Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[C:14]([C:27]3[N:28]=[N:29][CH:30]=[C:31]([O:33][CH3:34])[CH:32]=3)=[CH:15][N:16](S(C3C=CC(C)=CC=3)(=O)=O)[C:11]2=[CH:10][CH:9]=1.[OH-].[Na+]>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[C:14]([C:27]3[N:28]=[N:29][CH:30]=[C:31]([O:33][CH3:34])[CH:32]=3)=[CH:15][NH:16][C:11]2=[CH:10][CH:9]=1
Reactant: COc1cnnc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ccc(-c4ccccc4F)nc23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cnnc(-c2c[nH]c3ccc(-c4ccccc4F)nc23)c1
Temperature: 85 °C
Yield: 55.9 %

Procedure:
A glass microwave reaction vessel was charged with 5-(2-fluorophenyl)-3-(5-methoxypyridazin-3-yl)-1-tosyl-1H-pyrrolo[3,2-b]pyridine (16 mg, 0.034 mmol) and NaOH (0.3 mL, 0.300 mmol, 1M) in THF (1 mL). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 85° C. for 20 min. The mixture was diluted with water and extracted with CHCl3/iPrOH (4:1). The combined organic layers were dried, filtered and concentrated. The residue was purified with prep-TLC (eluting with 10% MeOH in DCM) to give 5-(2-fluorophenyl)-3-(5-methoxypyridazin-3-yl)-1H-pyrrolo[3,2-b]pyridine (6.0 mg, 0.019 mmol, 55.6% yield) as a light brown solid. MS (ESI, pos. ion) m/z: 321.0 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 12.05 (1 H, br. s.), 8.83 (2 H, s), 8.60 (1 H, s), 8.12 (1H, td, J=8.0, 1.7 Hz), 8.03 (1 H, d, J=8.6 Hz), 7.70 (1 H, dd, J=8.5, 2.1 Hz), 7.43-7.53 (1 H, m), 7.30-7.42 (2 H, m), 4.01 (3 H, s)
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:34][O:35][C:36]1[CH:37]=[C:38]([S:42](Cl)(=[O:44])=[O:43])[CH:39]=[CH:40][CH:41]=1.O>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([S:42]([C:38]4[CH:39]=[CH:40][CH:41]=[C:36]([O:35][CH3:34])[CH:37]=4)(=[O:44])=[O:43])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1cccc(S(=O)(=O)n2c(=O)n(-c3ccc(C(C)(C)C#N)cc3)c3c4cc(Br)ccc4ncc32)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 50 mg, 0.12 mmol) and triethylamine (24.4 mg, 0.24 mmol) in dichloromethane (6 ml) was added 3-methoxybenzene-1-sulfonyl chloride (37.08 mg, 0.18 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 30 mg (42%); 1H NMR (CDCl3, 300 MHz): δ 9.566 (s, 1H), 7.951-7.981 (d, 1H, J=9 Hz), 7.757-7.784 (d, 1H, J=8.1 Hz), 7.636-7.729 (m, 3H), 7.606-7.643 (dd, 1H, J=9 Hz, 2.1 Hz), 7.419-7.479 (m, 3H,), 7.208-7.230 (m, 1H), 6.957-6.963 (d, 1H, 1.8 Hz), 3.833 (s, 3H), 1.795 (s, 6H); MS: m/z 546 [M+-(OCH3)].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[OH:19])=[O:10])[CH:5]=[CH:6][CH:7]=1.N1CCCC[CH2:21]1.C(OC(OCC)OCC)C.Cl>N1C=CC=CC=1.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9](=[O:10])[C:11]3[C:12](=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[O:19][CH:21]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)Cc2cccc(F)c2)c(O)c1
Reactant: C1CCNCC1
Agent: Cl
Solvent: O
Solvent: CCOC(OCC)OCC
Solvent: c1ccncc1
Product: COc1ccc2c(=O)c(-c3cccc(F)c3)coc2c1
Temperature: 120 °C
Reaction time: 3.5 h

