Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg]Cl.[CH3:4][C:5]([C:8]1[Se:9][C:10]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][C:12](=O)[CH:13]=1)([CH3:7])[CH3:6].[F:19][B-:20]([F:23])([F:22])[F:21].[H+]>O1CCCC1>[F:19][B-:20]([F:23])([F:22])[F:21].[CH3:4][C:5]([C:8]1[CH:13]=[C:12]([CH3:1])[CH:11]=[C:10]([C:15]([CH3:18])([CH3:17])[CH3:16])[Se+:9]=1)([CH3:7])[CH3:6]
Reactant: C[Mg]Cl
Reactant: CC(C)(C)c1cc(=O)cc(C(C)(C)C)[se]1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: C1CCOC1
Product: Cc1cc(C(C)(C)C)[se+]c(C(C)(C)C)c1
Temperature: -20 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
Methyl magnesium chloride (40 mL of a 3 M solution in tetrahydrofuran, 0.12 mol) was added to a solution of 2,6-bis[1,1-dimethylethyl]selenopyran-4-one (22 g, 0.081 mol, prepared in Part C above ) in dry tetrahydrofuran (100 mL) which was initially maintained at -20° C. using a cold bath; the addition was effected at such a rate that the temperature in the reaction vessel did not exceed -15° C. The cold bath was removed, and the pale yellow solution was allowed to stir at room temperature for four hours, during which time a thick slurry formed. The mixture was then poured into ice/water (1 L) with rapid agitation, and tetrafluoroboric acid (200 mL of a 48% aqueous solution) was added. Stirring was continued for a further two hours, after which the mixture was extracted with dichloromethane (3×100 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give a tan residue, which was triturated with ether. The solid which resulted was collected by filtration, washed with ether and dried to give 2,6-bis(1,1-dimethylethyl)-4-methylselenopyrylium tetrafluoroborate (24.7 g, 85% yield) as an off-white solid which melted at 65°-66° C. The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy.
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.Br[C:13]1[CH:18]=[CH:17][C:16]2[O:19][CH2:20][O:21][C:15]=2[CH:14]=1>C1COCC1>[O:19]1[C:16]2[CH:17]=[CH:18][C:13]([C:7]3([OH:10])[CH2:6][CH2:5][C:4]4([O:3][CH2:2][CH2:1][O:11]4)[CH2:9][CH2:8]3)=[CH:14][C:15]=2[O:21][CH2:20]1
Reactant: Brc1ccc2c(c1)OCO2
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: C1CCOC1
Product: OC1(c2ccc3c(c2)OCO3)CCC2(CC1)OCCO2
Yield: 52 %

Procedure:
A solution of 1,4-cyclohexanedione monoethylene ketal in dry THF was reacted with the Grignard reagent prepared from 4-bromo-1,2-methylenedioxybenzene as described in example 1 to give the product (52%, mp: 95°-96° C.). Calc'd for C15H18O5 : C, 64.74%; H, 6.52%. Found: C, 64.41%; H, 6.41%.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[CH3:22][C:23]1([CH2:27][NH:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])[CH2:26][NH:25][CH2:24]1.C(N(CC)CC)C>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:25]4[CH2:26][C:23]([CH2:27][NH:28][C:29](=[O:34])[C:30]([F:32])([F:33])[F:31])([CH3:22])[CH2:24]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CC1(CNC(=O)C(F)(F)F)CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC1(CNC(=O)C(F)(F)F)CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Yield: 99.5 %

Procedure:
A mixture of 1 g (3.5 mmoles) of 1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 1.32 g (5.7 mmoles) of 3-methyl-3-trifluoroacetamidomethylazetidine hydrochloride and 2.3 g of triethylamine is heated under reflux in 12 ml of pyridine for 3 hours. The mixture is evaporated, water is added, and the product filtered. 1.6 g (100%) of 1-cyclopropyl-6,8-difluoro-7-(3-trifluoroacetamidomethyl-3-methyl-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are obtained, melting at 232°-7° C.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[CH3:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][NH:13]2)=[CH:9][CH:8]=1.S(=O)(=O)(O)O>>[CH3:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:12][NH:13]2)=[CH:9][C:8]=1[N+:1]([O-:4])=[O:2]
Reactant: Cc1ccc2c(-c3ccccc3)n[nH]c2c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc2[nH]nc(-c3ccccc3)c2cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 47.3 %

