Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]>O>[CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([OH:7])=[O:6])[CH3:2].[CH2:1]([O:3][C@H:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Solvent: O
Product: CCOC(=O)[C@@H](Cc1ccc(O)cc1)OCC
Product: CCO[C@@H](Cc1ccc(O)cc1)C(=O)O
Reaction time: 4 h

Procedure:
Ethyl (2RS) (+/−) 2-ethoxy-3-(4-hydroxyphenyl)propanoate (100 mg) was dissolved in water saturated 4-methyl-2-pentanone (18 ml) at room temperature. Immobilised Mucor miehei lipase immobilised on accurel EP 100 load: 187 klu/g (1 mg was added and the reaction mixture was shaken. The conversion of the racemic or enantiomerically enriched mixture of the ester was followed by the described isocratic HPLC procedures 1 and 2. Stirring was stopped at different times and ½ ml of the reaction mixture without enzyme was removed. Stirring was stopped after 4 hours and the reaction mixture stored at 3° C. for 18 hours. After this period of time the stirring of the reaction mixture was continued at room temperature.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6]O.[NH:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O>C1COCC1.O>[O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[NH:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11]
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Reactant: OC[C@H]1CCCO1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NN(C[C@H]1CCCO1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 205.7 %

Procedure:
To (R)-(tetrahydrofuran-2-yl)methanol (4.0 g, 39.2 mmol), di-tert-butyl hydrazine-1,2-dicarboxylate (3.64 g, 15.67 mmol) and triphenylphosphine (15.41 g, 58.7 mmol) in THF (100 mL) was added (E)-di-tert-butyl diazene-1,2-dicarboxylate (13.5 g, 5.87 mmol). The mixture was stirred at ambient temperature for 3 h then diluted with water and extracted with EtOAc (100 mL×2). The organic extract was washed with brine and concentrated. Purification by flash chromatography (silica gel, 5-30% EtOAc/hexane) afforded 10.2 g (82%) of (R)-di-tert-butyl 1-((tetrahydrofuran-2-yl)-methyl)-hydrazine-1,2-dicarboxylate, which was dissolved in a solution of 4M HCl in dioxane (40 mL) and stirred at ambient temperature overnight. The solvent was removed under reduced pressure and ethyl acetate (20 mL) was added with stirring. The solid precipitate was filtered, washed with ether (10 mL) and dried under vacuum to yield 7.8 g (97%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.48-1.63 (m, 1H), 1.73-1.88 (m, 2H), 1.90-2.02 (m, 1H), 2.84-3.01 (m, 2H), 3.61-3.71 (m, 1H), 3.72-3.83 (m, 1H), 3.97-4.08 (m, 1H), 5.76 (br, 5H); MS (ESI) m/z 117 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[CH2:20](Cl)[O:21][CH3:22].[NH4+].[OH-].O>C1COCC1>[CH3:20][O:21][CH2:22][O:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1
Reactant: COCCl
Reactant: N#Cc1ccc(CO)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: COCOCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.8 %

