Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.Cl[C:20]([O:22][CH3:23])=[O:21]>ClCCl>[CH3:23][O:22][C:20](=[O:21])[NH:12][C:10]1[O:11][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1
Reactant: COc1cccc2oc(N)nc12
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Nc1nc2c(OC)cccc2o1
Reaction time: 3.5 h
Yield: 52.9 %

Procedure:
To a stirred solution of 65 g (40 mmol) 4-methoxy-benzooxazol-2-yl-amine and 4.5 ml (56 mmol) pyridine in 250 ml dichoromethane at 0° C. was added dropwise a solution of 4.1 ml (49 mmol) methyl chloroformate in 50 ml dichoromethane and stirring continued for 3.5 hours. The mixture was then poured onto water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (dichloromethane) afforded 4.7 g (54%) (4-methoxy-benzooxazol-2-yl)-carbamic acid methyl ester as an off-white crystalline solid. EI-MS m/e (%): 222 (M+, 100), 190 (27), 163 (23).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[N:28]1([CH2:37][C:38](O)=[O:39])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29]1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N:28]1([CH2:37][C:38]([O:10][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]3[CH2:25][CH2:24]3)[CH:12]=2)[CH2:8][C:7]2[C:6]([Cl:26])=[CH:5][N+:4]([O-:27])=[CH:3][C:2]=2[Cl:1])=[O:39])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29]1
Reactant: O=C(O)Cn1ccc2ccccc21
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(Cn1ccc2ccccc21)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
A mixture of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.615 g, 1.463 mmol), 2-(1H-indol-1-yl)acetic acid (0.282 g, 1.610 mmol), EDC (0.842 g, 4.39 mmol), and DMAP (0.268 g, 2.195 mmol) in DCM (20 ml) was stirred at room temperature overnight. The reaction was washed with 1N HCl, aqueous NaHCO3 and brine; the organic phase was dried over Na2SO4 and evaporated to dryness. The crude was purified by flash chromatography on silica gel column (DCM/MeOH from 99/1 to 98/2) to afford (S)-4-(2-(2-(1H-indol-1-yl)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.615 g, 1.065 mmol, 72.8% yield). MS/ESI+ 577.2 [MH]+; [αD]=+5.500, c=0.44, DCM; 1H NMR (300 MHz, DMSO-d6) d ppm 8.52 (s, 2H), 7.48-7.63 (m, 1H), 7.27 (d, 1H), 7.13-7.19 (m, 2H), 7.10 (td, 1H), 7.00-7.05 (m, 1H), 6.99 (d, 1H), 6.92 (dd, 1H), 7.06 (t, 1H), 6.45 (dd, 1H), 6.02 (dd, 1H), 5.23 (d, 1H), 5.05 (d, 1H), 3.84 (d, 2H), 3.42 (dd, 1H), 3.20 (dd, 1H), 1.13-1.34 (m, 1H), 0.49-0.67 (m, 2H), 0.29-0.46 (m, 2H).
Reaction SMILES: O=[C:2]([CH2:6][CH3:7])[CH2:3][C:4]#[N:5].[NH2:8][C:9]1[N:13]=[CH:12][NH:11][N:10]=1>C(O)(=O)C>[CH2:6]([C:2]1[CH:3]=[C:4]([NH2:5])[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]=1)[CH3:7]
Reactant: Nc1nc[nH]n1
Reactant: CCC(=O)CC#N
Solvent: CC(=O)O
Product: CCc1cc(N)n2ncnc2n1
Temperature: 150 °C
Yield: 11.9 %