Procedure:
2-(3-Fluorophenyl)-1-(2-hydroxy-4-methoxyphenyl)ethanone (1.76 g) was dissolved in pyridine (88 ml). Piperidine (8.8 ml) and triethylorthoformate (88 ml) were added and the mixture was stirred at 120° C. for 3.5 hours. After pouring the mixture into water and acidification with conc. HCl the crude product was filtered. Purification by column chromatography using heptane-ethyl acetate (7:3) as an eluant afforded 3-(3-fluorophenyl)-7-methoxychromen-4-one. 1H NMR (400 MHz, d6-DMSO) δ: 8.57 (s, 1H), 8.06 (d, 1H, J 8.9 Hz), 7.45-7.50 (m, 3H), 7.21-7.25 (m, 1H), 7.20 (d, 1H, J 2.4 Hz), 7.12 (dd, 1H, J 8.9, 2.4 Hz), 3.92 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10]O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:10][C@@H:9]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
(2S)-2-(tert-Butoxycarbonylamino)-3-phenyl-1-propanol (2.0 g, 8.0 mmol) in anhydrous THF (50 mL) at 0° C. under a dry N2 atmosphere was treated with triphenylphosphine (2.5 g, 9.5 mmol) and diethyl azodicarboxylate (1.66 g, 9.5 mmol). The mixture was stirred at 0° C. for 1 hour, allowed to warm to ambient temperature and stirred overnight. The mixture was partitioned between water (50 mL) and ethyl acetate (2×50 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexanes:CH2Cl2, 1:1) to provide the title compound as a colorless oil (1.4 g, 76%). Rf=0.54 (hexanes:ethyl acetate, 2:1); 1H NMR (CDCl3) δ 7.32-7.19 (m, 5H), 3.01-2.90 (m, 1H), 2.70-2.56 (m, 2H), 2.30 (m, 1H), 2.03 (m, 1H), 1.44 (s, 9H).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])O.[N+]([C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1)([O-])=O.[C:20](=[O:23])([O-])[O-].[K+].[K+]>CS(C)=O>[C:5]1([O:23][C:20]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=[CH:1][C:3]=1[O:4][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1
Reactant: Oc1ccccc1O
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2ccccc2Oc2ccc(C#N)cc2)cc1

Procedure:
4,4'-(o-phenylenedioxy)dibenzonitrile was prepared from catechol (11.0 g., 0.100 mol.), 4-nitrobenzonitrile (32.56 g., 0.220 mol.), and anhydrous potassium carbonate (82.8 g., 0.600 mol.) in 300 mL of anhydrous dimethyl sulfoxide 80° C. for 20 h. It was obtained as white crystals, m.p. 117°-118° C., after recrystallization from isopropanol and heptane. IR spectrum (KBr pellet, cm-): 3100, 3065 (aromatic C-H), 2232 (C≡N), 1584, 1497 (aromatic C=C), 1270 (arylether).
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][CH2:8][CH:9]([CH:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH3:13])[CH2:10][NH2:11])=[O:6])[CH:2]=[CH2:3].Cl[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24].[OH-].[Na+]>O1CCCC1.O>[CH2:1]([O:4][C:5]([NH:7][CH2:8][CH:9]([CH2:10][NH:11][C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[CH:12]([O:14][Si:15]([C:18]([CH3:20])([CH3:19])[CH3:21])([CH3:16])[CH3:17])[CH3:13])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)NCC(CN)C(C)O[Si](C)(C)C(C)(C)C
Reactant: C=CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)NCC(CNC(=O)OCC=C)C(C)O[Si](C)(C)C(C)(C)C

