Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]1[OH:27])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:28][C:29]1([CH3:45])[O:34][CH:33]([C:35]([NH:37][CH2:38][CH2:39][C:40](O)=[O:41])=[O:36])[C:32]([CH3:44])([CH3:43])[CH2:31][O:30]1>>[CH3:28][C:29]1([CH3:45])[O:34][CH:33]([C:35]([NH:37][CH2:38][CH2:39][C:40]([O:27][C@@H:22]2[CH2:23][CH2:24][CH2:25][CH2:26][C@H:21]2[NH:20][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:41])=[O:36])[C:32]([CH3:44])([CH3:43])[CH2:31][O:30]1
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Reactant: CCCCCCCCCCCCCCCCCC(=O)N[C@@H]1CCCC[C@H]1O
Product: CCCCCCCCCCCCCCCCCC(=O)N[C@@H]1CCCC[C@H]1OC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Yield: 45.3 %

Procedure:
(1R,2R)-2-(N-Stearoylamino)cyclohexanol (3.81 g) and 2.59 g of 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid were reacted in the same manner as in Example 15 to obtain 2.82 g of the title compound (yield: 45%)
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]([CH2:30][N:31]([CH:37]1[CH2:39][CH2:38]1)[CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36])[C:9]([N:11]1[C@H:15]([C:16]([NH:18][C@:19]2([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:21][C@H:20]2[CH:22]=[CH2:23])=[O:17])[CH2:14][C@@H:13]([OH:29])[CH2:12]1)=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:45](Cl)([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46]>CN(C=O)C>[C:1]([O:5][C:6]([C@@H:8]([CH2:30][N:31]([CH:37]1[CH2:39][CH2:38]1)[CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36])[C:9]([N:11]1[C@H:15]([C:16]([NH:18][C@:19]2([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:21][C@H:20]2[CH:22]=[CH2:23])=[O:17])[CH2:14][C@@H:13]([O:29][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH2:12]1)=[O:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCCCN(C[C@H](C(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C)C1CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=CCCCN(C[C@H](C(=O)OC(C)(C)C)C(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C)C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.4 %

Procedure:
To a mixture of compound 1c (1.55 g, 2.75 mmoL) in 10 mL of DMF was added imidazole (0.47 g, 6.88 mmoL) and tert-butyldimethylsilyl chloride (826 mg, 5.50 mmoL). The mixture was stirred at rt for 18 h, concentrated in vacuo, and partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate, and concentrated in vacuo to obtain an off-white solid. Flash chromatography (eluting with methylene chloride and then ethyl acetate) gave (1R,2S)-ethyl 1-((3R,5S)-1-((S)-2-(tert-butoxycarbonyl)-3-(cyclopropyl(pent-4-enyl)amino)propanoyl)-3-(tert-butyldimethylsilyloxy)pyrrolidine-5-carboxamido)-2-vinylcyclopropanecarboxylate 1d as a white solid (1.75 g, 94%): LC-MS (Phenomenex 10 μm C18 HPLC column: 3.0×50 mm length. Gradient: 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B. Gradient time: 2 min. Hold time: 1 min. Flow rate: 5 mL/min. Detector Wavelength: 220 nm. Solvent A: 10% MeOH/90% H2O/0.1% TFA. Solvent B: 10% H2O/90% MeOH/0.1% TFA.) (Retention time: 2.51 min), MS m/z 677 (M++1).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:8]=[C:7]([N:9]2[CH2:13][C@@H:12]3[C@@H:14]([NH2:17])[CH2:15][CH2:16][C@@H:11]3[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[CH3:20][C:21]([CH3:23])=O.C(O)(=O)C.C([BH3-])#N>ClCCl>[CH:21]([NH:17][C@@H:14]1[C@@H:12]2[C@@H:11]([CH2:10][N:9]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:18])[F:19])[N:8]=3)[CH2:13]2)[CH2:16][CH2:15]1)([CH3:23])[CH3:20]
Reactant: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Reactant: CC(C)=O
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(3aR,4S,6aS)-2-(6-(Trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine from Example 264 Step A (44 mg, 0.162 mmol) and acetone (14.13 mg, 0.243 mmol) were combined in dichloromethane (0.5 mL). Acetic acid (0.5 mL) was added. The reaction mixture was stirred at ambient temperature for 30 minutes, then PS-cyanoborohydride (146 mg, 0.324 mmol) was added. After 18 hours, the reaction mixture was filtered and the solvent removed under a stream of nitrogen. The crude material was applied to a 4 g silica gel cartridge and purified with a gradient of 1-10% methanol in (2 N ammonia)/dichloromethane to give to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.57-7.52 (m, 1H), 6.99 (d, J=7.2, 1H), 6.55 (d, J=8.6, 1H), 3.62-3.54 (m, 1H), 3.54-3.45 (m, 2H), 3.25 (dd, J=10.7, 4.3, 1H), 3.03 (dd, J=11.8, 5.9, 1H), 2.83 (dt, J=12.4, 6.2, 1H), 2.76-2.67 (m, 1H), 2.49-2.41 (m, 1H), 2.02-1.92 (m, 2H), 1.45-1.29 (m, 3H), 1.06 (d, J=6.2, 3H), 1.03 (d, J=6.2, 3H); MS (ESI+) m/z 314 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[C:23](/[CH:25]=[CH:26]/[C:27]1([C:30]#[N:31])[CH2:29][CH2:28]1)#[N:24].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:23]([CH2:25][CH:26]([C:27]1([C:30]#[N:31])[CH2:29][CH2:28]1)[N:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1)#[N:24]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: N#C/C=C/C1(C#N)CC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)C4(C#N)CC4)c3)ncnc21
Reaction time: 16 h
Yield: 59.5 %

