added 800 ml of ethyl acetate and 500 ml of water to fractionate and the aqueous phase was extracted with 200 ml of ethyl acetate. The organic phases were collected, washed successively with water and with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated. The residue was purified by using silica gel chromatography (gradient eluent; hexane:ethyl acetate=15:1→7:1) to give 19.2 g of [(1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethyl]benzoate as a colorless oil.