Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][C@H:19]([C:27]([NH:29][C@H:30]([C:35]([O:37]C)=[O:36])[CH2:31][CH2:32][S:33][CH3:34])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[OH-].[Na+]>CO.CCOC(C)=O>[NH:1]([C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][C@H:19]([C:27]([NH:29][C@H:30]([C:35]([OH:37])=[O:36])[CH2:31][CH2:32][S:33][CH3:34])=[O:28])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.2 %

Procedure:
To a stirred solution of 2.0 g of Boc-Tyr-DAla-Phe-Met-OCH3 (prepared as in Step C of Example 1A) in 50 ml of methanol was added 8.0 ml of 1 N NaOH. Evaporation of the solution after stirring at room temperature for 1 hour gave a residue which was dissolved in 30 ml of EtOAc and washed with 1 N HCl (4×50 ml) and saturated NaCl (3×50 ml). The MgSO4 dried EtOAc solution was evaporated to a residue which was purified by chromatography on silica gel with a gradient of chloroform to 10% acetic acid in chloroform to give 1.12 g (57%) of Boc-Tyr-DAla-Phe-Met-OH, m.p. 135° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[CH:14]([C:19]([O:21][CH:22]([CH:24]4[CH2:26][CH2:25]4)[CH3:23])=[O:20])[C:15]([CH3:18])([CH3:17])[S:16][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:29]O.O>C(O)(=O)C.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[CH:14]([C:19]([O:21][CH:22]([CH:24]4[CH2:25][CH2:26]4)[CH3:23])=[O:20])[C:15]([CH3:18])([CH3:17])[S:16](=[O:29])[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(OC(=O)C1N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1(C)C)C1CC1
Reactant: OO
Agent: O=[W](=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(OC(=O)C1N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1(C)C)C1CC1
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
1-cyclopropylethyl 6-(2-phenylacetamido)-2,2-dimethylpenam-3-carboxylate (1.55 g.) was dissolved in acetic acid (8 cc) and sodium tungstate (10 mg.) was added thereto. To the stirred mixture was added, dropwise, 30% hydrogen peroxide (0.53 g.) while cooling in an ice bath and the mixture was stirred for a period of 30 minutes at this temperature. Water was added to the mixture and the aqueous solution was extracted with ethyl acetate. The ethyl acetate layer was washed in turn with a saturated aqueous solution of sodium bicarbonate, water, and a saturated aqueous solution of sodium chloride, dried and concentrated. The residue was dissolved in ether and the ether solution was allowed to stand. The precipitate was collected by filtration to yield crystals (1.53 g.) of 1-cyclopropylethyl 6-(2-phenylacetamido)-2,2-dimethylpenam-3-carboxylate-1-oxide, m.p. 153°-159° C.
Reaction SMILES: [N:1]([CH:4]([CH2:10][CH2:11]I)[C:5](OCC)=[O:6])=[N+:2]=[N-:3].[C:13]([O:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH2:20])([CH3:16])([CH3:15])[CH3:14]>>[N:1]([CH:4]1[CH2:10][CH2:11][N:20]([C@@H:19]([CH3:21])[C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:22])[C:5]1=[O:6])=[N+:2]=[N-:3]
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Reactant: CCOC(=O)C(CCI)N=[N+]=[N-]
Product: C[C@@H](C(=O)OC(C)(C)C)N1CCC(N=[N+]=[N-])C1=O

Procedure:
Using ethyl 2-azido-4-iodobutanoate and L-alanine tert-butyl ester, and the procedure described for Intermediate 33, the title compound was prepared as a mixture of two diastereoisomers.
Reaction SMILES: [N+:1]([C:4]([CH3:19])([CH3:18])[CH2:5][C:6]1[C:14]2[C:9](=[C:10]([N+:15]([O-])=O)[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)([O-:3])=[O:2].[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)(=O)C.N1C=CC=CC=1.[Pd]>[N+:1]([C:4]([CH3:19])([CH3:18])[CH2:5][C:6]1[C:14]2[C:9](=[C:10]([NH:15][S:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:28])=[O:27])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)([O-:3])=[O:2]
Reactant: CC(C)(Cc1c[nH]c2c([N+](=O)[O-])cccc12)[N+](=O)[O-]
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(Cc1c[nH]c2c(NS(=O)(=O)c3ccccc3)cccc12)[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 71 %