Procedure:
To a solution of 11.4 g of crude 2-(N-allyloxycarbonylaminomethyl)-3-(t-butyldimethylsilyloxy)butylamine in 67 ml of tetrahydrofuran and 56 ml of water was added 2.8 ml of allyl chloroformate dropwise, while keeping pH 8-8.5 with 4N sodium hydroxide solution. The reaction mixture was extracted three times with chloroform, and the combined organic layer was washed with brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent followed by column chromatography on silica gel (hexane:ethyl acetate=1:1) gave 5.34 g of 1-allyloxycarbonylamino-2-(N-allyloxycarbonylaminomethyl)- 3-t-butyldimethylsilyloxybutane.
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(=O)CCCCC1>C(OC(=O)C)C>[CH:23]12[CH2:28][CH:27]([CH2:25][CH2:24]1)[CH2:26][CH:22]2[CH2:21][N:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:8](=[O:20])[NH:9][C:10]1[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=1
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Solvent: CCOC(C)=O
Solvent: O=C1CCCCC1
Product: O=C(O)CSc1cnc(NC(=O)N(CC2CC3CCC2C3)C2CCCCC2)s1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid, from c-bicyclo[2.2.1]hept-2-yl-methylamine, cyclohexanone and 2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:48]([O:52][C:53]([C@@H:55]1[CH2:59][CH2:58][CH2:57][N:56]1[CH2:60][CH2:61]O)=[O:54])([CH3:51])([CH3:50])[CH3:49]>O1CCCC1.CCCCCCC>[C:48]([O:52][C:53]([C@@H:55]1[CH2:59][CH2:58][CH2:57][N:56]1[CH2:60][CH2:61][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)=[O:54])([CH3:51])([CH3:50])[CH3:49]
Reactant: Oc1ccc(Br)cc1Sc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1CCOc1ccc(Br)cc1Sc1cccc(F)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
4-Bromo-2-(3-fluoro-phenylsulfanyl)-phenol (2.898 g, 9.69 mmol) and triphenylphosphine (3.558 g, 13.6 mmol) was dissolved in tetrahydrofuran (70 mL) and cooled to 0° C. under an inert atmosphere. To the solution was added DEAD (2.81 mL, 14.27 mmol)dropwise. After 25 minutes was added 1-(2-hydroxy-ethyl)-pyrrolidine-2-(S)-carboxylic acid tertbutyl ester (2.504 g, 1.163 mmol) in THF (15 mL) via cannulation. The mixture was stirred at room temperature for 16 hours. Heptane (350 mL) and THF (100 mL) was added. The organic phase was then washed with water (4×50 mL) and then brine, dried (Na2SO4), filtered and the filtrate concentrated in the presence of silica gel. The crude products absorbed onto silica gel and eluted with a gradient of heptane-heptane ethyl acetate (85:15). The product was isolated after concentration of relevant fractions.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[Cl:13][CH2:14][CH2:15][OH:16]>C(#N)C>[CH3:8][S:9]([CH2:8][S:9]([O:16][CH2:15][CH2:14][Cl:13])(=[O:11])=[O:10])(=[O:11])=[O:10]
Reactant: OCCCl
Reactant: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CS(=O)(=O)OCCCl
Reaction time: 1 h

Procedure:
A solution of 133 g (1.32 mol.) of triethylamine in 400 ml of anhydrous acetonitrile was cooled to -30° to -40° C., and a solution of 100 g (0.88 mol.) of methanesulfonyl chloride in anhydrous acetonitrile (67 ml) was added dropwise at a rate that prevented the temperature from rising above -30° C. The mixture was stirred at -30° to -40° C. for 1 hour, and a solution of 35.4 g of 2-chloroethanol in anhydrous acetonitrile (30 ml) was added. The resulting mixture was stirred for 2 hours at -30° to -40° C. and then was filtered to separate triethylamine hydrochloride. The latter material was washed with ethyl acetate, the washings were combined with the filtrate, and the organic solution was concentrated in vacuo to an oil. A solution of the residual oil in ethyl acetate (1200 ml) was washed quickly with two portions (2×200 ml) of dilute sodium chloride solution and then with two portions (2×200 ml) of saturated sodium chloride solution, dried with magnesium sulfate, filtered, and concentrated in vacuo. The residual solid (70 g) was dissolved in methylene chloride (450 ml), the solution was filtered and diluted slowly with cyclohexane (450 ml). The mixture, protected from atmospheric moisture, was allowed to stand at room temperature for about an hour and was then stored at low temperatures (about 5° C.) overnight. The precipitate was collected by filtration, washed with cyclohexane, and dried in vacuo over phosphorus pentoxide: yield, 58.7 g (56%); m.p. 60°-62° C.; IR (cm-1, medium and strong bands) 3040, 3025, 2990 s, 2930, 2935 sh, 1465, 1430, 1415, 1390, 1370 s, 1320 s, 1240, 1200, 1185 s, 1175 s, 1165 s, 1125, 1070, 990 s, 955 s, 915 s, 870 s, 790 s, 765, 755, 665, 605 sh, 600, 525 s, 505, 465 s, 420; 1H NMR (300.6 MHz, CDCl3, Me4Si as internal reference), δ3.26 (s, CH3), 3.80 (t, CH2Cl), 4.65 (t, OCH2), 4.67 (s, SCH2S). Anal. Calcd. for C4H9ClO5S2C, 20.30; H, 3.83. Found: C, 20.26; H, 4.00.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.BrC1[CH:14]=[CH:15][C:16]([O:19][C@H:20]2[CH:27]3[CH2:28][N:23]4[CH2:24][CH:25]([CH2:29][CH:21]2[CH2:22]4)[CH2:26]3)=[N:17][CH:18]=1.C1(B(O)O)C=CC=CC=1>>[C:1]1([C:11]2[CH:14]=[CH:15][C:16]([O:19][C@H:20]3[CH:27]4[CH2:28][N:23]5[CH2:24][CH:25]([CH2:29][CH:21]3[CH2:22]5)[CH2:26]4)=[N:17][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1ccc(OC2C3CC4CC2CN(C4)C3)nc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: OB(O)c1ccccc1
Product: c1ccc(-c2ccc(OC3C4CC5CC3CN(C5)C4)nc2)cc1

