Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19]2[N:28]=[C:27]([N:29]([CH3:31])[CH3:30])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[CH:13][CH:12]=1)C1C=CC=CC=1.[Br:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[C:36]([O:44][C:45]([F:48])([F:47])[F:46])[CH:35]=1>CO.C(Cl)Cl.[Pd]>[Br:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19]3[N:28]=[C:27]([N:29]([CH3:31])[CH3:30])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:13][CH:12]=2)(=[O:42])=[O:41])=[C:36]([O:44][C:45]([F:47])([F:46])[F:48])[CH:35]=1
Reactant: CN(C)c1nc(NCc2ccc(NC(=O)OCc3ccccc3)cc2)nc2ccccc12
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CN(C)c1nc(NCc2ccc(NS(=O)(=O)c3ccc(Br)cc3OC(F)(F)F)cc2)nc2ccccc12
Temperature: 50 °C
Reaction time: 41.5 h
Yield: 74.4 %

Procedure:
To a solution of {4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-phenyl}-carbamic acid benzyl ester (318 mg, 0.744 mmol) in MeOH (3 mL) was added 5% Pd/C (30 mg). The mixture was stirred at 50° C. under hydrogen atmosphere for 41.5 hr, filtered through a pad of celite, and concentrated. To a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (505 mg, 1.49 mmol) in CH2Cl2 (12 mL) was added PVP (6 mL). To the resulting suspension was added a solution of the above residue in CH2Cl2 (10 mL). The mixture was stirred at ambient temperature for 1.5 days, filtered, poured into saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by medium-pressure liquid chromatography (NH-silica gel, 33% EtOAc in hexane) to give 4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-phenyl}-2-trifluoromethoxy-benzenesulfonamide (330 mg, 74%) as a pale brown solid.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[N:26]=1>>[CH:11]1[C:12]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20]([C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[N:26]=5)([OH:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: COc1cccc(Br)n1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Product: COc1cccc(C2(O)CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)n1
Yield: 98 %

Procedure:
Using a procedure similar to that described in example 1 except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and employing 2-bromo-6-methoxypyridine, the title compound was formed in 98% yield [ ] as a white solid, mp 193°-195° C. (dec). free base: 1H NMR (CDCl3, 300 MHz) 7.57 (dd, J=7.6, 7.6 Hz, 1H), 7.23 (m, 4H), 6.94 (m, 5H), 6.63 (d, J=8.0 Hz, 1H), 4.75 (s, 1H), 4.28 (s, 1H), 3.95 (s, 3H), 3.49 (s, 2H), 2.94 (m, 2H), 2.77 (m, 2H), 2.64 (d, J=1.2 Hz, 2H), 2.04 (m, 2H), 1.63 (m, 2H) MS (CI, CH4) m/z 413 (M+1,100), 441 (M+29,12), 395 (18) hydrochloride salt:
Reaction SMILES: [Br-].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:3]1.[O:31]=[C:32]1[NH:36][CH2:35][C:34](=[O:37])[N:33]1[CH2:38][CH2:39][O:40][C:41]1[CH:48]=[CH:47][C:44]([CH:45]=O)=[C:43]([N+:49]([O-:51])=[O:50])[C:42]=1[O:52][CH3:53].C(=O)([O-])[O-].[K+].[K+].O>CO>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:11]=[CH:45]/[C:44]2[CH:47]=[CH:48][C:41]([O:40][CH2:39][CH2:38][N:33]3[C:34](=[O:37])[CH2:35][NH:36][C:32]3=[O:31])=[C:42]([O:52][CH3:53])[C:43]=2[N+:49]([O-:51])=[O:50])=[N:3]1
Reactant: c1ccc([P+](Cc2n[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1c(OCCN2C(=O)CNC2=O)ccc(C=O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1c(OCCN2C(=O)CNC2=O)ccc(/C=C/c2n[nH]c3ccccc23)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.6 %