Procedure:
3-(2-Nitro-2-methylpropyl)-7-nitroindole (1.89 g, 7.2 mmol) is dissolved in ethyl acetate (75 mL) and 10% Pd/C is added (750 mg). The mixture is stirred under a balloon of nitrogen for 2-3 hours. The mixture is filtered to remove the Pd/C, and the filtrate is evaporated to give a crude oil. This crude 3-(2-nitro-2-methylpropyl)-7-aminoindole is immediately dissolved in pyridine (100 mL) and the solution is cooled with an ice bath to 0° C. Benzenesulfonyl chloride is added slowly, and the mixture is stirred for 5 minutes at this temperature before removing the ice bath. The reaction mixture is stirred overnight before being quenched by addition of 1N HCl and ethyl acetate. The aqueous layer is extracted with ethyl acetate several times and the combined organic extracts are washed twice with brine and dried over Na2SO4 to give a crude oil. The crude material is purified by flash chromatography (25% ethyl acetate/hexanes) to provide 1.9 g of 3-(2-nitro-2-methylpropyl)-7-benzenesulfonamidyl-indole (71%).
Reaction SMILES: [Na+].[Cl:2][C:3]1[CH:11]=[C:10]2[C:6](/[C:7](=[C:16](/[OH:22])\[C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)/[C:8](=[O:15])[N:9]2[C:12]([NH-:14])=[O:13])=[CH:5][C:4]=1[F:23].[I-].[Na+].[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=[O:32]>ClCCl>[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7](=[C:16]([O:22][C:31]([C:27]3[O:26][CH:30]=[CH:29][CH:28]=3)=[O:32])[C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:8](=[O:15])[N:9]2[C:12]([NH2:14])=[O:13])=[CH:5][C:4]=1[F:23]
Reactant: [NH-]C(=O)N1C(=O)/C(=C(\O)c2cccs2)c2cc(F)c(Cl)cc21
Reactant: O=C(Cl)c1ccco1
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)N1C(=O)C(=C(OC(=O)c2ccco2)c2cccs2)c2cc(F)c(Cl)cc21
Reaction time: 20 h

Procedure:
To a stirred suspension of (Z)- 6-chloro-5-fluoro-2,3-dihydro-3-(hydroxy-2-thienylmethylene)-2-oxo-1H-indole-1-carboxamide sodium salt (1.4 gm., 3.88 mmole) and sodium iodide (20 mg, 0.12 mmole) in 30 ml of dichloromethane was added 2-furoyl chloride (380 mg, 3.88 mmole). The resulting suspension was then stirred for 20 hr. at room temperature. The reaction suspension was filtered and washed with dichloromethane to remove unreacted 6-chloro-5-fluoro-2,3-dihydro-3-(hydroxy-2-thienylmethylene)-2-oxo-1H indole-1-carboxamide sodium salt. The filtrate was evaporated in vacuo to an orange solid which was chromatographed on a silica gel column (100 gm. silica gel) and eluted with dichloromethane to yield the crude titled compound as a solid. The solid was crystallized from dichloromethane and hexane to yield a yellow solid, 210 mg (12.6%): mp 215°-216° C. Anal. calcd. for C19H10ClFN2O5S: C, 52.73; H, 2.33; N, 6.47. Found: C, 52.66; H, 2.21; N, 6.46.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[C:16](Cl)(=[O:27])[O:17][CH2:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:5]([O:4][C:3]([N:2]([CH3:1])[CH:10]1[CH2:11][CH2:12][N:13]([C:16]([O:17][CH2:18][C:19]2[CH:20]=[C:21]([Cl:26])[CH:22]=[C:23]([Cl:25])[CH:24]=2)=[O:27])[CH2:14][CH2:15]1)=[O:9])([CH3:8])([CH3:6])[CH3:7]
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Reactant: O=C(Cl)OCc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)C1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1