Procedure:
4-Hydroxymethyl-benzonitrile (3.1 g, 23.3 mmoles) was combined with N,N-diisopropylethylamine (4.9 mL, 28 mmoles) in 100 mL of anhydrous THF. To this solution was added MOMCl (3.5 mL, 46.1 mmoles) and the mixture was stirred at room temperature for 16 hours. After this period a solution of NH4OH/H2O (1:1, 20 mL) was added (-MOMCl) and the solution was stirred for 15 minutes. After this period the reaction mixture was evaporated in vacuo (-THF) and the resulting mixture was extracted with DCM (3×30 mL). The combined DCM layer was dried over anhydrous Na2SO4, evaporated in vacuo, and the resulting crude product was purified using flash silica chromatography (0-20% EtOAc/Hexane) to yield 1.6 g (39% yield) of 4-Methoxymethoxymethylbenzonitrile as a colorless liquid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C@H:10]([C@@H:12]1[O:16][C:15](=[O:17])[C@H:14]([O:18][CH3:19])[C@@H:13]1[OH:20])[OH:11].Cl.[NH2:22][C@@H:23]1[C:29](=[O:30])[N:28]([CH3:31])[C:27]2[CH:32]=[CH:33][CH:34]=[CH:35][C:26]=2[O:25][CH2:24]1.C(C(CCCC)C([O-])=O)C.[Na+].C(Cl)Cl>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C@@H:10]([OH:11])[C@H:12]([OH:16])[C@@H:13]([OH:20])[C@@H:14]([O:18][CH3:19])[C:15]([NH:22][C@@H:23]1[C:29](=[O:30])[N:28]([CH3:31])[C:27]2[CH:32]=[CH:33][CH:34]=[CH:35][C:26]=2[O:25][CH2:24]1)=[O:17]
Reactant: CO[C@H]1C(=O)O[C@@H]([C@H](O)/C=C/c2ccccc2Br)[C@H]1O
Reactant: CN1C(=O)[C@@H](N)COc2ccccc21
Agent: CCCCC(CC)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CO[C@@H](C(=O)N[C@H]1COc2ccccc2N(C)C1=O)[C@H](O)[C@@H](O)[C@H](O)/C=C/c1ccccc1Br
Temperature: 25 °C

Procedure:
90 mg of 45 (0.22 mmol), 51 mg of 6 (0.22 mmol) and 93 mg of sodium 2-ethylhexanoate (0.56 mmol) in 2.0 mL of THF are successively introduced into a 10 mL round-bottomed flask, with stirring and under an argon atmosphere. The stirring is maintained at RT for 24 h. 20 mL of CH2Cl2 are added to the reaction medium. The mixture is successively washed with 10 mL of an HCl solution (1N), 10 mL of water saturated with NaCl. The organic phase is dried over anhydrous magnesium sulphate, filtered and then evaporated to dryness. The crude product is chromatographed on a silica cartridge (9 g, eluent, AcOEt/heptane:85/15). 49 mg of expected product Ex18 (white solid) are recovered.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(OCC)(=O)C>O1CCOCC1>[CH2:10]([NH:17][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)CBr
Reactant: NCc1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNCc1ccccc1
Temperature: 90 °C
Yield: 77.6 %

Procedure:
A solution of diisopropylethylamine (155 g, 1.2 mol) and benzylamine (96 g, 0.9 mol) was added dropwise to a solution of ethyl bromoacetate (100 g, 0.6 mol) in dioxane (1000 mL). The resulting suspension was heated at about 90° C. for about 5 hours, and then was cooled to ambient temperature. Standard extractive workup with ethyl acetate afforded the title product as a yellow oil (90 g; yield=80%). LC-MS: m/z=194 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.Cl[C:13]1[C:32](=O)N2CCN(CC3C=CC(OC)=CC=3)C(=O)C2=C[CH:14]=1.S(=O)(=O)(O)O>O1CCOCC1>[Cl:1][C:2]1[C:7](=[O:8])[N:6]2[C:13]([CH3:32])([CH3:14])[NH:11][C:9](=[O:10])[C:5]2=[CH:4][CH:3]=1
Reactant: COc1ccc(CN2CCn3c(ccc(Cl)c3=O)C2=O)cc1
Reactant: NC(=O)c1ccc(Cl)c(=O)[nH]1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CC1(C)NC(=O)c2ccc(Cl)c(=O)n21
Temperature: 100 °C