Procedure:
(1H-indazol-3-ylmethyl)triphenylphosphonium bromide (0.12 g, 0.26 mmol), 4-[2-(2,5-dioxoimidazolidin-1-yl)ethoxy]-3-methoxy-2-nitrobenzaldehyde (0.08 g, 0.24 mmol) obtained in Step 1 and potassium carbonate (0.07 g, 0.47 mmol) were dissolved in methanol (3.0 mL), followed by stirring at room temperature for 1.0 hour. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=9/1) to obtain (E)-3-(2-{4-[2-(1H-indazol-3-yl)vinyl]-2-methoxy-3-nitrophenoxy}ethyl)imidazolidine 2,4-dione (0.03 g, 32%).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][S:8]([CH2:11][C:12]1[CH2:13][CH2:14][N:15]([C:18](=[S:20])[OH:19])[CH2:16][CH:17]=1)(=[O:10])=[O:9].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)[N:29]2[CH2:32][C:31](=[O:33])[CH2:30]2)=[CH:24][CH:23]=1>O1CCCC1.O>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)[N:29]2[CH2:30][C:31]([CH2:7][S:8]([CH2:11][C:12]3[CH2:17][CH2:16][N:15]([C:18](=[S:20])[OH:19])[CH2:14][CH:13]=3)(=[O:9])=[O:10])([OH:33])[CH2:32]2)=[CH:24][CH:23]=1
Reactant: O=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reactant: CS(=O)(=O)CC1=CCN(C(O)=S)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(CC1=CCN(C(O)=S)CC1)CC1(O)CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
The phenolic ester of 4-({1-[bis(4-chlorophenyl)methyl]-3-hydroxyazetidin-3-yl}methylsulfonylmethyl)-3,6-dihydro-2H-pyridine-1-carbothioic acid is prepared in the following manner: 0.52 g of potassium tert-butoxide is added to a mixture of 0.72 g of the phenolic ester of 4-methylsulfonylmethyl-3,6-dihydro-2H-pyridine-1-carbothioic acid and 0.708 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one in 15 cm3 of dry tetrahydrofuran cooled under an inert atmosphere to −78° C. The reaction mixture is stirred at −78° C. for 4 hours and then 0.354 g of 1-[bis(4-chlorophenyl)-methyl]azetidin-3-one are added. After two hours at −78° C., the temperature is allowed to return to 20° C. The reaction mixture is diluted in 100 cm3 of water and then the tetrahydrofuran is evaporated off under 2.7 kPa at 40° C. The aqueous phase is extracted with twice 100 cm3 of ethyl acetate. The organic extracts are combined and dried over magnesium sulfate, concentrated under 2.7 kPa at 40° C. The residue obtained is chromatographed on silica (200 g of silica, Amicon, 20-45 μm, porosity 60Angstroem, column 5 cm in diameter), eluting with a cyclohexane:ethyl acetate (6:4 by volume) mixture. The fractions with an Rf={fraction (11/64)} (cyclohexane:ethyl acetate 6:4, silica plate, Merck reference 1.05719, Merck KGaA, 64721 Darmstatd, Germany) are combined and concentrated under 2.7 kPa at 40° C. to give 240 mg of the phenolic ester of 4-({1-[bis(4-chlorophenyl)methyl]-3-hydroxyazetidin-3-yl}methylsulfonylmethyl)-3,6-dihydro-2H-pyridine-1-carbothioic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][Cl:27])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>C1COCC1>[Cl:27][CH2:26][CH2:25][O:24][C:18]1[CH:17]=[C:16]2[C:21]([C:12]([S:8][C:4]3[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=3)[NH2:1])=[N:13][CH:14]=[N:15]2)=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: Nc1cccc(S)c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2c(Sc3cccc(N)c3)ncnc2cc1OCCCl
Reaction time: 0.5 h

Procedure:
In a round bottomed flask 3-aminothiophenol (279 mg, 2.23 mmol) was dissolved in 10 mL of dry THF. To this solution was added sodium hydride, 60% suspension in mineral oil, (86 mg, 2.23 mmol) and the reaction stirred for 30 minutes. 4-chloro-7-(2-chloro-ethoxy)-6-methoxy-quinazoline (610 mg, 2.23 mmol) from Example 35A was added as a 10 mL solution in THF, and the reaction stirred overnight at room temperature. The solution was then concentrated to dryness, and partitioned between ethyl acetate and water, and extracted with an additional portion of ethyl acetate. The extracts were combined, dried with magnesium sulfate, filtered, and concentrated to give 3-(7-(2-chloroethoxy)-6-methoxyquinazolin-4-ylthio)aniline as a yellow solid weighing 600 mg. 1H NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 7.47 (d, 2H), 7.17 (m, 1H), 6.83 (s, 1H), 6.72 (m, 2H), 4.51 (m, 2H), 4.05 (m, 3H), 3.89 (s, 3H), 3.51 (bs, 2H); LC-MS (ESI) m/z 362 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH2:15][CH:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1.Cl[CH2:23][CH2:24][N:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[C:33]3[CH:34]=[CH:35][CH:36]=[C:27]([C:28]=23)[S:26]1(=[O:38])=[O:37].C(=O)([O-])O.[Na+].O>CN1CCN(C)C1=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH2:15][CH:16]4[CH2:17][CH2:18][N:19]([CH2:23][CH2:24][N:25]5[C:29]6[CH:30]=[CH:31][CH:32]=[C:33]7[CH:34]=[CH:35][CH:36]=[C:27]([C:28]=67)[S:26]5(=[O:38])=[O:37])[CH2:20][CH2:21]4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCl
Reactant: Fc1ccc2[nH]c3c(c2c1)CN(CC1CCNCC1)CC3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: O=S1(=O)c2cccc3cccc(c23)N1CCN1CCC(CN2CCc3[nH]c4ccc(F)cc4c3C2)CC1
Reaction time: 16 h
Yield: 19.4 %

