Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11].[NH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(N(CC)CC)C>>[CH3:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: NCCN1CCOCC1
Reactant: Cc1cccc([N+](=O)[O-])c1Cl
Solvent: CCN(CC)CC
Product: Cc1cccc([N+](=O)[O-])c1NCCN1CCOCC1
Yield: 60.3 %

Procedure:
A solution of 2-chloro-3-nitrotoluene (180 mg, 1.0 mmol), 4-(2-aminoethyl)morpholine (0.54 mL, 4.1 mmol) and triethylamine (0.43 mL, 3.1 mmol) was heated to 180° C. by microwave for 20 min. The resultant mixture was purified by column chromatography on silica gel eluting with hexane/ethyl acetate(8/1-3/1) to afford 160 mg (59%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:26]=[C:25]2[C:20]([CH2:21][CH2:22][N:23]([CH2:27][CH2:28][CH2:29][CH2:30][N:31]3[C:35](=[O:36])[C:34]4=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]4[C:32]3=[O:41])[CH2:24]2)=[CH:19][CH:18]=1>N1C=CC=CC=1.S([O-])([O-])(=O)=O.[Cu+2]>[C:32]1(=[O:41])[N:31]([CH2:30][CH2:29][CH2:28][CH2:27][N:23]2[CH2:22][CH2:21][C:20]3[C:25](=[CH:26][C:17]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:18][CH:19]=3)[CH2:24]2)[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C1c2ccccc2C(=O)N1CCCCN1CCc2ccc(O)cc2C1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: c1ccncc1
Product: O=C1c2ccccc2C(=O)N1CCCCN1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.6 %

Procedure:
Trifluoromethanesulfonic anhydride (0.53 ml, 3.14 mmol) was added dropwise with stirring to an ice-cooled solution of 7-hydroxy-2-(4-phthalimidobutyl)-1,2,3,4-tetrahydroisoquinoline (1 g, 2.86 mmol) in anhydrous pyridine (10 ml). After stirring at room temperature for 18 h the reaction mixture was added to 10% aqueous Copper (II) sulfate (100 ml) and extracted into ethyl acetate (200 ml). The organic layer was separated, washed with 10% aqueous copper (II) sulfate (2×50 ml), dried (Na2SO4) and evaporated in vacuo. Chromatography on silica gel using 10-100% ethyl acetate-hexane gradient elution gave the title compound as a green oil (0.45 g, 33%).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:28])[N:4]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].ClC(Cl)(Cl)[C:31]([N:33]=C=O)=[O:32]>ClCCl.O1CCCC1>[C:31](=[O:32])([O:27][CH2:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:4]2[C:5]([CH3:18])=[CH:6][C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])=[C:2]([Br:1])[C:3]2=[O:28])=[CH:21][CH:22]=1)[NH2:33]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1ccc(CO)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1ccc(COC(N)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.3 %

Procedure:
Compound of Example 206 (0.868 g, 1.93 mmol) was suspended in dichloromethane (7.0 mL). Trichloroacetyl isocyanate (4.00 mL, 0.53 M in toluene, 2.12 mmol) was added. The resulting mixture was stirred at room temperature for 3 hours then diluted with tetrahydrofuran (50 mL) and Al2O3 (5.0 g) was added and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through a pad of Celite® washing with methonal. The filtrate was then concentrated and the residue was redissolved in tetrahydrofuran (30 mL). Al2O3 (5.0 g) was added and the mixture was heated to 40° C. for 3 hours. After cooling to room temperature, the reaction was filtered through a pad of Celite ® washing with methanol. The filtrate was concentrated and the resulting solid was washed with diethyl ether to give an off-white solid (0.831 g, 87%). 1H NMR (400 MHz, CDCl3) δ 7.54 (app q, J=7.7 Hz, 1H), 7.25 (d, J=8.2 Hz, 2H), 7.13 (d, J=8.2 Hz, 2H), 6.25 (app dt, J=2.0, 8.3 Hz, 1H), 6.86-6.30 (m, 1H), 5.97 (s, 1H), 5.32 (s, 2H), 5.18 (s, 2H), 5.02 (s, 2H), 4.81 (br s, 2H), 2.25 (s, 3H). ES-HRMS m/z 493.0580 (M+H calcd for C22H20BrF2N2O4 requires 493.0569).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:27]#[N:28])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])[CH:10]=2)=[O:5])C.[CH2:29]([O:31][C:32](=[O:38])[C:33]([CH3:37])([CH3:36])[CH2:34][NH2:35])[CH3:30]>C(O)C>[CH2:29]([O:31][C:32](=[O:38])[C:33]([CH3:37])([CH3:36])[CH2:34][NH:35][C:4]([C:6]1[N:7]=[C:8]([C:27]#[N:28])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])[CH:10]=2)=[O:5])[CH3:30]
Reactant: CCOC(=O)c1nc(C#N)c2cc(NC(=O)Nc3ccccc3)ccc2c1O
Reactant: CCOC(=O)C(C)(C)CN
Solvent: CCO
Product: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(NC(=O)Nc3ccccc3)ccc2c1O