Procedure:
6-Methyl-5-nitro-3-phenyl-1H-indazole can be obtained in the following way: 0.43 g of potassium nitrate is added over 5 minutes to a solution, cooled to a temperature in the region of 0° C., of 0.8 g of 6-methyl-3-phenyl-1H-indazole in 8 ml of an aqueous 98% sulfuric acid solution. The reaction mixture is stirred at a temperature in the region of 0° C. for 5 minutes and is then heated at a temperature in the region of 35-40° C. for 10 minutes and again cooled to a temperature in the region of 0° C. and stirred for 1 hour. The mixture is then poured into 50 g of ice, stirred at a temperature in the region of 0° C. for 1 hour, then filtered through sintered glass. The solid obtained is washed with 3 times 30 ml of water and partially dried and is then redissolved in 100 ml of ethyl acetate and the mixture is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue thus obtained is purified by chromatography on a silica column (particle size 40-63 μm), eluting successively with cyclohexane/ethyl acetate (90/10; 80/20 by volume) mixtures. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 0.46 g of 6-methyl-5-nitro-3-phenyl-1H-indazole is thus obtained in the form of a yellow crystalline solid melting at 164° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:16]([P:19](Cl)(Cl)=[O:20])([CH3:18])[CH3:17]>>[CH:16]([P:19]1(=[O:20])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:9][N:8]1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)([CH3:18])[CH3:17]
Reactant: CC(C)P(=O)(Cl)Cl
Reactant: Clc1ccc(NCc2ccccc2)cc1
Product: CC(C)P1(=O)c2ccccc2CN1c1ccc(Cl)cc1
Yield: 16 %

Procedure:
The procedure of Example 1 was employed utilizing N-(4-chlorophenyl)-N-benzylamine and isopropyl phosphonic dichloride to yield 1-isopropyl-2-(4-chlorophenyl)-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (2.9 g, 16% yield) as a white solid having a melting point of 172°-174° C. and the following analysis:
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@@H:9]1[CH2:14][N:13]([CH3:15])[C:12](=[O:16])[CH2:11][CH2:10]1)C1C=CC=CC=1>CO.[Pd]>[NH2:8][C@@H:9]1[CH2:14][N:13]([CH3:15])[C:12](=[O:16])[CH2:11][CH2:10]1
Reactant: CN1C[C@@H](N(Cc2ccccc2)Cc2ccccc2)CCC1=O
Agent: [Pd]
Solvent: CO
Product: CN1C[C@@H](N)CCC1=O
Yield: 101.6 %

Procedure:
450 mg (S)-5-dibenzylamino-1-methyl-piperidin-2-one are suspended in 25 ml of methanol and hydrogenated with 150 mg Pd/C 10% under a pressure of 3 bar and at a temperature of 60° C. After 16 hours the catalyst is removed by suction filtering and the filtrate is evaporated to dryness. 190 mg of the product are obtained as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]2[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:24])([CH3:23])[C:17]=2[CH:25]=1.ClC1C=CC=C(C(OO)=[O:34])C=1>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]2[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:23])([CH3:24])[C:17]=2[CH:25]=1)=[O:34]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccccn3)cc21
Solvent: ClC(Cl)Cl
Product: CC1(C)OC(=O)Nc2ccc(OCCCCS(=O)c3ccccn3)cc21
Reaction time: 8 h

Procedure:
A quantity of 3.58 gm (0.01 mol) 6-[4-(2-pyridylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one is dissolved in 100 ml of chloroform and mixed with 4.3 gm (0.025 mol) of m-chloroperbenzoic acid, under stirring. After stirring for two hours, a further 2 gm of m-chloroperbenzoic acid are added, and the mixture is left to stand overnight. The chloroform phase is extracted with water, the organic phase is dried with sodium sulfate, and the chloroform is distilled off. The non-uniform residue is purified by column chromatography [silica gel, particle size of 0.05 to 0.2 mm; chloroform/ethanol (40:1)]. The uniform fractions are combined, and the residue is triturated with ethyl acetate/ether. The crystals thus obtained are subjected to suction filtration and dried at 50° C.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]2=[N:4][C:3]=1[CH:17]=[O:18].[CH3:19][O:20][C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:22]>>[CH:17]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:2]=1[C:26]1[CH:27]=[CH:28][C:23]([C:21]([O:20][CH3:19])=[O:22])=[CH:24][CH:25]=1)=[O:18]
Reactant: O=Cc1nc2c(N3CCOCC3)ccnn2c1Br
Reactant: COC(=O)c1ccc(B(O)O)cc1
Product: COC(=O)c1ccc(-c2c(C=O)nc3c(N4CCOCC4)ccnn23)cc1