Procedure:
A mixture of 4-(8-fluoro-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-2-ylmethyl)piperidine (1 g), 2-(2-chloroethyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (0.94 g) and sodium hydrogen carbonate (0.59 g) in 1,3-dimethyl-2-imidazolidinone (25 cc) is brought to 150° C. for 16 hours. After return to a temperature in the vicinity of 25° C., this solution is poured into water (75 cc) and the mixture is extracted with ethyl acetate (3×75 cc). The combined organic phases are dried over magnesium sulphate and taken to dryness at 80° C. under reduced pressure (20 mm Hg: 2.7 kPa). The residue is purified by flash chromatography on a silica column under nitrogen at moderate pressure (0.5-1.5 bar) with a dichloromethane/methanol mixture (90:10 by volume) as eluent. 2-{2-[4-(8-Fluoro-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-2-ylmethyl)piperidino]ethyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (0.35 g), m.p. 228° C., is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH3:2].[NH2:21][CH2:22][C@@H:23]([C:25]1[CH:26]=[CH:27][C:28]([OH:36])=[C:29]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:30]=1)[OH:24]>>[CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([NH:21][CH2:22][C@H:23]([OH:24])[C:25]3[CH:26]=[CH:27][C:28]([OH:36])=[C:29]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:30]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: CCOC(=O)/C=C/c1ccc(N2CCC(=O)CC2)cc1
Product: CCOC(=O)/C=C/c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from (E)-3-[4-(4-oxo-piperidine-1-yl)-phenyl]-acrylic acid ethyl ester (which was obtained in Example 169) (0.27 g, 1.0 mmol) and N-[5-((1R)-2-Amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) (0.27 g, 1.1 mmol) according to the prodedure shown for Example 180 to give 0.40 g of yellow solid; m.p. 103-106° C.; 1H NMR (DMSO-d6) δ 1.24 (t, 3H), 1.20-1.45 (m, 2H), 1.75-1.95 (m, 2H), 2.55-2.95 (m, 5H), 2.92 (t, 3H), 3.67-3.85 (m, 2H), 4.14 (q, 2H), 4.46-4.50 (m, 1H), 6.34 (d, 1H), 6.96 (d, 1H), 6.79-7.05 (m, 3H), 7.05 (d, 1H), 7.17 (d, 1H), 7.56 (d, 2H); MS (ES) m/z: 504.0 (MH+).
Reaction SMILES: [Cl:1][C:2]([Cl:6])([Cl:5])[CH2:3][OH:4].[OH:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([OH:17])[CH:16]=1)[C:11](O)=[O:12].S(=O)(=O)(O)O>>[OH:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([OH:17])[CH:16]=1)[C:11]([O:4][CH2:3][C:2]([Cl:6])([Cl:5])[Cl:1])=[O:12]
Reactant: O=C(O)c1cc(O)cc(O)c1
Reactant: OCC(Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Product: O=C(OCC(Cl)(Cl)Cl)c1cc(O)cc(O)c1
Temperature: 90 °C
Yield: 61.4 %