Procedure:
A solution of tert-butyl methyl(piperidin-4-yl)carbamate (1.25 g, 5.83 mmol), 3,5-dichlorobenzyl carbonochloridate (1.537 g, 6.42 mmol) and sat. sodium bicarbonate (0.583 ml, 5.83 mmol) in DCM (15 ml) was stirred at RT for 72 hrs. The resulting mixture was extracted with DCM and the combined organic extracts were dried over MgSO4, filtered and concentrated under pressure to afford the title compound which was used without further purification.
Reaction SMILES: CC(C)([O-])C.[K+].Cl[C:8]1[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][N:9]=1.[Br:18][C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[NH2:22]>C1COCC1.[Cl-].[NH4+]>[Br:18][C:19]1[CH:20]=[C:21]([NH:22][C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][N:9]=2)[CH:23]=[C:24]([Cl:26])[CH:25]=1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: Nc1cc(Cl)cc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: FC(F)(F)c1ccnc(Nc2cc(Cl)cc(Br)c2)n1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
Potassium tert-butoxide (750 mg, 6.69 mmol) was added to a solution of 2-chloro-4-(trifluoromethyl)pyrimidine (406 mg, 2.23 mmol) and 3-bromo-5-chloroaniline (460 mg 2.23 mmol) in THF (20 mL) at 0° C. under a nitrogen atmosphere. The mixture was stirred at 70° C. for 12 hours. The mixture was then diluted with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by chromatography on silica gel to give N-(3-bromo-5-chlorophenyl)-4-(trifluoromethyl)pyrimidin-2-amine MS ESI calc'd. for C11H7BrClF3N3 [M+H]+ 352 and 354. found 352 and 354.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:6][CH2:5][CH2:4][NH:3]1.[CH2:13]([O:20][NH2:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.C(N(C(C)C)C)(C)C.C(Cl)CCl>CN(C=O)C.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH2:13]([O:20][NH:21][C:10](=[O:12])[CH2:9][CH2:8][C:7]1[C:2](=[O:1])[NH:3][CH2:4][CH2:5][CH:6]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NOCc1ccccc1
Reactant: O=C(O)CCC1=CCCNC1=O
Agent: CC(C)N(C)C(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: O=C(CCC1=CCCNC1=O)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 268 %

Procedure:
29 mg of 3-(2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid (g) was dissolved in 0.5 ml of DMF solution (0.171 mM). 30 mg of BnONH2—HCl (0.188 mM), 0.033 ml of diisopropyl methylamine (0.189 mM), 43 mg of EDC (0.224 mM) and 5 mg of DMAP (0.041 mM) were added thereto and the mixture was stirred for overnight at room temperature. The mixture was diluted with 7 ml of ethyl acetate and washed with 5% HCl (1 ml) and 1 ml of sat. NaHCO3 solution. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting compound was purified by column chromatography on Silica gel with methanol/chloroform (1:20) solvent mixture as an eluant to give 126 mg of the title compound (h) (yield: 55%).
Reaction SMILES: [C:1]1([C:12]([OH:14])=O)[CH:2]=[CH:3][CH:4]=[C:5]2[CH2:11][CH2:10][CH2:9][CH:8]=[CH:7][C:6]=12.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[NH2:38][CH:39]([CH2:49][C:50]1[CH:51]=[CH:52][C:53]2[O:57][CH2:56][C:55]([CH3:59])([CH3:58])[C:54]=2[CH:60]=1)[CH:40]([C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=1)[OH:41]>CN(C)C=O.C(OCC)(=O)C>[Cl:48][C:44]1[CH:43]=[C:42]([CH:40]([OH:41])[CH:39]([NH:38][C:12]([C:1]2[CH:2]=[CH:3][CH:4]=[C:5]3[CH2:11][CH2:10][CH2:9][CH:8]=[CH:7][C:6]=23)=[O:14])[CH2:49][C:50]2[CH:51]=[CH:52][C:53]3[O:57][CH2:56][C:55]([CH3:59])([CH3:58])[C:54]=3[CH:60]=2)[CH:47]=[CH:46][CH:45]=1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Reactant: CC1(C)COc2ccc(CC(N)C(O)c3cccc(Cl)c3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)COc2ccc(CC(NC(=O)c3cccc4c3C=CCCC4)C(O)c3cccc(Cl)c3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
To a solution of 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (239 mg, 1.27 mmol) in N,N-dimethylformamide (5 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (243 mg, 1.27 mmol) and 1-hydroxybenzotriazole monohydrate (195 mg, 1.27 mmol), and (1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-1-propanol (0.40 g, 1.21 mmol) was finally added. The mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and filtered using a glass filter filled with silica gel. The filtrate was washed with ethyl acetate and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give N-{(1RS,2SR)-2-(3-chlorophenyl)-1-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-2-hydroxyethyl}-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide (326 mg, 54%) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:11]([C:13]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)=[O:14])[N:12]=2)=[CH:4][CH:3]=1.[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)=[C:11]([C:13]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)=[O:14])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2[nH]c(-c3ccc(O)cc3)nc2C(=O)Nc2nccs2)cc1
Reactant: CN(C)CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1ccc(-c2[nH]c(-c3ccc(OCCN(C)C)cc3)nc2C(=O)Nc2nccs2)cc1

