Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2([CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4]1>C1COCC1>[O:3]1[C:7]2([CH2:12][CH2:11][C:10](=[CH:8][C:7]([O:3][CH2:4][CH3:5])=[O:6])[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4]1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 216.7 %

Procedure:
To a suspension of NaH (60% mineral oil suspension, 33.3 g, 832.38 mmol) in anhydrous THF (1 L) was added a solution of 1,4-dioxaspiro[4.5]decan-8-one (100 g, 640.29 mmol) in anhydrous THF (500 mL) dropwise at 0° C. in 1 h and the reaction mixture was stirred for another 1 h. Then triethyl phosphonoacetate (203.23 g, 832.38 mmol) was added dropwise to the above suspension at −20° C. in 1 h. The resulting mixture was allowed to warm to rt, stirred for another 2 h, then quenched with H2O (1 L) and extracted with EtOAC (1 L×3). The combined organic phases were washed with brine (1 L), dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/10) to give the title compound as pale yellow oil (157 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[O:5][C:6]=1Br.[Cl-].[CH3:13][Zn+]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[O:5][C:6]=1[CH3:13]
Reactant: C[Zn+]
Reactant: COC(=O)c1cc(Br)c(Br)o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)c(C)o1
Temperature: 25 °C
Reaction time: 20 h
Yield: 50.7 %

Procedure:
Methyl 4,5-dibromo-2-furancarboxylate (3.7 g, 13.03 mmol) [prepared according to Example 127] and trans-dichlorobis(triphenylphosphine)Palladium (II) (0.46 g, 0.65 mmol) were combined in THF (50 ml) to give a yellow suspension. A THF solution of methylzinc chloride (11.40 ml, 22.81 mmol) was added dropwise at room temperature. After stirring at ambient temperature for 20 h, the solution was concentrated and purified using silica gel and eluting with 0-30% ethyl acetate/hexane to generate the title compound as a white solid (1.45 g, 6.61 mmol, 51% yield): LC-MS (ES) m/z 220 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])[N:11]([CH3:28])[C:10]=1[C:29](O)=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32]([NH:35]C(C1N(C)C(CNS(C2C=CC=CC=2)(=O)=O)=CC(=O)C=1OCC1C=CC=CC=1)=O)([CH3:34])[CH3:33]>>[CH:32]([NH:35][C:29]([C:10]1[N:11]([CH3:28])[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])=[CH:13][C:14](=[O:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:30])([CH3:34])[CH3:33]
Reactant: CC(C)NC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2ccccc2)n1C
Reactant: Cc1cccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(C(=O)O)n2C)c1
Product: Cc1cccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(C(=O)NC(C)C)n2C)c1
Yield: 45.7 %

Procedure:
3-Benzyloxy-1-methyl-4-oxo-6-[(toluene-3-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid isopropylamide (17-04) (250.0 mg, 45.70%) was synthesized as a white solid from 3-benzyloxy-1-methyl-4-oxo-6-[(toluene-3-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid (13-04) (500.0 mg, 1.13 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid isopropylamide (17-01).
Reaction SMILES: [C:1]([CH:3]([O:7][C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([F:19])[C:17]=1[F:18])[CH2:14][CH:13]([CH:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][CH3:28])[CH2:22][CH2:21]1)[CH2:12][CH2:11]2)[CH2:4][CH2:5][CH3:6])#[CH:2].Cl>C(N(CC)C1C=CC=CC=1)C>[F:18][C:17]1[C:8]2[O:7][CH:3]([CH2:4][CH2:5][CH3:6])[CH:1]=[CH:2][C:9]=2[C:10]2[CH2:11][CH2:12][CH:13]([CH:20]3[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][CH3:28])[CH2:22][CH2:21]3)[CH2:14][C:15]=2[C:16]=1[F:19]
Reactant: C#CC(CCC)Oc1cc2c(c(F)c1F)CC(C1CCC(CCC)CC1)CC2
Agent: Cl
Solvent: CCN(CC)c1ccccc1
Product: CCCC1CCC(C2CCc3c4c(c(F)c(F)c3C2)OC(CCC)C=C4)CC1

