Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].O.[CH2:8]=[CH:9][CH:10]=[CH2:11]>CCCCCCCC.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Pd+2]>[CH2:2]([O:1][CH:8]=[CH:9][CH:10]=[CH:11][CH2:8][CH2:9][CH2:10][CH3:11])[CH:3]([CH2:5][OH:6])[OH:4]
Reactant: C=CC=C
Reactant: OCC(O)CO
Agent: [Pd+2]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: O
Solvent: CCCCCCCC
Product: CCCCC=CC=COCC(O)CO
Temperature: 80 °C
Yield: 69.6 %

Procedure:
In a 500-mL autoclave, charged were 70 g (0.76 mol) of glycerin, 0.7 g (2.3 mmol) of bis(acetylacetonato)palladium (II), 2.7 g (5.0 mmol) of triphenylphosphine-2,2′-disulfonic acid dipotassium salt dihydrate and 35 g of water. The mixture was heated to 80° C., whereby a water-soluble liquid phase was obtained. After cooling, a hydrocarbon solvent phase containing 100 g (1.85 mol) of 1,3-butadiene dissolved in 100 g of n-octane was introduced at a time into the autoclave. While stirring, the mixture was heated to 80° C. again. The initial pressure in the autoclave showed 0.9 Mpa. After stirring at 80° C. for 12 hours, the water phase and unreacted butadiene were removed. The residue was washed with water and n-octane was removed, whereby 106 g of octadienyl glyceryl ether was obtained as a pale yellow transparent oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[S:19][C:20]=1[Cl:21])\[C:13](O)=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:32][C@@H:33]1[C:40](=[O:41])[N:39]2[C@@H:34]1[S:35][CH2:36][C:37]([CH2:58][Cl:59])=[C:38]2[C:42]([O:44][CH:45]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43].P(Cl)(Cl)(=O)OC1C=CC=CC=1.CN1CCOCC1>ClCCl>[C:1]([O:5][C:6](=[O:30])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[S:19][C:20]=1[Cl:21])\[C:13]([NH:32][C@@H:33]1[C:40](=[O:41])[N:39]2[C@@H:34]1[S:35][CH2:36][C:37]([CH2:58][Cl:59])=[C:38]2[C:42]([O:44][CH:45]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:43])=[O:14])([CH3:9])[CH3:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)O)c(Cl)s1
Agent: Cl
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS[C@H]23)c(Cl)s1
Reaction time: 3 h
Yield: 88.5 %

Procedure:
To a suspension of (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)acetic acid (20 g, 39.2 mmol) and (6R,7R)-benzhydryl 7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, Hydrochloride (18.59 g, 41.2 mmol) in Dichloromethane (DCM) (300 mL) at −30° C. was added phenyl phosphorodichloridate (7.15 mL, 47.1 mmol), followed by dropwise 4-methylmorpholine (12.94 mL, 118 mmol) over 15 mins. The mixture was stirred at the same temperature over 3 h. LCMS indicated completion of the reaction. The reaction was quenched by addition of 10% aq. citric acid (120 mL), the organic solution was separated and washed with 5% NaHCO3, brine, and dried (Na2SO4), filtered, and concentrated. The residue was purified by CombiFlash automated silica gel chromatography (330 g column, 0-45% EtOAc/Hexanes) to afford (6R,7R)-benzhydryl 7-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)acetamido)-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (29.9 g, 34.7 mmol, 89% yield) as a light yellow foaming solid. LCMS: (M+H)+: 860.3
Reaction SMILES: CO.[S:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([O:19]CCCC)=[O:18])=[CH:11][C:6]=2[CH:5]=[CH:4]1.[OH-].[K+]>O>[S:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:11][C:6]=2[CH:5]=[CH:4]1
Reactant: CCCCOC(=O)CCOCCc1ccc2sccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCOCCc1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
To methanol (5 mL) solution of 5.00 g of butyl 3-(2-(1-benzothiophen-5-yl)ethoxy)propionate was added water (5 mL) solution of 1.10 g of potassium hydroxide, which was then stirred at room temperature for 2 hours. This reaction mixture was distilled off under reduced pressure, to which were added 30 mL of toluene and 30 mL of water. The pH was adjusted to 1.6 with 3.5 mL of 6 mol/L hydrochloric acid. The organic layer was separated, followed by distilling off the solvent under reduced pressure. Thereto were added 15 mL of toluene and 30 mL of cyclohexane. The precipitate was collected by filtration to provide 3.60 g of 3-(2-(1-benzothiophen-5-yl)ethoxy)propionic acid as white solid form.
Reaction SMILES: [CH2:1]([N:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:20]=O)[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].[P:40]([OH:43])([OH:42])[OH:41].P(Cl)(Cl)Cl>O>[CH2:1]([N:19]([CH:20]([P:40]([OH:43])(=[O:41])[OH:42])[P:40]([OH:43])(=[O:42])[OH:41])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[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]
Reactant: OP(O)O
Reactant: CCCCCCCCCCCCCCCCCCN(C=O)CCCCCCCCCCCCCCCCCC
Solvent: O
Solvent: ClP(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(P(=O)(O)O)P(=O)(O)O
Yield: 65 %