Procedure:
To a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine (61.4 mg, 0.195 mmol) and 1-[(E)-2-cyanovinyl]cyclopropanecarbonitrile (23 mg, 0.19 mmol) in ACN (2 mL) was added DBU (58 μL, 0.39 mmol) and the resulting mixture was stirred for 16 hours. The ACN was evaporated, and the residue was dissolved in ethyl acetate. This solution was washed with 1.0 N HCl, water, and brine, and dried over sodium sulfate, and the solvent removed in vacuo. Flash column chromatography (eluting with a gradient from 0-80% ethyl acetate in hexanes) afforded the product (49 mg, 58%).
Reaction SMILES: [ClH:1].[C:2](=[NH:9])(OCC)[CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.[CH2:17]([O:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([NH:24][NH2:25])=[O:23])[CH3:18].C(=N)(OCC)CCC.Cl>C(O)(C)C>[ClH:1].[NH:9]=[C:2]([NH:25][NH:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=1[O:19][CH2:17][CH3:18])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(=N)OCC
Reactant: CCOc1ccccc1C(=O)NN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCCC(=N)NNC(=O)c1ccccc1OCC
Temperature: 0 °C
Reaction time: 48 h

Procedure:
Ethyl butyrimidate hydrochloride from Example B (71.5 g, 472 mmol) is introduced into triethylamine (65 ml, 472 mmol) and cooled to 0° C. 2-Ethoxybenzohydrazide from Example A (85 g, 472 mmol) is suspended in 250 ml of isopropanol and added to the ethyl butyrimidate mixture. The reaction mixture is stirred at room temperature for 48 hours, the solid (triethylamine hydrochloride) is removed, and 25% strength hydrochloric acid (150 ml, 1.18 mol) is slowly added dropwise to the mother liquor at 0° C. to 5° C. The suspension of crystals is then stirred at 0° C. to 5° C. for 1 hour and the crystals are filtered with suction through a sintered funnel, washed with 100 ml of cold isopropanol and dried in a vacuum oven at 30° C. and 300 mbar overnight.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][CH:8]([NH:16]C(OCC1C=CC=CC=1)=O)[CH2:9][C:10]([CH3:15])([CH3:14])[CH2:11][CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:27])[CH2:7][C@@H:8]([NH2:16])[CH2:9][C:10]([CH3:15])([CH3:14])[CH2:11][CH2:12][CH3:13])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCCC(C)(C)CC(CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Product: CCCC(C)(C)C[C@H](N)CC(=O)OC(C)(C)C

