Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[C@@H:12]([O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[C@H:11]([CH3:24])[O:10][C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)=O.CC(C)=O.[H-].C([Al+]CC(C)C)C(C)C.CCCCCC>C(Cl)Cl>[CH2:1]([C@H:8]([C@@H:12]([O:13][Si:14]([CH:15]([CH3:17])[CH3:16])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:19])[CH3:20])[C@@H:11]([OH:10])[CH3:24])[CH2:9][OH:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[Si](O[C@H]1[C@H](C)OC(=O)[C@@H]1Cc1ccccc1)(C(C)C)C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C=O
Agent: [H-]
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)[Si](O[C@H]([C@H](CO)Cc1ccccc1)[C@H](C)O)(C(C)C)C(C)C
Temperature: 23 °C
Reaction time: 18 h
Yield: 71.1 %

Procedure:
To a solution of (3R,4R,5S)-3-benzyl-5-methyl-4-(triisopropylsilyloxy)-dihydrofuran-2(3H)-one (9.42 g, 26.0 mmol, 1.00 equiv) in CH2Cl2 (130 mL, 0.2 M) at −78° C. (dry ice/acetone bath) was added a 1 M solution of diisobutylaluminum hydride in hexane (DIBAL-H, 65.0 mL, 65.0 mmol, 2.50 equiv). The resulting colorless solution was removed from the cold bath and stirred at 23° C. for 18 h, cooled to 0° C. (ice water bath), and quenched with sat'd aqueous Rochelle's salt solution (200 mL) and Et2O (200 mL). The resulting slurry was stirred vigorously until the mixture became clear and biphasic (1.5 h) and the resulting phases were separated. The aqueous phase was extracted with Et2O (2×200 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated to provide an oil. Purification by automated silica gel column chromatography (0-20% acetone in hexanes) provided (2S,3R,4S)-2-benzyl-3-(triisopropylsilyloxy)pentane-1,4-diol (6.78 g, 71.2%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.35-7.08 (m, 5H), 4.11-3.96 (m, 1H), 3.95-3.77 (m, 2H), 3.57-3.40 (m, 1H), 3.09 (d, J=2.5 Hz, 2H), 2.93-2.76 (m, 2H), 2.04 (dd, J=5.7, 2.9 Hz, 1H), 1.35 (d, J=6.6 Hz, 3H), 1.12 (d, J =3.6 Hz, 1H), 1.05 (s, 20H); 13C NMR (101 MHz, CDCl3) δ 141.12, 129.10, 128.42, 125.98, 71.23, 59.84, 48.58, 34.81, 19.10, 18.18, 12.72; ESIMS m/z 365.3 ([M−H]−).
Reaction SMILES: [CH3:1][N:2]([CH3:52])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:50][CH3:51])=[C:12]([NH:15][C:16]3[N:17]=[C:18]([NH:35][C:36]4[C:41]([C:42]([NH:44][CH:45]([CH3:47])[CH3:46])=[O:43])=[C:40]([F:48])[C:39]([F:49])=[CH:38][CH:37]=4)[C:19]4[CH:24]=[CH:23][N:22](S(C5C=CC(C)=CC=5)(=O)=O)[C:20]=4[N:21]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].O.[OH-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:52][N:2]([CH3:1])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:50][CH3:51])=[C:12]([NH:15][C:16]3[NH:21][C:20]4=[N:22][CH:23]=[CH:24][C:19]4=[C:18]([NH:35][C:36]4[C:41]([C:42]([NH:44][CH:45]([CH3:47])[CH3:46])=[O:43])=[C:40]([F:48])[C:39]([F:49])=[CH:38][CH:37]=4)[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: COc1cc2c(cc1Nc1nc(Nc3ccc(F)c(F)c3C(=O)NC(C)C)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(C(=O)CN(C)C)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1Nc1nc(Nc3ccc(F)c(F)c3C(=O)NC(C)C)c3ccnc-3[nH]1)N(C(=O)CN(C)C)CC2
Temperature: 120 °C
Yield: 56.5 %