Procedure:
Compound 14b (3.0 g, 11 mmol) was subjected to Suzuki coupling conditions with [4-(methoxycarbonyl)phenyl]boronic acid using the procedure described in Example 38, Step A to obtain compound 58c as a gray solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C19H18N4O4: 367.1 (M+H). Found: 367.2.
Reaction SMILES: O/[CH:2]=[CH:3]/[C:4](=[O:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.[CH3:14][NH:15][CH3:16].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH3:14][N:15]([CH3:16])/[CH:2]=[CH:3]/[C:4](=[O:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CNC
Reactant: O=C(/C=C/O)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)/C=C/C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
A solution of (3E)-4-hydroxy-1-phenylbut-3-en-2-one (1.2 g, 7.4 mmol) in THF (20 mL) was added dimethylamine hydrochloride (1.8 g, 22.2 mmol), K2CO3 (6.1 g, 44.4 mmol) and the mixture was stirred at rt overnight. The mixture was concentrated and purified by flash column chromatography (PE/EtOAc=10:1) to give the title compound (0.6 g, 43%) as a yellow oil. [M+H] Calc'd for C12H15NO, 190; Found, 190.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@H:5]23)[CH:10]=1.[Cl:24][C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O>>[Cl:24][C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@H:5]23)[CH:10]=1
Reactant: OB(O)c1cccc(Cl)c1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(Br)cc3c1N2CC3
Product: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(-c3cccc(Cl)c3Cl)cc3c1N2CC3

Procedure:
The title compound was prepared by the method of Example 90 from tert-butyl (±)-cis-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (124 mg, 0.27 mmol) and corresponding 2,3-dichlorophenylboronic acid (104 mg, 0.54 mmol), to afford after chromatographic purification the title compound (157 mg, 99%) as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ 7.30-7.40 (m, 1H), 7.20 (s, 1H), 7.18 (d, 1H, J=3.6 Hz), 6.99 (s, 1H), 6.94 (s, 1H), 3.80-3.90 (m, 1H), 3.60-3.80 (m, 1H), 3.10-3.50 (m, 7H), 2.80-3.00 (m, 1H), 1.70-1.90 (m, 2H), 1.47 (s, 9H) ppm. MS (CI, NH3): 445 (base, M+H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH2:12].[C:13](OCC)(OCC)(OCC)[CH3:14]>C(O)C>[CH3:13][C:14]1[NH:1][C:2]2[C:11]3[C:6]([CH:5]=[CH:4][C:3]=2[N:12]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: Nc1ccc2ccccc2c1N
Reactant: CCOC(C)(OCC)OCC
Solvent: CCO
Product: Cc1nc2ccc3ccccc3c2[nH]1

Procedure:
To a solution of 7.38 g of 1,2-diaminonaphthalene in 175 ml of ethanol was added 8.56 ml of triethyl orthoacetate and the reaction mixture heated to reflux for 3.5 hours. The solvent was removed in vacuo and the residue partitioned between chloroform and water. The organic phase was separated, dried over magnesium sulfate and concentrated to a dark oil, 9.0 g.
Reaction SMILES: C1(C)C=CC(S(CC[O:12][C:13](=[O:52])[CH2:14][O:15][C:16]2[CH:21]=[C:20]([CH3:22])[C:19]([S:23]([N:26]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[N:28]=[C:27]3[S:35]([CH2:37][C:38]3[C:43]([CH3:44])=[C:42]([O:45][CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:41]=[CH:40][N:39]=3)=[O:36])(=[O:25])=[O:24])=[C:18]([CH3:51])[CH:17]=2)(=O)=O)=CC=1.C([O-])(O)=O.[Na+:58]>CC#N.O>[Na+:58].[CH3:22][C:20]1[CH:21]=[C:16]([CH:17]=[C:18]([CH3:51])[C:19]=1[S:23]([N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[S:35]([CH2:37][C:38]1[C:43]([CH3:44])=[C:42]([O:45][CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:41]=[CH:40][N:39]=1)=[O:36])(=[O:24])=[O:25])[O:15][CH2:14][C:13]([O-:52])=[O:12]
Reactant: COCCCOc1ccnc(CS(=O)c2nc3ccccc3n2S(=O)(=O)c2c(C)cc(OCC(=O)OCCS(=O)(=O)c3ccc(C)cc3)cc2C)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COCCCOc1ccnc(CS(=O)c2nc3ccccc3n2S(=O)(=O)c2c(C)cc(OCC(=O)[O-])cc2C)c1C
Temperature: 65 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
To a solution of 3,5-dimethyl-4-{2-[4-(3-methoxy-propoxy)-3-methyl-pyridin-2-yl-methanesulfinyl]-benzimidazole-1-sulfonyl}phenoxyacetic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 58, 1.6 g, 1.90 mmol) in 10 mL of CH3CN was added a solution of NaHCO3 (208 mg, 2.47 mmol, 1.3 eq) in 5 mL of H2O. The mixture was heated to 65° C. for 3 h. Thereafter all the volatile materials were removed under vacuum, the mixture was washed with EtOAc (2×), and then the aqueous layer was lyophilized overnight. The solid was dissolved in 80 mL of CH2Cl2, and then the mixture was filtered to remove insoluble material. The filtrate was concentrated and the residual oil was dissolved in 5 mL of CH2Cl2. EtOAc was added to the mixture to precipitate a white solid. The precipitate was collected by filtration, washed with EtOAc, and dried under vacuum to yield 800 mg (62%) of 3,5-dimethyl-4-{2-[4-(3-methoxy-propoxy)-3-methyl-pyridin-2-yl-methanesulfinyl]-benzimidazole-1-sulfonyl}phenoxyacetic acid sodium salt (Compound 33) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16]O>>[OH:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: CO
Reactant: Cc1cccc(C(=O)O)c1O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(C)c1O