Procedure:
Prepared from the product of Example 9F (496 mg, 1.60 mmol) and phenylboronic acid (480 mg, 3.1 mmol; Aldrich) according to Method B: 1H NMR (300 MHz, methanol-D4) δ ppm 1.75 (s, 1H), 2.00-2.25 (m, 6H), 2.98 (d, J=12.9 Hz, 2H), 3.15 (s, 2H), 3.51 (d, J=12.9 Hz, 2H), 5.33 (s, 1H), 6.90-6.96 (m, 1H), 7.30-7.38 (m, 1H), 7.40-7.48 (m, 2H), 7.54-761 (m, 2H), 7.94 (dd, J=8.6, 2.5 Hz, 1H), 8.35 (d, J=2.4 Hz, 1H), MS (ESI) m/z=307 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][NH:21][C:20](=[O:24])[CH:19]=3)=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1.Cl[CH2:28][C:29]1[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=1>>[CH3:34][N:32]1[CH:33]=[C:29]([CH2:28][N:21]2[CH:22]=[CH:23][C:18]([O:17][CH2:16][C:13]3[CH:14]=[CH:15][C:10]([O:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:25])[F:26])[CH:4]=4)=[CH:11][CH:12]=3)=[CH:19][C:20]2=[O:24])[CH:30]=[N:31]1
Reactant: Cn1cc(CCl)cn1
Reactant: O=c1cc(OCc2ccc(Oc3cccc(C(F)(F)F)c3)cc2)cc[nH]1
Product: Cn1cc(Cn2ccc(OCc3ccc(Oc4cccc(C(F)(F)F)c4)cc3)cc2=O)cn1

Procedure:
The title compound was prepared by a procedure similar to that described for E21 starting from 4-{[(4-{[3-(trifluoromethyl)phenyl]oxy}phenyl)methyl]oxy}-2(1H)-pyridinone and 4-(chloromethyl)-1-methyl-1H-pyrazole. LC-MS (ESI): m/z 456 [M+H]+; 3.40 min (ret time).
Reaction SMILES: C(C1C=C(C)C=C(C)C=1N[C:13]([C:15]1[S:16][CH:17]=[CH:18][C:19]=1[S:20]([NH:23][C:24]1[O:28][N:27]=[C:26]([CH3:29])[C:25]=1[Cl:30])(=[O:22])=[O:21])=[O:14])(=O)C.[NH2:31][C:32]1[C:37]([CH3:38])=[CH:36][C:35]([CH3:39])=[CH:34][C:33]=1[C:40](=[O:44])[CH:41]([CH3:43])[CH3:42]>>[Cl:30][C:25]1[C:26]([CH3:29])=[N:27][O:28][C:24]=1[NH:23][S:20]([C:19]1[CH:18]=[CH:17][S:16][C:15]=1[C:13]([NH:31][C:32]1[C:37]([CH3:38])=[CH:36][C:35]([CH3:39])=[CH:34][C:33]=1[C:40](=[O:44])[CH:41]([CH3:42])[CH3:43])=[O:14])(=[O:21])=[O:22]
Reactant: CC(=O)c1cc(C)cc(C)c1NC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Cl
Reactant: Cc1cc(C)c(N)c(C(=O)C(C)C)c1
Product: Cc1cc(C)c(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Cl)c(C(=O)C(C)C)c1

