Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([Si:6](OCC)([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:16]([OH:21])([CH2:19][CH3:20])([CH3:18])[CH3:17].[O-]CC.[Na+].C[Si](C)(C)Cl>>[C:16]([O:21][Si:6]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])([CH2:19][CH3:20])([CH3:18])[CH3:17]
Reactant: CCO[Si](OCC)(OCC)C1CCCC1
Reactant: CCC(C)(C)O
Agent: CC[O-]
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Product: CCO[Si](OCC)(OC(C)(C)CC)C1CCCC1
Yield: 78.6 %

Procedure:
In a 100 ml three-neck flask provided with a magnetic stirrer and a reflux condenser were charged 20.5 g (0.0882 mole) of cyclopentyl triethoxysilane, 128 g (1.46 mole) of tert-amyl alcohol and 0.953 g (14.0 m mole) of sodium ethoxide, which were then reacted with each other in an oil bath of 105° C. for 24 hours under stirring. Subsequently, trimethylchlorosilane was added to neutralize the alkali. Then, 19.0 g (0.0693 mole) of tert-amyloxy cyclopentyl diethoxysilane were obtained by vacuum distillation. Its structure was confirmed as in Example 1. The yield was 79%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[NH:12][CH:13]=[CH:14][N:15]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]>C(#N)C=C>[C:4]([CH2:5][CH2:6][N:15]1[CH:14]=[CH:13][N:12]=[C:11]1[S:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)#[N:1]
Reactant: O=[N+]([O-])c1ccc(Sc2ncc[nH]2)cc1
Solvent: C=CC#N
Product: N#CCCn1ccnc1Sc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 146.5 %

Procedure:
To acrylonitrile (10 ml) suspension of 2-(4-nitrophenylthio)imidazole (500 mg) was added 1,8-diazabicyclo[5.4.0]undecene-7 (0.04 ml), the reaction mixture was stirred for 1 hour under refluxing. The residue obtained by concentration was purified by use of a basic silica gel column chromatography (eluent: dichloromethane), the thus obtained solid was recrystallized from dichloromethane-tert-butylmethyl ether, there was obtained 1-(2-cyanoethyl)-2-(4-nitrophenylthio)imidazole (454 mg, yield: 74%) as colorless granular product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[NH:7][CH3:8].C(N(CC)CC)C.[C:20](Cl)(=[O:23])[CH2:21][CH3:22].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([N:7]([CH3:8])[C:20](=[O:23])[CH2:21][CH3:22])[CH:9]=1
Reactant: CCC(=O)Cl
Reactant: CNc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)N(C)c1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
5-chloro-N-methyl-2-nitroaniline (500 mg) was dissolved in methylene chloride anhydrous (9 mL), added with triethylamine (3 mL) and propionyl chloride (1 mL) and refluxed. Then, saturated sodium bicarbonate was added thereto and extracted with ethyl acetate. The extracted organic layer was washed with saturated sodium bicarbonate, dried with sodium sulfate, filtered and concentrated under reduced pressure. The concentrated filtrate was purified by column chromatography (silica gel, hexane/ethyl acetate) to obtain a target compound as a yellow solid.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][S:10][C:9]2=[CH:13][N+:14]([O-:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].C([OH:21])C.Cl>O>[C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][S:10][C:13](=[N:14][OH:16])[C:9]2=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])C=C1SCCN1Cc1ccccc1
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1C(=NO)SCCN1Cc1ccccc1

Procedure:
2.36 g (0.01 mol) of 3-phenylmethyl-2-nitromethylenethiazolidine are boiled under reflux in the mixture of 50 ml of 1N sodium hydroxide solution and 25 ml of ethanol until the dissolution of the starting substance (when, based on the TLC examination, no starting substance is detected in a sample taken from the reaction mixture). Then, the mixture is cooled, acidified by adding hydrochloric acid diluted to 1:1 with water (to a pH value of 1), the precipitated product is filtered off, washed with water and dried to give the title compound in a yield of 2,15 g (91%), m.p.: 225°-227° C.
Reaction SMILES: [C:1]([C:9]1[CH:13]=[CH:12][S:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:14]N1C(=O)CCC1=O.O>CN(C)C(=O)C.C(O)(=O)C>[C:1]([C:9]1[CH:13]=[C:12]([Br:14])[S:11][CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1ccsc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: O=C(c1ccccc1)c1csc(Br)c1
Reaction time: 8 h
Yield: 63.6 %