Procedure:
According to example 1, 1.63 g of 3-benzyloxycarbonylamino-5,5-dimethyl-octanoic acid tert-butyl ester and 0.2 g of 20% Pd/C furnished the title compound. 1HNMR (400 MHz; CDCl3): 0.84–0.89 (m, 9H), 1.13–1.39 (m, 6H), 1.43 (s, 9H), 2.25 (dd, 1H, J=8.4 Hz, 15.6 Hz), 2.35 (dd, 1H, J=4.4 Hz, 15.6 Hz), 2.79 (s, br, 2H), 3.25–3.35 (m, 1H). MS, m/z, 244.2 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Br[C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[C:23]([CH3:25])([CH3:24])[O:22][C:21]([NH:26][C@H:27]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[F:44])[CH2:28][CH2:29][O:30][Si](C(C)(C)C)(C)C)=[N:20][S:19]2(=[O:46])=[O:45])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:25][C:23]1([CH3:24])[O:22][C:21]([NH:26][C@H:27]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[F:44])[CH2:28][CH2:29][OH:30])=[N:20][S:19](=[O:46])(=[O:45])[CH:18]1[C:15]1[CH:14]=[CH:13][C:12]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:17][CH:16]=1
Reactant: Cc1ccccc1B(O)O
Reactant: CC1(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c2ccccc2F)=NS(=O)(=O)C1c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccccc1-c1ccc(C2C(C)(C)OC(N[C@@H](CCO)c3ccccc3F)=NS2(=O)=O)cc1
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 41.4 %

Procedure:
Under inert gas, 40 mg of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium were added to a mixture of 97 mg of 2-methylphenylboronic acid, 350 mg of [5-(4-bromophenyl)-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-1,4,3-oxathiazin-2-yl]-[(S)-3-(tert-butyldimethylsilanyloxy)-1-(2-fluorophenyl)propyl]amine and 571 mg of cesium carbonate in 4.5 ml of dioxane and 1.5 ml of water. After stirring at 95° C. for 30 minutes, the reaction was allowed to cool to room temperature, 50 ml of ethyl acetate were added and the organic phase was washed with 20 ml of water and 20 ml of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4 and concentrated by rotary evaporation. The crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. To detach the protecting group, the residue was dissolved in 4 ml of methanol, 0.4 ml of concentrated hydrochloric acid was added and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated by rotary evaporation, and the residue was taken up in 20 ml of dichloromethane and washed with 10 ml of water. The aqueous phase was extracted once again with 10 ml of dichloromethane, and the combined organic phases were dried using a phase separator cartridge (Chromabond® PTS) and concentrated by rotary evaporation. The crude product was purified in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined, the acetonitrile was removed under reduced pressure, and the aqueous residue was basified with saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The organic phase was dried over MgSO4 and concentrated by rotary evaporation, and the residue was taken up again in a mixture of acetonitrile and water and lyophilized. This gave the product (120 mg) with a molecular weight of 496.6 g/mol (C27H29FN2O4S); MS (ESI): m/e=497 (M+H+).
Reaction SMILES: [NH2:1][CH:2]1[C:22](=[O:23])[N:4]2[C:5]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)=[O:10])=[CH:6][CH2:7][S:8][C@H:3]12.C[Si](CC(N)=O)(C)C.[NH2:32][C:33]1[S:34][CH:35]=[C:36]([C:38](=[N:42][O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39](O)=[O:40])[N:37]=1.P(Cl)(Cl)(Cl)=O>C(OCC)(=O)C.O1CCCC1.CN(C)C=O>[NH2:32][C:33]1[S:34][CH:35]=[C:36]([C:38](=[N:42][O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]([NH:1][CH:2]2[C:22](=[O:23])[N:4]3[C:5]([C:9]([O:11][CH2:12][C:13]4[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=4)=[O:10])=[CH:6][CH2:7][S:8][C@H:3]23)=[O:40])[N:37]=1
Reactant: Nc1nc(C(=NOCc2ccccc2)C(=O)O)cs1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1nc(C(=NOCc2ccccc2)C(=O)NC2C(=O)N3C(C(=O)OCc4ccc([N+](=O)[O-])cc4)=CCS[C@H]23)cs1
Yield: 48 %