Procedure:
4.5 g (11.6 mmol) of 6-(1-ethynylbutoxy)-7,8-difluoro-2-(4-propylcyclohexyl)-1,2,3,4-tetrahydronaphthalene are heated at 200° C. for 2 h in 45 ml of N,N-diethylaniline. After cooling, the batch is added to a mixture of 2 N hydrochloric acid and ice, and the mixture is extracted with MTBE. The organic phase is washed with 2 N hydrochloric acid and water, and the solution is dried using sodium sulfate. The residue remaining after removal of the solvent is purified by column chromatography (SiO2, n-heptane:toluene=9:1), giving 5,6-difluoro-3-propyl-8-(4-propylcyclohexyl)-7,8,9,10-tetrahydro-3H-benzo[f]chromene as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([O:10][C:11]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22]2[N:23]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([CH:31]=O)=[CH:26][CH:25]=3)=[C:16]2[C:12]=1[CH2:13][NH:14][C:15]2=[O:40])(=[O:9])=[O:8].[NH:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([O:10][C:11]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22]2[N:23]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([CH2:31][N:41]2[CH2:45][CH2:44][CH2:43][CH2:42]2)=[CH:26][CH:25]=3)=[C:16]2[C:12]=1[CH2:13][NH:14][C:15]2=[O:40])(=[O:8])=[O:9]
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(=O)(=O)c1ccccn1)CNC2=O
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1cc(-c2cc3cc(CN4CCCC4)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(=O)(=O)c1ccccn1)CNC2=O
Yield: 31.8 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-(2-pyridinesulfonyloxy)-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (0.332 g, 0.589 mmol) was dissolved in acetonitrile (10.0 mL), and the solution was treated with pyrrolidine (0.983 mL, 11.8 mmol), acetic acid (0.674 mL, 11.8 mmol) and sodium triacetoxyborohydride (0.375 g, 1.77 mmol), followed by purification of the residue by flash column chromatography (chloroform/methanol=85/15) to obtain 4-(2-pyridinesulfonyloxy)-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-(pyrrolidin-1-ylmethyl)indol-2-yl]isoindolinone (0.116 g, 32%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])=[CH:9][NH:8][C:7]=1[CH3:17])=[O:5])[CH3:2].P(Cl)(Cl)(Cl)=O.CN(C)[CH:25]=[O:26]>>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])=[C:9]([CH:25]=[O:26])[NH:8][C:7]=1[CH3:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CCCN(C)C)c[nH]c1C
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(C)[nH]c(C=O)c1CCCN(C)C
Yield: 96 %

Procedure:
4-(3-Dimethylamino-propyl)-2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (600 mg, 2.5 mmol) was formylated using phosphorus oxychloride and dimethylformamide to give 645 mg (96% yield) of 4-(3-dimethylamino-propyl)-5-formyl-2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester. 1H-NMR (360 MHz, dimethylsulfoxide-d6) δ 12.15 (br s, 1H, NH), 9.59 (s, 1H, CHO), 4.19 (q, 2H, OCH2), 2.93 (m, 2H, CH2), 2.41 (s, 3H, CH3), 2.18 (m, 2H, CH2), 2.09 (s, 6H, N(CH3)2), 1.63 (m, 2H, CH2), 1.27 (t, 3H, CH3). MS m/z 266 [M+].
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([OH:20])[C:5]=1[O:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[CH2:31][CH3:32]>C(#N)C>[F:23][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([O:20][CH2:30][CH2:31][CH3:32])[C:5]=1[O:21][CH3:22]
Reactant: COc1c(OC(F)F)ccc(-c2ccc3c(c2)COC3=O)c1O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCOc1c(-c2ccc3c(c2)COC3=O)ccc(OC(F)F)c1OC
Temperature: 80 °C
Yield: 22 %

