Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[S:11][C:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])=[O:16])=[CH:13][N:14]=2)[CH:6]=[CH:7][CH:8]=1.Cl.[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:36])=[C:30]([S:32](Cl)(=[O:34])=[O:33])[CH:31]=1.CCN(CC)CC>C(Cl)Cl>[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:36])=[C:30]([S:32]([NH:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]3[S:11][C:12]([C:15](=[O:16])[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[CH3:23])=[CH:13][N:14]=3)[CH:4]=2)(=[O:34])=[O:33])[CH:31]=1
Reactant: Cc1ccccc1C(=O)c1cnc(Nc2cccc(CN)c2)s1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)c1cnc(Nc2cccc(CNS(=O)(=O)c3cc(F)ccc3C)c2)s1

Procedure:
A mixture of 35.8 mg (0.1 mmol)[2-(3-aminomethyl-phenylamino)-thiazol-5-yl]-o-tolyl-methanone; hydrochloride, 25 mg (0.12 mmol) 5-fluoro-2-methyl-benzenesulfonyl chloride (commercially available) and 69 ul (0.5 mmol) NEt3 in 3 ml DCM was stirred at 60° C. for 16 h. After evaporation of the volatiles the residue was taken up in 1.5 ml MeOH/formic acid 2/1 and subjected to reversed phase HPLC purification eluting with a gradient of acetonitrile/water. After evaporation of the product fractions 31 mg (62%) of the title compound was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=2)[N:12]=[C:11]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:27][C:28]1[CH:33]=[C:32](O)[CH:31]=[CH:30][C:29]=1[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH2:1]([O:8][C:9]1[N:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][O:22][C:32]3[CH:31]=[CH:30][C:29]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[C:28]([F:27])[CH:33]=3)=[CH:19][CH:20]=2)[N:12]=[C:11]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1ccc(O)cc1F
Reactant: CC(C)(C)c1cc(OCc2ccccc2)n(Cc2ccc(CO)cc2)n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(OCc2ccc(Cn3nc(C(C)(C)C)cc3OCc3ccccc3)cc2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a mixture of (4-([5-(benzyloxy)-3-tert-butyl-1H-pyrazol-1-yl]methyl)phenyl)methanol (0.60 g, 1.7 mmol), ethyl 3-(2-fluoro-4-hydroxyphenyl)propanoate (0.40 g, 1.9 mmol), tributylphosphine (0.85 mL, 3.4 mmol) and tetrahydrofuran (50 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.86 g, 3.4 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated under reduced pressure, diisopropyl ether was added to the residue, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:4) to give the title compound (0.82 g, yield 88%) as a colorless oil. MS: m/z 545 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Reactant: BrCCC1CCOCC1
Product: O=C(c1cn(CCC2CCOCC2)c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (prepared according to example 69) with 4-(2-bromo-ethyl)-tetrahydro-pyran (described in US 2004220214) gave the title compound. ES-MS m/e (%): 479.5(M+H+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH2:34]([O:36][C:37](=[O:52])[CH2:38][CH2:39][N:40]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C@H:41]([CH3:44])[CH2:42]O)[CH3:35].[N-:53]=[N+:54]=[N-:55]>O1CCCC1>[CH2:34]([O:36][C:37](=[O:52])[CH2:38][CH2:39][N:40]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C@H:41]([CH3:44])[CH2:42][N:53]=[N+:54]=[N-:55])[CH3:35]
Reactant: CCOC(=O)CCN(C(=O)OC(C)(C)C)[C@H](C)CO
Reactant: [N-]=[N+]=[N-]
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCN(C(=O)OC(C)(C)C)[C@H](C)CN=[N+]=[N-]

