Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:15]([O:16][CH3:17])=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([N+:18]([O-])=O)[CH:7]=1.[Cl-].[NH4+]>O.CO.[Fe]>[NH2:18][C:8]1[CH:7]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][Cl:1])[C:15]([O:16][CH3:17])=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cc(OC)c(OCCCCl)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(OC)c(OCCCCl)cc1N
Yield: 90 %

Procedure:
JP-A-2001-519788 describes a process for preparing a 5-alkoxy-4-halogenoalkoxyanthranilic acid compound from a 5-alkoxy-4-halogenoalkoxy-2-nitrobenzoic acid compound. For example, methyl 4-(3-chloropropoxy)-5-methoxy-2-nitrobenzoate is reacted with a very excessive amount of iron and ammonium chloride in a mixture of water and methanol, to give methyl 2-amino-4-(3-chloropropoxy)-5-methoxybenzoate (i.e., ethyl 4-(3-chloropropoxy)-5-methoxyanthranilate) in 90% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.CO.[CH3:17][Si](C=[N+]=[N-])(C)C>C1COCC1>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[C:4]([C:11]([F:12])([F:13])[F:14])[CH:3]=1
Reactant: Nc1ccc(C(=O)O)c(C(F)(F)F)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(N)cc1C(F)(F)F
Reaction time: 0.08 h

Procedure:
4-Amino-2-(trifluoromethyl)benzoic acid (10 g, 48.8 mmol) was suspended in THF (100 mL) and methanol (30 mL) and was cooled in an ice bath. (Trimethylsilyl)diazomethane (2 M solution in hexanes; 32 mL) was added drop-wise. The mixture was stirred for 5 minutes and then concentrated to afford methyl 4-amino-2-(trifluoromethyl)benzoate (quantitative yield) as a brown oil. 1H NMR (400 MHz, CDCl3): δ 7.78 (d, 1H), 6.99 (d, 1H), 6.77 (d, 1H), 4.18 (br s, 2H), 3.88 (s, 3H); GCMS for C9H8F3NO2: 219 (M+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C@H:28]3[NH:32][C:31](=[O:33])[C@H:30]([CH2:34][C:35]([OH:37])=[O:36])[CH2:29]3)=[CH:22][CH:21]=2)=[N:18][CH:19]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC[CH2:40][C:41]([CH3:46])([CH3:45])[C:42]([O-:44])=[O:43].[C:47](=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CS(C)=O>[CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C@H:28]3[NH:32][C:31](=[O:33])[C@H:30]([CH2:34][C:35]([O:37][CH2:47][O:44][C:42](=[O:43])[C:41]([CH3:46])([CH3:45])[CH3:40])=[O:36])[CH2:29]3)=[CH:22][CH:21]=2)=[N:18][CH:19]=1)=[NH:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(CCCl)C(=O)[O-]
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(-c2ccc(OC[C@@H]3C[C@@H](CC(=O)O)C(=O)N3)cc2)nc1
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)C(=O)OCOC(=O)C[C@@H]1C[C@@H](COc2ccc(-c3ccc(C(=N)NC(=O)OCc4ccccc4)cn3)cc2)NC1=O

Procedure:
Prepared from (3S,5S)-5-[[4-(5-benzyloxycarbonylamidino-2-pyridyl)phenyl]oxymethyl]-3-carboxymethyl-2-pyrrolidinone by reacting with chloromethylpivalate in dimethylsulphoxide in the presence of potassium carbonate and sodium iodide.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH2:12]=O.C[O-].[Na+].[BH4-].[Na+]>CO>[ClH:11].[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([NH:1][CH3:12])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: C=O
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNc1cccc(Cl)c1C(=O)O
Product: Cl
Temperature: 2.5 °C
Yield: 80 %