Procedure:
To a solution of 5-chloro-6-oxo-1,6-dihydropyridine-2-carboxamide (2, 1.4 g, 7.9 mmol) in 1,4-dioxane (20 mL), acetone (3, 4.6 g, 79 mmol) and concentrated sulfuric acid (0.038 g, 0.39 mmol) were added at room temperature and the reaction mixture was allowed to heat at 100° C. for 8 h. The reaction mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether and hexane, filtered and dried to afford 6-chloro-3,3-dimethyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione (4). Yield: 1.4 g, 83%; MS (ESI) m/z 213[M+1]+.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[O:11][CH3:12].[CH2:13](O)C>[Pd]>[CH3:13][C:6]1[CH:7]=[CH:2][C:3]([O:11][CH3:12])=[CH:4][C:5]=1[NH2:8]
Reactant: COc1cc([N+](=O)[O-])ccc1C
Reactant: CCO
Agent: [Pd]
Product: COc1ccc(C)c(N)c1
Yield: 97 %

Procedure:
To a suspension of 2-methyl-5-nitroanisole F1 (1.54 g; 9.21 mmol) in absolute ethanol (15 mL) was added 10% Pd/C catalyst (249 mg). The suspension was hydrogenated under a hydrogen filled balloon at atmospheric pressure and room temperature for 6.5 h. The reaction mixture was filtered through a Millex 0.45 micron filter and evaporated to dryness to provide 4-methyl-m-anisidine F2 (1.22 g; 8.89 mmol; 97% yield)
Reaction SMILES: BrCCCS(Cl)(=O)=O.NCC[CH2:12][CH2:13][S:14]([NH:17][CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24](=[O:41])[CH:25]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:16])=[O:15].[CH2:42]([N:44](CC)CC)C>ClCCl>[NH2:44][CH2:42][CH2:12][CH2:13][S:14]([NH:17][CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24](=[O:41])[CH:25]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:38])[CH3:39])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)(=[O:15])=[O:16]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)N1CCCC1CNS(=O)(=O)CCCCN
Agent: O=S(=O)(Cl)CCCBr
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)N1CCCC1CNS(=O)(=O)CCCN
Temperature: -10 °C
Reaction time: 2.5 h
Yield: 72 %

Procedure:
A solution of Part A 3-bromopropyl sulfonyl chloride (1.06 g, 4.8 mmol) in dichloromethane (5 mL) was added dropwise to a cooled (-10° C.) stirred solution of Example 6a, Part B amine (1.05 g, 3.02 mmol) and triethyl amine (1.44 mL, 9.6 mmol) in dichloromethane (15 mL), After a few minutes, a precipitate formed. The suspension was stirred at -10° C. for 2.5 hours, diluted with dichloromethane (35 mL) and washed with 1N HCl solution (2×15 mL). The dichloromethane solution was dried (MgSO4), filtered and the solvent was removed in vacuo. The crude oil was purified on silica gel (Merck, 150 mL) eluting with 50% ethyl acetate in hexane to give title compound as a white foam (1.160 g, 72%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.S(C1C=CC(C)=CC=1)(O[CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])(=O)=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:4]([Cl:9])[CH:3]=1
Reactant: Oc1ccc(Br)cc1Cl
Reactant: COCCOCCOS(=O)(=O)c1ccc(C)cc1
Product: COCCOCCOc1ccc(Br)cc1Cl

Procedure:
Prepared from 4-bromo-2-chlorophenol and 2-(2-methoxyethoxy)ethyl tosylate by the method of Example 42 (b).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:28])[C:9]2[CH:27]=[CH:26][C:12]3[N:13]([CH3:25])[C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][S:37]([NH2:40])(=[O:39])=[O:38])=[CH:32][CH:31]=1>>[ClH:1].[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][NH:16][C:14]2[N:13]([CH3:25])[C:12]3[CH:26]=[CH:27][C:9]([N:8]([CH3:28])[C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:29][C:30]5[CH:35]=[CH:34][C:33]([CH2:36][S:37]([NH2:40])(=[O:38])=[O:39])=[CH:32][CH:31]=5)[N:7]=4)=[CH:10][C:11]=3[N:15]=2)=[CH:19][CH:20]=1
Reactant: Nc1ccc(CS(N)(=O)=O)cc1
Reactant: CN(c1ccc2c(c1)nc(NCc1ccc(F)cc1)n2C)c1ccnc(Cl)n1
Product: CN(c1ccc2c(c1)nc(NCc1ccc(F)cc1)n2C)c1ccnc(Nc2ccc(CS(N)(=O)=O)cc2)n1
Product: Cl