Procedure:
Triphenylphosphine (12.0 g, 45.9 mmol) and diisopropyl azodicarboxylate (9.88 g, 45.9 mmol) were added at room temperature to a solution of 3-[tert-butoxycarbonyl-((R)-2-hydroxy-1-methyl-ethyl)-amino]-propionic acid ethyl ester in tetrahydrofuran (600 ml), then after 2 min diphenylphorphoryl azide (12.6 g, 45.9 mmol) was added. After 16 h the reaction mixture was concentrated and the residue purified by chromatography (SiO2; heptane-ethyl acetate gradient) to afford slightly impure 3-[tert-butoxycarbonyl-((R)-2-azido-1-methyl-ethyl)-amino]-propionic acid ethyl ester (8.82 g). This was dissolved in methanol (880 ml), then after addition of palladium (10% on activated charcoal, 1.6 g) and potassium carbonate (42.6 g, 308 mmol) the reaction mixture was hydrogenated at room temperature and atmospheric pressure for 16 h. Insoluble material was removed by filtration and the filtrate concentrated. Chromatography (SiO2; heptane/ethyl acetate 1:1, then dichloromethane/methanol/25% aq. ammonia solution 97.5:2.5:0.25) produced the title compound (2.20 g, 21%). White solid, MS (ISP)=229.4 (M+H)+.
Reaction SMILES: Cl.CO.C(O[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:14][CH2:13]1)=[O:10])(C)(C)C.[CH2:27]([O:29][CH2:30][CH3:31])[CH3:28]>>[CH:19]1([CH2:18][N:15]2[CH2:14][CH2:13][CH:12]([NH:11][C:9]([C:13]3[CH:12]=[CH:17][CH:28]=[C:27]4[C:14]=3[NH:15][C:31]3[CH:21]=[CH:20][CH:19]=[CH:18][C:30]=3[O:29]4)=[O:10])[CH2:17][CH2:16]2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CC2CCCCCCC2)CC1
Reactant: CCOCC
Agent: Cl
Solvent: CO
Product: O=C(NC1CCN(CC2CCCCCCC2)CC1)c1cccc2c1Nc1ccccc1O2
Reaction time: 18 h

Procedure:
15 ml of 10% HCl-methanol solution and 15 ml of diethyl ether were added to 1.66 g of 4-t-butoxycarbonylamino-1-cyclooctylmethylpiperidine, followed by stirring for 18 hours. The solvent was distilled off under reduced pressure, the obtained residue was washed with diethyl ether, and 1.44 g of the title compound as a white solid was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:12][CH:13]=2)[C:8]([S:29]([C:32]2[C:41]3[C:36](=CC=CC=3)[CH:35]=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[N:7]1.[CH:45]([NH2:48])([CH3:47])[CH3:46]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][NH:48][CH:45]([CH3:47])[CH3:46])=[CH:12][CH:13]=2)[C:8]([S:29]([C:32]2[C:41]3[C:36](=[CH:3][CH:2]=[CH:44][CH:43]=3)[CH:35]=[CH:34][CH:33]=2)(=[O:30])=[O:31])=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)c(S(=O)(=O)c2cccc4ccccc24)nn3Cc2cccc(Cl)c2)cc1
Reactant: CC(C)N
Solvent: C1CCOC1
Product: CC(C)NCCOc1ccc2c(c1)c(S(=O)(=O)c1cccc3ccccc13)nn2Cc1cccc(Cl)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 200.1 %

Procedure:
A solution of toluene-4-sulfonic acid 2-[1-(3-chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.339 g, 0.524 mmol) and isopropylamine (1.0 mL, 12 mmol) in THF (8 mL) was stirred at 70° C. in a sealed tube for 2 hours. Isopropylamine (1.0 mL, 12 mmol) was added, and the reaction mixture was stirred at 80° C. in a sealed tube for 2 hours. Isopropylamine (1.0 mL, 12 mmol) was added to the reaction mixture, and it was stirred at 80° C. in a sealed tube for 30 hours. After cooling to ambient temperature, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. It was washed with brine, dried with anhydrous magnesium sulfate, filtered, concentrated and dried in vacuo for 20 minutes at 80° C. to give {2-[1-(3-chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-isopropyl-amine as a yellow solid (0.280 g, 100%). It was dissolved in chloroform, and ethereal hydrochloride was added. The resulting solid was filtered and dried at 82° C. in vacuo for 14 hours. The result was the hydrochloride as a pale yellow solid (0.236 g): MP: 206-8° C.; Mass Spectrum (+EI, [M+H]+) m/z 534. 1HNMR (500 MHz, DMSO-d6): δ8.65-8.76 (m, 3H), 8.54-8.56 (m, 1H), 8.27 (d, 1H, J=8.17 Hz), 8.02-8.05 (m, 1H), 7.82 (d, 1H, J=9.27 Hz), 7.72 (dd, 1H, J=8.07 Hz and 7.57 Hz), 7.57-7.63 (m, 2H), 7.24-7.28 (m, 2H), 7.16-7.21 (m, 3H), 7.05 (d, 1H, J=7.81 Hz), 5.73 (s, 2H), 4.27 (t, 2H, J=5.00 Hz), 3.31-3.37 (m, 3H), 1.23 ppm (d, 6H, J=6.69 Hz). Elemental Analysis for C29H28ClN3O3S.1.00 HCl: Calcd: C, 61.05; H, 5.12; N, 7.36; Found: C, 60.68; H, 5.26; N, 7.14.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[N:18][CH:19]=3)[NH:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:33][C:34]([CH3:37])([OH:36])[CH3:35]>C(O)C.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:25][CH2:24][N:23]([CH2:33][C:34]([CH3:37])([OH:36])[CH3:35])[CH2:22][CH2:21]4)=[N:18][CH:19]=3)[NH:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(O)CCl
Reactant: Clc1ccc(-c2c[nH]c(-c3ccc(N4CCNCC4)nc3)n2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(O)CN1CCN(c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)c[nH]3)cn2)CC1
Yield: 54.6 %

