Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[CH:5][C:4]=2[CH:3]=1.BrN1C(=O)CCC1=O.[CH:24]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:24]1([NH:31][CH2:1][C:2]2[CH:15]=[CH:14][C:13]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH:6]=[CH:5][C:4]=3[CH:3]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cc1ccc2c(ccc3ccccc32)c1
Reactant: NC1CCCCCC1
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1Br
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc2c(c1)ccc1cc(CNC3CCCCCC3)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.9 %

Procedure:
2-Methylphenanthrene (2.00 g, 10.4 mmol) was brominated with N-bromosuccinimide (2.05 g, 11.5 mmol) and the product compound was added gradually to a suspension of cycloheptylamine (2.38 g, 21.0 mmol) and potassium carbonate (2.90 g, 21.0 mmol) in dimethylformamide (20 ml) with ice-cooling. The mixture was then stirred at room temperature for 16 hrs and, then, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2.11 g of a viscous liquid.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:24])([CH2:17][C:18]1=[O:23])[C@@H:12]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.[C:25]([OH:28])(=[O:27])[CH3:26]>>[C:25]([O:28][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:1])(=[O:27])[CH3:26]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: CC(=O)O
Product: CC(=O)O[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O

Procedure:
2α,3α-Epoxy-5α-pregnane-11,20-dione (500 mg.) was dissolved in glacial acetic acid (25 ml.), and the solution was heated on a steam-bath for 3 hours. Evaporation of the solution under reduced pressure gave an oil which was purified by preparative TLC in ethyl acetate-petrol, and foamed in vacuo to give the title compound as a white foam, [α]D + 93.5°.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[N:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[CH:23]=[C:22]([C:33]([F:36])([F:35])[F:34])[N:21]=3)[CH:17]=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:24]2[CH:23]=[C:22]([C:33]([F:34])([F:35])[F:36])[N:21]=[C:20]([C:18]3[CH:17]=[CH:16][N:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=4)[CH:19]=3)[N:25]=2)=[CH:31][CH:30]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)ccn2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)ccn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.2 %

Procedure:
To a cooled and stirred solution of 5-{4-[4-(4-fluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.27 g) in dichloromethane (4 ml) was added TFA (4 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N NaHCO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.16 g, 49%). MS (ISP) 480.9 [(M+H)+]; mp 282° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:15](Cl)(=[O:17])=[O:16])[C:5]2[O:10][S:9](=[O:12])(=[O:11])[C:8]([CH3:13])=[CH:7][C:6]=2[CH:14]=1.[NH3:19]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:15]([NH2:19])(=[O:17])=[O:16])[C:5]2[O:10][S:9](=[O:12])(=[O:11])[C:8]([CH3:13])=[CH:7][C:6]=2[CH:14]=1
Reactant: N
Reactant: CC1=Cc2cc(Br)cc(S(=O)(=O)Cl)c2OS1(=O)=O
Solvent: C1CCOC1
Product: CC1=Cc2cc(Br)cc(S(N)(=O)=O)c2OS1(=O)=O
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A solution of 180 g of 6-bromo-2,2-dioxo-3-methyl-1,2-benzoxathiin-8-ylsulfonyl chloride in 500 ml of tetrahydrofuran is added dropwise over 30 minutes to 307 ml of a 30% aqueous solution of ammonia. The mixture is stirred for 30 minutes at 20° C. and concentrated under reduced pressure at 45° C. The residue is triturated with 200 ml of ether. The precipitate is isolated, washed with water and dried at 45° C., affording 63.2 g of 6-bromo-2,2-dioxo-3-methyl-1,2-benzoxathiin-8-ylsulfonamide of m.p. 243°-245° C. (recrystallisation from ethanol).