Procedure:
137 parts of about 90% dioctadecylformamide and 20.5 parts of phosphorous acid were slowly reacted with 34.3 parts of phosphorus trichloride at 70°C and the mixture was maintained for 3 hours at this temperature. At this time, it was hydrolyzed with 500 parts of water. The product was filtered by suction, and the residue was dissolved in alcohol, precipitated again with acetone, isolated and dried in vacuo at 50°C over P2O5. N,N-dioctadecylaminomethanediphosphonic acid was obtained in a yield of 65%.
Reaction SMILES: [H-].[Na+].CO.[C:5](/[C:8](=[C:13](\[C:15]1[C:24]([NH:25][C:26]([O:28]CC)=O)=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)/[OH:14])/C(OC)=O)(=[O:7])[CH3:6]>C1C=CC=CC=1>[C:5]([C:8]1[C:26](=[O:28])[NH:25][C:24]2[C:15]([C:13]=1[OH:14])=[CH:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=1[CH:23]=2)(=[O:7])[CH3:6]
Reactant: CCOC(=O)Nc1cc2ccccc2cc1/C(O)=C(\C(C)=O)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: CC(=O)c1c(O)c2cc3ccccc3cc2[nH]c1=O
Temperature: 72 °C
Reaction time: 0.08 h

Procedure:
To a dispersion of sodium hydride (95%) (0.90 g, 37.5 mmol, 2.6 equiv) in benzene (100 ml) at room temperature under nitrogen was added dropwise methanol (3.0 ml, 2.37 g, 74.1 mmol, 5.2 equiv). After stirring for 5 minutes, methyl (2Z)-2-acetyl-3-{3-[(ethoxycarbonyl)amino]-2-naphthyl}-3-hydroxyprop-2-enoate (1-3) (5.06 g, 14.2 mmol, 1.0 equiv) was added and the reaction was heated to 72° C. for 20 hours. The solvent was evaporated under reduced pressure and the solid residue was stirred with water (50 ml) for 30 minutes followed by 1 N HCl (100 ml) for an additional 30 minutes. The solid was filtered, washed with water (100 ml) and hexanes (100 ml) and dried to yield 3-acetyl-4-hydroxybenzo[g]quinolin-2(1H)-one (1-4) as a yellow solid. LRMS m/z (M+H) 254.2 found, 254.1 required.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]=[O:11])=O)=[CH:4][CH:3]=1>[Pd].CO>[CH3:6][CH:5]([CH3:8])[CH2:4][CH2:3][O:11][CH2:10][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: O=CC(=O)c1ccc(O)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)CCOCCc1ccc(O)cc1
Yield: 40 %