Procedure:
(Reference: Ind. Acad. Sci. 1939, 49, 101-4.) A solution of 1-{5-[4-(3,4-dichloro-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-piperazine (155 mg, 0.41 mmol), sodium carbonate (66 mg, 0.62 mmol, 1.5 equiv) and 1-chloro-2-methyl-propan-2-ol (51 μl, 53 mg, 0.50 mmol, 1.2 equiv) in 50% aqueous ethanol (20 ml) under nitrogen atmosphere was heated at reflux overnight. The reaction mixture was then diluted with brine and extracted with ethyl acetate (3×25 ml). The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash column chromatography (50% THF/0.5% ammonium hydroxide/hexanes) provided the desired product (100 mg, 54%). MS m/z 446 (M++1).
Reaction SMILES: [BH4-].[Li+].[C:3]([O:7][C:8]([N:10]([CH3:18])[C:11]1([C:14](OC)=[O:15])[CH2:13][CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>O1CCCC1.CCOCC>[OH:15][CH2:14][C:11]1([N:10]([CH3:18])[C:8](=[O:9])[O:7][C:3]([CH3:4])([CH3:5])[CH3:6])[CH2:12][CH2:13]1
Reactant: COC(=O)C1(N(C)C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C1(CO)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
100 ml of a 2M solution of lithium borohydride in tetrahydrofuran is added to a solution of 23 g of the compound obtained in Step 2 in 100 ml of tetrahydrofuran. After stirring for 20 hours at ambient temperature and then refluxing for 8 hours, the reaction mixture is cooled to 0° C., hydrolysed, diluted with ether, separated, dried and concentrated. Chromatography of the residue over silica gel (dichloromethane/tetrahydrofuran: 95/5) allows the expected product to be isolated.
Reaction SMILES: Cl[C:2]1[C:14]2[CH2:13][CH2:12][CH:11]3[CH:7]([CH2:8][N:9]([CH2:15][CH2:16][CH3:17])[CH2:10]3)[C:6]=2[CH:5]=[C:4](Cl)[C:3]=1[NH2:19]>CO.C(OCC)(=O)C.[OH-].[Na+].[OH-].[OH-].[Pd+2]>[CH2:15]([N:9]1[CH2:8][CH:7]2[CH:11]([CH2:12][CH2:13][C:14]3[CH:2]=[C:3]([NH2:19])[CH:4]=[CH:5][C:6]=32)[CH2:10]1)[CH2:16][CH3:17]
Reactant: CCCN1CC2CCc3c(cc(Cl)c(N)c3Cl)C2C1
Agent: [Pd+2]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCN1CC2CCc3cc(N)ccc3C2C1
Yield: 86.2 %