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:14]([CH3:17])(=O)=O)=[N:7]2.O>CN(C=O)C>[Br:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:14][CH3:17])=[N:7]2
Reactant: COc1ccc2nc(S(C)(=O)=O)ccc2c1Br
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2nc(SC)ccc2c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The 5-bromo-2-methanesulfonyl-6-methoxy-quinoline was dissolved in 20 mL DMF and treated with 3 eq NaSCH3. After stirring 1 hour at room temperature the mixture was poured into water and extracted with ether. The crystalline product, 5-bromo-6-methoxy-2-methylsulfanyl-quinoline, was isolated in quantitative yield.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH3:17][C:18]([SH:21])([CH3:20])[CH3:19].O>CN(C=O)C>[Br:1][C:2]1[C:3]([S:21][C:18]([CH3:20])([CH3:19])[CH3:17])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: CC(C)(C)S
Reactant: O=Cc1cccc(Br)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)Sc1c(Br)cccc1C=O
Temperature: 110 °C
Yield: 98.1 %

Procedure:
A mixture of 3-bromo-2-fluorobenzaldehyde (5.0 g, 25 mmol), potassium carbonate (4.0 g, 30 mmol) and 2-methyl-2-propanethiol (5.5 mL, 49 mmol) in dry DMF (25 mL) was heated to 110° C. in a sealed tube for 16 h. The reaction mixture was cooled to RT, added to water (100 mL) and extracted with DCM (3×50 mL). The combined organic fractions were washed with water (50 mL), dried, and evaporated to afford 6.7 g (98%) of the crude title compound which was used without further purification. 1H NMR (300 MHz, CDCl3): δ 1.31 (s, 9H), 7.26-7.41 (m, 1H), 7.93-7.99 (m, 2H), 10.73 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[C:4]([O:16][CH:17]([F:19])[F:18])[CH:3]=1.C(O)CCC.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:36][CH2:37][CH:38]([OH:41])[CH2:39]O>C1(C)C=CC=CC=1>[F:18][CH:17]([F:19])[O:16][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[C:8]1([CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[O:41][CH:38]([CH2:37][Cl:36])[CH2:39][O:15]1
Reactant: O=C(Cn1cncn1)c1ccc(Cl)cc1OC(F)F
Reactant: OCC(O)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCCCO
Product: FC(F)Oc1cc(Cl)ccc1C1(Cn2cncn2)OCC(CCl)O1
Temperature: 60 °C

Procedure:
14.2 parts of 1-(4-chloro-2-difluoromethoxyphenyl)-2-(1H-1,2,4-triazolyl)ethan-1-one and 100 ml of n-butanol in 450 ml of abs. toluene are heated in the presence of 9.4 parts of p-toluenesulfonic acid for 5 hours under reflux, while removing the water of reaction with a water separator. After cooling to 60° C., 33 parts of 3-chloro-1,2-propanediol and a further 18 parts of p-toluenesulfonic acid are added and the batch is refluxed for 80 hours while removing the water of reaction with a water separator. The reaction mixture is cooled to room temperature, washed twice with saturated aqueous sodium carbonate solution and with 2×200 ml of water, dried over sodium sulfate and filtered. The solvent is removed in a rotary evaporator and the oily residue is chromatographed through a 50 cm column of silica gel with a 1:1 mixture of methylene chloride/diethyl ether as eluant. The solvent mixture is removed by evaporation, affording the title compound in the form of a pale yellow oil with a refractive index nD22 : 1.5336.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:28])[C:11]=1[C:12]([N:14]1[C:22]2[CH:21]=[CH:20][N:19]=[C:18]([NH:23][C:24](=[O:27])[CH2:25][CH3:26])[C:17]=2[CH:16]=[CH:15]1)=[O:13])[C:5]([O:7]C)=[O:6].[OH-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:28])[C:11]=1[C:12]([N:14]1[C:22]2[CH:21]=[CH:20][N:19]=[C:18]([NH:23][C:24](=[O:27])[CH2:25][CH3:26])[C:17]=2[CH:16]=[CH:15]1)=[O:13])[C:5]([OH:7])=[O:6]