Procedure:
6-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-2,3-difluoro-N-(1-methylethyl)benzamide (101 mg, 0.138 mmol) was dissolved in 1,4-dioxane (10 mL) and transferred to a 20 ml microwave vessel. Water (3 mL) and a solution of 6M NaOH (3 ml) and was added and reaction heated in microwave at 120° C. for 10 minutes. Resulting brown solution was diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution, water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure to afford a brown solid that was purified via chromatography on SiO2 to afford 6-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-2,3-difluoro-N-(1-methylethyl)benzamide (45 mg, 0.078 mmol) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06 (d, J=6.50 Hz, 6 H), 2.26 (s, 6 H), 3.10 (t, J=8.24 Hz, 2 H), 3.17 (s, 2 H), 3.77 (s, 3 H), 3.94-4.08 (m, 1 H), 4.17 (t, J=8.29 Hz, 2 H), 6.30 (br. s., 1 H), 6.86-6.99 (m, 2 H), 7.31-7.43 (m, 1 H), 7.50 (s, 1 H), 7.92-8.02 (m, 1 H), 8.51 (d, J=7.60 Hz, 1 H), 8.64 (s, 1 H), 9.31 (s, 1 H), 11.20 (br. s., 1 H). (ESIMS (M+H)+=579)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH:14]([CH:15]=O)[CH:13]2[CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8].C1(=O)NC(=O)C=C1.ClC1C=C(C=CC=1Cl)N.Cl.[NH2:41][OH:42].N1C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH:14]([CH:15]=[N:41][OH:42])[CH:13]2[CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CC2C(C=O)C2(c2ccc(Cl)c(Cl)c2)C1
Agent: Cl
Agent: Nc1ccc(Cl)c(Cl)c1
Agent: O=C1C=CC(=O)N1
Solvent: CCO
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC2C(C=NO)C2(c2ccc(Cl)c(Cl)c2)C1
Yield: 73 %

Procedure:
To a solution of tert-butyl 1-(3,4-dichlorophenyl)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (200 mg, 0.56 mmol, prepared from maleimide and 3,4-dichloroaniline according to the methods described in WO 2009141412 and WO 2008074716), in ethanol (10 mL) under nitrogen atmosphere were added hydroxylamine hydrochloride (78 mg, 1.12 mmol) and pyridine (0.23 mL, 2.86 mmol). The reaction mixture was refluxed for 5 h. After completion of the reaction as confirmed by TLC, the solvent was evaporated. The crude compound was extracted with ethyl acetate (70 mL). The organic layer was separated, washed with 5% HCl (5 mL), water (10 mL), dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 1:4 EtOAc:Pet Ether) to afford pure tert-butyl 1-(3,4-dichlorophenyl)-6-((hydroxyimino)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (152 mg, 73%) as a viscous oil as a mixture of isomers.
Reaction SMILES: [Br:1][C:2]1[N:6]2[C:7](Br)=[CH:8][N:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>C1COCC1.C(Cl)Cl.O>[CH2:12]([NH:19][C:10]1[C:5]2[N:6]([C:2]([Br:1])=[CH:3][N:4]=2)[CH:7]=[CH:8][N:9]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccccc1
Reactant: Brc1cncc2ncc(Br)n12
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Brc1cnc2c(NCc3ccccc3)nccn12
Temperature: 70 °C
Yield: 13.7 %