Procedure:
3.0 g of 3-benzoylthiophene was dissolved in 10 ml of N,N-dimethylacetamide and 1 ml of acetic acid, and 2.83 g of N-bromosuccinimide was added thereto, followed by stirring overnight. Water was added to the reaction solution, followed by extracting with diethyl ether. The extract was washed with an aqueous saturated sodium bicarbonate solution, dried over anhydrous magnesium and then evaporated. The residue was subjected to silica gel column chromatography and eluted with 10% ethyl acetate/hexan, to give 2.7 g of the target compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Cl:27])C(=O)C1.CCOC(C)=O>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]2)=[CH:6][C:7]=1[Cl:27]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)C1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(Cl)c2)C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
To a stirred solution of tert-butyl 3-(4-aminophenyl)pyrrolidine-1-carboxylate (2.00 g, CAS-908334-28-1) in DMF (15 ml) was added NCS (1.07 g) and the mixture was stirred at 70° C. for 1 hour. The reaction mixture was then cooled to room temperature and poured into EtOAc and extracted sequentially with water and with saturated brine. The organic layer was dried over Na2SO4 and then concentrated in vacuo. The residue was purified by column chromatography (SiO2, gradient: 0% to 55% EtOAc in hexanes) to afford tert-butyl (RS)-3-(4-amino-3-chlorophenyl)pyrrolidine-1-carboxylate (1.16 g, 51%) as a yellow oil which was used in the next step without further purification. MS (ISP): 299.0 ([{37Cl}M+H]+), 297.2 ([{35Cl}M+H]+), 243.0 ([{37Cl}M+H—C4H8]+), 241.1 ([{35Cl}M+H—C4H8]+).
Reaction SMILES: C[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11].Br([O-])(=O)=O.[Na+]>>[N+:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH:3]=[O:2])([O-:12])=[O:11]
Reactant: COCc1ccccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [O-][Br+2]([O-])[O-]
Product: O=Cc1ccccc1[N+](=O)[O-]

Procedure:
In the same manner as in Example 3, the operation was conducted, except that 0.67 g (4 mmols) of o-nitrobenzyl methyl ether was used in place of m-methoxybenzyl alcohol and also 0.2 g (1.35 mmols) of sodium bromate was used. With respect to the components in the reaction solution, the intended o-nitrobenzaldehyde was produced in an area ratio, as determined by gas chromatography, of 53.6% and 38.6% of o-nitrobenzyl methyl ether as a raw material was remained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:48]([CH3:49])=[CH:47][C:39]([O:40][CH:41]2[CH2:45][CH2:44][CH:43]([OH:46])[CH2:42]2)=[CH:38][C:37]=1[CH3:50]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:36]2[C:37]([CH3:50])=[CH:38][C:39]([O:40][CH:41]3[CH2:45][CH2:44][CH:43]([OH:46])[CH2:42]3)=[CH:47][C:48]=2[CH3:49])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2
Reactant: Cc1cc(OC2CCC(O)C2)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OC6CCC(O)C6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 3-(4-bromo-3,5-dimethylphenoxy)cyclopentanol following a procedure analogous to that described in Step 5 of Intermediate 1. Mass spectrum (ESI+): m/z=547 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[F:15][C:14]([F:17])([F:16])[C:12]1[CH:11]=[C:10]([C:18]2[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:32]3[CH:31]=[N:30][C:29]([NH2:28])=[CH:34][CH:33]=3)[CH:7]=2)[N:13]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)cn1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)(F)F)n3)ccn2)cn1

Procedure:
The title compound was prepared from 2-(2-chloro-pyridin-4-yl)-4-trifluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example B.4) (0.2 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.13 g, 0.6 mmol) according to the general procedure III. Obtained as a yellow solid (0.1 g, 43%). MS (ISP) 463.1 [(M+H)+]; mp 261.5° C.
Reaction SMILES: C([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([NH:19][CH2:20][CH:21]([C:23]2[O:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[CH:27]=2)[OH:22])[CH3:18])=[CH:12][CH:11]=1)(=O)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[OH:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH:17]([NH:19][CH2:20][CH:21]([C:23]2[O:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[CH:27]=2)[OH:22])[CH3:18])=[CH:14][CH:15]=1
Reactant: [H][H]
Reactant: CC(Cc1ccc(OC(=O)c2ccccc2)cc1)NCC(O)c1cc2ccccc2o1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(Cc1ccc(O)cc1)NCC(O)c1cc2ccccc2o1