Procedure:
Anhydrous methanol (10 ml) was charged in a dry round bottom flask at 20-25° C. under nitrogen atmosphere. 2-amino-6-chloro-benzoic acid (201 mg, 1.17 mmol) was added, followed by paraformaldehyde (351.1 mg, 1.17 mmol). The mixture was stirred and cooled to 0-5° C. A 30 wt % solution of sodium methoxide (0.975 ml, 5.26 mmol) was added dropwise, keeping the temperature at 0-5° C. while stirring. The mixture was allowed to warm to room temperate (r.t.). Then, the resulting solution was heated to reflux for 1.5 h, then cooled to r.t. Sodium borohydride (209.1 mg, 5.5 mmol) was added in one portion, and the resulting mixture was heated to reflux for 2 h, then cooled to r.t. The reaction was concentrated by removal of solvent under reduced pressure. Chloroform (30 ml) and DM water (20 ml) were added, the mixture was cooled to 0-5° C., and the pH was adjusted to pH=2-3 with 1N HCl while stirring. The organic phase was separated and kept aside. The extraction step with chloroform (30 ml) was repeated twice more, the organic phases were combined and dried over sodium sulfate. The solvent was removed under reduced pressure resulting in a yellowish solid. Yield: 80%. The purity of the isolated product (Intermediate I-A) was 97% (HPLC, area %).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:4].[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(#N)C>[Cl:15][C:11]1[CH:10]=[C:9]2[C:14]([C:6]([NH:5][C:3](=[O:4])[CH2:2][N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:7][NH:8]2)=[CH:13][CH:12]=1
Reactant: O=C(CCl)Nc1n[nH]c2cc(Cl)ccc12
Reactant: C1CNCCN1
Solvent: CC#N
Product: O=C(CN1CCNCC1)Nc1n[nH]c2cc(Cl)ccc12
Yield: 63.1 %

Procedure:
The process is performed as in Example 75, starting with 500 mg of 2-chloro-N-(6-chloro-1H-indazol-3-yl)acetamide, 15 cm3 of acetonitrile and 528 mg of piperazine. The reaction medium is refluxed for 1 hour and then concentrated to dryness under reduced pressure (2 kPa; 50° C.); the crude product is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a methylene chloride/methanol/aqueous ammonia mixture (90/10/1 by volume). The fractions containing the expected product are combined, concentrated under reduced pressure and then dried (90 Pa; 45° C.) to give 380 mg of N-(6-chloro-1H-indazol-3-yl)-1-piperazineacetamide in the form of a white foam.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C@:14]1([C@H:17]([N:19]2[CH:27]=[N:26][C:25]3[C:20]2=[N:21][CH:22]=[N:23][C:24]=3[O:28][CH3:29])[CH3:18])[CH2:16][O:15]1>>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C@:14]([OH:15])([C@H:17]([N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][CH:22]=[N:23][C:24]=2[O:28][CH3:29])[CH3:18])[CH2:16][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: COc1ncnc2c1ncn2[C@H](C)[C@@]1(c2ccc(F)cc2F)CO1
Product: COc1ncnc2c1ncn2[C@H](C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 77.4 %