Procedure:
A mixture of 3-oxopentanenitrile (1.0 g, 10.3 mmol) and 3-amino-1,2,4-triazole (0.91 g, 10.8 mmol) in 10 mL of acetic acid was heated in a pressure tube at 150° C. for 24 h. The reaction mixture was allowed to cool to room temperature, and solvent was removed in vacuo. The solid was removed via filtration. The filtrate partially upon standing at room temperature, and the solid was collected via filtration to give the title compound (200 mg, 12% yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][N:26]=1>>[F:18][C:17]1[C:12]2[N:13]([C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:28]4[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[N:26][CH:27]=4)[CH:3]=3)=[CH:10][N:11]=2)[CH:14]=[CH:15][C:16]=1[C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: COc1ccc(B(O)O)cn1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: COc1ccc(-c2cc(-c3cnc4c(F)c(C(C)(C)O)ccn34)ccc2F)cn1
Yield: 7 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 2-methoxypyridine-5-boronic acid were coupled in the same way as in Example 30 to give 2-{8-fluoro-3-[4-fluoro-3-(2-methoxypyridin-5-yl)phenyl]imidazo[1,2-α]pyridin-7-yl}propan-2-ol as an off-white solid (8 mg, 7%): m/z (ES+) 396 [MH+].
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:19])=[C:8]([CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16])[C:9](O)=[O:10].S(Cl)([Cl:22])=O.CN(C=O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:19])=[C:8]([CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16])[C:9]([Cl:22])=[O:10]
Reactant: COCCOc1c(S(C)(=O)=O)ccc(C(=O)O)c1C
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COCCOc1c(S(C)(=O)=O)ccc(C(=O)Cl)c1C
Temperature: 100 °C
Reaction time: 2 h

Procedure:
3-(2-Methoxyethoxy)-2-methyl-4-(methylsulfonyl)benzoic acid (100 g) and toluene (300 mL) were mixed, and thionyl chloride (47.5 g) and DMF (2.5 g) were added, followed by heating and stirring at 100° C. for 2 hours. After completion of the reaction, 180 mL of toluene was distilled off under reduced pressure to obtain a solution of 3-(2-methoxyethoxy)-2-methyl-4-(methylsulfonyl)benzoyl chloride.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH2:9][CH2:10]Cl)[CH2:6][CH2:7]Cl.[CH3:12][O:13][CH2:14][CH2:15][OH:16]>>[CH2:4]([N:5]([CH2:9][CH2:10][O:16][CH2:15][CH2:14][O:13][CH3:12])[CH2:6][CH2:7][O:16][CH2:15][CH2:14][O:13][CH3:12])[CH2:3][O:16][CH2:15][CH2:14][O:13][CH3:12]
Reactant: ClCCN(CCCl)CCCl
Reactant: COCCO
Agent: Cl
Product: COCCOCCN(CCOCCOC)CCOCCOC

Procedure:
To the mixture thus obtained, 51.6 g of tris(2-chloroethyl)amine hydrochloride (0.215 mole) are added. The mixture is then heated at the reflux temperature of the 2-methoxyethanol (125° C.) for 12 hours and then the solvent is removed by distillation under reduced pressure. The excess sodium 2-methoxyethanolate is neutralized by the addition of 11.6 cm3 aqueous HCl (10 N). The sodium chloride is filtered off and the solution is distilled.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O>>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:6]1[N:7]=[C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)[S:9][C:5]=1[C:3]([OH:2])=[O:4]
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Reactant: OB(O)c1ccccc1Cl
Product: COc1cc2ncn(-c3nc(-c4ccccc4Cl)c(C(=O)O)s3)c2cc1OC
Yield: 46.2 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 2-chlorophenylboronic acid (23.5 mg, 0.15 mmol) gave 4-(2-Chloro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (19.2 mg, 46%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.63 (br.s., 1 H); 8.82 (s, 1 H); 7.73 (s, 1 H); 7.59-7.65 (m, 2 H); 7.51 (td, 1 H); 7.46 (d, 1H); 7.39 (s, 1 H); 3.85 (s, 3 H); 3.81 (s, 3 H). MS m/z 416 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(OCC)(=O)C>[CH3:25][S:26]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=1)(=[O:28])=[O:27]
Reactant: COC(=O)c1ccc(OCCCCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCCCCCOS(C)(=O)=O)cc1
Reaction time: 2 h

Procedure:
To a solution of the compound 24 (3.58 g) and triethylamine (2.76 mL) in ethyl acetate (50 mL), methanesulfonyl chloride (0.78 mL) was slowly added under ice cooling. The reaction mixture was stirred under ice cooling for 2 hours. The reaction mixture was diluted with ethyl acetate (100 mL). The diluted solution was washed in turn with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel chromatography (ethyl acetate:methanol=1:0→10:1) to obtain the title compound (3.70 g) having the following physical properties.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.[NH2:15][C:16]1[CH:17]=[C:18]([CH:33]=[CH:34][CH:35]=1)[CH2:19][N:20]([CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>CCO>[CH:28]1([N:20]([CH2:19][C:18]2[CH:33]=[CH:34][CH:35]=[C:16]([NH:15][CH2:3][CH:2]([OH:1])[CH2:4][N:5]3[CH2:14][CH2:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH2:6]3)[CH:17]=2)[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(N)c1)C1CCCC1
Reactant: c1ccc2c(c1)CCN(CC1CO1)C2
Solvent: CCO
Product: CC(C)(C)OC(=O)N(Cc1cccc(NCC(O)CN2CCc3ccccc3C2)c1)C1CCCC1
Temperature: 100 °C
Yield: 23.2 %