Procedure:
N-[2-(4-Benzoyloxyphenyl)-1-methylethyl]-2-(2-benzofuranyl)-2-hydroxyethanamine (2 g) in ethyl acetate (150 ml) was hydrogenated over 5% palladium on charcoal at atmospheric pressure. After uptake of hydrogen had ceased the mixture was filtered and the filtrate evaporated to dryness. Chromatography of the residual oil on Kieselgel 60 (5% methanol in dichloromethane) gave the title compound, m.p. 135°-8°, (EtOAc-ether), as a 94:6 mixture of diastereoisomers.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20][C:21](=[O:23])[CH3:22])=[CH:16][C:17]=4[CH2:18][CH2:19][C:8]=3[C:7]1=[CH:6][CH2:5][C:4]2=[O:24])[CH3:2].C>C1C=CC=CC=1>[CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20][C:21](=[O:23])[CH3:22])=[CH:16][C:17]=4[CH2:18][CH2:19][C:8]=3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:24])[CH3:2]
Reactant: CC[C@]12CCC3=C(CCc4cc(OC(C)=O)ccc43)C1=CCC2=O
Solvent: c1ccccc1
Product: CC[C@]12CCC3=C(CCc4cc(OC(C)=O)ccc43)[C@@H]1CCC2=O

Procedure:
Hydrogenate 13β-ethyl-3-acetoxygona-1,3,5(10),8,14-pentaen-17-one (1.8 g.) dissolved in benzene (25 ml.) at atmospheric pressure in the presence of 10% palladized charcoal (100 mg.). After 1.1 molar equivalents of hydrogen has been absorbed (ca. 12hr.) filter off the catalyst, evaporate the filtrate under reduced pressure and recrystallize the residue from ethanol. Filter the red product through `Florisil` (60 g.) with benzene-petroleum (3:1), remove the solvent and recrystallize the product from ethanol to obtain the title product, m.p. 132.5°-134.5°; ultra-violet absorption peak at 277 mμ (ε 12,800).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br)=[CH:15][C:8]=2[O:7]1)=[O:5])[CH3:2].[OH:23][C:24]1[C:29]([CH2:30][CH2:31][CH3:32])=[C:28]([OH:33])[CH:27]=[CH:26][C:25]=1[C:34](=[O:36])[CH3:35].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>CCOCC.CN(C)C=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:33][C:28]3[CH:27]=[CH:26][C:25]([C:34](=[O:36])[CH3:35])=[C:24]([OH:23])[C:29]=3[CH2:30][CH2:31][CH3:32])=[CH:15][C:8]=2[O:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCc2ccc(OCCCCCBr)cc2O1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Solvent: CCOCC
Product: CCCc1c(OCCCCCOc2ccc3c(c2)OC(C(=O)OCC)CC3)ccc(C(C)=O)c1O
Yield: 83.1 %

Procedure:
A mixture of 1.2 g (3.23 mmoles) of racemic-7-[(5-bromopentyl)oxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid ethyl ester, 1.0 g (5.15 mmoles) of 2',4'-dihydroxy-3'-propylacetophenone, 1.8 g (13.0 mmoles) of anhydrous potassium carbonate, 30 ml of acetone, and 15 ml of N,N-dimethylformamide was stirred and refluxed for 6 hr. After being cooled, the mixture was diluted with ether. The ether phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue (2.1 g) was chromatographed on 50 g of silica gel. Elution with 19:1 toluene-ethyl acetate afforded 1.3 g (83%) of racemic-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid ethyl ester as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)=[O:4].[CH:12]1(Br)[CH2:16][CH2:15][CH2:14][CH2:13]1.[H-].[Na+]>>[CH:12]1([O:11][C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: BrC1CCCC1
Reactant: COC(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1ccc(OC2CCCC2)cc1
Temperature: 0 °C
Yield: 99.5 %