Procedure:
A solution of 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (3.35 g.) and trimethylsilylacetamide (9.2 g.) in ethyl acetate (50 ml.) and a solution of 2-(2-aminothiazol-4-yl)-2-benzyloxyiminoacetic acid (syn isomer, 2.77 g.), trimethylsilylacetamide (0.9 g.), N,N-dimethylformamide (0.9 g.) and phosphoryl chloride (3.84 g.) in tetrahydrofuran (30 ml.) were treated in a similar manner to that of Example 4 to give 4-nitrobenzyl 7-[2-(2-aminothiazol-4-yl)-2-benzyloxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 2.85 g.).
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([C:20](=[O:27])[CH:21]=[C:22]([OH:26])[C:23](O)=[O:24])[C:8](=[O:19])[N:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH:10]=1.[OH:33][C:34]1[C:42]2[N:41]=NN[C:38]=2[CH:37]=[CH:36]C=1.C([O-])(O)=O.[Na+].O>CN(C)C=O.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([C:20](=[O:27])[CH:21]=[C:22]([OH:26])[C:23]([NH:41][C@H:42]2[CH2:38][CH2:37][CH2:36][C@@H:34]2[OH:33])=[O:24])[C:8](=[O:19])[N:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH:10]=1
Reactant: O=C(O)C(O)=CC(=O)c1cc(Cc2ccc(F)cc2F)cn(Cc2ccccc2F)c1=O
Reactant: Oc1cccc2[nH]nnc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CCC[C@@H]1O)C(O)=CC(=O)c1cc(Cc2ccc(F)cc2F)cn(Cc2ccccc2F)c1=O
Reaction time: 0.5 h

Procedure:
To a chilled solution of the 4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-hydroxy-4-oxobut-2-enoic acid 8 (150 mg, 0.338 mmol) in dimethylformamide (DMF) (2.0 mL), was added hydroxybenzotriazole (HOBT) (50 mg, 0.372 mmol), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EDCI-HCl (71 mg, 0.372 mmol). The resulting mixture was stirred for 30 min. A solution of (1S,2S)-(+)-trans-2-aminocyclopentanol hydrochloride and NaHCO3 (31 mg, 0.372 mmol) was added. The resulting mixture was stirred for 2 h at 0-5° C. Thin layer chromatography (TLC) analysis indicated completion, hence cold water was added to the reaction mixture and then extracted with ethyl acetate (2×20 mL). The combined organic phase was separated and washed with water twice, then once with 1N HCl solution, then saturated aqueous NaHCO3 solution. Concentration in vacuo afforded the crude product which was passed through a short plug of silica gel eluting with chloroform, the eluent was concentrated and the residual triturated with hexanes affording the product as a yellow solid in 117 mg (66.0%). The residual solvent was removed in vacuo affording pure product as a yellow solid, mp 60.0-62.9° C., [α]20D +24.0 (c 0.01, MeOH), UV (MeOH) 396 nm (ε 14,455), 318 nm (ε 6327). 1H NMR (CDCl3, 500 MHz): δ 15.33 (bs, 1H), 8.16 (d, 1H, J=2.0 Hz), 8.08 (s, 1H), 7.61-6.85 (m, 9H), 5.22 (s, 2H), 4.11 (m, 1H), 3.94 (m, 1H), 3.78 (s, 1H), 2.23 (m, 1H), 2.10 (m, 1H), 1.88 (m, 1H), 1.78 (m, 2H), 1.59 (m, 1H). 13C NMR (CDCl3, 125 MHz): δ 181.3, 180.6, 163.4, 163.3, 162.4, 162.1, 162.0, 161.4, 161.3, 160.4, 160.1, 160.0, 159.2, 145.5, 143.9, 142.3, 141.6, 132.4, 132.4, 132.3, 131.5, 131.4, 131.3, 131.3, 131.2, 130.7, 130.6, 125.0, 124.9, 124.8, 122.8, 122.7, 122.5, 122.2, 122.2, 122.1, 122.1, 117.1, 115.9, 115.7, 115.6, 111.9, 111.9, 111.8, 111.7, 104.7, 104.5, 104.3, 98.3, 79.5, 79.3, 61.0, 60.6, 51.5, 47.7, 47.3, 32.9, 32.8, 32.7, 30.8, 30.7, 30.5, 21.7, 21.5. HRMS (M+H)+ calculated mass 527.1794 for C28H26F3N2O5. found 527.1799.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:30]2[NH:34][C:33](=[O:35])[O:32][N:31]=2)[CH:5]=[CH:6][C:7]=1[S:8]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[CH:17][CH:18]=2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].[F:36][C:37]([F:48])([F:47])[C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1>>[F:36][C:37]([F:48])([F:47])[C:38]1[CH:43]=[CH:42][C:41]([C:2]2[C:7]([S:8]([N:11]3[C:19]4[C:14](=[CH:15][C:16]([C:20]5[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=5)=[CH:17][CH:18]=4)[CH2:13][CH2:12]3)(=[O:10])=[O:9])=[CH:6][CH:5]=[C:4]([C:30]3[NH:34][C:33](=[O:35])[O:32][N:31]=3)[CH:3]=2)=[CH:40][CH:39]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=c1[nH]c(-c2ccc(S(=O)(=O)N3CCc4cc(-c5ccc(C(F)(F)F)cc5)ccc43)c(Cl)c2)no1
Product: O=c1[nH]c(-c2ccc(S(=O)(=O)N3CCc4cc(-c5ccc(C(F)(F)F)cc5)ccc43)c(-c3ccc(C(F)(F)F)cc3)c2)no1