Procedure:
To freshly distilled 2,2,2-trichloroethanol (25 mL) was added 3,5-dihydroxybenzoic acid 4.50 g, 29.2 mmol) followed by concentrated sulfuric acid (1.0 mL), and mixture was stirred vigorously and heated at 90° C. for 48 h under nitrogen. The reaction mixture was cooled and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography eluting with CH2Cl2 gradually increasing to 1:10 diethyl ether/CH2Cl2, to give (2,2,2-trichloroethyl) 3,5-dihydroxybenzoate as a viscous oil (5.12 g, yield 61.4%).
Reaction SMILES: [CH2:1]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([N:26]([CH2:35][CH3:36])[C:27]([CH:29]2[CH2:31][CH:30]2[C:32](Cl)=[O:33])=[O:28])=[CH:22][CH:21]=1)([O-:19])=[O:18].C(Cl)(=O)C(Cl)=O.S(Cl)(Cl)=O>C(Cl)Cl>[CH2:35]([N:26]([C:23]1[CH:24]=[CH:25][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=1)[C:27]([CH:29]1[CH2:31][CH:30]1[C:32]([N:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:33])=[O:28])[CH3:36]
Reactant: CCN(C(=O)C1CC1C(=O)Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCCCNCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCCN(Cc1ccccc1)C(=O)C1CC1C(=O)N(CC)c1ccc([N+](=O)[O-])cc1

Procedure:
In a manner similar to Preparation 32 react N-octylbenzenemethanamine with 2-[[(4-nitrophenyl)(ethyl)amino]carbonyl]cyclopropane-1-carbonyl chloride (prepared from the acid and oxalyl chloride or thionyl chloride) in methylene chloride to obtain the title compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2[O:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:16][C:10]=2[CH2:9]1)C1C=CC=CC=1.[H][H]>CCO.[Pd]>[C:17]1([C:15]2[O:14][C:11]3[CH2:12][CH2:13][NH:8][CH2:9][C:10]=3[CH:16]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc(CN2CCc3oc(-c4ccccc4)cc3C2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: c1ccc(-c2cc3c(o2)CCNC3)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 47.9 %

Procedure:
To a solution of 5-benzyl-2-phenyl-4,5,6,7-tetrahydrofuro[3, 2-c]pyridine (1.5 g, 0.00649 mol) in EtOH (30 mL) under nitrogen was added Pd—C(10%) (200 mg, 0.3 mmol). Hydrogen (1 atm) was applied and the reaction mixture was stirred for 3 to 4 h at RT. After consumption of starting materials as determined by TLC, the reaction mixture was filtered through Celite® (diatomaceous earth), washing with EtOH. The filtrate was concentrated to afford a solid which was washed with ether to afford 2-phenyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridine (620 mg, 48%).
Reaction SMILES: C(OC([N:8]1[CH:12]([C:13]([N:15]2[CH2:19][CH2:18][CH2:17][CH:16]2[C:20]#[N:21])=[O:14])[CH2:11][CH2:10][CH:9]1[CH2:22][O:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([NH2:34])=[CH:26][CH:25]=1)=O)(C)(C)C.N1C=CC=CC=1.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl>[C:20]([C@@H:16]1[CH2:17][CH2:18][CH2:19][N:15]1[C:13]([C@H:12]1[NH:8][C@@H:9]([CH2:22][O:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([NH:34][S:42]([CH3:41])(=[O:44])=[O:43])=[CH:26][CH:25]=2)[CH2:10][CH2:11]1)=[O:14])#[N:21]
Reactant: CC(C)(C)OC(=O)N1C(COc2ccc(N)c3ccccc23)CCC1C(=O)N1CCCC1C#N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(OC[C@H]2CC[C@@H](C(=O)N3CCC[C@H]3C#N)N2)c2ccccc12

Procedure:
The compound of Example 97A (32 mg, 0.07 mmol) was dissolved in CH2Cl2 (1 mL) and pyridine (0.5 mL) in a microwave reaction tube. Methanesulfonyl chloride (6.0 μL, 0.21 mmol) was added. It was reacted under microwave condition at 130° C. for 20 minutes. The mixture was filtered and purified by reverse phase HPLC to give the desired sulfonamide.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[CH:10][NH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Mg]Br)C.[F:20][C:21]([F:38])([F:37])[CH:22]1[CH2:24][N:23]1[S:25]([C:28]1[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=1[CH3:36])(=[O:27])=[O:26]>COC(C)(C)C.CCOCC.[Cu]I>[CH3:36][C:29]1[CH:30]=[C:31]([CH3:35])[CH:32]=[C:33]([CH3:34])[C:28]=1[S:25]([NH:23][CH:22]([CH2:24][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:11][CH:10]=1)[C:21]([F:38])([F:20])[F:37])(=[O:26])=[O:27]
Reactant: Cc1cc(C)c(S(=O)(=O)N2CC2C(F)(F)F)c(C)c1
Reactant: c1ccc(-c2cccc3[nH]ccc23)cc1
Agent: [Cu]I
Agent: CC[Mg]Br
Solvent: COC(C)(C)C
Solvent: CCOCC
Product: Cc1cc(C)c(S(=O)(=O)NC(Cc2c[nH]c3cccc(-c4ccccc4)c23)C(F)(F)F)c(C)c1
Reaction time: 0.5 h
Yield: 44.5 %