Procedure:
1-Cyano-4-hydroxy-7-(3-phenyl-ureido)-isoquinoline-3-carboxylic acid ethyl ester (40 mg, 0.106 mmol) was dissolved/suspended in ethanol (3 mL) and 3-Amino-2,2-dimethyl-propionic acid ethyl ester (46 mg, 0.318 mmol) was added via syringe. The reaction was brought to reflux and maintained for 50 h. The reaction was cooled, concentrated and purified by medium pressure liquid chromatography (15 to 60% ethyl acetate in hexanes) to give the product as a white solid which was used immediately in the following reaction.
Reaction SMILES: C(Cl)(Cl)Cl.[CH2:5]([O:7][C:8]([CH:10]1[CH:18]2[C:13]3([CH:22]=[CH:21][CH:20]=[CH:19][C:14]3=[N:15][CH2:16][CH2:17]2)[S:12][CH2:11]1)=[O:9])[CH3:6].[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>C(N(CC)CC)C>[CH2:5]([O:7][C:8]([CH:10]1[CH:18]2[C:13]3([CH:22]=[CH:21][CH:20]=[CH:19][C:14]3=[N:15][CH2:16][CH2:17]2)[S:12][CH:11]1[C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=1[Cl:23])=[O:9])[CH3:6]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CCOC(=O)C1CSC23C=CC=CC2=NCCC13
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1C(C(=O)c2ccccc2Cl)SC23C=CC=CC2=NCCC13
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To 30 ml of chloroform were added 0.60 g of 1,2,3,4-tetrahydro-benzo[b]thieno[2,3-c]pyridine-3-carboxylic acid ethyl ester synthesized in Example 1, 0.64 ml of triethylamine, and 523 mg of 2-chlorobenzoyl chloride, and the mixture was stirred for one hour at room temperature. The reaction mixture was washed with ml of water and then with 30 ml of an aqueous sodium hydrogencarbonate solution having a pH of 9.0, and also with 30 ml of water. The chloroform layer was dried by sodium sulfate and the solvent was distilled off under reduced pressure to provide 614 mg (yield of 67%) of 2 -(2-chlorobenzoyl)-1,2,3,4-tetrahydro-benzo[b]thieno[2,3-c]pyridine-3-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:28][CH2:29][CH2:30][N:31]2[CH2:35][CH2:34][CH2:33][C:32]2=[O:36])[C:7]2[C:16]3[CH:15]=[C:14]([CH2:17][CH2:18][C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:20])[CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:27]=1.ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:49].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[NH2:49][C:9]1[C:8]2[N:27]=[C:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]([CH2:28][CH2:29][CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][C:32]3=[O:36])[C:7]=2[C:16]2[CH:15]=[C:14]([CH2:17][CH2:18][C:19]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[O:20])[CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: [NH4+]
Reactant: COCCc1nc2cnc3ccc(CCC(=O)N4CCOCC4)cc3c2n1CCCN1CCCC1=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Product: COCCc1nc2c(N)nc3ccc(CCC(=O)N4CCOCC4)cc3c2n1CCCN1CCCC1=O
Reaction time: 0.17 h