Procedure:
An autoclave was charged with isoamyl acetal of p-hydroxyphenylglyoxal (20 g, 65 mmol), palladium catalyst (2 g, 10% Pd/C 2 mmol) and methanol (150 ml, 5% HCl). After purging with nitrogen, the autoclave was pressured to 50 psig with hydrogen. After three (3) hours, the pressure dropped to 15 psig. The reaction was then recharged with hydrogen to 50 psig for one (1) hour. Then, it was further charged with hydrogen to 200 psig and was allowed to carry out the reaction overnight at 40° C. Analysis indicated a 40% yield of the product 4-2[2'(3''-methylbutoxy)ethyl]phenol, identified by MS m/z 208 (M+), 165, 137.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[NH:4][C:5](=[S:13])[N:6]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7]=1[NH2:8].[CH:15](O)=O>>[CH2:9]([N:6]1[C:7]2[N:8]=[CH:15][NH:1][C:2]=2[C:3](=[O:14])[NH:4][C:5]1=[S:13])[CH:10]([CH3:11])[CH3:12]
Reactant: O=CO
Reactant: CC(C)Cn1c(N)c(N)c(=O)[nH]c1=S
Product: CC(C)Cn1c(=S)[nH]c(=O)c2[nH]cnc21
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
5,6-Diamino-1-isobutyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.22 g, 1.0 mmol) was suspended in formic acid (1.5 mL) and this solution was heated at 100° C. for 1 h. Excess formic acid was evaporated off under reduced pressure. 10% Sodium hydroxide (1.5 mL) was added to the orange solid and the resulting solution was heated at 100° C. for 15 minutes. Water was added and the pH of the solution adjusted to pH 4 with dilute acetic acid. The resulting slurry was stirred for 0.5 h at ambient temperature, then the precipitate was collected by filtration and washed with water. Yield: (0.21 g, 90%).
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@:3]21[CH2:25][C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:12]=1[CH2:11]2)[N:19]=[C:18]([C:22]([OH:24])=O)[CH:17]=[CH:16]3.[NH:26]1[CH2:31][CH2:30][CH:29]([N:32]2[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[CH2:35][O:34][C:33]2=[O:42])[CH2:28][CH2:27]1.C(Cl)CCl.C(N(CC)CC)C>CN(C=O)C>[O:42]=[C:33]1[O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[N:32]1[CH:29]1[CH2:30][CH2:31][N:26]([C:22]([C:18]2[CH:17]=[CH:16][C:15]3[C:20](=[CH:21][C:12]4[CH2:11][C@:3]5([C:4]6[C:5](=[N:6][CH:7]=[CH:8][CH:9]=6)[NH:10][C:2]5=[O:1])[CH2:25][C:13]=4[CH:14]=3)[N:19]=2)=[O:24])[CH2:27][CH2:28]1
Reactant: O=C1OCc2ccccc2N1C1CCNCC1
Reactant: O=C(O)c1ccc2cc3c(cc2n1)C[C@]1(C3)C(=O)Nc2ncccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc2cc3c(cc2n1)C[C@]1(C3)C(=O)Nc2ncccc21)N1CCC(N2C(=O)OCc3ccccc32)CC1

Procedure:
A mixture of (S)-2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridine]-2-carboxylic acid (15 mg, 0.045 mmol, described in Intermediate 9), 1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one (12 mg, 0.045 mmol), EDC (10 mg, 0.050 mmol), HOIST (7 mg, 0.050 mmol), and N,N,N-triethylamine (0.006 mL, 0.045 mmol) was stirred in DMF (2.5 mL) at ambient temperature for 18 h. The reaction mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions were combined and concentrated to give the title compound. MS: m/z=546 (M+1). HRMS: m/z=546.2132; calculated m/z=546.2136 for C32H28N5O4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH:7]=[C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=[O:11])[O:9]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[H][H]>[Ni].C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:10]([OH:11])=[O:9])=[CH:18][CH:19]=1
Reactant: [H][H]
Reactant: COc1ccc(C=C2OC(=O)c3ccccc32)cc1
Agent: [Ni]
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(CCc2ccccc2C(=O)O)cc1