Procedure:
Into a 3-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-hydroxy-3-methylbenzoic acid (50 g, 328.63 mmol, 1.00 equiv) and methanol (800 mL). This was followed by the addition of thionyl chloride (20 mL) dropwise with stirring. The resulting solution was stirred overnight at 80° C. The resulting mixture was concentrated under vacuum. The residue was diluted with 1000 mL of ethyl acetate. The resulting mixture was washed with 2×800 mL of NaOH (cold). The resulting mixture was washed with 2×500 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 25 g (46%) of methyl 2-hydroxy-3-methylbenzoate as brown oil. 1H NMR (300 MHz, DMSO-d6) δ 2.19 (s, 3H), 3.90 (s, 3H), 6.83-6.88 (m, 1H), 7.41-7.44 (m, 1H), 7.64-7.66 (m, 1H), 10.87 (b, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)=[C:8]([OH:10])[CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].I[CH:23]([CH3:25])[CH3:24]>CC(C)=O.C(Cl)Cl>[CH3:24][CH:23]([O:10][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15]1)[CH3:25]
Reactant: CC(C)I
Reactant: O=[N+]([O-])c1ccc(-n2cccc2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(C)Oc1cc([N+](=O)[O-])ccc1-n1cccc1
Yield: 71.1 %

Procedure:
To a stirred mixture of 3.6 g (0.02 mole) of 5-nitro-2-(1H-pyrrol-1-yl)phenol and 3.7 g (0.27 mole) of potassium carbonate in 40 ml of acetone was added 4.5 g (0.027 mole) of 2-iodopropane. After complete addition the mixture was stirred at reflux for approximately 16 hours. The reaction mixture was cooled, and the solvent evaporated under reduced pressure to leave a residue. The residue was dissolved in methylene chloride, filtered, and the filtrate evaporated under reduced pressure to leave residue. The residue was purified by column chromatography on silica gel, eluting with toluene, to yield 3.5 g of 1-(1-methylethoxy-4-nitrophenyl)pyrrole (mp 59°-61° C.).
Reaction SMILES: [CH2:1](Br)[CH:2]([CH3:4])[CH3:3].[OH:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC(C)C)c([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 44 h
Yield: 87.3 %

Procedure:
Isobutyl bromide (10.5 mL, 95.8 mmol) was added to a suspension of methyl 4-hydroxy-3-nitrobenzoate (6.26 g, 31.8 mmol) and potassium carbonate (13.2 g, 95.5 mmol) in dry DMF (40 mL). The resulting mixture was stirred at 90° C. for 44 hours and then cooled to room temperature. Subsequently, ice-water (80 mL) was added to the cooled mixture. The precipitated crystalline product was collected by filtration, washed with water (50 mL), and dried for 30 min in air. The dried crystalline product was then washed with hexane (40 mL), and dried in air to give 7.03 g (yield 87%) of the desired compound in the form of a pale orange crystalline product.
Reaction SMILES: [S:1]=[C:2]1[NH:6][C@H:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][CH2:3]1.[CH2:14]1COCC1>>[CH3:14][S:1][C:2]1[CH2:3][CH2:4][C@@H:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[N:6]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(=S)N1
Reactant: C1CCOC1
Product: CSC1=N[C@H](C(=O)OC(C)(C)C)CC1
Reaction time: 3.5 h
Yield: 91 %