Procedure:
A mixture of 6,8-dichloro-2-propyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindol-7-yl-amine (800 mg, 2.67 mmol) and 20% palladiumhydroxide on carbon in methanol (50 ml) was hydrogenated over night at room temperature. The catalyst was filtered, and the solvent was removed under vacuum to yield the crude product. The residue was dissolved in ethyl acetate and 1 M NaOH solution. The aqueous phase was once more extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to give the pure product (530 mg, 86%).
Reaction SMILES: [C:1]([C:3]1[C:4]([SH:11])=[N:5][C:6]([CH3:10])=[CH:7][C:8]=1[CH3:9])#[N:2].[OH:12]S(O)(=O)=O>>[CH3:9][C:8]1[CH:7]=[C:6]([CH3:10])[N:5]=[C:4]2[S:11][N:2]=[C:1]([OH:12])[C:3]=12
Reactant: Cc1cc(C)c(C#N)c(S)n1
Reactant: O=S(=O)(O)O
Product: Cc1cc(C)c2c(O)nsc2n1
Temperature: 105 °C
Reaction time: 3 h

Procedure:
3-Cyano-4,6-dimethyl-2-mercaptopyridine (4.7 g, 28.6 mmol) is dissolved in H2SO4(60 ml, 98%) and then stirred at 105° C. for 3 h. The reaction is monitored by HPLC-MS. The reaction solution is cooled to 25° C. and then poured onto ice. The product eventually (15 min) precipitates out as a voluminous solid and is filtered off with suction and washed with H2O. The residue is taken up with aqueous Na2CO3 solution (pH 8-9) and the product is extracted with EtOAc. The solvent is distilled off under reduced pressure and the residue (white solid) is dried (Na2SO4).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:15]12[NH:26][CH:23]([CH2:24][CH2:25]1)[CH2:22][C:21]1[CH:20]=[CH:19][C:18]([NH:27][C:28]3[N:33]=[C:32]([NH:34][C:35]4[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=4[C:37]([NH:39][CH3:40])=[O:38])[C:31]([Cl:45])=[CH:30][N:29]=3)=[CH:17][C:16]2=1.[CH3:46][C:47]([CH3:49])=O.ClC(Cl)C>C(O)(=O)C>[Cl:45][C:31]1[C:32]([NH:34][C:35]2[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=2[C:37]([NH:39][CH3:40])=[O:38])=[N:33][C:28]([NH:27][C:18]2[CH:19]=[CH:20][C:21]3[CH2:22][CH:23]4[N:26]([CH:47]([CH3:49])[CH3:46])[CH:15]([CH2:25][CH2:24]4)[C:16]=3[CH:17]=2)=[N:29][CH:30]=1
Reactant: CC(C)=O
Reactant: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC(C3)N2)ncc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC(C3)N2C(C)C)ncc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.1 %

Procedure:
Sodium triacetoxyborohydride (100 mg, 0.47 mmol) was added to a solution of 2-[2-(12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamino)-5-chloro-pyrimidin-4-ylamino]-N-methyl-benzamide (100 mg, 0.23 mmol), acetone (0.034 mL, 0.47 mmol), acetic acid (1 drop) and dichloroethane (5 mL). The reaction was stirred at room temperature for 18 h. The reaction was then quenched with saturated aqueous NaHCO3 (5 mL), extracted with CH2Cl2 (2×5 mL), dried over MgSO4, filtered, and concentrated to afford the title compound as off-white solid (89 mg, 82%). 1HNMR (400 MHz, DMSO-d6) δ 11.6 (s, 1H), 9.3 (s, 1H), 8.8-8.7 (m, 2H), 8.2 (s, 1H), 7.8 (d, 1H, J=7.8 Hz), 7.5 (appt t, 1H, J=8.1 Hz), 7.4 (d, 1H, J=8.6), 7.3 (s, 1H), 7.1 (appt t, 1H, J=7.6 Hz), 6.9 (d, 1H, J=8.3 Hz), 3.9 (m, 1H), 3.6 (m, 1H), 3.0 (dd, 1H, J=17.2, 4.6 Hz), 2.8 (d, 3H, J=4.3 Hz), 2.4 (m, 1H), 2.2 (d, 1H, J=17.2 Hz), 2.1-2.0 (m, 2H), 1.6 (m, 1H), 1.5 (m, 1H), 1.1 (d, 3H, J=5.9 Hz), 0.9 (d, 3H, J=5.9 Hz); MS (m/e) 477 (M+1); mp 202-205° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.CN1CCOCC1.Cl.[NH2:43][CH2:44][C:45]([O:47]C(C)(C)C)=[O:46].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH:43][CH2:44][C:45]([OH:47])=[O:46])=[O:31])=[CH:33][CH:34]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(Cl)cc3)C(=O)N2c2ccc(Cl)cc2)cc1
Reactant: CC(C)(C)OC(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(Cl)cc3)C(=O)N2c2ccc(Cl)cc2)cc1
Reaction time: 0.17 h