Procedure:
3-{4′-Trifluoromethyl-6-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-biphenyl-3-yl}-4H-[1,2,4]oxadiazol-5-one was synthesized from 3-{3-Chloro-4-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-4H-[1,2,4]oxadiazol-5-one (Example 6) by Suzuki-type reaction with 4-trifluoromethyl-phenyl boronic acid under conditions described in Example 11.
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[O:6][C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.C([Li])CCC.CN(C)[CH:30]=[O:31].P(=O)(O)(O)O>O1CCCC1.CCCCCC.C(OCC)(=O)C>[C:9]1([C:7]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:6][C:5]3[CH:21]=[CH:22][C:2]([CH:30]=[O:31])=[CH:3][C:4]=3[O:8]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Agent: O=P(O)(O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Temperature: -10 °C

Procedure:
5-Bromo-2,2-diphenyl-1,3-benzodioxol (70 g) in 440 ml of tetrahydrofuran are treated at -78° C. with 125 ml of a 1.6M solution of butyllithium in n-hexane. After 10 minutes 40 ml of dimethylformamide are added thereto and the mixture is left to warm to -10° C. Thereafter, 70 ml of 20% aqueous phosphoric acid and 500 ml of ethyl acetate are added, the organic phase is separated and evaporated. The residue is recrystallized from 130 ml of ethanol. 49.5 g of 2,2-diphenyl-1,3-benzodioxol-5-carbaldehyde are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:17][C:18]([C:20]2[S:21][C:22]([Br:26])=[CH:23][C:24]=2[NH2:25])=[O:19])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[CH2:27](O)C>>[Br:26][C:22]1[S:21][C:20]2[C:18](=[O:19])[N:17]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH2:11][N:12]4[CH2:16][CH2:15][CH2:14][CH2:13]4)=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:27]=[N:25][C:24]=2[CH:23]=1
Reactant: COc1cc(NC(=O)c2sc(Br)cc2N)ccc1OCCN1CCCC1
Reactant: CCO
Product: COc1cc(-n2cnc3cc(Br)sc3c2=O)ccc1OCCN1CCCC1

Procedure:
A solution of 3-amino-5-bromothiophene-2-carboxylic acid [3-methoxy-4-(2-pyrrolidin-1-ylethoxy)phenyl]amide (415 mg) was heated in ethyl o-formate (12.4 mL) at 105° C. overnight; the ethanol produced was distilled off. The reaction solution was then mixed with ethyl acetate and water. The aqueous phase was extracted several times with ethyl acetate, and then the combined organic phases were dried over sodium sulfate and concentrated. The product with the molecular weight of 450.36 (C19H20BrN3O3S) was obtained in this way; MS (ESI): 451, 453 (M+H+).
Reaction SMILES: C([O:8][C:9]([C:11]1[N:12]=[C:13]([CH2:29][O:30][CH3:31])[C:14]2[C:19]([C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:10])C1C=CC=CC=1.[OH-].[K+]>CCO>[CH2:22]([O:21][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:29][O:30][CH3:31])=[N:12][C:11]=1[C:9]([OH:10])=[O:8])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COCc1nc(C(=O)OCc2ccccc2)c(OCc2ccccc2)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COCc1nc(C(=O)O)c(OCc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.2 %

