Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:15]([O:17]CC)=O)[C:13]=1[Cl:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1.Cl.ClC1C=CC(NN)=CC=1.C(Cl)Cl.CO.Cl.CCOCC>>[ClH:14].[CH2:1]([C:8]1[C:13]2[C:12]([C:15](=[O:17])[N:29]([C:26]3[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)[N:30]=2)=[CH:11][NH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cncc(Cc2ccccc2)c1Cl
Reactant: COc1ccc(NN)cc1
Agent: Cl
Agent: NNc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: COc1ccc(-n2nc3c(Cc4ccccc4)c[nH]cc-3c2=O)cc1
Yield: 30 %

Procedure:
Following a similar procedure to that described in Example 4, except using ethyl 3-benzyl-4-chloro-5-pyridinecarboxylate and 4-methoxyphenylhydrazine hydrochloride instead of ethyl 4-chloro-3-propyl-5-pyridinecarboxylate and 4-chlorophenylhydrazine hydrochloride, the title compound was prepared, after trituration with CH2Cl2-Me-OH—HCl—Et2O, in 30% yield as a cream solid, mp 179-185° C.; 1H NMR (360 MHz, DMSO-d6) δ3.78 (3H, s), 4.00 (2H, m), 7.01 (2H, d, J 9.2 Hz), 7.21 (1H, t, J 7.3 Hz), 7.31 (2H, t, J 7.3 Hz), 7.41 (1H, s), 7.42 (2H, d, J 7.0 Hz), 8.05 (2H, d, J 9.2 Hz), 8.56 (1H, s), 12.52 (1H, br s); MS (ES+) m/z 332 [MH]+. Anal. found: C, 65.36; H, 4.86; N, 11.25. C20H17N3O2.HCl requires: C, 65.31; H, 4.93; N, 11.42%.
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].[OH-].[Na+].Cl[O:12]C(C)(C)C.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1.[Br:75][C:76]1[CH:81]=[C:80](/[CH:82]=[CH:83]/[C:84]2[CH:89]=[C:88]([F:90])[CH:87]=[CH:86][C:85]=2[F:91])[C:79]([F:92])=[CH:78][N:77]=1>C(O)CC.O>[Br:75][C:76]1[CH:81]=[C:80]([C@@H:82]([NH:2][C:1](=[O:8])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[C@@H:83]([C:84]2[CH:89]=[C:88]([F:90])[CH:87]=[CH:86][C:85]=2[F:91])[OH:12])[C:79]([F:92])=[CH:78][N:77]=1
Reactant: CC(C)(C)OCl
Reactant: CC(C)(C)OC(N)=O
Reactant: Fc1ccc(F)c(/C=C/c2cc(Br)ncc2F)c1
Agent: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCO
Product: CC(C)(C)OC(=O)N[C@H](c1cc(Br)ncc1F)[C@H](O)c1cc(F)ccc1F
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To tert-butyl carbamate (206 mg, 1.76 mmol) in propanol (1 mL) was added sodium hydroxide (69.1 mg, 1.73 mmol) in water (1.9 mL) followed by tert-butyl hypochlorite (0.195 mL, 1.73 mmol). After 5 min, the solution was cooled to 0° C. and treated with a solution of (DHQD)2PHAL (22.1 mg, 0.028 mmol) in propanol (0.9 mL). The reaction was diluted with propanol (1.25 mL) and treated with (E)-2-bromo-4-(2,5-difluorostyryl)-5-fluoropyridine (89 mg, 0.28 mmol) as a solid in one portion. To this was added potassium osmate dihydrate (8.4 mg, 0.023 mmol) as a solid in one portion. The reaction was allowed to gradually warm to room temperature in the dewar over 8 h. The reaction was cooled to 0° C. and quenched by addition of sodiumthiosulfate (210 mg) in water (1 mL). The reaction was stirred at room temperature for 30 min. The reaction was extracted with ether (2×). The ethereal was washed with water (2×), then brine, dried over magnesium sulfate, and concentrated to give a solid (quant.). The material was used without purification. Mass spec.: 447.1 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[CH2:5][C:4](=[O:15])[CH:3]=1.[C:16]1([N:22]=[C:23]=S)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(#[N:27])C>>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH:6]1[CH2:7][C:2]2[NH:1][N:27]=[C:23]([NH:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:3]=2[C:4](=[O:15])[CH2:5]1
Reactant: CC#N
Reactant: NC1=CC(=O)CC(c2ccccc2Cl)C1
Reactant: S=C=Nc1ccccc1
Product: O=C1CC(c2ccccc2Cl)Cc2[nH]nc(Nc3ccccc3)c21