Procedure:
[4-((2R,3R)-1-(4-Chlorophenyl)-3-{[2-(4-chlorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetic acid, 302.1 mg, 0.585 mmol) was dissolved in DCM (6 ml). N-Methylmorpholine (190 μl, 1.728 mmol) and tert-butyl glycinate hydrochloride (133.4 mg, 0.80 mmol) were added. After 10 minutes, TBTU (224.3 mg, 0.67 mmol) was added and the reaction mixture was stirred for 60 h. The intermediate tert-butylester of the title compound was confirmed. M/z: 626.88 (M−H). DCM (10 ml) and water (15 ml) were added and the mixture was acidified to pH of 3 using KHSO4 (2M). The organic phase was washed with water (2×15 ml). The combined aqueous phases were extracted with DCM (10 ml), dried over Na2SO4, filtered and concentrated. A solution of the residue (500 mg) in DCM (10 ml) and TFA (4 ml) was stirred overnight. The solvent was removed under reduced pressure. Toluene was added and evaporated to assist the removal of TFA. The residue was purified with preparative HPLC on a C8 column. A gradient from 20 to 50% MeCN in 0.1M ammonium acetate buffer was used as eluent. After lyophilisation, the title compound was obtained as a white solid (166.9 mg, 50%). H-NMR (400 MHz, DMS-d6): 3.51 (d, 2H), 4.33 (d, 1H), 4.34 (s, 1H), 4.36 (s, 1H), 4.47 (s, 2H), 5.17 (d, 1H), 6.96 (d, 2H), 7.16-7.21 (m, 2H), 7.35 (d, 4H), 7.54-7.59 (m, 2H), 7.83-7.90 (brs, 1H), 7.91-7.95 (m, 2H). M/z: 571.04 (M−H) and 572.88 (M+H).
Reaction SMILES: FC(F)(S([O:16][S:17]([C:20]([F:32])([F:31])[C:21]([F:30])([F:29])[C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])(=[O:19])=[O:18])(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.[C:34]1([S:40]([N:43]2[C:47]3[CH:48]=[N:49][C:50]([C:53]#[N:54])=[C:51](O)[C:46]=3[C:45]3[CH:55]=[C:56]([C:59]4[CH:60]=[N:61][N:62]([CH3:64])[CH:63]=4)[CH:57]=[N:58][C:44]2=3)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N1C=CC=CC=1.Cl>C(Cl)Cl>[C:34]1([S:40]([N:43]2[C:47]3[CH:48]=[N:49][C:50]([C:53]#[N:54])=[C:51]([O:16][S:17]([C:20]([F:31])([F:32])[C:21]([F:30])([F:29])[C:22]([F:27])([F:28])[C:23]([F:24])([F:25])[F:26])(=[O:18])=[O:19])[C:46]=3[C:45]3[CH:55]=[C:56]([C:59]4[CH:60]=[N:61][N:62]([CH3:64])[CH:63]=4)[CH:57]=[N:58][C:44]2=3)(=[O:41])=[O:42])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: Cn1cc(-c2cnc3c(c2)c2c(O)c(C#N)ncc2n3S(=O)(=O)c2ccccc2)cn1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1cc(-c2cnc3c(c2)c2c(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(C#N)ncc2n3S(=O)(=O)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.2 %