Procedure:
To a solution of 2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (170 mg, 0.899 mmol) in EtOH (10 mL) was added tert-butyl 3-aminobenzyl(cyclopentyl)carbamate (313 mg, 1.08 mmol) and the solution heated at 100° C. in a sealed tube overnight. The solvent was then evaporated off and the residue purified by prep-TLC to give 100 mg compound as colorless oil (280 mg, 65%). LCMS (m/z): 480.3 (M+1)
Reaction SMILES: Cl[C:2]1[C:11]([C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:22])=[CH:7][CH:8]=2)[N:3]=1.[CH3:23][S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CC#N>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>[F:22][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[C:11]([C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])[C:2]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[S:24][CH3:23])=[N:3]2)=[CH:8][CH:7]=1
Reactant: CSc1ccccc1B(O)O
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cc2ccc(F)cc2nc1Cl
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: [Na+]
Solvent: CC#N
Solvent: O
Product: CSc1ccccc1-c1nc2cc(F)ccc2cc1[C@H](C)NC(=O)OC(C)(C)C
Temperature: 85 °C
Yield: 92.9 %

Procedure:
A mixture of (S)-tert-butyl (1-(2-chloro-7-fluoroquinolin-3-yl)ethyl)carbamate (382 mg, 1.2 mmol), 2-(methylthio)phenylboronic acid (257 mg, 1.3 eq), Na2CO3 (623 mg, 5.0 eq), Pd(PPh3)4 (93 mg, 5%), MeCN (9 mL) and water (3 mL) was heated to 85° C. under N2 overnight. After cooling to rt, the reaction was partitioned between EtOAc (10 mL) and water (5 mL). The organic layer was separated, washed, dried and concentrated. The residue was purified by column chromatography on silica gel to give a white solid (S)-tert-butyl (1-(7-fluoro-2-(2-(methylthio)phenyl)quinolin-3-yl)ethyl)carbamate (460 mg, 94.8%). Mass Spectrum (ESI) m/e=413 (M+1).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)=[O:3].[N+:13]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O)([O-:15])=[O:14].[OH-].[Na+]>CO>[N+:10]([C:6]1[CH:5]=[C:4]([C:2](=[O:3])/[CH:1]=[CH:19]/[C:18]2[CH:21]=[CH:22][CH:23]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=2)[CH:9]=[CH:8][CH:7]=1)([O-:12])=[O:11]
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(/C=C/c1cccc([N+](=O)[O-])c1)c1cccc([N+](=O)[O-])c1
Reaction time: 16 h
Yield: 89.4 %

Procedure:
3-Nitroacetophenone (2.23 g, 0.0135 mol) [Aldrich] and 3-nitrobenzaldehyde (2.04 g, 0.0135 mol) [Aldrich] were dissolved in methanol (20 mL), and sodium hydroxide (1.3 g, 0.032 mol) was added. The mixture was stirred for 16 hours. The solid formed was filtered and washed with water to give the desired product (3.6 g, 89%). LCMS for C15H11N2O5 (M+H)+: m/z=299.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.CO.[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH:26]=O.[BH3-]C#N.[Na+]>C(O)(=O)C>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][CH2:26][C:25]2[CH:28]=[CH:29][C:30]([Cl:31])=[C:23]([Cl:22])[CH:24]=2)[N:13]=1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Clc1nc(NCCNCc2ccc(Cl)c(Cl)c2)c2ncn(C3CCCC3)c2n1
Reaction time: 0.5 h