Procedure:
To 280 ml of an ethanol solution containing 20.0 g (79.3 mmol) of 3-(4-methoxybenzylidene)phthalide were added 16.6 ml (119 mmol) of triethylamine and Raney nickel (available from Kawaken Finechemical, developed nickel catalyst NTD-65, 24 ml), and the resulting mixture was stirred at 80° C. for 2.5 hours under pressure with hydrogen (10 atm).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[C:10]([N:12]1[C@@H:19]([C:20]#[CH:21])[CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:28]1CCOCC1.C(OC(Cl)=O)C(C)C.O1CCOCC1.OS([O-])(=O)=O.[K+]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[C:10]([N:12]1[C@@H:19]([C:20]#[CH:21])[CH2:18][CH2:17][C@H:13]1[C:14]([NH2:28])=[O:16])=[O:11])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C#C[C@H]1CC[C@@H](C(=O)O)N1C(=O)[C@@H](NC(=O)OC(C)(C)C)C1CCCC1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: C1CCOC1
Product: C#C[C@H]1CC[C@@H](C(N)=O)N1C(=O)[C@@H](NC(=O)OC(C)(C)C)C1CCCC1
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (5R)-1-{(2S)-2-((tert-butoxycarbonyl)amino)-2-cyclopentylethanoyl}-5-ethynyl-L-proline (1.28 g, 3.38 mmol) in THF (25 mL) at −15° C. under nitrogen, was added 4-methylmorpholine (0.44 mL, 4.05 mmol), and isobutylchloroformate (0.5 mL, 3.72 mmol) over 2 minutes. The reaction mixture was stirred at −15° C. under nitrogen for 30 minutes, and a solution of 0.5 MNH3 in dioxane (34 mL, 16.90 mmol) was added. The reaction mixture diluted with water, the pH adjusted to 4 by the addition of 4% KHSO4 and extracted with ethyl acetate (3×). The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by flash column chromatography (5% MeOH/CH2Cl2) to provide the titled compound. MS (CI) m/e 364 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8](OC2C=CC=CC=2)=[O:9])[S:4][C:3]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].O.[NH2:23][NH2:24]>O1CCCC1>[NH:23]([C:8]([NH:7][C:5]1[S:4][C:3]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:2]([CH3:1])[CH:6]=1)=[O:9])[NH2:24]
Reactant: CCOC(=O)c1sc(NC(=O)Oc2ccccc2)cc1C
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1sc(NC(=O)NN)cc1C
Reaction time: 2.5 h
Yield: 89 %

Procedure:
To a stirred suspension of ethyl 3-methyl-5-(phenoxycarbonylamino)-thiophene-2-carboxylate (18.89 g, 61.86 mmol) in tetrahydrofuran (130 mL) was added hydrazine monohydrate (19.0 mL, 391.7 mmol). The resulting reaction mixture was stirred for 2.5 h, and then concentrated in vacuo. The residue was triturated with ethyl acetate to afford ethyl 5-(hydrazinecarboxamido)-3-methylthiophene-2-carboxylate as a yellowish solid in 89% yield (13.30 g): MS (ES+) m/z 244.2 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]2[C:9]3[C:14]([NH:15][C:16]4[CH:25]=[CH:24][C:19]5[NH:20][C:21](=[O:23])[S:22][C:18]=5[CH:17]=4)=[N:13][CH:12]=[N:11][C:10]=3[S:26][C:5]=2[CH2:4]1.[C:27]([O:31][C:32]([NH:34][C@H:35]([C:39](O)=[O:40])[CH2:36][CH2:37][OH:38])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[OH:38][CH2:37][CH2:36][C@@H:35]([NH:34][C:32](=[O:33])[O:31][C:27]([CH3:29])([CH3:28])[CH3:30])[C:39](=[O:40])[NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]2[C:9]3[C:14]([NH:15][C:16]4[CH:25]=[CH:24][C:19]5[NH:20][C:21](=[O:23])[S:22][C:18]=5[CH:17]=4)=[N:13][CH:12]=[N:11][C:10]=3[S:26][C:5]=2[CH2:4]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)O
Reactant: NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1
Product: CC(C)(C)OC(=O)N[C@H](CCO)C(=O)NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1