Procedure:
Using 1H-1,2,4-triazole (74 mg) and (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-[6-methoxy-9(9H)-purinyl]ethyl]oxirane (183 mg), Compound 47 (171 mg) was obtained as colorless prisms by the same way as in Example 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@H:9]([CH2:17][OH:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.O>CS(C)=O>[C:1]([O:5][C:6]([N:8]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C@H:9]([CH:17]=[O:18])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@H](CO)Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@H](C=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 2.38 g (6.98 mmoles) of N-(t-butoxycarbonyl)-N-benzyl-L-phenylalaninol from Example 11 in 3.8 mL (27.2 mmoles) of triethylamine at 10° C. was added a solution of 4.33 g (27.2 mmoles) of sulfur trioxide pyridine complex in 17 mL of dimethyl sulfoxide. The mixture was warmed to room temperature and stirred for one hour. Water (16 mL) was added and the mixture was extracted with 20 mL of ethyl acetate. The oragnic layer was washed with 20 mL of 5% citric acid, 20 mL of water, 20 mL of brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 2.37 g (100% yield) of N-(t-Butoxycarbonyl)-N-benzyl-L-phenylalaninal.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Cl:6][C:7]1[C:8]([CH3:19])=[C:9]([NH:13][C:14](=[O:18])[CH:15]=NO)[CH:10]=[CH:11][CH:12]=1>>[Cl:6][C:7]1[C:8]([CH3:19])=[C:9]2[C:10]([C:15](=[O:2])[C:14](=[O:18])[NH:13]2)=[CH:11][CH:12]=1
Reactant: Cc1c(Cl)cccc1NC(=O)C=NO
Reactant: O=S(=O)(O)O
Product: Cc1c(Cl)ccc2c1NC(=O)C2=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
To 2.5 g of concentrated sulfuric acid was added 2.5 g of N-(3-chloro-2-methylphenyl)-2-(hydroxyimino)acetamide at 50° C., and the mixture was stirred at 80° C. for 30 minutes. The reaction mixture was poured into 200 g of ice, and a deposited precipitate was collected by filtration to obtain 1.3 g of 6-chloro-7-methyl-1H-indole-2,3-dione of the formula:
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[CH3:11])=[O:2].[CH2:12]([O:14][C:15](=[O:18])[CH2:16]Cl)[CH3:13].CC[O-].[Na+].O>C1C=CC=CC=1.C(O)C>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH:1]2[O:2][CH:16]2[C:15]([O:14][CH2:12][CH3:13])=[O:18])=[C:4]([CH3:11])[CH:5]=1)#[N:8]
Reactant: Cc1cc(C#N)ccc1C=O
Reactant: CCOC(=O)CCl
Agent: CC[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1OC1c1ccc(C#N)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
A mixture of 4-formyl-3-methylbenzonitrile (1.5 g, 10.3 mmol) and chloroacetic acid ethyl ester (1.2 g, 10 mmol) were dissolved in 60 mL of dry benzene. Freshly prepared EtONa (12.4 mmol) in 8 mL of ethanol was added, and the mixture were stirred at room temperature for 2 hours. The mixture was added water, then extracted with EA, dried over Na2SO4 and distilled off solvent to afford 1.7 g of crude ethyl 3-(4-cyano-2-methylphenyl)oxirane-2-carboxylate. MS m/z: 232 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([NH2:9])[NH:4][N:3]=1.IC.[C:12](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[NH2:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([NH2:9])[N:4]([CH3:12])[N:3]=1
Reactant: N#Cc1c(N)n[nH]c1N
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: Cn1nc(N)c(C#N)c1N
Yield: 16.2 %