Procedure:
A mixture of 4-Benzyloxy-1-methoxymethyl-isoquinoline-3-carboxylic acid benzyl ester (198 mg, 0.48 mmol), KOH (325 mg, 5 mmol) and EtOH (10 ml) was stirred at ambient temperature for 18 h before the solvent was evaporated in vacuo. To the residue was added water (25 ml) and the mixture was washed with Et2O (2×25 ml). Then the solution was acidified by addition of aqueous 6N HCl and extracted with EtOAc (25 ml). The organic phase was dried over MgSO4 and concentrated in vacuo to give the title compound as a yellow oil (140 mg); MS-(+)-ion: M+1=324.1.
Reaction SMILES: [OH:1]O.O.[N:4]1([CH2:13][C:14]2[CH:15]=[CH:16][C:17]3[C:21]([S:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)=[C:20]([C:31]([OH:33])=[O:32])[S:19][C:18]=3[CH:34]=2)[C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[N:6]=[CH:5]1.Cl>C(O)(=O)C>[N:4]1([CH2:13][C:14]2[CH:15]=[CH:16][C:17]3[C:21]([S:22]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)=[O:1])=[C:20]([C:31]([OH:33])=[O:32])[S:19][C:18]=3[CH:34]=2)[C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[N:6]=[CH:5]1
Reactant: COc1cccc(Sc2c(C(=O)O)sc3cc(Cn4cnc5cnccc54)ccc23)c1
Reactant: OO
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc(S(=O)c2c(C(=O)O)sc3cc(Cn4cnc5cnccc54)ccc23)c1
Temperature: 100 °C

Procedure:
Hydrogen peroxide in water (0.07 ml of 30% w/v, 0.58 mmol) was added to a mixture of 6-(1H-Imidazo[4,5-c]pyridin-1-ylmethyl)-3-[(3-methoxyphenyl)sulfanyl]benzo[b]thiophene-2-carboxylic acid (Example 23--218 mg, 0.49 mmol) in acetic acid (2 ml), and 2M hydrochloric acid (2 ml). The solution was heated to 100° C. for 1 hour. The solution was cooled and the solvents were evaporated under reduced pressure. The residue was dissolved in a hot mixture of aqueous sodium hydroxide (5 ml of 1M) and methanol (5 ml). After acidifying the solution with acetic acid, and cooling, the precipitate was collected by filtration to give the title compound as a colourless solid (95 mg).
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1Cl.O.N[C:12]1[C:25]2[C:24](=[O:26])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:27])[C:16]=2[C:15](NC2C=CC(N)=CC=2)=[CH:14][CH:13]=1.C1C(N)=CC=C(N)C=1>CC(C)=O>[CH:19]1[C:18]2[C:17](=[O:27])[C:16]3[C:25](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:24](=[O:26])[C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(Nc2ccc(N)c3c2C(=O)c2ccccc2C3=O)cc1
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: Nc1ccc(N)cc1
Solvent: CC(C)=O
Solvent: O
Product: O=C1c2ccccc2C(=O)c2ccccc21
Reaction time: 0.55 h

Procedure:
1-18.4 g of cyanuric chloride was placed into a beaker. A small amount of crushed ice and water were added for pulping for 0.1-1 h; during which, 1-17.4 g of 1-amino-4-(p-aminoanilino) anthraquinone in 200 ml of acetone was added with the cyanuric chloride, and condensed for 4-5 h. The temperature was increased to 40° C. p-phenylene diamine was added and condensed for 4-5 h, to obtain an anthraquinone dye comprising triazinyl group and amino group.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1.[CH:30]1([NH2:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>CN(C)C=O>[CH:30]1([NH:36][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH2:13][CH2:14][O:15][C:16]4[CH:22]=[CH:21][C:20]([C:23]5[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=5)=[CH:19][C:17]=4[CH:18]=3)=[O:11])=[CH:5][CH:4]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CCO3)cc1
Reactant: NC1CCCCC1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CNC4CCCCC4)cc2)CCO3)cc1

Procedure:
A solution of N-(4-chloromethylphenyl)-7-(4-methyl-phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.15 g) and cyclohexylamine (0.17 ml) in dimethylformamide (10 ml) was stirred at room temperature for 2.5 hours. The solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethanol-hexane to give N-(4-((cyclohexylamino)methyl)phenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 114) (0.09 g) as colorless crystals.