Procedure:
281 mg of the product obtained in Stage 1 of Example 7, 4 ml of methanol, 0.2 ml of 3,4-dichloro-benzaldehyde and 0.2 ml of acetic acid are mixed together and the reaction medium is agitated for 2 hours and 30 minutes, 0.1 g of NaBH3CN is added and agitation is carried out at ambient temperature for 1 hour. After evaporating the solvent, the residue is chromatographed on silica eluting with CH2Cl2/methanol/ammonium hydroxide (95/0.5/0.33) and 278.4 mg of expected product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][C:11]2[CH:16]=[C:15](F)[CH:14]=[CH:13][C:12]=2[N+:18]([O-:20])=[O:19])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[N:21]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][C:11]2[CH:16]=[C:15]([N:24]3[CH2:23][CH2:22][N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25]3)[CH:14]=[CH:13][C:12]=2[N+:18]([O-:20])=[O:19])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(Nc1cc(F)ccc1[N+](=O)[O-])c1cccc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-])c1cccc(Cl)c1
Yield: 11.4 %

Procedure:
N-(1-(3-Chlorophenyl)ethyl)-5-fluoro-2-nitrobenzenamine (522 mg, 1.8 mmol), t-butyl piperazine-1-carboxylate (329 mg, 1.8 mmol), N,N-diisopropylethylamine (457 mg, 3.5 mmol) were stirred at 90° C. in dry acetonitrile (50 mL) for 24 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 25% ethyl acetate in hexanes to afford the title compound (95 mg, 12% yield). 1H NMR (400 MHz, CDCl3): δ 8.70 (s, 1H), 8.06 (d, 1H), 7.33-7.21 (m, 4H), 6.15 (d, 1H), 5.58 (s, 1H), 4.53 (m, 1H), 3.43 (m, 4H), 3.21 (m, 2H), 3.13 (m, 2H), 1.63 (d, 3H), 1.46 (s, 9H); MS (ESI) m/z: Calculated for C23H29ClN4O4: 460.19; Observed: 483.3 (M++Na).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=2[N:7]=[C:6]1Cl)[C:2]#[C:3][CH3:4].[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:6]2[N:5]([CH2:1][C:2]#[C:3][CH3:4])[C:13]3[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=3[N:7]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC#CCn1c(Cl)nc2c1c(=O)n(C)c(=O)n2C
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Yield: 56.9 %

Procedure:
8-Chlorotheophylline (4.9 g) and potassium carbonate (5 g) were dissolved in N,N-dimethylformamide (100 ml), and 1-bromo-2-butyne (2.4 ml) was added thereto. After stirring at room temperature overnight, the reaction mixture was diluted with ethyl acetate, and washed with water. Insoluble white solid was collected through filtration, and washed with ethyl acetate to give 3.8 g of 7-(2-butynyl)-8-chloro-1,3-dimethyl-3,7-dihydropurine-2,6-dione. Then, the resulting 7-(2-butynyl)-8-chloro-1,3-dimethyl-3,7-dihydropurine-2,6-dione (1.8 g) and 1-piperazine carboxylic acid tert-butyl ester (3.7 g) were stirred at 150° C. for 1 hour. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, and dried over an hydrous magnesium sulfate. The solvent was removed by distillation at reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.6 g of the title compound from a fraction eluted with hexane-ethyl acetate (1:4).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:10]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20]>C1COCC1.C(N(CC)C(C)C)(C)C>[F:15][C:16]([F:26])([F:27])[C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([NH:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:10]=1)=[O:20]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: COC(=O)c1cc(N)cc2[nH]cnc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]cnc12
Temperature: 0 °C

Procedure:
To a solution of methyl 6-amino-1H-benzimidazole-4-carboxylate (266 mg) in dehydrated THF (12 mL), N,N-diisopropylethylamine (284 μL) was added, and the solution was stirred under ice-cooling. To this solution, 2-(trifluoromethyl)benzoyl chloride (284 μL) in dehydrated THF (5 mL) was added slowly dropwise, and stirred at the same temperature for 3 hours. After ice water was added, THF was removed under reduced pressure, and aqueous saturated sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified on NH silica gel column chromatography (ethyl acetate→ethyl acetate/MeOH) to obtain the titled compound (309 mg) as pale yellow powder.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:21])=[C:11]([F:20])[C:12]=3[C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:7](=[O:22])[C:6]([C:23]([O:25]CC)=[O:24])=[CH:5]2)[CH2:3][CH2:2]1.O.S(=O)(=O)(O)O>C(O)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:21])=[C:11]([F:20])[C:12]=3[C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCCCC#Cc1c(F)c(F)cc2c(=O)c(C(=O)OCC)cn(C3CC3)c12
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CCCCC#Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Yield: 77.2 %