Procedure:
The title compound was prepared following the procedure of example two with N5-(2-chloro-pyrimidin-4-yl)-N2-(4-fluoro-benzyl)-1,N5-dimethyl-1H-benzoimidazole-2,5-diamine (99 mg, 0.25 mmol) and (4-amino-phenyl)-methanesulfonamide (46 mg, 0.25 mmol) as a white solid (50 mg, 34%). 1H NMR (300 MHz, d6-DMSO) δ9.16 (S, 1H), 7.75-7.78 (m, 3H), 7.38-7.46 (m, 3H), 7.08-7.24 (m, 6H), 6.84 (dd, J=8.2 and 1.6 Hz, 1H), 6.75 (br s, 2H), 5.61 (d, J=6.0 Hz, 1H), 4.57 (d, J=5.7 Hz, 2H), 4.15 (s, 2H), 3.56 (s, 3H), 3.43 (s, 3H). MS (ESI) m/z=547 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:22][OH:23])=[C:4]([NH:8][CH2:9][C:10]2[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[S:12][C:11]=2[C:19](O)=[O:20])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.CN(C=O)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O>[Br:1][C:2]1[C:3]([CH2:22][OH:23])=[C:4]([N:8]2[C:19](=[O:20])[C:11]3[S:12][C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:14][C:10]=3[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1cc(CNc2cccc(Br)c2CO)c(C(=O)O)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc2c(s1)C(=O)N(c1cccc(Br)c1CO)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 59 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 114f (540 mg, 1.36 mmol), triethylamine (275 mg, 2.72 mmol) and anhydrous DMF (10 mL). Benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP, 782 mg, 1.77 mmol) was added, and the reaction was stirred at room temperature for 16 h. After this time, the reaction was diluted with water (20 mL), and the resulting suspension was filtered. The filter cake was dissolved in methylene chloride (40 mL), and the solution was washed with saturated aqueous sodium bicarbonate (10 mL), and water (10 mL), and dried over sodium sulfate. The drying agent was removed by filtration, and the solvent was evaporated under reduced pressure. The resulting residue was purified by flash chromatography to afford a 60% yield of 114g (305 mg) as a white solid: mp 55-56° C.; 1H NMR (500 MHz, CDCl3) δ 7.65 (d, 1H, J=8.0 Hz), 7.25 (m, 1H), 7.20 (d, 1H, J=8.0 Hz), 6.89 (s, 1H), 4.68 (s, 2H), 4.66 (s, 2H), 1.46 (s, 9H).
Reaction SMILES: [ClH:1].[CH:2]([C:5]1[CH:18]=[C:17]2[C:8]([N:9]3[C:14]([CH2:15][O:16]2)=[N:13][NH:12][C:11](=[O:19])[C@H:10]3[CH3:20])=[CH:7][C:6]=1[C@H:21]([C:23]1([CH3:27])[CH2:26][NH:25][CH2:24]1)[CH3:22])([CH3:4])[CH3:3].[Si]([O:35][CH2:36][CH:37]=O)(C(C)(C)C)(C)C.[BH3-]C#N.[Na+]>CO.C(O)(=O)C>[ClH:1].[OH:35][CH2:36][CH2:37][N:25]1[CH2:24][C:23]([C@@H:21]([C:6]2[CH:7]=[C:8]3[C:17](=[CH:18][C:5]=2[CH:2]([CH3:3])[CH3:4])[O:16][CH2:15][C:14]2[N:9]3[C@H:10]([CH3:20])[C:11](=[O:19])[NH:12][N:13]=2)[CH3:22])([CH3:27])[CH2:26]1