Procedure:
2-(4-Hydroxyphenyl)-5-(4-methylphenyl)-N-(2-thiazolyl)imidazole-4-carboxamide, 2-dimethylaminoethanol, triphenylphosphine and diethyl azodicarboxylate are reacted and treated in the same manner as in Example 24 to give 2-(4-(2-dimethylaminoethyloxy)phenyl)-5-(4-methylphenyl)-N-(2-thiazolyl)imidazole-4-carboxamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C:10](=[CH:11][C:12]3[C:17]2=[N:16][CH:15]=[C:14]([O:22][CH2:23][CH3:24])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([BH3-])#N.[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][CH:15]=[C:14]([O:22][CH2:23][CH3:24])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOc1cnc2c(c1)cc1n2[C@H](C)CN(C(=O)OC(C)(C)C)C1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCOc1cnc2c(c1)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21

Procedure:
This compound was prepared in analogy to Example 3, intermediate i) from (R)-7-ethoxy-4-methyl-3,4-dihydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester and sodium cyanoborohydride.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([NH:15][C:16](=[O:31])[C:17]1[CH:22]=[CH:21][C:20]([C:23]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])=[C:19]([CH3:30])[CH:18]=1)[C:5]1[NH:9][C:8]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:7]=2[N:6]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C.ClCl>ClCCl.ClCCl.C(O)C>[Cl:14][C:12]1[CH:11]=[CH:10][C:8]2[NH:9][C:5]([C@@H:4]([NH:15][C:16](=[O:31])[C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[O:24])=[C:19]([CH3:30])[CH:18]=3)[CH2:3][CH2:2][NH:1][S:33]([CH3:32])(=[O:35])=[O:34])=[N:6][C:7]=2[CH:13]=1
Reactant: Cc1cc(C(=O)N[C@@H](CCN)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Reactant: CS(=O)(=O)Cl
Agent: ClCl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc(C(=O)N[C@@H](CCNS(C)(=O)=O)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 37 %

Procedure:
Prepared analogously to Example 125 from N-[(1S)-3-amino-1-(5-chloro-1H-benzimidazol-2-yl)propyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide, methanesulfonic acid chloride, and triethylamine in dichloromethane. Yield: 37%; Rf value: 0.30 (silica gel; dichloromethane/ethanol=9:1); C24H28ClN5O4S (518.04); mass spectrum: (M+H)+=518/520 (chlorine isotope) and (M−H)−=516/518 (chlorine isotope).
Reaction SMILES: [C@@H:1]1([N:10]2[CH:14]=[CH:13][CH:12]=[C:11]2[CH:15]=[O:16])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[C:17]([C:20]1C=C(C=O)NC=1)#[C:18]C>>[C:18]([C:13]1[CH:12]=[C:11]([CH:15]=[O:16])[N:10]([C@@H:1]2[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]2[OH:3])[CH:14]=1)#[C:17][CH3:20]
Reactant: CC#Cc1c[nH]c(C=O)c1
Reactant: O=Cc1cccn1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: CC#Cc1cc(C=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1

Procedure:
4-Propynyl-1-(β-D-ribofuranosyl)pyrrole-2-carbaldehyde (Compound 18) was synthesized in the same manner as used for Compound 17, starting with 4-propynyl-2-pyrrolecarbaldehyde (Compound 16) (Non-patent Document 40) (266 mg, 2.0 mmol). After purification by RP-HPLC, Compound 18 was obtained (39 mg, 7%, 2 steps).
Reaction SMILES: [Br-].[O:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]1[CH2:13][CH2:14][CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH:39]=O.CC(C)([O-])C.[K+]>O1CCCC1>[Cl:35][C:36]1[CH:37]=[C:38](/[CH:39]=[CH:15]\[CH2:14][CH2:13][N:4]2[C:5](=[O:12])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:3]2=[O:2])[CH:41]=[CH:42][CH:43]=1
Reactant: O=C1c2ccccc2C(=O)N1CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CC/C=C\c1cccc(Cl)c1
Temperature: -75 °C
Reaction time: 0.33 h
Yield: 81.7 %