Procedure:
To a solution of 3,5-dibromo-imidazo[1,2-a]pyrazine (D) (200 mg, 0.72 mmol) in THF (9 ml) was added benzylamine (0.393 ml, 3.6 mmol) and diisopropylethylamine (DIPEA) (0.627 ml, 3.6 mmol). The mixture was heated at 70° C. for 3 days. The mixture was then cooled to rt, diluted with DCM and water. The organic layer was washed with brine, dried and concentrated. The residue was purified on a silica gel column to give 30 mg of the title compound.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:16][CH2:15][C:12]2([CH2:14][CH2:13]2)[C:11](=[O:17])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)([O-])=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.[OH-].[Na+].[Cl-].[Mg+2].[Cl-]>CC(O)C>[CH2:2]([N:9]1[CH2:16][CH2:15][C:12]2([CH2:13][CH2:14]2)[C@H:11]([OH:17])[CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CN(Cc2ccccc2)CCC12CC2
Agent: Cl
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)([O-])OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: [Cl-]
Solvent: CC(C)O
Product: O[C@@H]1CN(Cc2ccccc2)CCC12CC2
Temperature: 35 °C
Reaction time: 96 h

Procedure:
A mixture of 300 mg of 6-benzyl-6-aza-spiro[2.5]octan-4-one hydrochloride (1.19 mmol, 1 equiv.), 1.5 ml of 2-propanol and 28 ml of 30 mM aq. TRIS-HCl buffer (pH 8.1) was heated to 35° C. The pH was re-adjusted to 8.0. The reaction was started by adding β-NAD (1 mg; free acid; Roche Diagnostics Cat. No. 10 004 626) and ketoreductase KRED-NADH-117 (29.3 mg; Codexis [ex. Biocatalytics]). The suspension was stirred at 35° C. keeping the pH constant at 8.0 by the controlled addition (pH-stat) of 1.0 M aq. sodium hydroxide solution. After roughly 80 area % conversion and 1 d, further 2-propanol (0.3 ml), β-NAD (3 mg; free acid; Roche Diagnostics Cat. No. 10 004 626), ketoreductase K RED-NADH-117 (30 mg; Codexis [ex. Biocatalytics]) and magnesium chloride (12.7 mg) were added. After 4 d, 98.5 area % conversion and 5.9 ml consumption of 1.0 M aq. sodium hydroxide solution the reaction mixture was stopped by the addition of sodium chloride (9 g), ethyl acetate (30 ml) and filter aid (1 g Dicalite Speedex). The mixture was stirred 30 min. and filtered. The filtrate was extracted 3 times with 30 ml ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the crude product in over 99.9% e.e. Purification by flash chromatography provided the title compound as a colorless oil.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:7])[CH2:4][CH2:5][Cl:6].[OH-].[Na+].[C:10]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)(=[O:12])[CH3:11]>CC(O)C.O>[Cl:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2][O:20][C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:10](=[O:12])[CH3:11])=[CH:19][CH:18]=1
Reactant: OC(CCl)CCCl
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(=O)Nc1ccc(OCC(O)CCCl)cc1
Reaction time: 16 h
Yield: 53.5 %