Procedure:
To a stirring solution of crude 1-{3-[2-(2-methoxyethyl)-8-(3-morpholin-4-yl-3-oxopropyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one, (0.85 g) in dichloromethane (75 mL) was added 3-chloroperoxybenzoic acid (60% pure, 500 mg, 1.91 mmol). After 18 hours concentrated ammonium hydroxide (50 mL) was added and the reaction was vigorously stirred for 10 minutes. p-Toluenesulfonyl chloride (690 mg, 3.60 mmol) was added in one portion and the mixture was stirred for one hour. The fractions were separated and aqueous fraction was extracted with chloroform (3×50 mL). The combined organic fractions were concentrated under reduced pressure. Purification by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a gradient of 0-30% CMA in chloroform) followed by recrystallization from acetonitrile provided 75 mg of 1-{3-[4-amino-2-(2-methoxyethyl)-8-(3-morpholin-4-yl-3-oxopropyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one as a pale yellow solid, mp 168-170° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:35]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.CCN(CC)CC.[Cl-]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:35]1([C:41]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[N:17]=[C:16]([NH:18][C:19]4[CH:20]=[C:21]5[C:25](=[CH:26][CH:27]=4)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]5)[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)N5CCOCC5)c4)nc4ccccc34)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (100 mg, 0.22 mmol) and morpholine-4-carbonyl chloride (51 μL, 0.44 mmol) in CH2Cl2 (2 mL) was added Et3N (61 μL, 0.44 mmol) and catalytic amount of DMAP. The reaction mixture was stirred at RT for 2 h after which 2 equivalents each of morpholine-4-carbonyl chloride and Et3N were added. After 2 h of stirring another 2 equivalents of both the chloride and Et3N were added and continued to stir at ambient temperature for 16 hours. The reaction was concentrated in vacuo and the residue was purified by flash chromatography on silica (12:1 CH2Cl2:MeOH). The product tert-butyl 5-(2-(3-(morpholine-4-carboxamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate was isolated. (80 mg, 65%)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[O:10][C:9](=[O:11])[N:8]([CH2:12][C:13]#[N:14])[C:5]2=[N:6][CH:7]=1.BrC1[CH:17]=[C:18]2[O:24]C(=O)N(C)C2=NC=1>>[C:13]([CH2:12][N:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:18](=[O:24])[CH3:17])[CH:3]=[C:4]2[O:10][C:9]1=[O:11])#[N:14]
Reactant: N#CCn1c(=O)oc2cc(Br)cnc21
Reactant: Cn1c(=O)oc2cc(Br)cnc21
Product: CC(=O)c1cnc2c(c1)oc(=O)n2CC#N

Procedure:
The method of operation is the same as that used for the synthesis of the compound of Example 1 (coupling with 1-ethoxy-1-(trimethylstannyl)ethylene). 6-bromo-3-(cyanomethyl)oxazolo[4,5-b]pyridin-2(3H)-one from Preparation 3 is used instead of the 6-bromo-3-methyloxazolo[4,5-b]pyridin-2(3H)-one from Preparation 2. The yield obtained is 60%. ##STR48##
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([Cl:12])([Cl:11])[Cl:10])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl[C:14]([S:16]Cl)=[O:15]>ClC1C=CC=CC=1>[O:15]=[C:14]1[NH:1][C:2]([C:9]([Cl:10])([Cl:11])[Cl:12])=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[S:16]1
Reactant: CCOC(=O)/C=C(\N)C(Cl)(Cl)Cl
Reactant: O=C(Cl)SCl
Solvent: Clc1ccccc1
Product: CCOC(=O)c1sc(=O)[nH]c1C(Cl)(Cl)Cl
Temperature: 65 °C
Reaction time: 1 h
Yield: 37.8 %