Procedure:
To 50 g of methyl p-hydroxybenzoate were added 82 g of cyclopentyl bromide. The mixture was cooled to 0° C. and 24 g of sodium hydride (in a 50% mineral oil suspension) were added in small portions. Ice bath cooling was continued until the resulting effervescence terminated. The reaction mixture then was heated to 75° C. for four hours, cooled, and 25 mL of ethanol was added dropwise. The resulting mixture was evaporated to dryness, and the residue was dissolved in a mixture of water and ether. The ether layer was separated and washed with cold 5% aqueous sodium hydroxide and then with water. The ether layer then was dried over magnesium sulfate and evaporated to dryness to give about 72 g of crude methyl p-cyclopentyloxybenzoate. The crude ester was added to 400 mL of ethylene glycol containing 100 g of potassium hydroxide. The mixture was refluxed for several hours and then was transferred to a 4 L beaker. A mixture of ice and water was added. The resulting mixture then was placed in a separatory funnel and was washed with ether. The aqueous layer was acidified by addition of concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water, and recrystallized from methanol to obtain 44.1 g of p-cyclopentyloxybenzoic acid. A solution of 8.7 g (0.024 mole) of p-cyclopentyloxybenzoic acid in 250 mL of anhydrous ether was prepared. The solution was cooled to 5° C.-10° C. and 8.85 g of thionyl chloride followed by two drops of pyridine were added. The mixture was allowed to warm to room temperature and was stirred overnight. The mixture then was evaporated to dryness, and the oily residue of p-cyclopentyloxybenzoyl chloride was dissolved in 150 mL of 1,2-dichloroethane for use as described in Example 10 below.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([Cl:21])=[C:5]([C:7]2[C:14]3[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=3[NH:12][C:10](=[O:11])[CH:9]([OH:20])[N:8]=2)[CH:6]=1.[C:22](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH3:22][N:12]1[C:10](=[O:11])[CH:9]([OH:20])[N:8]=[C:7]([C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=2[Cl:21])[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]1=2
Reactant: O=C([O-])[O-]
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)C(O)N=C(c2ccccc2Cl)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.5 %

Procedure:
To a stirring solution of lorazepam (3.21 g, 1.0×10-2 mol) in anhydrous dimethylformamide (100 ml) was added anhydrous powdered potassium carbonate (1.52 g, 1.1×10-2 mol) followed by iodomethane (0.69 ml, 1.1×10-2 mol). The mixture was stirred at room temperature for 20 hours. The solvent was evaporated under vacuum, the residue was treated with water (100 ml) and was stirred at room temperature for 2 hours. The resulting fine light yellow solid was collected by filtration and was dried under vacuum to afford 3.3 g (98%) of lormetazepam as a pale yellow solid: m.p. 201°-203° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[N:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([OH:20])=[C:12]([C:21]2[NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[S:23](=[O:32])(=[O:31])[N:22]=2)[C:11]1=[O:33].CO.[BH4-].[Li+].Cl>O1CCCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([OH:20])=[C:12]([C:21]2[NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[S:23](=[O:32])(=[O:31])[N:22]=2)[C:11]1=[O:33]
Reactant: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1N=Cc1ccccc1Br
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1NCc1ccccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 265A (0.068 g, 0.129 mmol) in tetrahydrofuran (3.0 mL) and methanol (0.011 mL, 0.258 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.184 mL, 0.368 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of approximately 2-4, diluted with water (8.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with dichloromethane/diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 4.11 (brs, 2 H) 6.24 (t, J=6.80 Hz, 1 H) 7.06 (t, J=7.54 Hz, 1 H) 7.28 (m, 3 H) 7.56 (m, 3 H) 7.67 (m, 4 H) 8.08 (dd, J=7.91, 1.29 Hz, 1 H) 16.27 (s, 1 H). (ESI−) m/z 524 (M−H)−.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([O:15][C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([C:25]#[C:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:19]=1)([CH3:14])([CH3:13])[CH3:12].N1C=CC=CC=1>C(Cl)Cl>[C:11]([O:15][C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[C:20]([C:25]#[C:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:19]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)c(C#Cc2ccccc2)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1ccc(NS(=O)(=O)c2ccccc2)c(C#Cc2ccccc2)n1
Reaction time: 1 h

Procedure:
Benzenesulfonyl chloride (20 μl, 0.4 mmol) diluted with 400 μl DCM is added to a mixture of tert-butyl-N-[5-amino-6-(2-phenylethynyl)pyridin-2-yl]carbamate B5a (40 mg, 0.13 mmol), pyridine (32 μl, 0.4 mmol) and 400 μl DCM at RT and stirred for 1 h. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 37 mg (64%). HPLC-MS: M+H=450; tR=2.16 min (*Method—2).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[S:17])[NH:4][C:5]([C:8]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[C:18]([O:22][C:23]([N:25]1[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:34](O)=[O:35])[CH:31]=2)[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].O.N1(O)C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CO.CN(C=O)C>[C:11]1([C:8]2([C:5]3[NH:4][C:3](=[S:17])[C:2]([NH:1][C:34]([C:30]4[CH:31]=[C:32]5[C:27](=[CH:28][CH:29]=4)[CH2:26][N:25]([C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[CH2:33]5)=[O:35])=[CH:7][CH:6]=3)[CH2:10][CH2:9]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(C(=O)O)cc2C1
Reactant: Nc1ccc(C2(c3ccccc3)CC2)[nH]c1=S
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2ccc(C(=O)Nc3ccc(C4(c5ccccc5)CC4)[nH]c3=S)cc2C1
Reaction time: 16 h