Procedure:
3-(((4-Chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-isobutyryl-4,6-dimethylphenyl)-2-thiophenecarboxamide was synthesized in the same fashion as for N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide (Example 39) except that 2′-amino-3′,5′-dimethyl-2-methylpropiophenone was used instead of 2′-amino-3′,5′-dimethylacetophenone.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:15][CH:14]3[CH:10]([CH2:11][NH:12][CH2:13]3)[CH2:9]2)[N:3]=1.[N:16]1[N:17]=[C:18]([C:21]2[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=2[C:23](O)=[O:24])[NH:19][CH:20]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:15][CH:14]3[CH:10]([CH2:11][N:12]([C:23]([C:22]4[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=4[C:18]4[NH:19][CH:20]=[N:16][N:17]=4)=[O:24])[CH2:13]3)[CH2:9]2)[N:3]=1
Reactant: O=C(O)c1ccccc1-c1nnc[nH]1
Reactant: Cc1ccnc(N2CC3CNCC3C2)n1
Product: Cc1ccnc(N2CC3CN(C(=O)c4ccccc4-c4nnc[nH]4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 27 and 2-(4H-[1,2,4]triazol-3-yl)benzoic acid. MS (ESI) mass calcd. for C20H21N7O, 375.55; m/z found, 376.2 [M+H]+. 1H NMR (CDCl3): 8.18-8.04 (m, 3H), 7.55.7.42 (m, 2H), 7.39-7.33 (m, 1H), 6.39 (d, J=5.0 Hz, 1H), 3.96-3.79 (m, 2H), 3.77-3.63 (m, 2H), 3.62-3.55 (m, 1H), 3.46-3.37 (m, 2H), 3.15-3.06 (m, 1H), 3.05-2.98 (m, 1H), 2.95-2.90 (m, 1H), 2.33 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH:14][C:15]([C:17]1[S:18][C:19]([Cl:22])=[CH:20][CH:21]=1)=[O:16])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][CH2:24][N:25](C(C)C)[CH:26]([CH3:28])[CH3:27].CN(C([O:39]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:13][NH:14][C:15]([C:17]1[S:18][C:19]([Cl:22])=[CH:20][CH:21]=1)=[O:16])[C:10]([N:25]1[CH2:24][CH2:23][O:39][CH2:27][C@@H:26]1[CH3:28])=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CNC(=O)c1ccc(Cl)s1)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: C[C@H]1COCCN1C(=O)[C@H](CNC(=O)c1ccc(Cl)s1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Intermediate 1 from step 1.1 was dissolved in 10 ml DCM and (3S)-methyl morpholine hydrochloride (276 mg, 2 mmol) was added followed by DIPEA (1.4 ml, 8 mmol) and HATU (761 mg, 2 mmol). After 1 h stirring at RT the reaction mixture was evaporated to dryness and the product was isolated by preparative HPLC.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Cl.[N:12]1([C:18]([O:20][CH2:21][C:22]([NH:24][CH3:25])=[O:23])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)C(C)C)(C)C>ClCCCl>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][CH2:21][C:22]([NH:24][CH3:25])=[O:23])=[O:19])[CH2:17][CH2:16]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CNC(=O)COC(=O)N1CCNCC1
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)COC(=O)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 70 °C
Yield: 89 %

Procedure:
1.84 g (11.6 mmol) of 2-chloro-5-nitropyridine are added to a solution of 2.05 g (8.62 mmol) of 2-(methylamino)-2-oxoethyl 1-piperazinecarboxylate hydrochloride, obtained in step 5.2., and 3.85 ml (22.4 mmol) of N,N diisopropylethylamine in 55 ml of 1,2-dichloroethane. This reaction mixture is maintained at 70° C. for 5 hours. The mixture is allowed to cool to room temperature and concentrated under reduced pressure, and the residue thus obtained is purified by chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol. 2.48 g of product are obtained in the form of a pale yellow solid, and are used without further purification in the following step.
Reaction SMILES: [CH2:1]([N:7]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[S:8]([C:11]1[CH:20]=[CH:19][C:14]2[N:15]=[C:16]([CH3:18])[S:17][C:13]=2[CH:12]=1)(=[O:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:27][O:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)(=[O:31])=[O:30].CCCCCC>C(OCC)(=O)C>[S:29]([C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)([O-:31])(=[O:30])=[O:28].[CH2:21]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[S:8]([C:11]1[CH:20]=[CH:19][C:14]2[N+:15]([CH3:27])=[C:16]([CH3:18])[S:17][C:13]=2[CH:12]=1)(=[O:10])=[O:9])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CCCCCCN(CCCCCC)S(=O)(=O)c1ccc2nc(C)sc2c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCCN(CCCCCC)S(=O)(=O)c1ccc2c(c1)sc(C)[n+]2C
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 130 °C
Yield: 78.9 %