Procedure:
To a stirred suspension of (3-(1,3-dioxoisoindolin-2-yl)propyl)triphenylphosphonium bromide (17.6 g, 33.2 mmol) in tetrahydrofuran (170 mL) at ambient temperature was added 3-chlorobenzaldehyde (3.76 mL, 33.2 mmol), and the resulting mixture was cooled with a dry-ice acetone bath to −75° C. Solid potassium t-butoxide (3.72 g, 33.2 mmol) was added, and stirring was continued in the bath for an additional 20 minutes; the temperature was −80° C. The cooling bath was removed, and when the internal temperature reached −30° C., the flask was placed in a water-ice bath. The temperature eventually settled at 10° C. and was maintained for 2 hours. The reaction mixture was poured into a separatory funnel containing water (250 mL), and this was extracted with ethyl acetate (250 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel, eluting with 90/10 hexanes/ethyl acetate, to afford (Z)-2-(4-(3-chlorophenyl)but-3-enyl)isoindoline-1,3-dione as a white solid (8.46 g, 82% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.ClC1C(Cl)=CC=CC=1N1CCN([CH2:29][CH2:30][CH:31]2[CH2:33][O:32]2)CC1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:29][CH2:30][CH:31]2[CH2:33][O:32]2)[CH2:11][CH2:10]1
Reactant: Clc1cccc(N2CCN(CCC3CO3)CC2)c1Cl
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(CCC2CO2)CC1
Yield: 87 %

Procedure:
Prepared from 24 and 1-(2-methoxyphenyl)piperazine in a similar fashion as described above for 28a. Yield: 87%, 1H NMR (CDCl3): δ 2.60 (m, 2H), 2.67 (s, 4H), 2.78 (dd, J 4.9, 4.0), 3.00 (m, 1H), 3.10 (s, 4H), 3.86 (s, 3H), 6.86 (dd, J 7.8, 1.3, 1H), 6.88-7.03 (m, 3H). 13C NMR (CDCl3): δ 30.2, 47.2, 50.7, 51.0, 53.5, 55.2, 55.4, 111.2, 118.3, 121.1, 123.0, 141.4, 152.3.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].C[O:8][C:9]([C:11]1[C:15]([NH:16][C:17]([C:19]2[C:24]([NH:25][C:26]3[CH:27]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:23][CH:22]=[C:21]([CH:32]3[CH2:34][CH2:33]3)[N:20]=2)=[O:18])=[CH:14][N:13]([CH3:35])[N:12]=1)=O>>[OH:6][CH:3]([CH2:4][OH:5])[CH2:2][NH:1][C:9]([C:11]1[C:15]([NH:16][C:17]([C:19]2[C:24]([NH:25][C:26]3[CH:27]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:23][CH:22]=[C:21]([CH:32]3[CH2:34][CH2:33]3)[N:20]=2)=[O:18])=[CH:14][N:13]([CH3:35])[N:12]=1)=[O:8]
Reactant: NCC(O)CO
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: Cn1cc(NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)c(C(=O)NCC(O)CO)n1
Yield: 15 %

Procedure:
According to the general method described in step 5 of example 27, reaction of 3-amino-propane-1,2-diol with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (15%) as sticky solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])[CH2:11][O:10][C:9]1([CH3:20])[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][O:16][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:11][O:10][C:9]1([CH3:20])[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(CO)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(COS(C)(=O)=O)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a solution of 1.55 g of 4(S)-(3-hydroxy-2,2-dimethyl-propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester [177198-40-2] in 22 ml of methylene chloride at room temperature under argon is added 3.49 ml of triethylamine and 0.855 ml of methanesulfonyl chloride. The mixture is stirred at room temperature for 13 hours. The reaction is quenched by addition of 35 ml of 0.5M HCl. The mixture is extracted with methylene chloride. The organic layer is concentrated, dried over sodium sulphate and concentrated. The crude title compound is obtained as an orange oil. Rf=0.52 (1:1 EtOAc-heptane); Rt=3.64 (gradient I).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[S:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.O>CS(C)=O>[O:18]1[CH2:4][CH:17]1[C:16]1[CH:15]=[CH:14][C:13]([C:9]2[S:8][CH:12]=[CH:11][N:10]=2)=[CH:20][CH:19]=1
Reactant: C[S+](C)C
Reactant: O=Cc1ccc(-c2nccs2)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: c1csc(-c2ccc(C3CO3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To a suspension of 0.063 g (1.5 mmol) of sodium hydride in DMSO (10 mL) was added 0.300 g (1.47 mmol) of trimethylsulfonium iodide as a solution in DMSO (5 mL). After stirring at room temperature for 5 min 0.130 g (0.687 mmol) of the above aldehyde was added as a solution in DMSO (5 mL). The mixture was allowed to stir at room temperature for 2 h. The mixture was poured into H2O and washed with EtOAc. The combined organic phase was washed with H2O, dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to provide 0.129 g (92.3%) of 2-(4-oxiranyl-phenyl)-thiazole as a clear oil.