Procedure:
To a solution of 1-amino-5-(2-chlorophenyl)cyclohexen-3-one (2.0 g) in acetonitrile (50 ml) was added phenyl isothiocyanate (1.2 g), and the mixture was refluxed for 15 hours. Under reduced pressure, the solvent was evaporated, and to the residue were added ethanol (20 ml) and hydrazine hydrate (0.55 g). The mixture was refluxed for 1 hour, and under reduced pressure, the solvent was evaporated. The residue was washed with ethyl acetate to give yellow crystals of 6-(2-chlorophenyl)-3-phenylamino-4,5,6,7-tetrahydroindazol-4-one (0.8 g).
Reaction SMILES: [CH3:1][Si:2]([C:7]1[C:12]([F:13])=[C:11]([F:14])[C:10]([F:15])=[C:9]([F:16])[C:8]=1[F:17])(OC)OC.S(Cl)([Cl:20])=O.[ClH:22].[NH+]1C=CC=CC=1>>[CH3:1][Si:2]([C:7]1[C:12]([F:13])=[C:11]([F:14])[C:10]([F:15])=[C:9]([F:16])[C:8]=1[F:17])([Cl:20])[Cl:22]
Reactant: O=S(Cl)Cl
Reactant: Cl
Reactant: CO[Si](C)(OC)c1c(F)c(F)c(F)c(F)c1F
Agent: c1cc[nH+]cc1
Product: C[Si](Cl)(Cl)c1c(F)c(F)c(F)c(F)c1F
Reaction time: 16 h

Procedure:
81.68 g (0.300 mol) methyl(pentafluorophenyl)dimethoxysilane, 109 mL (1.50 mol, 178.4 g) thionylchloride and 3.69 g (0.0319 mol) pyridinium hydrochloride are refluxed and stirred for 16 h. Excess of SOCl2 is evaporated and methyl(pentafluorophenyl)dichlorosilane isolated by vacuum-distillation.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16](=[O:18])[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CS(C)=O>[CH2:19]([O:1][C:2]1[C:3]([C:16](=[O:18])[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Reactant: BrCc1ccccc1
Solvent: CS(C)=O
Product: CC(=O)c1cc2c(cc1OCc1ccccc1)C(C)(C)CCC2(C)C
Yield: 75.4 %

