Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:26]/[OH:27])/[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([OH:23])=[O:22])=[C:15](/[CH:18]=[CH:19]\[CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1.[C:52]([O:58][CH:59](I)[CH3:60])(=[O:57])[C:53]([CH3:56])([CH3:55])[CH3:54]>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:26]/[OH:27])/[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([O:23][CH:59]([O:58][C:52](=[O:57])[C:53]([CH3:56])([CH3:55])[CH3:54])[CH3:60])=[O:22])=[C:15](/[CH:18]=[CH:19]\[CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(I)OC(=O)C(C)(C)C
Reactant: C/C=C\C1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\O)c3csc(N)n3)[C@H]2SC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C/C=C\C1=C(C(=O)OC(C)OC(=O)C(C)(C)C)N2C(=O)C(NC(=O)/C(=N\O)c3csc(N)n3)[C@H]2SC1
Reaction time: 0.75 h
Yield: 22 %

Procedure:
To a mixture of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-1-propenyl]-3-cephem-4-carboxylic acid (250 mg, 0.61 mmol), K2CO3 (124 mg, 0.90 mmol) and 18-crown-6 (24 mg) in DMF (2.5 ml) was added 1-pivaloyloxyethyl iodide (461 mg, 1.8 mmol) at 5° C. and the mixture was stirred for 45 min at the same temperature. The mixture was diluted with ethyl acetate, washed with water and evaporated under reduced pressure. The residue was chromatographed on a column of silica gel (10 g) and the column was eluted with chloroform containing 1% methanol. The fractions containing the desired product were combined and evaporated under reduced pressure. The residue was dissolved in a small amount of benzene and freeze-dried to give 72 mg (21%) of the product as an amorphous powder.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.[Cl:27][CH2:28][CH2:29][CH2:30]/[C:31](=[CH:35]\[C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH:46]=[C:45]([CH3:47])[N:44]=[CH:43]2)=[C:38]([O:48][CH3:49])[CH:37]=1)/[C:32]([OH:34])=[O:33].Cl.Cl.[CH3:52][O:53][C:54]([O:63][CH3:64])([C:57]1[CH:62]=[CH:61][N:60]=[CH:59][CH:58]=1)[CH2:55]N>CN(C=O)C.O.C(OCC)(=O)C.C(Cl)CCl>[Cl:27][CH2:28][CH2:29][CH2:30]/[C:31](=[CH:35]\[C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH:46]=[C:45]([CH3:47])[N:44]=[CH:43]2)=[C:38]([O:48][CH3:49])[CH:37]=1)/[C:32]([O:34][CH2:55][C:54]([O:63][CH3:64])([O:53][CH3:52])[C:57]1[CH:58]=[CH:59][N:60]=[CH:61][CH:62]=1)=[O:33]
Reactant: COC(CN)(OC)c1ccncc1
Reactant: COc1cc(/C=C(\CCCCl)C(=O)O)ccc1-n1cnc(C)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1cc(/C=C(\CCCCl)C(=O)OCC(OC)(OC)c2ccncc2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.8 %

Procedure:
EDC (1.28 g), HOBT (902 mg) and IPEA (2.33 mL) were sequentially added to a solution of 5-chloro-2-{1-[3-methoxy-4-(4-methylimidazol-1-yl)phenyl]-(E)-methylidene}valeric acid trifluoroacetic acid salt (1 g) and β,β-dimethoxy-4-pyridineethaneamine dihydrochloride (740 mg) as a known compound (CAS #167897-36-1) in DMF (15 mL), and the reaction solution was stirred at room temperature for 12 hours. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The resulting organic layer washed with brine and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: heptane:ethyl acetate=1:2) to obtain 822 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][C:6]2[N:7]=[CH:8][NH:9][C:5]=2[CH:4]=1>Br>[NH:7]1[C:6]2[CH:10]=[CH:11][C:3]([OH:2])=[CH:4][C:5]=2[N:9]=[CH:8]1
Reactant: COc1ccc2nc[nH]c2c1
Agent: Br
Product: Oc1ccc2[nH]cnc2c1
Temperature: 25 °C
Yield: 154.9 %