Procedure:
To a solution of 500 g (3.5 mole) of 1,4-dichloro-2-butanol was added, dropwise, 500 ml (6.25 mole) of a 50% sodium hydroxide solution. The mixture was stirred for 16 hr and then 500 ml of water was added, dropwise, with the temperature maintained below 35° C. The mixture was extracted with 500 ml of isopropyl ether, dried over sodium sulfate and concentrated to give an oil which was purified by distillation. To 14.3 g (0.1 mole) of the purified epoxide was added a solution of 15.1 g (0.1 mole) of 4-acetamidophenol in 150 ml of 2-propanol and 4 g of (0.1 mole) of sodium hydroxide in 10.0 ml of water. The mixture was stirred for 15 hr and then poured into 400 ml of water at 0° C. The crude, collected solid was washed with water and allowed to air dry. The solid was suspended in 350 ml of acetone, collected by filtration, and washed with additional portions of acetone. The filtrate was concentrated under reduced pressure to give 13.8 g (53% yield) of solid. A portion of this solid was recrystallized from tetrahydrofuran to give cream-colored solid, m.p. 124°-127° C.
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:39])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[N:10][C:9]=2[N:28]([C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[CH2:35][CH2:34][CH2:33]3)[CH:29]=1)=[O:5])C.[CH3:40][NH2:41]>CO>[CH3:40][NH:41][C:4]([C:6]1[C:7](=[O:39])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]4)=[CH:17][CH:16]=3)=[N:10][C:9]=2[N:28]([C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[CH2:35][CH2:34][CH2:33]3)[CH:29]=1)=[O:5]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2c1=O
Reactant: CN
Solvent: CO
Product: CNC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2c1=O
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8-indan-5-yl-2-[4-(4-methyl-piperazine-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester Cpd 1 (Example 1(g), 5 mg) in 1 mL of methanol was added 1 mL of methylamine (40 wt. % in water). The solution was stirred at 70° C. for 30 minutes. The solvent was evaporated and the product was purified by preparative HPLC. 1.7 mg of 8-indan-5-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methylamide
Reaction SMILES: C(O)(=O)CCCCCCCCCCCCCCCCC.[NH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:29][NH2:30].O.[C:32]([NH2:51])(=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49].[NH2:52]CCNCCNCCN.[F:62][C:63]1[C:64]([O:76][C:77]([F:105])=[C:78]([F:104])[C:79]([F:103])([F:102])[C:80]([F:101])([F:100])[C:81]([F:99])([F:98])[C:82]([F:97])([F:96])[C:83]([F:95])([F:94])[C:84]([F:93])([F:92])[C:85]([F:91])([F:90])[C:86]([F:89])([F:88])[F:87])=[C:65]([S:72](Cl)(=[O:74])=[O:73])[C:66]([F:71])=[C:67]([F:70])[C:68]=1[F:69].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[C:32]([NH2:51])(=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49].[NH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:29][NH2:30].[F:62][C:63]1[C:64]([O:76][C:77]([F:105])=[C:78]([F:104])[C:79]([F:103])([F:102])[C:80]([F:101])([F:100])[C:81]([F:99])([F:98])[C:82]([F:97])([F:96])[C:83]([F:95])([F:94])[C:84]([F:93])([F:92])[C:85]([F:91])([F:90])[C:86]([F:89])([F:88])[F:87])=[C:65]([S:72]([NH2:52])(=[O:74])=[O:73])[C:66]([F:71])=[C:67]([F:70])[C:68]=1[F:69]
Reactant: O=S(=O)(Cl)c1c(F)c(F)c(F)c(F)c1OC(F)=C(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CCCCCCCCCCCCCCCCCC(=O)O
Agent: CCCCCCCCCCCCCCCCCC(N)=O
Agent: NCCNCCNCCN
Solvent: Cc1ccccc1
Solvent: O
Product: NS(=O)(=O)c1c(F)c(F)c(F)c(F)c1OC(F)=C(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 0.5 h

Procedure:
Stearic acid (285 g, 1 mol) and triethylenetetramine (146 g, 1 mol) was reacted at 163°-166° C. until one mole of water was evolved (28 minutes). To 20.0 g (0.05 mol) of the resulting triethylenetetramine monostearamide dissolved in 200 ml. of toluene was added a mixture of 80.7 g (0.12 mol) of perfluorodecenyloxybenzene sulfonyl chloride and 7.0 g of sodium carbonate over a period of 15 minutes while the temperature was held at 75°-80° C. After 1/2 hour more at 85° C., the solution was decanted from the sodium chloride and the solvent was removed by distillation to yield the product, 2.4 perfluorodecenyloxybenzenesulfonamide triethylenetetramine monostearamide, a tan, hard, waxy, solid with good water, oil and soil repellancy.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([CH:28]4[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37]C(C)(C)C)=O)[CH2:30][CH2:29]4)[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:42](O)(C(F)(F)F)=O.C(N(CC)CC)C.C(OC(=O)C)(=O)C.[ClH:63]>C(Cl)Cl>[ClH:63].[ClH:63].[CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([CH:28]4[CH2:34][CH2:33][CH2:32][N:31]([C:35](=[O:37])[CH3:42])[CH2:30][CH2:29]4)[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc(C2CCCN(C(=O)OC(C)(C)C)CC2)ns1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCCC(c2nsc(Nc3ncc(Sc4ccccn4)cc3Oc3cccnc3C)n2)CC1
Yield: 95.2 %