Procedure:
3,5-Diamino-4-cyanopyrazole (6.1 g) prepared as in Example 3, iodomethane (3.1 ml), anhydrous potassium carbonate (7.6 g) and acetone (120 ml) were heated under reflux for 18 hours. The mixture was filtered, and the filtrate was concentrated to a viscous oil. Trituration of the oil with water gave a precipitate of 3,5-diamino-4-cyano-1-methylpyrazole (1.1 g), m.p. 194°-196° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]3([O:17][CH2:18][C:19]([O:21]C)=[O:20])[CH2:16][CH2:15][CH2:14]3)=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:23]1([C:31](O)=[O:32])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH2:24]1.CN1CCOCC1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:25]12[CH2:24][CH:23]([C:31]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([C:8]4[S:12][C:11]([C:13]5([O:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:16][CH2:15][CH2:14]5)=[N:10][CH:9]=4)=[CH:4][CH:3]=3)=[O:32])[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2
Reactant: O=C(O)C1Cc2ccccc21
Reactant: COC(=O)COC1(c2ncc(-c3ccc(N)cc3)s2)CCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)COC1(c2ncc(-c3ccc(NC(=O)C4Cc5ccccc54)cc3)s2)CCC1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of Example 24B (0.150 g, 0.470 mmol), 1,2-dihydrocyclobutabenzene-1-carboxylic acid (0.070 g, 0.470 mmol), N-methylmorpholine (0.103 mL, 0.940 mmol), and 1-hydroxybenzotriazole hydrate (0.080 g, 0.940 mmol) in N,N-dimethylformamide-(2 mL) was added 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (0.115 g, 0.589 mmol). The solution was heated to 50° C. for 3 h, cooled to room temperature, and partitioned between H2O (2 mL) and ethyl acetate (2 mL). The layers were separated, and the aqueous was extracted with additional ethyl acetate (2×2 mL). The combined organics were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in methanol (5 mL) and 2 N NaOH (0.50 mL) was added. After 5 h, the methanol was removed under reduced pressure. The aqueous was acidified with 10% HCl to pH 1. The solid was filtered and air-dried. Purification of the residue by RP-HPLC (preparative reversed-phase high pressure liquid chromatography) using a Zorbax SB-C18 7M 21.2×250 mm column with UV detection analyzed at 220 and 254 nM (preparative method: water with 0.1% trifluoroacetic acid and CH3CN with 0.1% trifluoroacetic acid gradient 5-95% CH3CN over 30 minutes at 15 mL/min) provided the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.67-1.94 (m, 2 H), 2.39-2.47 (m, 4 H), 3.31-3.40 (m, 2 H), 3.93 (s, 2 H) 4.44 (dd, J=4.9 and 2.9 Hz, 1 H), 7.09-7.31 (m, 4 H), 7.56-7.68 (m, 2 H), 7.67-7.78 (m, 2 H), 8.07 (s, 1 H), 10.37 (s, 1 H); MS (ESI) m/z 435 [M+H]+.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:30][CH2:31][CH2:32][NH:33][C:34](=[O:36])[CH3:35].CC(O)=O>CCO>[C:34]([NH:33][CH2:32][CH2:31][NH:30][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[CH:8]2)=[O:4])(=[O:36])[CH3:35]
Reactant: CC(=O)NCCN
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=O)NCCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (25 mg, 0.065 mmol) and N-(2-amino-ethyl)-acetamide in EtOH (3 mL) was refluxed for 48 h. After cooling to r.t., AcOH (0.1 mL) was added, and solvent was evaporated in vacuo. The residue was purified by silica gel chromatography (0-3% MeOH/CH2Cl2) to give 12 mg of the title compound as a light yellow solid. MS: (+) m/z 457.35 (M+1).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[S:9][C:8]([C:10]#[N:11])=[CH:7][CH:6]=1)=[O:4].[N:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C@@H:14]([NH:20][C:21](=[O:38])[O:22][CH:23]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1)[CH2:13]2.CCOCC>C(OCC)(=O)C>[Br-:1].[F:37][C:33]1[CH:32]=[C:31]([CH:23]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[O:22][C:21]([NH:20][C@@H:14]2[CH:15]3[CH2:16][CH2:17][N+:12]([CH2:2][C:3]([C:5]4[S:9][C:8]([C:10]#[N:11])=[CH:7][CH:6]=4)=[O:4])([CH2:19][CH2:18]3)[CH2:13]2)=[O:38])[CH:36]=[CH:35][CH:34]=1
Reactant: O=C(N[C@H]1CN2CCC1CC2)OC(c1cccc(F)c1)c1cccc(F)c1
Reactant: N#Cc1ccc(C(=O)CBr)s1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: N#Cc1ccc(C(=O)C[N+]23CCC(CC2)[C@@H](NC(=O)OC(c2cccc(F)c2)c2cccc(F)c2)C3)s1
Product: [Br-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.6 %

Procedure:
5-(2-Bromoacetyl)thiophene-2-carbonitrile (33.4 mg, 0.14 mmol) was added to a solution of (R)-bis(3-fluorophenyl)methyl quinuclidin-3-ylcarbamate (54 mg, 0.14 mmol, prepared as in example 1) in ethyl acetate (2 ml). The resulting solution was stirred at room temperature for two days, then 5-(2-bromoacetyl)thiophene-2-carbonitrile (3.4 mg, 0.015 mmol) was added, and the stirring was kept for additional 16 hours. Et2O was added and the precipitate was recovered by filtration to afford (R)-3-((bis(3-fluorophenyl)methoxy)carbonylamino)-1-(2-(5-cyanothiophen-2-yl)-2-oxoethyl)-1-azoniabicyclo[2.2.2]octane bromide (68 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)=[CH:24][CH:23]=3)[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.ClC1C=CC=C(C(OO)=[O:43])C=1.S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:22]3[CH:23]=[CH:24][C:25]([C:28]4[CH:33]=[CH:32][N+:31]([O-:43])=[CH:30][CH:29]=4)=[CH:26][CH:27]=3)=[O:34])[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: O=C(c1ccc(-c2ccncc2)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccc(-c2cc[n+]([O-])cc2)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Temperature: -20 °C
Reaction time: 21 h