Procedure:
To a stirred solution of 115 mg (0.60 mmol) of 4-phenylindole in 2 mL of tert-butyl methyl ether at room temperature was added 0.25 mL (0.75 mmol) of a 3 M solution of ethyl magnesium bromide in ether. The mixture stirred for 30 minutes and then 22.8 mg (0.12 mmol) of copper (I) iodide was added. After 30 minutes, a solution of 87.9 mg (0.30 mmol) of 2-trifluoromethyl-1-(2,4,6-trimethylbenzenesulfonyl)aziridine in 1 mL of tert-butyl methyl ether was added. After 18 hours, the reaction was quenched with 1 mL of ice-cold water. After 10 minutes, the reaction mixture was diluted with dichloromethane, filtered through CELITE® filter aid, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (12 g) eluting with ethyl acetate-hexanes (0-30% gradient) to afford an off-white solid. A second chromatography by preparative TLC eluting with ethyl acetate-hexanes (3:7) afforded 65 mg (22%) of the title compound as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[O:9][C:4]=2[CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([F:25])[C:23]=1F)[CH:19]=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:11][C:8]1([CH3:10])[O:7][C:6](=[O:12])[C:5]2[CH:13]=[CH:14][C:2]([O:1][C:23]3[C:16]([F:15])=[CH:17][C:18]([CH:19]=[O:20])=[CH:21][C:22]=3[F:25])=[CH:3][C:4]=2[O:9]1
Reactant: CC1(C)OC(=O)c2ccc(O)cc2O1
Reactant: O=Cc1cc(F)c(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)c2ccc(Oc3c(F)cc(C=O)cc3F)cc2O1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
7-Hydroxy-2,2-dimethyl-benzo[1,3]dioxin-4-one (I-1a: 12.9 g) and 3,4,5-trifluorobenzaldehyde (5.0 g) and potassium carbonate (27.6 g) were combined in dimethylformamide (100 mL) and stirred as the reaction mixture was heated to 80° C. After 24 hours, the reaction mixture was cooled to ambient temperature, combined with water, and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered, and evaporated. The residue was purified by column chromatography on silica gel eluting with 5-10% ethyl acetate in heptane to give the title compound (I-1b-2).
Reaction SMILES: [CH3:1]O.[CH3:3][C:4]1[N:5]([CH2:17][C:18]2C=NC=NC=2)[C:6]2[C:11]([C:12]=1[C:13]([O:15]C)=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2.[OH-].[K+].Cl>O>[CH:17]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]([C:13]([OH:15])=[O:14])=[C:4]1[CH3:3])([CH3:18])[CH3:1]
Reactant: COC(=O)c1c(C)n(Cc2cncnc2)c2ccccc12
Reactant: CO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1c(C(=O)O)c2ccccc2n1C(C)C
Yield: 58 %