Procedure:
To 130.14 g (1.00 mole) of ethyl acetoacetate was added 1.5 g of sodium. The reaction temperature increased spontaneously to 50° C. The reaction mixture was cooled with an ice bath. To the cooled reaction mixture was added, with vigorous stirring at 30°-50° C., 144.3 g (1.00 mole) of trichloroacetonitrile in 30 minutes. After complete addition of the trichloroacetonitrile, the reaction mixture was cooled with a dry ice bath. No precipitate of the ethyl 2-acetyl-3-amino-4,4,4-trichlorocrotonate formed. Part of the above product was stirred with 100 ml. of concentrated 28-30% ammonium hydroxide for 2 hours. The reaction mixture was then extracted with ether. The ether solution was dried (CaSO4) and concentrated to give 180 g (82.5%) of crude ethyl 3-amino-4,4,4-trichlorocrotonate. Part of this crude material (20 g) was distilled at 0.5 mm Hg to give 11.7 g of pure product, m.p. 91°-95° C. To a cold (10° C.) solution of 21.8 g (0.0937 mole) of crude ethyl 3-amino-4,4,4-trichlorocrotonate in 15 ml. of chlorobenzene was added 13.5 g (0.103 mole) of chlorocarbonylsulfenyl chloride. The reaction temperature rose spontaneously to 35° C. after the ice water bath was removed. The reaction mixture was stirred at 65° C. for 1 hour, cooled and triturated with petroleum ether to give 10.3 g (38%) of ethyl 2,3-dihydro-2-oxo-4-trichloromethyl-5-thiazolecarboxylate, m.p. 109°-110° C. A mixture of 14.5 g (0.05 mole) of ethyl 2,3-dihydro-2-oxo-4-trichloromethyl-5-thiazolecarboxylate, 10.4 g (0.05 mole) of phosphorus pentachloride, and 100 ml. of phosphorus oxychloride was held at reflux for 7 days. Excess phosphorus oxychloride was removed under reduced pressure. The residue was treated with ice water and the aqueous mixture was extracted with ether. The ether solution was extracted with 10% sodium hydroxide, dried (CaSO4) and concentrated under reduced pressure to give 3.2 g of oil which was chromatographed on silica gel using 5% ethyl acetate-petroleum ether as eluant. The first 1.2 l. of eluant gave 2.27 g of solid which was recrystallized from petroleum ether at low temperature to give 2.13 g (13.8%) of ethyl 2-chloro-4-trichloromethyl-5-thiazolecarboxylate, m.p. 42.5°-43.5° C.
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([C:11]1[O:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:13][C:12]=1[CH2:22][CH2:23][CH3:24])=[O:10].[CH2:25]([N:27]([CH3:35])[C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][N:29]=1)[CH3:26]>>[CH2:25]([N:27]([CH3:35])[C:28]1[N:29]=[CH:30][C:31]([NH:34][C:9]([C:11]2[O:15][C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:13][C:12]=2[CH2:22][CH2:23][CH3:24])=[O:10])=[CH:32][CH:33]=1)[CH3:26]
Reactant: CCN(C)c1ccc(N)cn1
Reactant: CCCc1nc(-c2ccccc2)oc1C(=O)ON1C(=O)CCC1=O
Product: CCCc1nc(-c2ccccc2)oc1C(=O)Nc1ccc(N(C)CC)nc1