Procedure:
To 3-amino-6-(1-phenylcyclopropyl)pyridine-2(1H)-thione (106 mg, 0.437 mmol) was added 2-(tert-butoxycarbonyl)isoindoline-5-carboxylic acid (115 mg, 0.437 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (67.0 mg, 0.437 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (84 mg, 0.437 mmol), and DMF (437 μL) before it was stirred at ambient T for 16 h. The reaction mixture was diluted with methanol before it was passed through a cartridge of cation exchange resinto give tert-butyl 5-(6-(1-phenylcyclopropyl)-2-thioxo-1,2-dihydropyridin-3-ylcarbamoyl)isoindoline-2-carboxylate after concentration. MS (ESI) m/z: Calculated: 487.2; Observed: 488.4 (M++H).
Reaction SMILES: C[O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[NH:21][CH:22]=[C:23]([C:25]#[N:26])[N:24]=3)=[O:19])=[C:13]([C:27]3[CH2:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH2:29][CH:28]=3)[CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[OH-].[Na+].O>C1COCC1.CO>[C:25]([C:23]1[N:24]=[C:20]([C:18]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([C:5]3([C:3]([OH:4])=[O:2])[CH2:6][CH2:7][O:8][CH2:9][CH2:10]3)=[CH:12][C:13]=2[C:27]2[CH2:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH2:29][CH:28]=2)=[O:19])[NH:21][CH:22]=1)#[N:26]
Reactant: COC(=O)C1(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCC(C)(C)CC3)c2)CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CC=C(c2cc(C3(C(=O)O)CCOCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.1 %

Procedure:
To a solution of 4-[4-[(4-cyano-1H-imidazole-2-carbonyl)-amino]-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-tetrahydro-pyran-4-carboxylic acid methyl ester (as prepared in Example 16, step (f), 129 mg, 0.279 mmol) in 2 mL of 1:1 THF/MeOH was added 6 N NaOH (400 μL, 2.40 mmol). After stirring at RT for 2 d, the mixture was treated with 10 mL of H2O and washed with EtOAc (3×10 mL). The aqueous layer was acidified to pH=5 with 15% citric acid and extracted with 10:1 EtOAc-MeOH (3×10 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to afford 119 mg (95%) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.20 (d, 1H, J=8.8 Hz), 8.00 (s, 1H), 7.37 (dd, 1H, J=8.8, 2.3 Hz), 7.24 (d, 1H, J=2.3 Hz), 5.75 (m, 1H), 3.91 (m, 2H), 3.61 (t, 2H, J=11.5 Hz), 2.49 (m, 2H), 2.30 (m, 2H), 2.08 (m, 2H), 1.95 (m, 2H), 1.60 (t, 2H, J=6.1 Hz), 1.09 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C25H28N4O4, 449.2 (M+H). found 449.2.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([NH:26][C@H:27]([C:30]([OH:32])=O)[CH2:28][OH:29])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].[C:33]1([CH2:39][CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.OS1C2C=CC=CC=2N=C1>CN(C)C=O.C(OCC)(=O)C>[CH2:19]([O:18][C:16]([NH:26][CH:27]([CH2:28][OH:29])[C:30]([N:45]1[CH2:46][CH2:47][N:42]([CH2:41][CH2:40][CH2:39][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:43][CH2:44]1)=[O:32])=[O:17])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Reactant: c1ccc(CCCN2CCNCC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O[SH]1C=Nc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NC(CO)C(=O)N1CCN(CCCc2ccccc2)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.1 %

Procedure:
Dicyclohexylcarbodiimide (1.58 g) was added to an ice-cooled solution of 2.0 g of N-carbobenzyloxyserine, 1.57 g of 1-(3-phenylpropyl)piperazine and 1.04 g of 1-hydroxybenzotiazole in 30 ml of N,N-dimethylformamide. The mixture was stirred at room temperature for 24 hours, then diluted with ethyl acetate, washed in sequence with two portions of 4% aqueous sodium hydrogen carbonate, one portion of water and one portion of saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2.39 g of 1-[2-(benzyloxycarbonylamino)-3-hydroxypropionyl]-4-(3-phenylpropyl}piperazine. Melting point 95°-97° C.