Procedure:
tert-Butyl 4-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)azepane-1-carboxylate (70.4 mg, 0.119 mmol) was dissolved in CH2Cl2 (2 mL) and TFA (2 mL) was added. After 10 minutes the reaction was concentrated and placed on high vacuum pump to remove excess TFA. The residue was dissolved in CH2Cl2 (2 mL) and triethylamine (82.3 μL, 0.591 mmol) and acetic anhydride (16.7 μL, 0.177 mmol) were added. After 10 minutes the reaction was partitioned between saturated aqueous NaHCO3 and EtOAc, dried over sodium sulfate, filtered and concentrated. The residue was purified over silica gel (10% methanol in EtOAc) to afford 1-(4-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)azepan-1-yl)ethanone dihydrochloride (68.2 mg, 0.112 mmol, 95.2% yield) as a solid after HCl salt formation. Mass spectrum (apci) m/z=534.2 (M+H-2HCl).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[N:11]=[C:12]([CH3:14])[NH:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[N:20]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23](Br)[CH:22]=2)=[O:18].[I-:39].[Na+].CN[C@@H]1CCCC[C@H]1NC.N>[Cu]I.O1CCOCC1>[NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[N:20]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23]([I:39])[CH:22]=2)=[O:18]
Reactant: [I-]
Reactant: Cc1ccc(S(=O)(=O)n2c(C(=O)c3cnn(-c4ccc5nc(C)[nH]c5c4)c3N)cc3ccc(Br)cc32)cc1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: N
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2c(C(=O)c3cnn(-c4ccc5[nH]c(C)nc5c4)c3N)cc3ccc(I)cc32)cc1
Temperature: 108.5 °C
Reaction time: 20 h
Yield: 62.1 %

Procedure:
A mixture consisting of [5-amino-1-(2-methyl-3H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-[6-bromo-1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone (1 g), copper (I) iodide (161 mg), sodium iodide (508 mg), trans-N,N′-dimethylcyclohexane-1,2-diamine (267 μl), and anhydrous dioxane (5 ml) was stirred in a pressure-proof container at 105 to 112° C. under a nitrogen atmosphere for 20 hours. The reaction mixture was poured into an aqueous solution of 2 M ammonia, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol/dichloromethane=0/100 to 20/100) to give [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-[6-iodo-1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone (0.67 g, 62%).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[CH:6]([OH:29])[CH:7]([NH:11][C:12]([C@@H:14]2[C@H:18]3[CH2:19][CH2:20][CH2:21][C@H:17]3[CH2:16][N:15]2C(OC(C)(C)C)=O)=[O:13])[CH2:8][CH2:9][CH3:10])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([NH:4][C:5](=[O:30])[CH:6]([OH:29])[CH:7]([NH:11][C:12]([C@@H:14]2[C@H:18]3[CH2:19][CH2:20][CH2:21][C@H:17]3[CH2:16][NH:15]2)=[O:13])[CH2:8][CH2:9][CH3:10])[CH2:3][CH2:2]1
Reactant: CCCC(NC(=O)[C@@H]1[C@H]2CCC[C@H]2CN1C(=O)OC(C)(C)C)C(O)C(=O)NC1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC(NC(=O)[C@H]1NC[C@@H]2CCC[C@@H]21)C(O)C(=O)NC1CC1