Procedure:
With a procedure similar to example 50 above, 2-phenyl-4-propyl-oxazole-5-carboxylic acid [6-(ethyl-methyl-amino)-pyridin-3-yl]-amide was prepared from 2-phenyl-4-propyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester and N2-ethyl-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C21H24N4O2 (m/e) 364, obsd 365 (M+H).
Reaction SMILES: [NH:1]([CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)/[C:7](=[CH:15]\[C:16]2[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=2)/[C:6]=1[CH3:24])[OH:2].[CH3:25][N:26]=[C:27]=[O:28]>C1COCC1>[F:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:15]\[C:16]1[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=1)/[C:6]([CH3:24])=[C:5]2[CH2:4][CH2:3][N:1]([OH:2])[C:27]([NH:26][CH3:25])=[O:28]
Reactant: CSc1ccc(/C=C2/C(C)=C(CCNO)c3cc(F)ccc32)cc1
Reactant: CN=C=O
Solvent: C1CCOC1
Product: CNC(=O)N(O)CCC1=C(C)/C(=C/c2ccc(SC)cc2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (Z)-3-(2-hydroxaminoethyl)-5-fluoro-2-methyl-1-(4-methylthiobenzylidene)-indene from Example 3, Method A, Step 4 (34 mg, 0.1 mmol) in THF (0.5 mL), there was added methyl isocyanate (11.4 mg, 0.2 mmol) and the mixture stirred at room temperature for 1 hour. The solvent was evaporated and the residue triturated with hexane and filtered to afford the title product as a yellow-orange solid, mp: dec 138° C.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.O.[NH2:33][NH2:34]>CN(C=O)C>[N+:28]([C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][C:19]2[C:3]3[C:4](=[O:18])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:34][N:33]=2)=[CH:23][CH:24]=1)([O-:30])=[O:29]
Reactant: O=C(CCc1ccc([N+](=O)[O-])cc1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Reactant: NN
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(CCc3ccc([N+](=O)[O-])cc3)n[nH]c2c2cccnc2n1-c1ccccc1
Yield: 97.2 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-3-(4-nitrophenyl)propyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (104 mg, 0.25 mmol, prepared in Synthetic Example 7) in DMF (2 ml) was added hydrazine monohydrate (80%, 40 μl, 11.0 mmol, 4.0 eq.), and the mixture was treated in the same manner as in Example 9 to give 3-[2-(4-nitrophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (100 mg, 97%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([OH:34])=[CH:29][CH:28]=3)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:48][CH2:49][CH2:50]Br>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([O:34][CH2:50][CH2:49][Br:48])=[CH:29][CH:28]=3)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3cc(O)ccc3n2C(=O)OC(C)(C)C)c2cc(OCc3ccccc3)ccc21
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(C)OC(=O)n1nc(-c2cc3cc(OCCBr)ccc3n2C(=O)OC(C)(C)C)c2cc(OCc3ccccc3)ccc21
Temperature: 25 °C

Procedure:
A suspension of 2.22 g of 5-benzyloxy-3-(1-tert-butoxycarbonyl-5-hydroxy-1H-indol-2-yl)indazole-1-carboxylic acid tert-butyl ester and of 3.90 g of cesium carbonate in 22 ml of 1,2-dibromoethane is heated at 80° C. for 40 hours and then cooled to ambient temperature and evaporated under reduced pressure in a rotary evaporator. The reaction crude is purified by flash chromatography (silica 40-63 μm), eluent: dichloromethane; 2 g of 5-benzyloxy-3-[5-(2-bromoethoxy)-1-tert-butoxycarbonyl-1H-indol-2-yl]-indazole-1-carboxylic acid tert-butyl ester are isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][C:15]=2[Cl:22])[N:11]([CH3:23])[N:10]=1.[H-].[Na+].Cl[C:27]1[C:32]([Cl:33])=[CH:31][C:30]([C:34]([F:37])([F:36])[F:35])=[CH:29][N:28]=1.O>COCCOC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:27]3[C:32]([Cl:33])=[CH:31][C:30]([C:34]([F:37])([F:35])[F:36])=[CH:29][N:28]=3)=[CH:16][C:15]=2[Cl:22])[N:11]([CH3:23])[N:10]=1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(CO)cc1Cl
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(COc2ncc(C(F)(F)F)cc2Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.1 %