Procedure:
0.7 g of ethyl 1-cyclopropyl-6,7-difluoro-8-(1-hexinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate is refluxed for 3 hours in a mixture of 6 ml of glacial acetic acid, 0.5 ml of water and 0.1 ml of concentrated sulphuric acid. The reaction mixture is treated with 100 ml of water, and the solid is filtered off with suction and dried. 0.5 g of 1-cyclopropyl-6,7-difluoro-8-(1-hexinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is obtained (85% of theory).
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(O)C>[CH2:16]([N:8]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:11][N:10]=[N:9]1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCBr
Reactant: c1ccc(-c2nnn[nH]2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCn1nnnc1-c1ccccc1
Reaction time: 4 h
Yield: 46 %

Procedure:
5-Phenyltetrazole (29.2 g, 0.2 mole) was placed in 300 ml of ethanol and sodium methylate (11 g, 0.2 mole) added. On the addition of bromohexane (33 g, 0.2 mole), the solution cleared immediately. The mixture slowly became cloudy on four hours refluxing. Filtering followed by stripping gave 21.2 g of a yellow liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([O:8][CH3:17])=[O:7]
Reactant: CO
Reactant: Cc1ccc(C(=O)O)c(O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C)cc1O
Temperature: 25 °C
Yield: 90 %

Procedure:
4-Methylsalicylic acid (100 g, 658 mmoles) was dissolved in anhydrous methanol (500 mL) and concentrated sulfuric acid (25 mL) was added carefully. The solution was refluxed for 18 hours, then cooled to room temperature. The reaction mixture was concentrated to about 150 mL, and ethyl acetate (250 mL) was added. The ethyl acetate solution was washed twice with saturated aqueous sodium bicarbonate (250 mL portions) and then with saturated aqueous sodium chloride (100 mL). The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered, and evaporated to a clear, reddish-brown liquid. This crude product was vacuum distilled (oil pump) to afford a clear, viscous liquid that solidified on standing to afford 98.1 g (90% yield) of methyl 4-methylsalicylate.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:10]=[C:11]([NH:17][C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH:20]=[CH:21][N:22]3[CH3:27])[C:12]([C:15]#[N:16])=[N:13][CH:14]=1.[OH-].[Na+].OO.CC(O)=[O:34]>CCO.CS(C)=O>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:10]=[C:11]([NH:17][C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH:20]=[CH:21][N:22]3[CH3:27])[C:12]([C:15]([NH2:16])=[O:34])=[N:13][CH:14]=1
Reactant: CC(=O)O
Reactant: Cn1ccc2c(Nc3nc(N[C@@H]4CCCC[C@@H]4N)cnc3C#N)cccc21
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: Cn1ccc2c(Nc3nc(N[C@@H]4CCCC[C@@H]4N)cnc3C(N)=O)cccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The compound 5-((1R,2S)-2-aminocyclohexylamino)-3-(1-methyl-1H-indol-4-ylamino)pyrazine-2-carbonitrile (18 mg) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (50%, 1.0 mL) were added. The mixture was stirred at room temperature for 20 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (9 mg). MS 380.5 (M+H); UV 221.2, 273.8, 322.5 nm; t 0.518 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]([OH:11])[CH3:10])=[CH:4][CH:3]=1.BrC1C=CC(C(O)[C:21](=[O:23])C)=CC=1>>[CH:21]([O:11][CH:9]([CH3:10])[C:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)=[O:12])=[O:23]
Reactant: CC(O)C(=O)c1ccc(Br)cc1
Reactant: CC(=O)C(O)c1ccc(Br)cc1
Product: CC(OC=O)C(=O)c1ccc(Br)cc1

Procedure:
1-(4-bromophenyl)-2-hydroxypropan-1-one and 1-(4-bromophenyl)-1-hydroxypropan-2-one
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26]2>>[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[C:26]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Reactant: O=C1Cc2cc(Cl)ccc2N1
Product: Cc1c(C=C2C(=O)Nc3ccc(Cl)cc32)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Yield: 38.8 %

Procedure:
The title compound was prepared under the same conditions as described in Example 15 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-chloro-1,3-dihydro-indol-2-one as starting materials to give 2-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-morpholin-4-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (31 mg, 38.8%) as a yellow solid.