Reactant: CCC(=O)Nc1nccc2c1ccn2C(=O)c1c(Cl)cc(C(=O)OC)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(=O)Nc1nccc2c1ccn2C(=O)c1c(Cl)cc(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
A mixture of methyl 3,5-dichloro-4-{[4-(propanoylamino)-1H-pyrrolo[3,2-c]pyridin-1-yl]carbonyl}benzoate (250 mg, 0.59 mmol) and sodium hydroxide (23 mg, 0.59 mmol) in tetrahydrofuran and water (1:1) was stirred at room temperature for about 1 hour. Tetrahydrofuran was removed in vaccuo and aqueous layer was diluted with water (5 mL) and acidified with hydrochloric acid (2N, upto pH 2). The solid thus obtained was filtered and dried to afford 3,5-dichloro-4-{[4-(propanoylamino)-1H-pyrrolo[3,2-c]pyridin-1-yl]carbonyl}benzoic acid (170 mg, 70%). The material was taken as such for the next step.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.C1C(=O)N([Br:23])C(=O)C1>CN(C=O)C>[Br:23][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:11]([C:12]#[N:13])[C:3]=2[C:2]([F:14])([F:1])[F:15])[NH:7][CH:6]=1
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]cc(Br)c2c1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cold solution of 4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.047 g, 0.22 mmol) in DMF (2 mL), under N2, was added a solution of NBS (0.043 g, 0.24 mmol) in DMF (0.5 mL). The mixture was stirred in the ice bath for 30 min and then at rt for 1 h. The mixture was partitioned between Et2O and an aqueous solution of Na2S2O3. The organic phase was washed with water and sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by radial chromatography (5-50% EtOAc-hexanes gradient) to afford the title compound: 1H NMR (400 MHz, CDCl3+few drops of CD3OD) δ 11.52 (bs, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.48-7.45 (m, 2H).
Reaction SMILES: [C:1]1(=O)[O:5][CH2:4][CH2:3][O:2]1.O[C:8]1[CH:21]=[CH:20][C:11]([C:12]([C:14]2[CH:19]=[CH:18]C=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1.C1(C)C=CC=CC=1>[I-].[Na+].C1(C)C=CC=CC=1.O>[OH:2][CH2:3][CH2:4][O:5][C:1]1[CH:18]=[CH:19][C:14]([C:12]([C:11]2[CH:20]=[CH:21][CH:8]=[CH:9][CH:10]=2)=[O:13])=[CH:15][CH:16]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: O=C1OCCO1
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(c1ccccc1)c1ccc(OCCO)cc1
Temperature: 176 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
A mixture of ethylene carbonate (124.6 g; 1.07 eq.), sodium iodide (6.3 g; 0.03 eq.), 4-hydroxybenzophenone (262 g; 1 eq.) and toluene (8.1 g) was heated. At 99° C. a clear solution was obtained. The reaction mixture was heated with reflux condenser to 176° C. over one hour, during which gas evolution occurred. After an additional ½ hour at 176° C., the reaction mixture was cooled to 122° C. and toluene (350 g) and water (24 g) was added. The lower phase was cut and discarded. More water (14 g) was added and the lower phase was again cut and discarded. Water and toluene (95 g in total) was azeotropically removed, reaching a boiling point of 111° C. More toluene (114 g) was added and the product was isolated by filtration at 8° C. In total, 302 g of 4-(2-hydroxyethoxy)benzophenone (94%) was obtained after drying as white crystals (99.8% chromatographic purity).