Procedure:
125 mg (326 μmol) (RS)-6-{[7-(aminomethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yl]amino}-1,3-benzothiazol-2(3H)-one (prepared according to example 20) were transformed in analogy to example 23 using N-(tert-butoxycarbonyl)-L-homoserine to give after working up and purification 32.2 mg (16%) of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([Cl:9])[S:6][C:5]=1[S:10]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:12])=[O:11])(=[O:3])[CH3:2].Br.C(O)(=O)C.C1C=C[NH+]=CC=1.Br[Br-]Br.[BH4-].[Na+]>C1COCC1>[Cl:9][C:7]1[S:6][C:5]2[S:10](=[O:11])(=[O:12])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH2:2][CH:1]([OH:3])[C:4]=2[CH:8]=1
Reactant: COc1ccc(NS(=O)(=O)c2sc(Cl)cc2C(C)=O)cc1
Agent: Br
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(N2CC(O)c3cc(Cl)sc3S2(=O)=O)cc1
Temperature: 3 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
The product from Step B (4.20 g, 12.14 mmol) was dissolved in THF (40 mL) containing 30% HBr in acetic acid (0.1 equiv, 0.25 mL) and cooled to 3° C. A solution of pyridinium bromide perbromide (4.32 g, 13.52 mmol) in THF (20 mL) was added and the reaction mixture allowed to warm to room temperature. The THF was evaporated and the residue dissolved in ethanol (40 mL); this solution was cooled (3° C.), sodium borohydride (pellets, 3.25 g, 86.03 mmol) added and the reaction mixture stirred at 5° C. for 1 hr followed by heating at reflux temperature for 1 hr. The reaction mixture was evaporated to a residue which was suspended in water and the pH of this suspension was adjusted to 7 with saturated aqueous ammonium chloride. This mixture was extracted with ethyl acetate (3×50 mL) and the combined extracts were dried (MgSO4). The products from two such reactions were purified by column chromatography (silica gel, 1:1 ethyl acetate/hexane) to give the desired product (3.6 g), mp 127°-132° C.; this material was used in the next reaction.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28].[CH2:29](Br)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[CH2:29]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCOC(=O)CCc1ccc(O)c(-c2cc(CCC(=O)OCC)ccc2O)c1
Reactant: CCCCCCBr
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc(CCC(=O)OCC)cc1-c1cc(CCC(=O)OCC)ccc1O
Yield: 79.9 %

Procedure:
To 4 ml of a DMF solution containing 97 mg (0.2513 mmol) of 2,2'-dihydroxy-5,5'-bis (2-ethoxycarbonylethyl) biphenyl and 363.7 μl (2.513 mmol) of hexyl bromide, there were added 41.6 mg (0.3109 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated overnight at room temperature. The reaction mixture was filtered by suction through Celite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and aqueous sodium chloride solution in this sequence and was dried by adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 10 g of WAKO-gel C-200, eluent: hexane and toluene/ethyl acetate of 100/1) to obtain 94.4 mg (0.2008 mmol, 80%) of 2-hexyloxy-2'-hydroxy-5,5'-bis (2ethoxycarbonylethyl) biphenyl as an oily product.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([OH:15])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=[N+]=[N-].Cl>CC(O)C>[NH2:1][CH2:4][C@@H:5]([OH:15])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1
Reactant: [N-]=[N+]=NC[C@@H](O)COc1ccc(F)cc1
Agent: Cl
Solvent: CC(C)O
Product: NC[C@@H](O)COc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of (R)-1-azido-3-(4-fluoro-phenoxy)-propan-2-ol (4.83 g, 22.9 mmol) NaBH4 (1.73 g, 45.8 mmol) in iPrOH (100 mL) was stirred at 80° C. for 24 h. After cooling to RT, aq. HCl (200 mL, 0.25 M) was added, washed with CH2Cl2 (100 mL). Saturated aq. K2CO3 (150 mL) was added to the aqueous phase. The product was extracted with CH2Cl2 (2×100 mL), extracts were dried over Na2SO4 and evaporated. The residue was dried under vacuum. White solid, 2.20 g (11.9 mmol, 52%). LCMS [M+H]+ 186.1
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C@H:6]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[S:21][C:22]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)=[CH:23][CH:24]=3)=[CH:14][CH:13]=2)[CH2:7][C:8]([O:10]C)=[O:9])=[N:2]1.[Li+].[OH-]>C1COCC1.CO>[O:1]1[CH:5]=[CH:4][C:3]([C@H:6]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]3[S:21][C:22]([C:25]4[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=4)=[CH:23][CH:24]=3)=[CH:16][CH:17]=2)[CH2:7][C:8]([OH:10])=[O:9])=[N:2]1
Reactant: COC(=O)C[C@@H](c1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1)c1ccon1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C[C@@H](c1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1)c1ccon1
Temperature: 25 °C
Yield: 82.7 %