Procedure:
Compound 12 (0.845 g, 2 mmol) is treated with TFA (5 ml) in DCM (10 ml) at 0° C. for 2 hr. The mixture is evaporated to dryness. The yellow syrup so obtained is dissolved in DCM (20 ml) to make a stock solution of 13 (0.1 M) for the next step.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:4]2[C:9]([C:10]=1[C:11](O)=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[N:20]1([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[C:29]([O:28][C:26]([N:20]1[CH2:25][CH2:24][N:23]([C:11]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:2]=2[Cl:1])=[O:12])[CH2:22][CH2:21]1)=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: O=C(O)c1c(Cl)n(-c2ccccc2)c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(Cl)n(-c3ccccc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
To a solution of 2-chloro-1-phenyl-1H-indole-3-carboxylic acid (cf. CA 1079739) (3.00 g, 11.0 mmol), tert-butyl 1-piperazinecarboxylate (2.06 g, 11.0 mmol), EDC (2.33 g, 12.1 mmol) and HOAT (1.73 g, 12.7 mmol) in DMF (12 ml) was added NMM (3.65 ml, 33.1 mmol), and the reaction mixture was stirred at room temperature overnight. The mixture was quenched with water and extracted with EA. The organic layer was separated, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (EA/HEP 1:3). 4.51 g of the title compound were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][C:13]([OH:15])=O)(=[O:11])=[O:10])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.[NH2:20][CH2:21][CH2:22][S:23]([OH:26])(=[O:25])=[O:24].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][C:13]([NH:20][CH2:21][CH2:22][S:23]([OH:26])(=[O:25])=[O:24])=[O:15])(=[O:10])=[O:11])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1
Reactant: NCCS(=O)(=O)O
Reactant: O=C(O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F)NCCS(=O)(=O)O

Procedure:
Under the conditions of Example 2(a), 3.012 g (10 mmol) of 2-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]acetic acid, 1.252 g (10 mmol) of 2aminoethanesulfonic acid, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is dissolved in distilled water, extracted with ethyl acetate, and converted into the free acid by treatment with acidic cation exchanger. The title compound is obtained by freeze-drying the aqueous solution.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[Br:17][C:18]1[CH:19]=[C:20]([CH2:24][C:25](O)=[O:26])[CH:21]=[N:22][CH:23]=1.Cl.CN(C)CCCN=C=NCC.N1CCCCC1>C(Cl)Cl.C1(C)C=CC=CC=1>[Br:17][C:18]1[CH:19]=[C:20]([C:24]2[C:25](=[O:26])[NH:1][C:2]3[C:3]([C:4]=2[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=3)[CH:21]=[N:22][CH:23]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=C(O)Cc1cncc(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCNCC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2)c1-c1cncc(Br)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
A solution of 2-amino-5-chlorobenzophenone (230 mg, 1.00 mmol), 5-bromo-3-pyridineacetic acid (215 mg, 1.00 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI) (230 mg; 1.20 mmol) in DCM (2.5 mL) was stirred overnight at room temperature. Toluene (2.5 mL) and piperidine (0.2 mL) were then added and the resulting solution was heated to approximately 100° C., allowing the DCM to evaporate from the reaction mixture. After 2 h, the reaction was allowed to cool and stirring was continued at room temperature overnight. The precipitate that formed was filtered and washed with toluene. This crude product was dissolved in chloroform and extracted with water (4×), dried over potassium carbonate (K2CO3) and concentrated to afford the pure quinolinone product (285 mg, 69%). 1H NMR (300 MHz, DMSO-d6) δ 12.4 (br.s, 1H), 8.45 (d, 1H, J=3.0 Hz), 8.21 (d, 1H, J=1.3 Hz), 7.86 (t, 1H, J=1.5 Hz), 7.64 (dd, 1H, J=8.9, 2.3 Hz, 1H), 7.46 (d, 1H, J=8.6 Hz), 7.44-7.31 (m, 3H), 7.28-7.21 (m, 2H), 6.94 (d, 1H, J=2.0 Hz). MS: 413.0 (M+H).