Procedure:
To a stirring solution of 5-(4-(difluoromethoxy)-2-hydroxy-3-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.25 mmol) in acetonitrile (10 mL) was added potassium carbonate (103.5 mg, 0.75 mmol) and propyl bromide (92.2 mg, 0.75 mmol) and the resultant reaction mixture was heated to 80° C. for 3 h. The reaction mixture was cooled to RT and filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) to afford title compound as a solid (20 mg, 22%).
Reaction SMILES: [OH:1][CH:2]([CH2:13][N:14]([CH2:28][CH2:29][S:30]([OH:33])(=[O:32])=[O:31])[CH2:15][CH:16]([OH:27])[CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:34]([O:38]CC)(=O)[CH2:35][OH:36]>C1(C)C=CC=CC=1>[CH2:5]([N:4]([CH2:3][CH:2]([OH:1])[CH2:13][N:14]([CH2:28][CH2:29][S:30]([OH:33])(=[O:31])=[O:32])[CH2:15][CH:16]([OH:27])[CH2:17][N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:35](=[O:36])[CH2:34][OH:38])[C:35](=[O:36])[CH2:34][OH:38])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCOC(=O)CO
Reactant: CCCCCCCCNCC(O)CN(CCS(=O)(=O)O)CC(O)CNCCCCCCCC
Solvent: Cc1ccccc1
Product: CCCCCCCCN(CC(O)CN(CCS(=O)(=O)O)CC(O)CN(CCCCCCCC)C(=O)CO)C(=O)CO
Temperature: 100 °C
Reaction time: 7.5 h
Yield: 86.6 %

Procedure:
A reactor was charged with 10 g (0.02 mole) of 11,15-dihydroxy-13-sulfoethyl-9,13,17-triazapentacosane, 50 ml of toluene and 5.1 ml (0.05 mole) of ethyl glycolate, and the contents were heated to 100° C. and continuously stirred for 7.5 hours while purging ethanol formed with a nitrogen stream. After completion of a reaction, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (on 200 g of silica gel, developing solvent: chloroform/methanol=100/1→20/1), thereby obtaining 10.6 g (isolation yield: 91%) of 3,11-dioctyl-2,12-dioxo-7-sulfoethyl-3,7,11-triaza-1, 5,9,13-tridecanetetraol.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][CH2:10][CH2:11][NH:12][S:13]([CH2:16][CH2:17][C:18]([OH:20])=O)(=[O:15])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:22][CH2:23][CH2:24][C:25]1[C:33]2[S:32][C:31](=[O:34])[NH:30][C:29]=2[C:28]([OH:35])=[CH:27][CH:26]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(C(C)C)CC)(C)C.Cl>CN(C)C=O>[OH:35][C:28]1[C:29]2[NH:30][C:31](=[O:34])[S:32][C:33]=2[C:25]([CH2:24][CH2:23][NH:22][C:18](=[O:20])[CH2:17][CH2:16][S:13]([NH:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:14])=[O:15])=[CH:26][CH:27]=1
Reactant: NCCc1ccc(O)c2[nH]c(=O)sc12
Reactant: O=C(O)CCS(=O)(=O)NCCOCCc1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCS(=O)(=O)NCCOCCc1ccccc1)NCCc1ccc(O)c2[nH]c(=O)sc12
Temperature: -15 °C
Reaction time: 0.08 h