Procedure:
1,1,2,2,3,3,4,4,4-Nonafluorobutanesulfonic anhydride (0.75 g, 0.40 mL, 1.3 mmol) was added dropwise to a suspension of 9-benzenesulfonyl-5-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (106 mg, 0.25 mmol) in pyridine (0.7 mL, 8.0 mmol) and dry DCM (7 mL) at 0° C. The reaction mixture was then allowed to warm to ambient temperature and stirred for 4 h. The reaction mixture was treated with 1N hydrochloric acid (6 mL) and the phases were separated. The aqueous phase was extracted with DCM (2×10 mL), the combined organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was purified by chromatography (silica, 2 g column, Si-SPE, gradient of DCM/EtOAc) and further trituration with pentane (2 mL) to afford the title compound as a white solid (150 mg, 84%). 1H NMR (CDCl3, 400 MHz): 9.95 (s, 1H), 8.99 (d, J=2.1 Hz, 1H), 8.74 (d, J=2.1 Hz, 1H), 8.35-8.32 (m, 2H), 7.86 (d, J=0.8 Hz, 1H), 7.74-7.68 (m, 2H), 7.61-7.56 (m, 2H), 4.04 (s, 3H). LCMS (Method G): RT=4.80 min, M+H+=713.
Reaction SMILES: [CH2:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[C:16]2[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH:2]([CH3:4])[CH3:3].[F:26][C:27]([F:37])([F:36])[C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30]Br.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:5]([CH2:30][C:29]1[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=1[C:27]([F:26])([F:36])[F:37])[S:6]([C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[C:16]2[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:23])=[O:24])[CH2:18][CH2:17]2)=[CH:13][CH:14]=1)(=[O:8])=[O:7])[CH:2]([CH3:3])[CH3:4]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: CC(C)CNS(=O)(=O)c1ccc(C=C2CCN(S(C)(=O)=O)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CN(Cc1ccccc1C(F)(F)F)S(=O)(=O)c1ccc(C=C2CCN(S(C)(=O)=O)CC2)cc1
Temperature: 110 °C
Yield: 54.9 %

Procedure:
A mixture of N-isobutyl-4-(1-methanesulfonyl-piperidin-4-ylidenemethyl)-benzenesulfonamide (375 mg, 0.97 mmol), 2-(trifluoromethyl)benzyl bromide (289 mg, 1.22 mmol) and K2CO3 (201 mg, 1.46 mmol) in DMF (5 mL) was heated at 110° C. for 6 hours. The cooled mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-100% EtOAc in cyclohexane) and concentrating the residue from Et2O gave the title compound (290 mg, 55%). 1H NMR (400 MHz, DMSO) δ 7.83 (d, J=8.3 Hz, 2H), 7.70-7.73 (m, 3H), 7.49 (t, J=8.1 Hz, 3H), 6.51 (s, 1H), 4.46 (s, 2H), 3.22 (dt, J=30.4, 5.7 Hz, 4H), 2.96 (d, J=7.3 Hz, 2H), 2.89 (s, 3H), 2.49-2.50 (m, 4H), 1.39-1.40 (m, 1H), 0.70 (d, J=6.6 Hz, 6H). LCMS (m/z, Method B) ES+ 544.9 [M+1]+.
Reaction SMILES: C(N(CC)CC)C.Br[CH:9]([N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12].[Cl:21][C:22]1[N:27]=[C:26]([OH:28])[CH:25]=[CH:24][CH:23]=1>C(#N)C>[Cl:21][C:22]1[N:27]=[C:26]([O:28][CH:9]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)C(=O)C(Br)n1cncn1
Reactant: Oc1cccc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)C(=O)C(Oc1cccc(Cl)n1)n1cncn1
Yield: 52 %

Procedure:
50.5 g (0.5 mol) of triethylamine were added dropwise to 123 g (0.5 mol) of crude 1-bromo-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-one and 65 g (0.5 mol) of 6-chloro-2-hydroxy-pyridine in 250 ml of absolute acetonitrile at 24° to 30° C., while stirring. The mixture was stirred at room temperature for 3 hours and filtered and the filtrate was concentrated in vacuo. After treatment with water, the residue crystallized out. 76.6 g (52% of theory) of 1-(6-chloropyridin-2-yl-oxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-one of melting point 103°-105° C. were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=O.[C:13]1([CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:27])[CH2:24][C:25]#[N:26])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[OH:1][C:2]1[CH:3]=[C:4](/[CH:5]=[C:24](/[C:23]([NH:22][CH2:21][CH2:20][CH2:19][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:27])\[C:25]#[N:26])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: N#CCC(=O)NCCCc1ccccc1
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Product: N#C/C(=C\c1ccc([N+](=O)[O-])c(O)c1)C(=O)NCCCc1ccccc1

Procedure:
M-39 was prepared with 3-hydroxy-4-nitro benzaldehyde and N-3-phenyl-n-propyl cyanoacetamide under similar conditions as described for M28.