Procedure:
A solution of 5-methoxybenzimidazole (500 mg, 3.374 mmol) in 48% hydrobromic acid (10 mL) was refluxed for 2 hours. The reaction was cooled to room temperature, the solvent removed by rotary evaporation under vacuum, and the residue azeotroped with toluene (50 mL) to provide the title compound as a tan solid (701 mg, 96%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[NH:38][N:37]=[N:36][N:35]=3)[CH2:24][CH:23]2[OH:39])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[NH:38][N:37]=[N:36][N:35]=3)[CH2:24][C:23]2=[O:39])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: O=C(NC1(C(=O)NC2CCN(c3ccccc3-c3nnn[nH]3)CC2O)CCCCC1)c1cc2ccccc2o1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(NC1(C(=O)NC2CCN(c3ccccc3-c3nnn[nH]3)CC2=O)CCCCC1)c1cc2ccccc2o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 43.1 %

Procedure:
To the solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-[2-(1H-tetrazol-5-yl)phenyl]piperidin-3-ol (120 mg, 0.22 mmol) obtained in Step 2 in 5 ml of dimethyl sulfoxide (DMSO), was added 0.093 ml of triethylamine (0.66 mmol). The reaction mixture was cooled to 0° C. Pyridine-SO3 complex (103 mg, 0.66 mmol) was added to the reaction mixture, which was then stirred for about 2 hours at room temperature. The reaction mixture was diluted with 100 ml of ethyl acetate, washed with brine. The resulting organic layer was dried on sodium sulfate. The resulting residue was purified with column chromatography to give 50 mg of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.[O:16]1[CH2:21][CH2:20][CH2:19][O:18][CH:17]1[C:22]1[N:26]([CH3:27])[C:25](I)=[N:24][CH:23]=1>C1COCC1.[OH-].[NH4+].CCOC(C)=O.[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:18]1[CH2:19][CH2:20][CH2:21][O:16][CH:17]1[C:22]1[N:26]([CH3:27])[C:25]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:8]=2)=[N:24][CH:23]=1
Reactant: Clc1ccnc2ccsc12
Reactant: Cn1c(C2OCCCO2)cnc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1c(C2OCCCO2)cnc1-c1cc2nccc(Cl)c2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.1 %

Procedure:
To a solution of 7-chlorothieno[3,2-b]pyridine (1) [Klemm, L. H.; Louris, J. N.; Boisvert, W.; Higgins, C.; Muchiri, D. R.; J. Heterocyclic Chem., 22, 1985, 1249-1252](11.7 g, 69.0 mmol) in THF (300 mL) was added, at −78° C., a solution of n-BuLi (30.46 mL, 76 mmol, 2.5 M in hexanes) and the reaction mixture was stirred for 10 min. A solution of ZnCl2 (76.15 mL, 76 mmol, 1.0 M in Et2O) was added and the mixture was stirred at RT for 10 min. Pd(PPh3)4 (2.287 mg, 0.104 mmol) was added along with a solution of 39 (5.82 g, 19.79 mmol) in THF (20 mL) and the reaction mixture was heated to reflux under an atmosphere of N2 gas for 4 hours. The reaction was then cooled to RT, and diluted with ammonium hydroxide and EtOAc. The organic phase was collected, dried over Na2SO4, filtered and concentrated. The resultant material was triturated with Et2O to afford the title compound 40 (5.79 g, 87% yield) as a white solid. MS (m/z): 336.1 (M+H).
Reaction SMILES: [CH2:1]([N:8]([CH2:25][CH:26](OCC)OCC)[C:9]([CH:11]([NH2:24])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19]C(C)(C)C)=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([NH:40][C:41](=[O:51])[NH:42][CH:43]([CH2:48]C=C)[CH2:44][C:45](O)=[O:46])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(O)=O>[CH2:33]([NH:40][C:41]([N:42]1[CH:43]([CH3:48])[CH2:44][C:45](=[O:46])[N:24]2[CH:11]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)[C:9](=[O:10])[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:25][CH:26]12)=[O:51])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: C=CCC(CC(=O)O)NC(=O)NCc1ccccc1
Reactant: CCOC(CN(Cc1ccccc1)C(=O)C(N)Cc1ccc(OC(C)(C)C)cc1)OCC
Solvent: O=CO
Product: CC1CC(=O)N2C(Cc3ccc(O)cc3)C(=O)N(Cc3ccccc3)CC2N1C(=O)NCc1ccccc1
Yield: 44.1 %