Procedure:
A mixture of Compound 20 (2.0 g, 5.0 mmol) and p-toluenesulfonic acid methyl ester (1.4 g, 7.5 mmol) was heated in a pressure tube at 130° C. for 2 hours. The mixture was allowed to cool to room temperature, and the resulting mass was dissolved in ethyl acetate (4 ml). The combined mixture was then added drop wise to hexane (40 ml). A sticky dark brown solid separated which was washed with hexane and dried under vacuum to yield 2.3 g (78%) of Compound 21 which was used without any further purification. The structure of this compound is given below:
Reaction SMILES: C(S([C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:9]2[CH:18]=[C:19]([C:22]3[C:23]([C:46]4[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=4)=[N:24][N:25]([C:27]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:26]=3)[CH:20]=[CH:21][C:8]=2[N:7]=1)(=O)=O)C.[H-].[Na+].O.[C:56](OCC)(=[O:58])C>O1CCCC1.CO>[F:17][C:14]1[CH:15]=[CH:16][C:11]([N:10]2[C:9]3[CH:18]=[C:19]([C:22]4[C:23]([C:46]5[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=5)=[N:24][N:25]([C:27]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH:26]=4)[CH:20]=[CH:21][C:8]=3[N:7]=[C:6]2[O:58][CH3:56])=[CH:12][CH:13]=1
Reactant: CCS(=O)(=O)c1nc2ccc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)nc3-c3ccc(F)cc3)cc2n1-c1ccc(F)cc1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1nc2ccc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)nc3-c3ccc(F)cc3)cc2n1-c1ccc(F)cc1

Procedure:
50 mg 2-(ethylsulfonyl)-1-(4-fluorophenyl)-6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]-1H-benzo[d]imidazole obtained in Example 138 was dissolved in 0.5 mL tetrahydrofuran and 3 mL methanol, then 28 mg sodium hydride was added thereto, and the mixture was heated for 3 hours under reflux under nitrogen atmosphere. After the reaction mixture was cooled, water and ethyl acetate were added thereto, and the organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give 1-(4-fluorophenyl)-6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]-2-methoxy-1H-benzo[d]imidazole. This product was subjected to deprotection of the trityl group in the same manner as in Example 84 and then purified by NAM silica gel chromatography (ethyl acetate/methanol), to give 18 mg of the title compound as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11]C)[N:7]([CH3:13])[C@H:6]1[N:14]([CH3:17])[CH2:15][CH2:16][C@@:5]21[CH3:18].B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[OH:11])[N:7]([CH3:13])[C@H:6]1[N:14]([CH3:17])[CH2:15][CH2:16][C@@:5]21[CH3:18]
Reactant: COc1cc2c(cc1Br)[C@]1(C)CCN(C)[C@@H]1N2C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CN1CC[C@@]2(C)c3cc(Br)c(O)cc3N(C)[C@@H]12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
cis-(±)-5-Bromo-1,2,3,3a,8,8a-hexahydro-6-methoxy-1,3a,8-trimethylpyrrolo[2,3-b]indole (11 g) was dissolved in dry DCM (200 ml) and added dropwise at 0° C. to a stirred solution of BBr3 in DCM (300 ml). The mixture was warmed to room temperature and stirred overnight under nitrogen. The mixture was quenched with aq. Na2CO3 and aq. NaHCO3 until basic at 0° C. The organic layer was dried and evaporated to a foam (10 g). The IR, NMR and Mass Spectra confirmed the purity and identity of this product.