Procedure:
A solution of the product from step b) (3.89 g), 7-(2-aminoethyl)4-hydroxy-1,3-benzothiazol-2(3H)-one hydrochloride (3.22 g), bromotripyrrolidinophosphonium hexafluorophosphate, PyBroP, (6.32 g) in dimethylformamide (50 ml) was cooled to -15° C. and diisopropylethylamine (9.0 ml) was added dropwise over 5 minutes. The solution was stirred at -15° C. for 5 min then allowed to warm to 13° C. over 4 hours. This mixture was then added dropwise over 40 min to dilute hydrochloric acid (2N, 500 ml) and after stirring over the weekend the solid was collected by filtration. This solid was dried in vacuo to give the subtitle compound (4.5 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][CH2:14][CH3:15])[N:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33]([C:34]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=1)[C:5]2=[O:53].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:70](Cl)(=[O:72])[CH3:71]>C(Cl)Cl>[C:70]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][CH2:14][CH3:15])[N:6]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33]([C:34]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[N:32]=[N:31][N:30]=3)=[CH:21][CH:22]=1)[C:5]2=[O:53])(=[O:72])[CH3:71]
Reactant: CC(=O)Cl
Reactant: CCCCc1nc2ccc(N)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1nc2ccc(NC(C)=O)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 58.4 %

Procedure:
To a solution of 0.12 g (0.17 mmol) of the aminoquinazolinone from Example 40 in 2 mL of CH2Cl2 was added 33 mg (0.32 mmol) of triethylamine followed by 10 mg of dimethylaminopyridine. The reaction mixture was cooled to 0° C. and treated with 14 mg (0.19 mmol) of acetyl chloride. The solution was allowed to warm to room temperature at which time a further 0.3 equivalents of acetyl chloride was added and the mixture was stirred overnight. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography over silica gel eluting with 50% EtOAc/hexanes containing a gradually increasing concentration of CH2Cl2 to 10% to give 0.073 g of the title compound, 57% yield. 1H-NMR (CDCl3 250 MHz): 0.88 (t, 3H, J=7.08 Hz), 1.32 (m, 2H), 1.70 (m, 2H), 2.19 (s, 3H), 2.64 (3 line m, 2H, J=7.2 Hz), 5.30 (bs, 2H), 6.89-6.98 (m, 8H), 7.09 (d, 2H, J=8.1 Hz), 7.20-7.35 (m, 10H), 7.46 (m, 2H), 7.66 (d, 1H, J=8.8 Hz), 7.73 (bs, 1H), 7.92 (m, 1H), 8.14 (d, 1H), 8.26 (dd, 1H, J=8.8, 2.3 Hz).
Reaction SMILES: [C:1]([C:5]1[CH:16]=[CH:15][C:14]2[C:13]3[CH:12]=[C:11]([CH3:17])[S:10][C:9]=3[C:8](=O)[C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.NN.[OH-].[K+]>C(O)COCCO.O>[C:1]([C:5]1[CH:16]=[CH:15][C:14]2[C:13]3[CH:12]=[C:11]([CH3:17])[S:10][C:9]=3[CH2:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc2c(s1)C(=O)c1cc(C(C)(C)C)ccc1-2
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: Cc1cc2c(s1)Cc1cc(C(C)(C)C)ccc1-2
Temperature: 80 °C
Reaction time: 0.67 h