Reaction SMILES: [C:1]([N:3]=[C:4]1[N:8]([C@@H:9]2[C:14]3[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=3[O:12][C:11]([CH2:23][CH3:24])([CH2:21][CH3:22])[C@H:10]2[OH:25])[CH2:7][CH2:6][S:5]1)#[N:2].[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1.C(OCC)(=O)C>[C:26]([O:25][C@H:10]1[C@H:9]([N:8]2[CH2:7][CH2:6][S:5][C:4]2=[N:3][C:1]#[N:2])[C:14]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=2[O:12][C:11]1([CH2:23][CH3:24])[CH2:21][CH3:22])(=[O:28])[CH3:27]
Reactant: CCC1(CC)Oc2ccc(C#N)cc2[C@@H](N2CCSC2=NC#N)[C@@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCC1(CC)Oc2ccc(C#N)cc2[C@@H](N2CCSC2=NC#N)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of trans-4-(2-cyanoiminothiazolidin-3-yl)-2,2-diethyl-3,4-dihydro-3-hydroxy-2H-1-benzopyran-6carbonitrile -(0.28 g) and acetic anhydride (0.15 ml) in pyridine (1.4 ml) was stirred overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate, and then washed with 5% aqueous hydrochloric acid, saturated sodium bicarbonate solution and brine successively. The extract was dried over anhydrous magnesium sulfate and evaporated in vacuo to give a residue of trans-3-acetoxy-4-(2-cyanoiminothiazolidin-3-yl)-2,2-diethyl-3,4-dihydro-2H-1-benzopyran-6-carbonitrile, which was dissolved in toluene (12.5 ml) and thereto was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.35 ml). The reaction mixture was heated at 100° C. with stirring for an hour and 40 minutes. The solvent was evaporated in vacuo. The residue was triturated with ethyl acetate and recrystallized from 85% aqueous acetonitrile to give 4-(2-cyanoiminothiazolidin-3-yl)-2,2-diethyl-2H-1-benzopyran-6-carbonitrile (0.18 g).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17]O)=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:21])=O>C1COCC1>[Cl:21][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:11][CH:12]=1
Reactant: OCCc1ccc(OCCN2CCCCC2)cc1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Product: ClCCc1ccc(OCCN2CCCCC2)cc1
Yield: 91.9 %

Procedure:
2-[4-(2-Piperidin-1-yl-ethoxy)-phenyl]-ethanol (4.23 g, 16.98 mmol) was dissolved in 200 ml of THF. HCl gas was bubbled through the solution at 0° C. for 5 minutes. Still at 0° C. the thionyl chloride (2.48 ml, 33.9 mmol) was added dropwise. The reaction mixture was heated at reflux for 2 hours before it was concentrated. 1-{2-[4-(Chloro-ethyl)-phenoxy]-ethyl}-piperidine (4.74 g, 15.6 mmol) was isolated as a brown semisolid; Yield 92%; MS: 268.3 (M+H)+
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[CH:6][C:5]([N+:20]([O-:22])=[O:21])=[C:4]([Cl:23])[CH:3]=1.[Br-].[CH2:25]([O:27][C:28](=[O:33])[CH2:29][CH2:30][CH2:31][Zn+])[CH3:26].Cl>O1CCCC1.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>[Cl:23][C:4]1[C:5]([N+:20]([O-:22])=[O:21])=[CH:6][C:7]([O:8][CH2:9][C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[C:2]([CH2:31][CH2:30][CH2:29][C:28]([O:27][CH2:25][CH3:26])=[O:33])[CH:3]=1
Reactant: COc1ccc(F)c(F)c1COc1cc([N+](=O)[O-])c(Cl)cc1Br