Procedure:
In dichloromethane (10 ml), 1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine (300 mg) obtained in Example A-1 was dissolved, followed by the addition of 3-chloroperbenzoic acid (382 g) at −20° C. The resulting mixture was stirred at −20° C. for 21 hours. An aqueous solution of sodium sulfite was added to decompose an excess peroxide. Dichloromethane and a saturated aqueous solution of sodium bicarbonate were added to separate an organic layer. After drying the organic layer over anhydrous magnesium sulfate, the residue obtained by distilling off the solvent was purified by chromatography on a silica gel column (2-5% methanol—dichloromethane). After the solvent was distilled off, ether was added to the residue to solidify it, followed by collection through filtration, whereby the title compound (200 mg, 63%) was obtained as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[CH:8][C:7]([CH3:16])=[N:6]3)[N:3]=1.[N+:17]([O-])([OH:19])=[O:18]>S(=O)(=O)(O)O>[N+:17]([C:11]1[CH:12]=[C:13]2[C:4]([N:3]=[C:2]([CH3:1])[CH:15]=[CH:14]2)=[C:5]2[C:10]=1[CH:9]=[CH:8][C:7]([CH3:16])=[N:6]2)([O-:19])=[O:18]
Reactant: Cc1ccc2ccc3ccc(C)nc3c2n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1ccc2cc([N+](=O)[O-])c3ccc(C)nc3c2n1
Temperature: 100 °C

Procedure:
2,9-Dimethyl-1,10-phenanthroline (h) (20 g) was dissolved in a mixture of sulfuric acid (120 ml) and nitric acid (40 ml), and the mixture was heated at 100° C. for 12 hours with stirring. The resulting solution was poured into ice water (300 ml), and the formed precipitate was collected. The precipitate was dissolved in water (500 ml) and neutralized with sodium hydroxide. The resulting precipitate was collected and recrystallized from methanol (300 ml) to give the desired 5-nitro-2,9-dimethyl-1,10-phenanthroline (i) (yield=8.8 g).
Reaction SMILES: [CH2:1]([C:3]1([CH2:20][CH3:21])[CH2:12][C:11]([CH3:14])([CH3:13])[C:10]2[C:5](=[C:6]([CH:17]([CH3:19])[CH3:18])[CH:7]=[C:8]([C:15]#[CH:16])[CH:9]=2)[O:4]1)[CH3:2].[CH3:22][O:23][C:24](=[O:53])[C:25]([C:28]1[CH:33]=[CH:32][C:31](C#CC2C=C(C3CC3)C3OC4(CC4)CC(C)(C)C=3C=2)=[CH:30][CH:29]=1)([CH3:27])[CH3:26].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:22][O:23][C:24](=[O:53])[C:25]([C:28]1[CH:29]=[CH:30][C:31]([C:16]#[C:15][C:8]2[CH:9]=[C:10]3[C:5](=[C:6]([CH:17]([CH3:19])[CH3:18])[CH:7]=2)[O:4][C:3]([CH2:1][CH3:2])([CH2:20][CH3:21])[CH2:12][C:11]3([CH3:14])[CH3:13])=[CH:32][CH:33]=1)([CH3:27])[CH3:26]
Reactant: C#Cc1cc(C(C)C)c2c(c1)C(C)(C)CC(CC)(CC)O2
Reactant: COC(=O)C(C)(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCC1(CC)CC(C)(C)c2cc(C#Cc3ccc(C(C)(C)C(=O)OC)cc3)cc(C(C)C)c2O1