Procedure:
A solution of crude 3-(3-Benzyl-ureido)-hex-5-enoic acid [1-[benzyl-(2,2-diethoxy-ethyl)-carbamoyl]-2-(4-tert-butoxy-phenyl)-ethyl]-amine (3.26 g, 4.95 mmol) in formic acid (100 mL) was stirred at room temperature for 13 h. The solvent was removed under reduced pressure and then diluted with EtOAc, washed with water and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo. The residue was purified by chromatography and recrystallized on ethyl acetate and hexane to give the 8-Benzyl-6-(4-hydroxy-benzyl)-2-methyl-4,7-dioxo-hexahydro-pyrazino[1,2-a]pyrimidine-1-carboxylic acid benzylamide (1.12 g, 3 step yield: 38%). 1H NMR (CDCl3, 300 MHz) δ 7.5˜7.3 (m, 5H), 7.2 (d, J=7.01, 2H), 6.80 (m, 5H), 6.5 (d, J=8.76, 2H), 5.6 (m, 1H), 5.25 (t, J=4.7, 1H), 4.55 (m, 1H), 4.5˜4.25 (m, 4H, OH), 3.5˜3.3 (m, 2H), 3.25-3.1 (m, 2H), 2.2 (t, J=7.2, 2H) 1.36 (m, 3H) MS ESI 513 (M+H), 535 (M+Na).
Reaction SMILES: C([N:8]([CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:9][C:10]([F:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(O)C.[OH-].[OH-].[Pd+2]>[CH:18]1([NH:8][CH2:9][C:10]([F:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CCOC(=O)C(C)(F)CN(Cc1ccccc1)C1CCCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CCOC(=O)C(C)(F)CNC1CCCC1
Yield: 84.8 %

Procedure:
A solution of ethyl 3-(benzyl(cyclopentyl)amino)-2-fluoro-2-methylpropanoate (3.5 g, 11.4 mmol) in ethanol (30 mL) was hydrogenated with Pd(OH)2 (20%, 400 mg, 0.57 mmol) in presence of TFA (11.4 mmol) at atmospheric pressure for 20 h. The reaction mixture was filtered through celite. The filtrate was concentrated and diluted to EtOAc/H2O, aqueous layer was basified to pH=11-12 by 1N NaOH. The organic layer was then dried and concentrated to give the product (2.1 g, 85%) as light yellow liquid. [M+H] calc'd for C11H20FNO2, 218; found 218.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][OH:12]>C[O-].[Na+]>[CH3:11][O:12][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(C(=O)O)cn1

Procedure:
To a suspension of 6-chloropyridine-3-carboxylic acid (4.15 g) in methanol (40 cc), 4 M methanolic sodium methylate solution (40 cc) is added. The mixture is heated under reflux for 60 hours. The solvent is distilled off under reduced pressure (4 kPa). The residue is taken up in distilled water (100 cc) and the mixture is acidified to pH 5 with hydrochloric acid in 11.9 M aqueous solution. The precipitate produced is separated by filtration, washed with distilled water (5×10 cc) and dried in the air. 6-Methoxypyridine-3-carboxylic acid (3.3 g) is produced, m.p. 180° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[C:14]=1[O:15][CH2:16][C@@H:17]1[CH2:19][O:18]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.NCC1CCN([C:28]2[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=2[S:36]([NH2:39])(=[O:38])=[O:37])CC1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[C:14]=1[O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][NH:6][CH2:5][CH:13]1[CH2:14][CH2:2][N:39]([S:36]([C:29]2[CH:28]=[CH:33][C:32]([O:34][CH3:35])=[CH:31][CH:30]=2)(=[O:37])=[O:38])[CH2:11][CH2:12]1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: Brc1ccc2[nH]c3ccccc3c2c1OC[C@@H]1CO1
Reactant: COc1ccc(S(N)(=O)=O)c(N2CCC(CN)CC2)c1
Product: COc1ccc(S(=O)(=O)N2CCC(CNC[C@H](O)COc3c(Br)ccc4[nH]c5ccccc5c34)CC2)cc1
Yield: 100.9 %