Procedure:
To a mixed solution of methanol (10 mL) and water (2 mL), methyl 2-methyl-1-(pyrimidin-5-ylmethyl)-1H-indole-3-carboxylate (110 mg, 0.39 mmol) and potassium hydroxide (50 mg, 0.98 mmol) was added. The mixture was stirred at reflux for 12 hours. Then the reaction mixture was acidified by hydrochloric acid aqueous solution (1N) to adjust pH=6 and extracted with dichloromethane (10 mL*3). The organic layers were combined and concentrated to give 1-isopropyl-2-methyl-1H-indole-3-carboxylic acid (60 mg, 58%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.C(P(CCCC)CCCC)CCC.[CH2:36](O)[CH2:37][CH2:38][OH:39].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])(=[O:12])=[O:11])[CH:5]=[C:6]([CH:7]=1)[O:8][CH2:36][CH2:37][CH2:38][OH:39]
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2C(F)(F)F)c1
Reactant: OCCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2ccccc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a solution of 5-methyl-3-(2-trifluoromethylphenylsulfonyloxy)phenol (665 mg, 2.0 mmol), as prepared in the preceding step, tri-n-butylphosphine (607 mg, 3.0 mmol), and 1,3-propanediol (760 mg, 10 mmol) in anhydrous tetrahydrofuran (20 mL) was added 1,1'-(azodicarbonyl)dipiperidine (757 mg, 3.0 mmol). The mixture was stirred at room temperature overnight. Hexane (30 mL) was added to the mixture, and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (2:1 hexane/ethyl acetate) to give the title compound as a colorless oil (745 mg, 94%). 1H-NMR (300 MHz, CDCl3) δ 8.13 (d, J=7.2 Hz, 1 H), 7.99 (d, J=7.2 Hz, 1 H), 7.80 (t, J=7.6 Hz, 1 H), 7.70 (t, J=7.3 Hz, 1 H), 6.63 (s, 1 H), 6.48 (s, 1 H), 6.46 (s, 1 H), 4.02 (t, J=6.0 Hz, 2 H), 3.81 (m, 2 H), 2.25 (s, 3 H), 1.99 (m, 2 H), 1.61 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[NH:19][C:14]3=[CH:15][N:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:20]([O:24][C:25](=[O:31])[NH:26][CH2:27][CH2:28][O:29][NH2:30])([CH3:23])([CH3:22])[CH3:21].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[N:30][O:29][CH2:28][CH2:27][NH:26][C:25](=[O:31])[O:24][C:20]([CH3:22])([CH3:21])[CH3:23])[C:11]2[NH:19][C:14]3=[CH:15][N:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(c1ccc(Cl)c(Cl)c1)c1cc2ccncc2[nH]1
Reactant: CC(C)(C)OC(=O)NCCON
Agent: Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCON=C(c1ccc(Cl)c(Cl)c1)c1cc2ccncc2[nH]1
Yield: 51.5 %

Procedure:
(3,4-Dichlorophenyl)(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (Example 127) (92 mg, 0.32 mmol) and tert-butyl[2-(aminooxy)ethyl]carbamate (58 mg, 0.33 mmol) were combined in ethanol (5 mL). The pH was adjusted to ca. 4 using 1 M ethereal hydrogen chloride and the react ion mixture was refluxed for 14 h. The solvent was removed under vacuum. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution and then brine, dried over sodium sulfate, and concentrated to a solid. Purification by Biotage chromatography (silica gel, 97:3 CH2Cl2:CH3OH) produced tert-butyl 2-[[[(3,4-dichlorophenyl)(1H-pyrrolo[2,3-c]pyridin-2-yl)methylene]amino]oxy]ethylcarbamate (74 mg, 51%) as a yellow foam: 1H NMR (300 MHz CD3OD) δ 1.39 (9H, s), 3.50-3.54 (2H, m), 4.26-4.39 (2H, m), 6.35 (0.35H, s), 6.62 (0.65H, s), 7.38-7.77 (4H, m), 8.04-8.11 (1H, m), 8.72 (0.35H, s), 8.93 (0.65H, s); ESI MS m/z 449 [C21H22Cl2N4O3+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[Br:9][C:10]1[CH:11]=[C:12]([CH:16]=O)[CH:13]=[N:14][CH:15]=1>C(O)C>[Br:9][C:10]1[CH:11]=[C:12]([C:16]2[S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)[CH:13]=[N:14][CH:15]=1
Reactant: O=Cc1cncc(Br)c1
Reactant: Nc1ccccc1S
Solvent: CCO
Product: Brc1cncc(-c2nc3ccccc3s2)c1
Temperature: 100 °C
Yield: 48.5 %

Procedure:
To a mixture of 2-aminothiophenol (500 mg, 3.99 mmol) and 5-bromo-3-pyridinecarboxaldehyde (743 mg, 3.99 mmol) was added ethanol (10 mL). The mixture was then heated to reflux (100° C.) overnight under ambient air. After cooling, the mixture was dried under vacuum then redissolved in methylene chloride (100 ml). Solution was washed with water (100 ml) and brine (50 ml), and dried over sodium sulfate. The crude material was run through a plug of silica (16% ethyl acetate in hexanes), and precipitated from methanol to give 564 mg of the material 10 in 49% yield.