Procedure:
To a solution of thiolactam 1b (10.50 g, 52.2 mmol) in 200 mL THF at rt, was added Mel (13.0 mL, 208.7 mmol). The mixture was stirred for 3.5 h, then concentrated. The residue was partitioned between CH2Cl2 and sat. NaHCO3 and the aqueous phase was extracted with CH2Cl2 (3×). The combined organic extract was dried (Na2SO4) and concentrated to afford 10.17 g (91%) of the title compound, 1c, as a brown oil. 1H NMR (300 MHz, CDCl3) δ 4.60 (dd, J=6.2, 7.3, 1H), 2.83–2.58 (m, 2H), 2.49 (s, 3H), 2.37–2.22 (m, 1H), 2.17–2.03 (m, 1H), 1.48 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C[O-].[Na+].Br[CH:13]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)[C:14]([O:16][CH3:17])=[O:15]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(S(C)(=O)=O)cc2)cc1
Reactant: Oc1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(Oc1ccc(Cl)cc1)c1ccc(Oc2ccc(S(C)(=O)=O)cc2)cc1
Yield: 68.6 %

Procedure:
To a solution of 1.38 g of p-chlorophenol and 0.585 g of sodium methoxide in 10 ml of methanol is added a solution of 3.53 g of methyl α-bromo-α-[p-(p-methylsulfonylphenoxy)phenyl]acetate in 15 ml of methanol. The mixture is refluxed for 20 hours, chilled and filtered to give 2.71 g of white crystals, mp 182°-183° C. Recrystallization by heating in 75 ml of acetone and adding 20 ml of dichloromethane, followed by adding hexane gives on chilling the product as white crystals, mp 182°-183° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])=[CH:4][C:3]=1[C:21]#[C:22][CH2:23][OH:24].CCO.[Cl-].[NH4+]>[Fe].O>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:18])([F:19])[F:20])=[CH:4][C:3]=1[CH:21]=[CH:22][CH2:23][OH:24]
Reactant: Nc1c(C#CCO)cc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cc(-c2ccccc2C(F)(F)F)cc(C=CCO)c1N
Temperature: 80 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
3-(4-Amino-5-nitro-2′-trifluoromethyl-biphenyl-3-yl)-prop-2-yn-1-ol (131 mg, 0.390 mmol, as prepared in Example 10, step A) was placed in an 8 mL vial equipped with a magnetic stir bar, and EtOH (4 mL) was added via syringe followed by water (1 mL). Ammonium chloride (10 eq., 209 mg, 3.90 mmol) and Fe powder (5 eq., 109 mg, 1.95 mmol) were added as solids. The vial was tightly capped, placed in a heated block, and stirred at 80° C. for 16 h. The reaction was cooled to RT, filtered, and the solids were washed three times with MeOH (5 mL). The filtrate was concentrated under reduced pressure, the residue was dissolved in EtOAc (20 mL) and washed with water (20 mL), and the aqueous layer was extracted three times with EtOAc (10 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure, yielding 95 mg of the title compound as a 1:1 mixture with 3-(4,5-diamino-2′-trifluoromethylbiphenyl-3-yl)-prop-2-yn-1-ol. The mixture was carried through to the next step.
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1>>[N:1]1([S:11]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=3)=[O:19])=[CH:21][CH:22]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Reactant: Nc1cccc(O)c1
Product: O=C(Nc1cccc(O)c1)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with 3-aminophenol (29 mg, 0.26 mmol) using method C. The residue was purified using flash chromatography eluting with 0-50 EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(3-hydroxyphenyl)benzamide as an off-white solid. Yield: 38 mg (35%). 1H-NMR: 8.21 (d, J=8.5 Hz, 2H), 7.80 (d, J=8.5 Hz, 2H), 7.61 (d, J=8.0 Hz, 1H), 7.24-7.08 (m, 3H), 7.06 (t, J=8.0 Hz, 1H), 6.48 (ddd, J=8.0, 2.0, 1.0 Hz, 1H), 6.41 (t, J=2.0 Hz, 1H), 6.36 (ddd, J=8.0, 2.0, 1.0 Hz, 1H), 3.84-3.80 (m, 2H), 2.45 (t, J=7.0, 2H), 1.67-1.59 (m, 2H).