Procedure:
Prepared from 3-bromo-4-[(2S)-oxiranylmethoxy]-9H-carbazole (0.083 g, 0.26 mmol) and (4-aminomethyl-1-piperidinyl) 4-methoxybenzenesulfonamide (0.142 g, 0.5 mmol) according to procedure used for Example 2 to give 0.079 g of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:10][CH:9]([C:11](=[O:30])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:15][C:14]=2[F:29])[NH:8][N:7]=1)=[O:5])[CH3:2].N1C=CC=CC=1.[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]=[C:45]=[O:46])=[CH:40][CH:39]=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH2:10][CH:9]([C:11](=[O:30])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:15][C:14]=2[F:29])[N:8]([C:45](=[O:46])[NH:44][C:41]2[CH:42]=[CH:43][C:38]([Cl:37])=[CH:39][CH:40]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C1=NNC(C(=O)Nc2ccc(-c3ccccc3S(C)(=O)=O)cc2F)C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1=NN(C(=O)Nc2ccc(Cl)cc2)C(C(=O)Nc2ccc(-c3ccccc3S(C)(=O)=O)cc2F)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(3-Fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester (1.520 g) in methylene chloride (12 ml) was added pyridine (4 equiv.) and 4-chlorophenyl isocyanate (1.25 equiv.). Stirred at room temperature for 16 hours. Evaporated and recorded crude 1H: 80156×134RM1—revealed expected product and relatively clean. Purified by silica gel chromatography, eluant 10-100% EtOAc in hexane over 25 mins. Collected 1-(4-chloro-phenylcarbamoyl)-5-(3-fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester (1.480 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:12]1[CH:20]=[CH:19][C:15]3[O:16][CH2:17][O:18][C:14]=3[CH:13]=1)=[C:6]([OH:21])[C:5]2=[O:22].[Br:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>N1C=CC=CC=1>[O:16]1[C:15]2[CH:19]=[CH:20][C:12]([C:7]3[O:8][C:9]4[C:4]([C:5](=[O:22])[C:6]=3[OH:21])=[CH:3][C:2]([NH:1][S:30]([C:27]3[CH:28]=[CH:29][C:24]([Br:23])=[CH:25][CH:26]=3)(=[O:32])=[O:31])=[CH:11][CH:10]=4)=[CH:13][C:14]=2[O:18][CH2:17]1
Reactant: Nc1ccc2oc(-c3ccc4c(c3)OCO4)c(O)c(=O)c2c1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: c1ccncc1
Product: O=c1c(O)c(-c2ccc3c(c2)OCO3)oc2ccc(NS(=O)(=O)c3ccc(Br)cc3)cc12
Yield: 91.6 %

Procedure:
100 mg (336 pmol) of 6-amino-2-(benzo[1,3]dioxol-5-yl)-3-hydroxy-4H-chromen-4-one obtained in Example 24 was dissolved in 3 ml of pyridine, and the mixture was reacted with 2 molar equivalents of 4-bromobenzenesulfonylchloride at room temperature for 5 hours. After the reaction was completed, the product was diluted with 10 ml. of water, and the obtained solid was filtered. Then the resulting product was washed with water and ethylether, and dried to give 159 mg of the title compound in a yield of 91.6%.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:10].[F:24][C:25]1([F:37])[O:29][C:28]2[CH:30]=[CH:31][CH:32]=[C:33]([C:34](O)=[O:35])[C:27]=2[O:26]1>>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:4]2[C@H:3]([CH2:2][NH:1][C:34]([C:33]3[C:27]4[O:26][C:25]([F:37])([F:24])[O:29][C:28]=4[CH:30]=[CH:31][CH:32]=3)=[O:35])[CH2:8][C@H:7]3[C@@H:5]2[CH2:6]3)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1
Reactant: O=C(O)c1cccc2c1OC(F)(F)O2
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3cccc4c3OC(F)(F)O4)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 2,2-difluoro-benzo[1,3]dioxole-4-carboxylic acid. LC-MS (basic): tR=0.94 min; [M+H]+=516.1.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:12](Cl)(=[O:14])[CH3:13]>N1C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12](=[O:14])[CH3:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccc2ncccc2c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2ncccc2c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 68.9 %