Reactant: CC(C)c1cc2c(cc1[C@@H](C)C1(C)CNC1)N1C(=NNC(=O)[C@H]1C)CO2
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)c1cc2c(cc1[C@@H](C)C1(C)CN(CCO)C1)N1C(=NNC(=O)[C@H]1C)CO2
Temperature: 70 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
To a solution of (R)-7-isopropyl-4-methyl-6-[(R)-1-(3-methyl-azetidin-3-yl)-ethyl]-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloric acid (Example #133, Step G, 0.083 g, 0.233 mmol) in MeOH (3 mL) and acetic acid (0.3 mL) was added 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (0.122 g, 0.699 mmol) and the reaction mixture was stirred at 70° C. overnight. NaBH3CN (0.073 g, 1.164 mmol) was added and the reaction mixture was stirred at 70° C. for 1 h. The reaction mixture was cooled to ambient temperature. The solvent was removed in vacuo and the residue was purified by prep-HPLC (Table 3, Method 26) to give (R)-6-{(R)-1-[1-(2-hydroxy-ethyl)-3-methyl-azetidin-3-yl]-ethyl}-7-isopropyl-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloric acid (0.0291 g, 31%) as a solid. 1H NMR (CD3OD-d4, 400 MHz): δ 7.04 (s, 1H), 6.84 (s, 1H), 4.81-4.78 (m, 1H), 4.62 (s, 2H), 4.15 (d, J=10.8 Hz, 1H), 4.04 (d, J=10.8 Hz, 1H), 3.93 (d, J=10.8 Hz, 1H), 3.86 (d, J=10.8 Hz, 1H), 3.77-3.69 (m, 2H), 3.38 (m, 2H), 3.12-3.04 (m, 2H), 1.56 (s, 3H), 1.45 (d, J=6.8 Hz, 3H), 1.42-1.35 (m, 3H), 1.34-1.27 (m, 3H), 1.19-1.12 (m, 3H). LC/MS (Table 1, Method 4) Rt=1.761 min.; MS m/z: 401 [M+H]+. SFC (Table 1, Method 28) Rt=5.52 min.
Reaction SMILES: [Br:1]Br.[CH:3]([O:5][CH2:6][CH3:7])=[CH2:4].C(N(C(C)C)CC)(C)C.[C:17]([Si:21]([CH3:41])([CH3:40])[O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([CH:38]=[O:39])=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[C:34]=2[OH:35])=[CH:25][CH:24]=1)([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[Br:1][CH2:4][CH:3]([O:5][CH2:6][CH3:7])[O:35][C:34]1[C:33]([O:36][CH3:37])=[CH:32][CH:31]=[C:30]([CH:38]=[O:39])[C:29]=1[C:26]1[CH:25]=[CH:24][C:23]([O:22][Si:21]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:41])[CH3:40])=[CH:28][CH:27]=1
Reactant: COc1ccc(C=O)c(-c2ccc(O[Si](C)(C)C(C)(C)C)cc2)c1O
Reactant: BrBr
Reactant: C=COCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(CBr)Oc1c(OC)ccc(C=O)c1-c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Reaction time: 0.25 h
Yield: 97.4 %