Procedure:
1-(3-Hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)-ethanone (0.103 g, 0.418 mmol) in DMSO (1 mL) was alkylated with benzylbromide (0.100 g, 0.585 mmol, 0.070 mL) as described in Example 21. Aqueous workup gave 1-(3-benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)ethanone 0.106 g (75% crude) as a yellow oil: 1H-NMR (400 MHz, CDCl3) δ 7.74 (s, 1H, ArH), 7.45 (m, 5H, ArH), 6.88 (s, 1H, ArH), 5.12 (s, 2H, OCH2), 2.59 (s, 3H, CH3), 1.66 (br s, 4H, 2CH2), 1.28 (s, 6H, 2CH3), 1.25 (s, 6H, 2CH3).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:7]=3[C:6]=2[C:5]=1[Cl:25].[F:26][C:27]1[CH:36]=[CH:35][C:30]([O:31][CH2:32][CH2:33]Br)=[CH:29][CH:28]=1>CN(C=O)C>[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:33][CH2:32][O:31][C:30]3[CH:35]=[CH:36][C:27]([F:26])=[CH:28][CH:29]=3)[C:8]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:16][CH2:17][C:7]=3[C:6]=2[C:5]=1[Cl:25]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccc(Cl)c(Cl)c3c2CC1
Reactant: Fc1ccc(OCCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCOc3ccc(F)cc3)c3ccc(Cl)c(Cl)c23)CC1
Reaction time: 0.42 h
Yield: 84.8 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 68 mg, 1.7 mmol) was added to a solution of tert-butyl 9,10-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.40 g, 1.1 mmol) in DMF (6 mL). After 25 min, 4-fluorophenoxy ethyl bromide (0.34 mL, 2.3 mmol) was added. The reaction was quenched with saturated aqueous NH4Cl after 22 h and extracted with A EtOAc (3×15 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40M) with heptane/EtOAc (17:3) to give 0.46 g (82%) of a white solid: mp 163.5-165.5° C.; 1H NMR (300 MHz, CDCl3) δ 7.16 (m, 2H), 6.92 (m, 2H), 6.70 (m, 2H), 4.44 (m, 2H), 4.12 (m, 2H), 3.73 (m, 4H), 3.51 (m, 2H), 3.12 (m, 2H), 1.48 (s, 9H); IR (diffuse reflectance) 1675, 1507, 1449, 1405, 1365, 1354, 1298, 1249, 1242, 1221, 1209, 1170, 1120, 835, 828 cm−1; MS (FAB) m/z 493 (M+H+), 494, 493, 492, 439, 438, 437, 436, 435, 57, 42; HRMS (EI) calcd for C25H27Cl2FN2O3 492.1383, found 492.1385; Anal. Calcd for C25H27Cl2FN2O3: C, 60.86; H, 5.51; N, 5.68, found: C, 60.93; H, 5.60; N, 5.69.
Reaction SMILES: BrC1C=CC(S(OCC[CH:14]2[CH:21]3[CH2:22][CH:17]4[CH2:18][CH:19]([CH2:23][CH:15]2[CH2:16]4)[CH2:20]3)(=O)=O)=CC=1.[I-:24].[Na+].C[C:27]([CH3:29])=O>>[C:19]12([CH2:29][CH2:27][I:24])[CH2:18][CH:17]3[CH2:22][CH:21]([CH2:14][CH:15]([CH2:16]3)[CH2:23]1)[CH2:20]2
Reactant: CC(C)=O
Reactant: [I-]
Reactant: O=S(=O)(OCCC1C2CC3CC(C2)CC1C3)c1ccc(Br)cc1
Agent: [Na+]
Product: ICCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 72 h
Yield: 75 %

Procedure:
To a solution of 2-adamantylethyl 4-bromobenzenesulfonate (Preparation 92, 1.0 g, 2.5 mmol) in acetone (25 ml) was added sodium iodide (0.75 g, 5 mmol) and the reaction mixture was left to stir at room temperature for 72 h. The resulting precipitate was filtered and the filtratc was diluted with water (100 ml) and extracted with dichlioromethane (100 ml). The extract was washed with brine (100 ml), dried (MgSO4) and concentrated in vacuo to give the title compound as a white crystalline solid (0.54 g, 75%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[CH:33]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14]([N:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:33][C:24]3[CH:25]=[CH:26][C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:23]=3)[CH2:7][CH2:6]2)=[CH:15][CH:16]=1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: O=Cc1ccc2ccccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc5ccccc5c4)CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.4 %

Procedure:
To 10 mL of a chloroform solution containing 500 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 232 mg of 2-naphthoaldehyde, 100 mg of acetic acid was added, and stirred at room temperature for 2 hours. To the reaction mixture, 526 mg of sodium triacetoxyborohydride was added, and stirred for 14 hours. Aqueous saturated sodium hydrogen carbonate solution was added, and the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform:methanol=10:1], to give 0.41 g of 7-methoxy-1-(2-(4-((naphthalen-2-yl)methylamino)piperidin-1-yl)ethyl)quinoxalin-2(1H)-one as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[C:9]([N:16]1[CH2:21][CH2:20][CH:19](O)[CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOC(C)=O>[C:12]([O:11][C:9]([N:16]1[CH2:21][CH2:20][CH:19]([O:8][C:5]2[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:18][CH2:17]1)=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1ccc(Cl)nc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.2 %