Procedure:
Quinolin-6-ol (135 g, 0.93 mol) was dissolved in pyridine (500 mL) and cooled to 0° C. in an ice-bath under a flow of nitrogen. Acetyl chloride (79 mL, 1.16 mol) was added to the reaction mixture slowly. Then it was stirred at room temperature for 3 hours. The mixture was partitioned between ethyl acetate (400 mL) and saturated aqueous NaHCO3 (200 mL). The organic phase was separated and washed with brine (5*200 mL). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography to afford 120 g of acetic acid quinolin-6-yl ester as white solid (69% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.[Br:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1I>>[Br:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[S:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(S)c1
Reactant: Fc1ccc(I)c(Br)c1
Product: COc1cccc(Sc2ccc(F)cc2Br)c1

Procedure:
Prepared from 3-methoxy-benzenethiol and 2-bromo-4-fluoro-1-iodo-benzene.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[S:11][C:12]4[C:17]([N:18]=3)=[CH:16][CH:15]=[C:14]([C:19]3([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:21][CH2:20]3)[N:13]=4)=[CH:9][C:4]=2[N:3]=[CH:2]1.CN1CCCN2C1=NCCC2.[C:39]([O:43][CH2:44][CH3:45])(=[O:42])[CH:40]=[CH2:41]>C(#N)C>[C:22]1([C:19]2([C:14]3[N:13]=[C:12]4[S:11][C:10]([C:8]5[CH:7]=[CH:6][C:5]6[N:1]([CH2:41][CH2:40][C:39]([O:43][CH2:44][CH3:45])=[O:42])[CH:2]=[N:3][C:4]=6[CH:9]=5)=[N:18][C:17]4=[CH:16][CH:15]=3)[CH2:20][CH2:21]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(C2(c3ccc4nc(-c5ccc6[nH]cnc6c5)sc4n3)CC2)cc1
Reactant: C=CC(=O)OCC
Agent: CN1CCCN2CCCN=C12
Solvent: CC#N
Product: CCOC(=O)CCn1cnc2cc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2-(1H-benzo[d]imidazol-5-yl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (100 mg, 0.271 mmol) was added acetonitrile (2.7 mL) before 7-methyl-1,5,7-triazabicyclo(4.4.0)dec-5-ene (1.949 μL, 0.014 mmol) and ethyl acrylate (36.2 μL, 0.326 mmol) were added and stirred at ambient temperature for 2 h to give a 2:1 mixture of regioisomers. Ethyl 3-(5-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)-1H-benzo[d]imidazol-1-yl)propanoate was obtained after regioisomer separation via SFC (Column: ChiralPak AD-H; Mobile Phase: 50:50 liquid CO2/isopropanol with 0.2% isopropylamine). MS (ESI) m/z: Calculated: 468.2; Observed: 469.2 (M++H).
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[N:9]=[C:10]([NH:13][C:14]([C:16]2[C:21]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[CH:20][CH:19]=[C:18]([CH3:29])[N:17]=2)=[O:15])[S:11][CH:12]=1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[OH:6][CH2:7][C:8]1[N:9]=[C:10]([NH:13][C:14]([C:16]2[C:21]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[CH:20][CH:19]=[C:18]([CH3:29])[N:17]=2)=[O:15])[S:11][CH:12]=1
Reactant: Cc1ccc(Nc2cncnc2)c(C(=O)Nc2nc(C(C)(C)O[SiH2]C(C)(C)C)cs2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(Nc2cncnc2)c(C(=O)Nc2nc(CO)cs2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
To a solution of 40 mg (0.088 mmol) of 6-Methyl-3-(pyrimidin-5-ylamino)-pyridine-2-carboxylic acid [4-(tert-butyl-dimethyl-silanyloxymethyl)-thiazol-2-yl]-amide in 1 ml of methylene chloride was added 200 mg (1.75 mmol, 20.0 equiv.) of Trifluoroacetic acid. After stirring for 2 h at room temperature, saturated sodium carbonate solution was added, and the pH was adjusted to 8. The aqueous phase was extracted three times with methylene chloride. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vaccuo. The residue (28 mg, yellow solid) was triturated with Diisopropyl ether, filtered and dried to yield the title compound (17 mg, 57%) as a light yellow solid, MS (ISP): m/e=343.1 (M+H+).
Reaction SMILES: [H-].[Na+].Cl.[CH2:4]1[O:17][C:16]2[C:6](=[CH:7][C:8]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10][C:9]=3[CH:15]=2)[O:5]1.[F:18][C:19]1[CH:30]=[CH:29][C:22]([C:23]([CH2:25][CH2:26][CH2:27][Cl:28])=[O:24])=[CH:21][CH:20]=1.O>CN(C=O)C>[ClH:28].[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([CH2:25][CH2:26][CH2:27][N:12]2[CH2:13][CH2:14][C:8]3[CH:7]=[C:6]4[O:5][CH2:4][O:17][C:16]4=[CH:15][C:9]=3[CH2:10][CH2:11]2)=[O:24])=[CH:29][CH:30]=1
Reactant: c1c2c(cc3c1OCO3)CCNCC2
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCCN1CCc2cc3c(cc2CC1)OCO3)c1ccc(F)cc1
Temperature: 0 °C