Procedure:
A mixture of 2.40 g (0.0095 mol) of 6-(tert-butyl)-2-methyl-8H-indeno[2,1-b]thiophen-8-one and 2.6 mL (0.05 mol) of hydrazine monohydrate in 25 mL of diethylene glycol was stirred at 80° C. in 40 min and then refluxed for 1 h. The resulting mixture was cooled to r.t., treated with a solution of 2.68 g (0.035 mol) of KOH in 9.4 mL of water and subsequently refluxed for 2 h. The resulting mixture was poured in 150 mL of water, the precipitate was filtered, washed 5 times with 100 mL of water and dried. Yield 1.25 g (54%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:11][O:12][C:13](=[O:35])[CH:14]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:15]OS(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[CH3:11][O:12][C:13](=[O:35])[CH:14]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:15][S:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: Fc1ccc(S)cc1
Reactant: COC(=O)C(COS(=O)(=O)c1ccc(C)cc1)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(CSc1ccc(F)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 4-fluorothiophenol (1.24 g, 9.65 mmol) in N,N-dimethyl formamide (10 ml) was treated with sodium hydride (240 mg, 9.37 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. 2-tert-Butoxycarbonylamino-3-(toluene-4-sulfonyloxy)-propionic acid methyl ester (3 g, 8.04 mmol) in N,N dimethyl formamide (ml) was added, the resulting mixture was stirred for two hours and then concentrated in vacuo. The residue was dissolved in ethyl acetate (100 ml) and washed with water (2*80 ml) and brine. The organic layer was dried (anhydrous magnesium sulfate) and concentrated in vacuo to give, after purification by flash chromatography on silica gel, 2-tert-butoxycarbonylamino-3-(4-fluoro-phenylsulfanyl)-propionic acid methyl ester (2.28 g, 83%) as a yellow oil.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[Cl:5][C:6]1[S:7][C:8]([CH:12]=O)=[C:9]([Cl:11])[N:10]=1.C1(C)C=CC=CC=1>C(=O)([O-])[O-].[Na+].[Na+].O.CC1C=CC(S(O)(=O)=O)=CC=1>[Cl:5][C:6]1[S:7][C:8]([CH:12]2[O:4][CH2:1][CH2:2][O:3]2)=[C:9]([Cl:11])[N:10]=1
Reactant: O=Cc1sc(Cl)nc1Cl
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1nc(Cl)c(C2OCCO2)s1
Temperature: 25 °C
Yield: 93.6 %

Procedure:
In a round bottom flask equipped with a Dean-Stark trap was charged ethylene glycol (2.3 mL, 41.1 mmol), 2,4-dichloro-1,3-thiazole-5-carbaldehyde (2.5 g, 13.7 mmol), and toluene (35 mL). To this solution was added 4-methylbenzene-1-sulfonic acid hydrate (210 mg, 1.1 mmol). The reaction mixture was stirred at reflux overnight. After cooling to room temperature, the solution was poured in 10% sodium carbonate solution (50 mL). The mixture was extracted with EtOAc (2×35 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo, affording 2,4-dichloro-5-(1,3-dioxolan-2-yl)-1,3-thiazole (2.9 g, 93% yield). The product was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([N:16]1[C@@H:23]([CH2:24][CH3:25])[CH2:22][CH2:21][C@H:17]1[C:18](O)=[O:19])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:28](CC)CC)C.ClC(OCC)=O.N>C1COCC1.O1CCOCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([N:16]1[C@@H:23]([CH2:24][CH3:25])[CH2:22][CH2:21][C@H:17]1[C:18]([NH2:28])=[O:19])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCN(CC)CC
Reactant: CC[C@H]1CC[C@@H](C(=O)O)N1C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC[C@H]1CC[C@@H](C(N)=O)N1C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
N-(tert-butoxycarbonyl)-L-leucyl-(5S)-5-ethyl-L-proline was mixed with triethylamine (0.426 mL, 3.25 mmol) in THF (4 mL) and cooled to 0° C. followed by the addition of ethyl chloroformate (0.287 mL, 3.0 mmol). After 20 minutes, 0.5 M ammonia in dioxane (6 mL) was added. After 4 hours, the mixture was concentrated, and the residue was partitioned between 1 N HCl and ethyl acetate. The organic extracts were washed with saturated NaHCO3, dried (Na2SO4), filtered, concentrated under reduced pressure and purified by flash chromatography (80% to 100% ethyl acetate/hexane) to provide the titled compound. MS (ESI) m/z 356 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH:5]([CH3:28])[CH2:6][C:7]1[CH:11]=[C:10]([CH3:12])[N:9]([CH2:13][C:14]2[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=2[O:21][CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]=1)[CH3:2].[CH3:30]I>C1COCC1>[CH2:1]([O:3][C:4](=[O:29])[C:5]([CH3:30])([CH3:28])[CH2:6][C:7]1[CH:11]=[C:10]([CH3:12])[N:9]([CH2:13][C:14]2[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=2[O:21][CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[N:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)Cc1cc(C)n(Cc2cc(Br)ccc2OCC2CCCC2)n1
Reactant: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Cc1cc(C)n(Cc2cc(Br)ccc2OCC2CCCC2)n1
Temperature: -78 °C
Reaction time: 3 h
Yield: 38.4 %