Procedure:
A solution of 2-chloro-5-hydroxy pyridine (5.00 g, 38.60 mmol), 1-Boc-4-hydroxypiperidine (9.32 g, 46.31 mmol) and triphenyl phosphine (15.19 g, 57.90 mmol) in THF (200 mL) at 0° C. was treated dropwise with diisopropylazodicarboxylate (11.14 mL, 57.90 mmol). The mixture was stirred at room temperature for 18 hours, diluted with EtOAc, washed with water and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (25-40% EtOAc in petrol (40-60° C.)) gave 4-(6-chloro-pyridin-3-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (5.70 g, 47%) as a pale yellow residue. 1H NMR (300 MHz, CDCl3) δ 8.06 (d, J=2.8 Hz, 1H), 7.23-7.16 (m, 2H), 4.51-4.41 (m, 1H), 3.75-3.64 (m, 2H), 3.40-3.29 (m, 2H), 1.99-1.86 (m, 2H), 1.83-1.67 (m, 2H), 1.47 (s, 9H). LCMS (m/z, Method A) ES+ 311.1 [M+1]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]3[S:21][C:20]4[N:22]=[CH:23][CH:24]=[N:25][C:19]=4[N:18]([CH2:26][O:27][CH3:28])[C:17]=3[CH:29]=2)[C:10]=1[CH3:11])=O)C.[NH3:30]>O1CCCC1>[CH3:28][O:27][CH2:26][N:18]1[C:17]2[CH:29]=[C:13]([CH2:12][N:9]3[C:10]([CH3:11])=[C:6]([C:4]([NH2:30])=[O:3])[N:7]=[CH:8]3)[CH:14]=[CH:15][C:16]=2[S:21][C:20]2[N:22]=[CH:23][CH:24]=[N:25][C:19]1=2
Reactant: CCOC(=O)c1ncn(Cc2ccc3c(c2)N(COC)c2nccnc2S3)c1C
Reactant: N
Solvent: C1CCOC1
Product: COCN1c2cc(Cn3cnc(C(N)=O)c3C)ccc2Sc2nccnc21
Temperature: 100 °C

Procedure:
To a solution of 0.7 g of ethyl[1-[10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl]-5-methylimidazol-4-yl]carboxylate in tetrahydrofuran (10 ml) was added 50 ml of aqueous ammonia. After sealing, the resulting mixture was heated to 100° C. for 24 hours.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([S:24](=[O:27])(=[O:26])[NH2:25])[C:16]=1[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:11]([OH:13])=[O:12])=[O:6].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[O:6]=[C:5]1[CH2:4][CH2:3][CH2:2][N:7]1[C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([S:24](=[O:27])(=[O:26])[NH2:25])[C:16]=1[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:11]([OH:13])=[O:12]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(NC(=O)CCCCl)c1Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cc(C(=O)O)cc(N2CCCC2=O)c1Oc1ccccc1