Procedure:
The sodium hydride obtained by washing 1.95 g of the 54% dispersion (0.042 moles) with benzene was used to prepare the sodium salt from 4.54 g. of 2,3,4,5-tetrahydro-7,8-methylenedioxy-1H-3-benzazepine hydrochloride in 50 ml of DMF as described in Example 35. Treatment of the suspension with 4.41 g of 3-(4-fluorobenzoyl)propyl chloride (0.022 moles) for 24 hours at 55°-60° followed by decomposition with 200 ml of ice water gave an oil-water suspension. The base was recovered by extraction with benzene (3 × 50 ml), the combined extracts washed once with water, then dried, and the solvent distilled in the rotary evaporator. To the residual oil, 3N hydrochloric acid was added and the mixture digested for an hour. After cooling the salt was filtered off, mp 195°14 197°. Two further recrystallizations from water gave the above-named product as a buff colored salt, mp 209°-210°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1C=C[C:18]([S:21]([CH2:24]C#N)(=[O:23])=[O:22])=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11](=[C:24]([S:8]([CH3:5])(=[O:10])=[O:9])[S:21]([CH3:18])(=[O:23])=[O:22])[C:12]#[N:13])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: N#CCS(=O)(=O)c1ccc(Cl)cc1
Reactant: N#CCS(=O)(=O)c1ccc(F)cc1
Product: CS(=O)(=O)C(=C(C#N)S(=O)(=O)c1ccc(F)cc1)S(C)(=O)=O

Procedure:
The titled compound was prepared in an analogous fashion to Intermediate 2 except that 2-(4-fluoro-benzenesulfonyl) acetonitrile is utilized in place of 2-(4-chlorobenzenesulfonyl) acetonitrile.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl[C:13]1[C:14]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)=[CH:23][C:15]=2[S:16][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[C:35]1([SH:41])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O>[C:35]1([S:41][C:13]2[C:14]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)=[CH:23][C:15]=3[S:16][C:17]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Sc1ccccc1
Reactant: CCOC(=O)c1sc2cc(OCc3cccnc3)ccc2c1Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1sc2cc(OCc3cccnc3)ccc2c1Sc1ccccc1
Temperature: 60 °C
Yield: 78.6 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU--1.46 ml, 9.5 mmol) was added to a mixture of ethyl 3-chloro-6-(3-pyridylmethoxy)benzo[b]thiophene-2-carboxylate (Preparation 4, 3.0 g, 8.6 mmol) and thiophenol (1.76 ml, 17.2 mmol) in dimethylformamide (15 ml) under a nitrogen atmosphere. The solution was heated to 60° C. for 5 hours and then partitioned between diethyl ether and water. The organics were separated and washed with water, dried (magnesium sulfate) and evaporated under reduced pressure. The residue was flash chromatographed on silica gel using diethyl ether, and then ethyl acetate, as eluant. The isolated product was crystallised from diethyl ether and hexane to give the title compound as a colourless solid (2.85 g).