Procedure:
Following General Procedure B and using 2,2-diethyl-6-ethynyl-8-isopropyl-4,4-dimethyl chroman (Intermediate 29, 0.069 g, 0.24 mmol), methyl-2-(4-iodophenyl)-2-methyl-propionate (Reagent 2, 0.146 g, 0.48 mmol), triethyl amine (3 mL), copper(I)iodide (0.025 g, 0.13 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.075 g, 0.107 mmol) followed by flash column chromatography over silica gel (230–400 mesh) using 5% ethyl acetate in hexane as the eluent, the title compound was obtained as a yellow oil (0.070 g, 62%).
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]1=[O:23])([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BH4-].[Na+]>C(O)C>[CH3:9][C:2]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH:12]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:11]1=[O:23])([CH3:1])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(c1ccccc1)N1CCC(=O)C(c2ccccc2)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(c1ccccc1)N1CCC(O)C(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
4.0 g (0.013 mol) of 1-(α,α-dimethylbenzyl)-2,4-dioxo-3-phenylpiperidine prepared by the method of Reference Example 18, was dissolved in 50 ml of ethanol, and 0.27 g (0.007 mol) of sodium- borohydride was added thereto at room temperature. The mixture was stirred at room temperature for 30 minutes, and then ethanol was distilled off under reduced pressure. Water was added to the residue, and precipitated crystals were collected by filtration. The crude product thereby obtained was recrystallized from ethanol to obtain 3.6 g (yield: 90.0%) of the desired compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([NH:14][C:15]3[C:16]4[CH:17]=[N:18][NH:19][C:20]=4[CH:21]=[CH:22][CH:23]=3)=[N:10][CH:11]=[CH:12][N:13]=2)[CH:5]=[C:4]([S:24][CH3:25])[N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:31]>O1CCOCC1>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([NH:14][C:15]3[C:16]4[CH:17]=[N:18][NH:19][C:20]=4[CH:21]=[CH:22][CH:23]=3)=[N:10][CH:11]=[CH:12][N:13]=2)[CH:5]=[C:4]([S:24]([CH3:25])=[O:31])[N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cc(-c2nccnc2Nc2cccc3[nH]ncc23)nc(C)n1
Solvent: C1COCCO1
Product: Cc1nc(-c2nccnc2Nc2cccc3[nH]ncc23)cc(S(C)=O)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of N-(3-(2-methyl-6-(methylthio)pyrimidin-4-yl)pyrazin-2-yl)-1H-indazol-4-amine (20 mg, 0.057 mmol) and 3-chloroperoxybenzoic acid (14.82 mg, 0.086 mmol, Aldrich, St. Louis, Mo.—77%) in dioxane (1 mL) was stirred at room temperature for 2 h. LCMS showed no starting material left. The reaction mixture was used for the next step of reaction without purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N#N.C(=O)([O-])[O-].[K+].[K+].Br[CH:29]1[CH2:33][CH2:32][N:31]([CH3:34])[C:30]1=[O:35]>CN(C=O)C.C(Cl)(Cl)Cl.CO>[CH2:13]([O:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([O:1][CH:29]2[CH2:33][CH2:32][N:31]([CH3:34])[C:30]2=[O:35])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN1CCC(Br)C1=O
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccccc2)cc(OC2CCN(C)C2=O)c1
Reaction time: 0.25 h

Procedure:
Methyl 3-hydroxy-5-(benzyloxy)benzoate (4.75 g) (CAS No. 54915-31-0] was dissolved in DMF in single necked round bottomed flask fitted with stop cock with N2(g) balloon. Potassium carbonate (8.4 g) was added and reaction was stirred for 15 min. 3-Bromo-1-methyl-pyrrolidine-2-one (4.91 g) (Intermediate 5) [J. Med. Chem., 1987, 30, 1995-98] was added to reaction mixture in three different portions at room temperature. The reaction was stirred at ambient temperature for 16 h and monitored by TLC using 10% methanol: chloroform as mobile phase. After 16 h, TLC showed completion of reaction mixture and formation of one polar spot. The reaction mixture was diluted with ice-cold water and extracted with EtOAc. All organic layers were combined and washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to get crude thick liquid product. The crude product was purified by flash column chromatography. The desired product was eluted at 50% of EtOAc: Chloroform. Pure white solid was obtained after column purification (6.1 g).