Reactant: CCOC(=O)CCC[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)CCCc1cc(Cl)c([N+](=O)[O-])cc1OCc1c(OC)ccc(F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-bromo-2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-1-nitrobenzene (2.04 g) in tetrahydrofuran (10 mL) were added 4-ethoxy-4-oxobutylzinc bromide (0.5 mol/L tetrahydrofuran solution, 12 mL) and tetrakis(triphenylphosphine)palladium(0) (0.2 g), and the mixture was stirred at room temperature under an argon atmosphere overnight. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1−3/2) to give ethyl 4-[5-chloro-2-(2,3-difluoro-6-methoxybenzyloxy)-4-nitro-phenyl]butyrate (0.72 g). This material was dissolved in tetrahydrofuran (5 mL). To the solution were added methanol (5 mL) and nickel(II) bromide (11 mg). To the mixture was added sodium borohydride (0.12 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 30 minutes. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1−3/2) to give the title compound (0.41 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[CH:7]=1.[I:19]N1C(=O)CCC1=O>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[C:16]([I:19])[C:9]=23)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]ccc12
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: COc1ccc(F)cc1-c1ccnc2[nH]cc(I)c12
Reaction time: 1 h

Procedure:
To a solution of Example 14A (22.4 g, 92 mmol) in acetonitrile (1 L) under nitrogen was added N-iodosuccinimide (21.84 g, 97 mmol) at ambient temperature. After stirring approximately 1 hour the reaction was complete. Solids started to crash out of the mixture and they were filtered off and washed with acetonitrile to provide the title compound as a solid. The filtrate was concentrated, mixed with 50 mL of dichloromethane, and sonicated for 30 minutes. Some solid did not dissolve and was filtered, washed with dichloromethane, and dried to give additional title compound. The filtrate was purified on an Analogix MPLC using a silica gel column eluting with 30-40% ethyl acetate/heptanes to give additional title compound. MS (ESI+) m/z 369.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10](O)=[O:11])=O)=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].O.[NH2:19][NH2:20]>C(O)(=O)C>[NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]2[CH2:8][CH2:9][C:10](=[O:11])[NH:19][N:20]=2)=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: Nc1ccc(C(=O)CCC(=O)O)cc1[N+](=O)[O-]
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(C2=NNC(=O)CC2)cc1[N+](=O)[O-]

Procedure:
18.1 gm of 3-(4-amino-3-nitro-benzoyl)-propionic acid were reacted, as in Example 1a, with 18.1 gm of hydrazine hydrate in 200 ml of glacial acetic acid, yielding the desired compound which had a melting point above 330° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH3:23])=[C:5]([C:9]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2F)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])[CH3:2].C(N(CC)CC)C.[CH2:31]([N:33]([CH2:38][CH3:39])[CH2:34][CH2:35][CH2:36][NH2:37])[CH3:32]>C(#N)C>[CH2:31]([N:33]([CH2:38][CH3:39])[CH2:34][CH2:35][CH2:36][NH:37][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[S:13]([NH:12][C:9]1[C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:23])[C:3]([CH2:1][CH3:2])=[CH:11][CH:10]=1)(=[O:15])=[O:14])[CH3:32]
Reactant: CCN(CC)CCCN
Reactant: CCc1ccc(NS(=O)(=O)c2ccccc2F)c(C(=O)O)c1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCc1ccc(NS(=O)(=O)c2ccccc2NCCCN(CC)CC)c(C(=O)O)c1C
Yield: 10.8 %

Procedure:
A solution of Example 230C (40 mg, 0.12 mmol), triethylamine (0.1 mL), and N,N-diethyl-1,3-propanediamine (0.1 mL) in acetonitrile (1.0 mL) was heated to 200° C. for 1 hour on a Personal Chemistry microwave instrument. The mixture was then purified by reverse phase HPLC to provide the desired product (5.8 mg, 10.8%). 1H NMR (DMSO-d6) δ 1.07 (t, 3H), 1.12 (t, 6H), 2.19 (s, 3H), 2.53 (q, 2H), 3.05-3.12 (m, 8H), 6.02 (br s, 1H), 6.62-6.66 (m, 2H), 6.84 (d, 1H), 7.03 (d, 1H), 7.40 (t, 1H), 7.52 (d, 1H), 8.98 (br s, 1H), 9.50 (br s, 1H); MS (ESI(+)) m/e 448 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[NH:12][C:13]1[C:22]([NH:23][S:24]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)(=[O:26])=[O:25])=[N:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.C([O-])([O-])=O.[K+].[K+].O>CO>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:33])=[O:2])=[C:5]([NH:12][C:13]2[C:22]([NH:23][S:24]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)(=[O:25])=[O:26])=[N:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:6]=1
Reactant: COC(=O)c1ccc(OC)cc1Nc1nc2ccccc2nc1NS(=O)(=O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)O)c(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccnc2)c1
Reaction time: 1 h
Yield: 94.1 %

Procedure:
Methyl-4-methoxy-2-({3-[(pyridin-3-ylsulfonyl)amino]quinoxalin-2-yl}amino)benzoate (2200 mg; 4.73 mmol; 1 eq) and K2CO3 (8.5 g; 61.44 mmol; 13 eq) are taken up in MeOH (100 mL) and water (25 mL) and heated up to 60° C. overnight. The reaction mixture is concentrated to half the volume and some black residue is removed by filtration. The clear solution is neutralised with aqueous citric acid 10%. After 1 h at 4° C., the precipitate formed is filtered off and washed with water. After drying under vacuum at 40° C. overnight, it affords 2.01 g (94%) of the title compound as a yellow powder. 1H NMR (DMSO-d6) δ 13.17 (s, 1H), 12.49 (br s, 1H), 12.27 (s, 1H), 9.25 (d, J=1.9 Hz, 1H), 9.08 (d, J=2.6 Hz, 1H), 8.81-8.79 (m, 1H), 8.47-8.43 (m, 1H), 7.98 (d, J=9.0 Hz, 1H), 7.93 (br s, 1H), 7.68-7.60 (m, 2H), 7.44-7.40 (m, 2H), 6.70 (dd, J=8.7, 2.6 Hz, 1H), 3.91 (s, 3H). HPLC (max plot) 99%; Rt 4.04 min. LC/MS: (ES+): 452.3, (ES−): 450.3.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[CH2:3]1.Cl.[Cl:12][C:13]1[CH:30]=[CH:29][C:16]([C:17]([N:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)N)=[O:18])=[CH:15][CH:14]=1>C(O)(=O)C>[Cl:12][C:13]1[CH:30]=[CH:29][C:16]([C:17]([N:19]2[C:2]3[CH2:3][CH:4]([C:8]([OH:10])=[O:9])[CH2:5][CH2:6][C:7]=3[C:22]3[C:21]2=[CH:26][CH:25]=[C:24]([O:27][CH3:28])[CH:23]=3)=[O:18])=[CH:15][CH:14]=1
Reactant: O=C1CCCC(C(=O)O)C1
Reactant: COc1ccc(N(N)C(=O)c2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc2c(c1)c1c(n2C(=O)c2ccc(Cl)cc2)CC(C(=O)O)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
3-Oxocyclohexanecarboxylic acid (27.2 mg, 0.19 mmol) was added to a stirred solution of 4-chloro-N-(4-methoxyphenyl)benzohydrazide hydrochloride (50 mg, 0.16 mmol) in acetic acid (0.5 mL), the mixture was heated at 80° C. under nitrogen for 3 h, then it was allowed to cool to ambient temperature and stirred overnight. Ice-water (2 mL) was poured into the cold reaction mixture and the formed precipitate was collected by filtration, carefully washed with water and dried in vacuo to yield the title compound (50 mg, 82%) as an off-white solid. C21H18ClNO4, Mr=383.82; 1H NMR (400 MHz, DMSO-d6) d: 1.79-1.87 (m, 1H), 2.11-2.14 (m, 1H), 2.57-2.75 (m, 5H), 6.73 (dd, J=2.8/9.0 Hz, 1H), 6.97 (d, J=2.8 Hz, 1H), 7.06 (d, J=9.2 Hz, 1H), 7.62-7.69 (m, 4H); LCMS (ESI) tR: 2.82 min (>99%, ELSD), m/z: 384.0 [M+1]+.