Procedure:
To a solution of 3-{1-[5-bromo-2-(2-cyclopentylmethoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-2-methyl-propionic acid ethyl ester (0.14 g, 0.3 mmol) in dry THF (5 ml) under a N2 atmosphere at −78° C. was added lithium bis(trimethylsislyl)amide (1.8 ml, 1M in THF). The mixture was stirred for 1 hour before addition of a THF solution (1 ml) of MeI (0.255 g, 0.18 mmol). After stirring 3 hours more at −78° C. the mixture was left at RT for 16 hours. The reaction was quenched with sat NH4Cl solution and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4) and evaporated to dryness. The residue was purified by MPLC (10 g SiO2 cartridge, eluent 95-90% iso-hexane-5-10% EtOAc) to yield 0.033 g of 3-{1-[5-bromo-2-(2-cyclopentylmethoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-2,2-dimethyl-propionic acid ethyl ester which was converted to the title compound following the method in Example 1, Step 8.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:32]=[CH:31][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:30])[C@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:33](Cl)([CH3:36])(=[O:35])=[O:34].N1C=CC=CC=1>CC(C)=O>[OH:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:14](=[O:30])[C:13]=1[C:8]1[NH:7][C:6]2[CH:31]=[CH:32][C:3]([NH:2][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Yield: 90.3 %

Procedure:
A solution of Example 39H (2.76 g, 5.80 mmol), mesyl chloride (1.79 mL, 23.2 mmol), and pyridine (3.75 mL, 46.4 mmol) in acetone (80 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give the desired product (2.71 g, 90%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.43 (m, 1 H) 0.74 (m, 7 H) 1.34 (m, 1 H) 1.57 (m, 3 H) 2.15 (m, 2 H) 3.08 (m, 3 H) 7.56 (m, 3 H) 7.75 (m, 3 H) 8.16 (m, 1 H) 10.26 (m, 1 H) 13.76 (m, 1 H).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:25]#[N:26])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[C:8]([S:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:42]=[N+:43]=[N-:44])(C)C.C1(C)C=CC=CC=1>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]3[NH:44][N:43]=[N:42][N:26]=3)=[CH:15][CH:16]=2)[C:8]([S:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCCCc1nnc(SCc2ccc([N+](=O)[O-])cc2)n1Cc1ccc(OC(C#N)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCc1nnc(SCc2ccc([N+](=O)[O-])cc2)n1Cc1ccc(OC(c2ccccc2)c2nnn[nH]2)cc1

Procedure:
A mixture of 3-butyl-4-[[4-[1-cyano-1-phenyl-methoxy]phenyl]methyl]-5-(4-nitrobenzylthio)-4H-1,2,4-triazole (from Example 3, Step B), trimethyltin azide (3.5 equivalents), and toluene is stirred at reflux for about 2 days. The mixture is then cooled and concentrated in vacuo. The residue is partitioned between 0.5N HCl and ethyl acetate. The ethyl acetate phase is dried (MgSO4), filtered, and concentrated. The residue is taken up in methanol and stirred with silica gel (4-5 g per mmol of cyano starting material) for about 1 hour. The mixture is then evaporated in vacuo to give a dry powder, which is layered on top of a column of silica gel packed in CH2Cl2. Elution of the column with a gradient of methanol in CH2Cl2 affords the title compound.