Procedure:
The compound 3-(γ-chlorobutyrylamino)-4-phenoxy-5-sulfamylbenzoic acid (11.5 g) and anhydrous potassium carbonate (11.5 g) were slurried in dioxane (350 ml) and stirred under reflux overnight. The solvent was removed under reduced pressure and the residue taken up in a small volume of water. After acidification with 3 N acqueous HCl, the product separated as a gum. Methylene chloride was added and the mixture stirred for 1 hour. The product 3-(2-oxo-1-pyrrolidinyl)-4-phenoxy-5-sulfamylbenzoic acid, now in the form of a powder, was filtered, washed with water, and air-dried to give 7.5 g (61% on two steps). A sample was recrystallized from aq. dioxane to give colorless crystals with m.p. 282°-285°; ir (Nujol) 3400, 3250, 2600 (broad), 1735, 1660, 1600, and 1575 cm-1 ; nmr (d6 -DMSO) 1.2-2.3 (m, 4H), 3.41 (t, J=6, 2H), 6.7-7.5 (m, C6H5), 7.65 (s, SO2NH2), 8.15 (d, J=2, CH), and 8.46 ppm (d, CH); mass spectrum m/e 283 (100%) and 376 (M+).
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1(C(O)=O)[CH2:6][C:5]([F:8])([F:7])[CH2:4]1.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.[Cl:30][C:31]1[CH:32]=[C:33]([C:38]2[C:46]([C:47]([NH2:49])=[O:48])=[C:41]3[CH2:42][NH:43][CH2:44][CH2:45][N:40]3[N:39]=2)[CH:34]=[CH:35][C:36]=1[F:37].C[N:51]([CH:53]=[O:54])C>C1(C)C=CC=CC=1>[Cl:30][C:31]1[CH:32]=[C:33]([C:38]2[C:46]([C:47]([NH2:49])=[O:48])=[C:41]3[CH2:42][N:43]([C:53]([NH:51][C:3]4([CH:2]([F:1])[F:12])[CH2:4][C:5]([F:7])([F:8])[CH2:6]4)=[O:54])[CH2:44][CH2:45][N:40]3[N:39]=2)[CH:34]=[CH:35][C:36]=1[F:37]
Reactant: O=C(O)C1(C(F)F)CC(F)(F)C1
Reactant: CN(C)C=O
Reactant: NC(=O)c1c(-c2ccc(F)c(Cl)c2)nn2c1CNCC2
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: NC(=O)c1c(-c2ccc(F)c(Cl)c2)nn2c1CN(C(=O)NC1(C(F)F)CC(F)(F)C1)CC2
Temperature: 85 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
To a solution of Intermediate 304E (26.3 mg, 0.141 mmol) in toluene (3 mL) was added TEA (0.090 mL, 0.643 mmol) and DPPA (0.059 mL, 0.257 mmol) and the resulting solution was heated at 85° C. for 1 h. The reaction mixture was cooled to RT and to it was added a solution of Intermediate 185B (40 mg, 0.129 mmol) in DMF (1 mL) and stirred at RT for 8 h. It was concentrated and the residue was extracted with ethyl acetate (3×10 mL). The combined organic layer was dried over sodium sulfate, filtered and the filtrate concentrated. The crude product was further purified by preparative HPLC to afford Compound 304 as an off-white solid (18 mg, 28%). HPLC retention times 1.57 min. and 1.59 min. (Methods E and L respectively). ES(MS): m/z=478 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.90 (d, J=1.5 Hz, 1H), 7.72-7.63 (m, 3H), 7.45-7.21 (m, 2H), 6.47-6.11 (m, 1H), 4.77 (s, 2H), 4.17 (t, J=5.3 Hz, 2H), 3.88 (t, J=5.3 Hz, 2H), 3.06-2.91 (m, 2H), 2.90-2.76 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH2:5][CH2:4][CH:3]=1.Cl[N-:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[Na+].[Br-].[Br-].[Br-].C[N+](C)(C)C1C=CC=CC=1.C[N+](C1C=CC=CC=1)(C)C.C[N+](C1C=CC=CC=1)(C)C.O>C1COCC1>[CH3:1][C:2]12[N:8]([S:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)(=[O:10])=[O:11])[CH:6]1[CH2:5][CH2:4][CH2:3]2
Reactant: Cc1ccc(S(=O)(=O)[N-]Cl)cc1
Reactant: CC1=CCCC1
Agent: C[N+](C)(C)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2C3CCCC32C)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1-methylcyclopent-1-ene (CAS number 693-89-0; 50.0 g, 609.75 mmol) iii and sodium chloro(4-methylbenzenesulfonyl)azanide (CAS number 127-65-1; 192 g, 680.85 mmol) in THF (2500 ml) was added trimethylphenylammonium tribromide (13.3 g, 61.57 mmol). The reaction was stirred vigorously at 25° C. for 12 hours. The reaction mixture was poured into water (1500 ml) and the organics were extracted with ethyl acetate (3×1000 ml). The combined organics were washed with water (500 ml), brine (500 ml), dried over sodium sulfate and concentrated in vacuo. This was then purified by column chromatography (silica, 0-2.5% ethyl acetate/n-hexane) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:8]=[C:9]([CH2:23][N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[C:10]=1[N:11]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:12])=[O:4].[CH2:37](O)[C:38]#[C:39][CH3:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:8]=[C:9]([CH2:23][N:24]2[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]2)[C:10]=1[N:11]([S:13]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:37][C:38]#[C:39][CH3:40])=[CH:20][CH:21]=1)(=[O:15])=[O:14])[CH3:12])=[O:4]
Reactant: COC(=O)c1cc(-c2ccccc2)cc(CN2CCN(C)CC2)c1N(C)S(=O)(=O)c1ccc(O)cc1
Reactant: CC#CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)N(C)c2c(CN3CCN(C)CC3)cc(-c3ccccc3)cc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.9 %