Procedure:
3-(2-chloro-6-fluorophenyl)-5-(2-chloro-4-hydroxymethylphenyl) 1-methyl-1H-1,2,4-triazole (0.50 g) is dissolved in 1,2-dimethoxyethane (20 ml) and cooled to 0° C., to which is added sodium hydride (60%, 0.07 g) and the reaction mixture is stirred for 15 minutes. Then, a solution of 2,3-dichloro-5-trifluoromethyl pyridine (0.34 g) in 1,2-dimethoxyethane (10 ml) is added dropwise and stirred for 3 hours. On completion of the reaction, the reaction solution is warmed to room temperature and poured into water and extracted with ether. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography to give 0.62 g of desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Cl:11][C:12]1[C:17]([CH:18]=[O:19])=[C:16]([F:20])[C:15]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:14][CH:13]=1.[OH-].[K+].O>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:18]([C:17]3[C:12]([Cl:11])=[CH:13][CH:14]=[C:15]([O:21][CH2:22][C:23]([F:25])([F:26])[F:24])[C:16]=3[F:20])[OH:19])=[CH:6][NH:7][C:8]2=[N:9][CH:10]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: O=Cc1c(Cl)ccc(OCC(F)(F)F)c1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: OC(c1c(Cl)ccc(OCC(F)(F)F)c1F)c1c[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 5-bromo-7-azaindole (67, 291 mg, 1.48 mmol) in methanol mL) were added 6-Chloro-2-fluoro-3-(2,2,2-trifluoro-ethoxy)-benzaldehyde (523, 400.0 mg, 1.6 mmol) and potassium hydroxide (1.49 g, 26.6 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 48 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 25% ethyl acetate in hexane to give the compound (524, 300 mg, 42%). MS (ESI) [M+H+]+=453.1, 455.1.
Reaction SMILES: C(=O)([S:3][CH2:4][C:5]1([CH3:11])[CH2:9][O:8][C:7](=[O:10])[NH:6]1)C.[OH-].[Na+].O>CO>[SH:3][CH2:4][C:5]1([CH3:11])[CH2:9][O:8][C:7](=[O:10])[NH:6]1
Reactant: CC(=O)SCC1(C)COC(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(CS)COC(=O)N1
Reaction time: 2.5 h

Procedure:
To a solution of S-(4-methyl-2-oxooxazolidin-4-yl)methyl ethanethioate (6.07 g, 31.2 mmol) in methanol (30 ml) was added 5.0 M NaOH in H2O (10 ml, 50 mmol). The solution was stirred for 2.5 hour, concentrated in vacuo, suspended in ethyl acetate (400 ml), washed three times with 100 ml 5% NaHSO4, 100 ml saturated NaCl, dried on MgSO4, and concentrated in vacuo. The material was used without any further purification. LRMS (ESI/APCI) m/z 148 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]#[C:19][CH3:20])=[CH:12][CH:11]=1)(=[O:9])=[O:8])C.[OH-].[Na+].Cl>C1COCC1.CO>[CH2:17]([O:16][C:13]1[CH:12]=[CH:11][C:10]([S:7]([NH:6][CH2:5][C:4]([OH:21])=[O:3])(=[O:9])=[O:8])=[CH:15][CH:14]=1)[C:18]#[C:19][CH3:20]
Reactant: CC#CCOc1ccc(S(=O)(=O)NCC(=O)OCC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCOc1ccc(S(=O)(=O)NCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
To a solution of 0.30 g (0.965 mmol) of the product of Example 20 in 10 mL of THF/methanol (1:1) was added 4.8 mL of a 1.0N sodium hydroxide solution and the reaction was stirred overnight at room temperature and then acidified to pH 2 with 10% HCl solution. The resulting mixture was extracted with dichloromethane and the combined organics were dried over MgSO4, filtered and concentrated in vacuo to provide 0.238 g (83%) of the sulfonamide as a white solid. Electrospray Mass Spec 281.9 (M−H)−
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([O:18][CH3:19])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:20][N:21]([CH:23](OC)OC)[CH3:22]>C1(C)C=CC=CC=1>[C:4]([C:3]1[CH:6]=[C:7]([O:18][CH3:19])[C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:9][C:2]=1[N:1]=[CH:20][N:21]([CH3:23])[CH3:22])#[N:5]
Reactant: COc1cc(C#N)c(N)cc1OCc1ccccc1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: COc1cc(C#N)c(N=CN(C)C)cc1OCc1ccccc1

Procedure:
2-amino-4-benzyloxy-5-methoxy benzonitrile (102 g, 400 mmol) in toluene (1.51) was reacted with DMF-DMA (110 ml, 780 mmol) at reflux for 5 hours. The solvent was evaporated, the residue triturated with ether to give title compound as yellow solid.