Procedure:
To a solution of 61.6 (0.12 mmol) in 3:1 THF/MeOH (2.8 mL) was added 1N LiOH (0.7 mL). The mixture was stirred for 1 Hour at room temperature, quenched with 1N HCl (0.8 mL), and extracted with EtOAc. The combined organic layers were washed with water and brine, dried (Na2SO4), and concentrated to afford 61 (47 mg, 83%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.29 (d, 1H), 7.68 (d, 2H), 7.62 (d, 2H), 7.28 (d, 1H), 7.20 (d, 2H), 7.09 (d, 1H), 6.95 (d, 2H), 6.07 (d, 1H), 5.19 (s, 2H), 4.56 (t, 1H), 3.36 (dd, 1H), 2.99 (dd, 1H).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:28])[C@@H:7]([NH:15][C:16]([C:18]1[NH:27][C:21]2=[CH:22][N:23]=[C:24]([Cl:26])[CH:25]=[C:20]2[CH:19]=1)=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C>C1COCC1>[Cl:26][C:24]1[CH:25]=[C:20]2[CH:19]=[C:18]([C:16]([NH:15][C@@H:7]([CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]([OH:28])=[O:5])=[O:17])[NH:27][C:21]2=[CH:22][N:23]=1
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)c1cc2cc(Cl)ncc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium hydroxide solution (2.5 mL,2M, 5.1 mmol) was added to a solution of 2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-phenylpropionic acid ethyl ester (EXAMPLE 41, 940 mg, 2.5 mmol) in THF (30 mL) and the reaction mixture was stirred at rt for 16 h. The solvent was removed in vacuo and the solid partitioned between hydrochloric acid (2M, 40 mL) and ethyl acetate (3×40 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo to give the title compound as a yellow solid. m/z (ES+)=344 [M+H]+; RT=3.29 min.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:11]1[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:13][CH2:12]1.C1C[O:31]CC1>>[OH:31][CH:17]([CH:14]1[CH2:13][CH2:12][O:11][CH2:16][CH2:15]1)[C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19]
Reactant: O=C(CC1CCOCC1)OCc1ccccc1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: O=C(OCc1ccccc1)C(O)C1CCOCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A 1.0 M sodium bistrimethylsilylamide solution in THF (13.0 ml, 12.82 mmol) was added to anhydrous THF (15 ml), and the mixture was cooled to −78° C. A solution of benzyl 2-(tetrahydro-2H-pyran-4-yl)acetate (2.5 g, 10.68 mmol) in anhydrous THF (20 ml) was added dropwise to the mixture over 30 min. The mixture was stirred at −78° C. for one hr, and a solution of n-benzyl-benzenesulfonyloxaziridine (3.35 g, 12.82 mmol) in anhydrous THF (30 ml) was added dropwise thereto over one hr. The mixture was stirred at −78° C. for one hr, was quenched with saturated ammonium chloride, and was extracted with ether. The organic layer was washed with water and saturated brine and was dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gel column (hexane:ethyl acetate=8:2) to give the title compound as an oil (2.1 g, yield 78%).