Procedure:
To a solution of 0.810 g (1.59 mmol) of the product of Example 73 and 0.594 mL (7.95 mmol) of 2-butyn-1-ol in 8 mL of THF, was added 2.08 g (7.95 mmol) of triphenylphosphine and then 1.25 mL (7.95 mmol) of diethyl azodicarboxylate. The mixture was stirred at room temperature for 18 h, diluted with ethyl acetate, washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel with 2% methanol/dichloromethane to provide 0.830 g (93%) of the desired product as a beige solid. Electrospray Mass Spec 562.1 (M+H)+
Reaction SMILES: [F:1][C:2]1[C:10]([O:11]S(C)(=O)=O)=[C:9]2[C:5]([CH:6]=[C:7]([C:16]([O:18]CC)=[O:17])[NH:8]2)=[CH:4][C:3]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=1.O1CCCC1.CO.[OH-].[K+]>O>[F:1][C:2]1[C:10]([OH:11])=[C:9]2[C:5]([CH:6]=[C:7]([C:16]([OH:18])=[O:17])[NH:8]2)=[CH:4][C:3]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)nc3)c(F)c(OS(C)(=O)=O)c2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2cc3cc(C(=O)O)[nH]c3c(O)c2F)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 104.8 %

Procedure:
To a mixture of ethyl 6-fluoro-7-[(methylsulfonyl)oxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate (3.1 g), tetrahydrofuran (25 mL) and methanol (25 mL) was added a solution of potassium hydroxide (85%, 1.9 g) in water (15 mL). The mixture was stirred at room temperature for 15 h and then concentrated in vacuo. The residue was partitioned between ethyl acetate and aqueous citric acid solution. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated to give a light pink solid, which was washed with ethyl acetate-hexane to give the title compound (2.52 g, 100%) as a light pink solid. MS 365 (MH+).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][NH2:8])=[CH:4][CH:3]=1.F[C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>>[CH3:1][C:2]1[S:6][C:5]([CH2:7][NH:8][C:15]2[CH:16]=[N:17][CH:18]=[CH:10][C:11]=2[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccncc1F
Reactant: Cc1ccc(CN)s1
Product: Cc1ccc(CNc2cnccc2C(=O)O)s1
Yield: 7 %

Procedure:
The title compound was prepared in 7% yield from 5-methylthiophen-2-ylmethylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 8.27 (br s, 1H), 7.84 (br s, 1H), 7.57 (d, 1H, J=4.8 Hz), 6.87 (d, 1H, 3.2 Hz), 6.65 (d, 1H, J=2.3 Hz), 4.65 (s, 2H), 2.38 (s, 3H). [M+H] calc'd for C12H12N2O2S, 249. found 249.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[NH:9][C:8]2=[O:18])[CH2:3][CH2:2]1.Cl[C:20]1[CH:25]=[C:24]([C:26]([N:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30][CH2:29]2)=[O:27])[CH:23]=[CH:22][N:21]=1.CCN(C(C)C)C(C)C.CN(C=O)C>O>[N:28]1([C:26]([C:24]2[CH:23]=[CH:22][N:21]=[C:20]([N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[CH2:13][CH2:12][C:11]5[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=5[NH:9][C:8]4=[O:18])[CH2:5][CH2:6]3)[CH:25]=2)=[O:27])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Reactant: O=C(c1ccnc(Cl)c1)N1CCc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccnc(N2CCC(N3CCc4ccccc4NC3=O)CC2)c1)N1CCc2ccccc21

Procedure:
100 mg (0.41 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one were added to 110 mg (0.43 mmol) (2-chloropyridin-4-yl)-(2,3-dihydro-indol-1-yl)-methanone and 3.0 mL (17.4 mmol) DIPEA. The reaction mixture was refluxed for 5 h with stirring. Then 1 mL DMF were added and the mixture was stirred overnight at 130 C. After cooling water was added, the precipitate formed was suction filtered and purified by preparative HPLC. The product fractions were combined and evaporated down i. vac.