Procedure:
To a solution of Br2 (0.397 mL, 7.74 mmol) in CH2Cl2 (30 mL) at 0° C. was added drop-wise ethyl vinyl ether (0.92 mL, 9.68 mmol) until the solution turned colorless. The mixture was stirred for 15 min and diisopropylethyamine (2.71 mL, 15.48 mmol) was added followed by a drop-wise addition of a solution of 11 (1.5 g, 3.87 mmol) in CH2Cl2 (15 mL) The mixture was stirred for 12 h under an argon atmosphere to give an orange-red solution. After complete consumption of staring material, as determined by TLC. the mixture was poured onto saturated aqueous NaHCO3 and extracted with CH2Cl2 (3×50 mL). The combined extracts were washed with brine (100 mL), dried (Na2SO4), filtered and evaporated in vacuo to give an orange-red oil. Purification by flash column chromatography (SiO2, 10% EtOAc/Hexanes) gave 13 (1.92 g, 92% yield) as a colorless syrupy liquid. (1.92 g, 92% yield). Rf=0.42 (1:5 EtOAc/hexanes). IR (thin film) 2956, 2930, 2857, 1684 cm−1. 1H NMR (300 MHz, CDCl3) δ 9.64 (1H, s), 7.85 (1H, d, J=9 Hz), 7.25-7.18 (2H, m), 7.03 (1H, d, J=9 Hz), 6.93 (2H, d, J=9 Hz), 5.01 (1H, dd, J's=7, 4 Hz), 3.98 (3H, s), 3.56 (1H, m), 3.31 (1H, m), 3.09 (2H, m), 1.05 (2H, t, 7 Hz), 1.01 (9H, s), 0.24 (6H, s). 13C NMR (75 MHz, CDCl3) δ 191.5, 157.02, 155.8, 141.7, 140.6, 132.5, 128.5, 125.2, 119.7, 111.0, 103.7, 64.5, 55.9, 31.8, 25.6, 18.2, 14.9, −4.4. HRMS calcd. for C24H34O5SiBr (MH+) 509.1359. Found 509.1356.
Reaction SMILES: [CH2:1]([CH:3]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:4][C:5]1[CH:9]=[CH:8][S:7][CH:6]=1)[CH3:2].[C:14](=O)=[O:15].CC(C)=O.C(N1CCCCC1)=O.Cl>O1CCCC1>[CH2:1]([CH:3]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:4][C:5]1[CH:9]=[C:8]([CH:14]=[O:15])[S:7][CH:6]=1)[CH3:2]
Reactant: CCCCC(CC)Cc1ccsc1
Reactant: O=C=O
Agent: Cl
Agent: O=CN1CCCCC1
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCCCC(CC)Cc1csc(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
3-(2-Ethylhexyl)-thiophene (19.6 g, 100 mmol) and anhydrous tetrahydrofuran (250 mL) were charge into a 500 ml flask. The solution was cooled to −78° C. with dry ice/acetone. N-butyl lithium (40 mL, 2.5 M in hexane, 100 mmol) was dropped into the solution. After addition, the reaction solution was warmed to room temperature and stirred for 30 min. Then, the solution was cooled to −78° C. again and 1-formylpiperidine (13.6 g, 120 mmol) was added in one shot. The reaction solution was allowed to warm slowly to room temperature and stirred at room temperature for overnight. The solution was acidified with hydrochloric acid (2 N) and then extracted with ether (2×100 mL). The organic extracts were combined and washed with distilled water (2×100 mL), dried over anhydrous magnesium sulfate and rotary evaporated to remove the solvent. The residue was run through a silica-gel column using ethyl acetate/hexanes (1/10, v/v, Rf=0.3) as the eluent to give a colorless liquid product (18.4 g, 78% yield). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.86 (s, 1H), 7.56 (s, 1H), 7.34 (s, 1H), 2.59 (d, 2H, J=6.8 Hz), 1.58 (m, 1H). 1.18-1.34 (m, 8H), 0.84 (t, 6H, J=7.2 Hz); (Note: contain about 5% of 3-substituted isomer).
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH2:21][CH2:22][CH3:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([OH:20])=[CH:15][CH:14]=3)=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].Br[C:25]([CH3:32])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[NH:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH2:21][CH2:22][CH3:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][C:25]([CH3:32])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:15][CH:14]=3)=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCCn1c(-c2ccc(NC(C)=O)cc2)cc2cc(O)ccc21
Product: CCCn1c(-c2ccc(NC(C)=O)cc2)cc2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
The above compound was prepared from 2-(4-acetamino-phenyl)-1-propyl-1H-indole-5-ol and ethyl 2-bromo-2-methyl-propanoate using a procedure analoguous to that of Example 10.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:12][C@@H:11]([NH:13][C:14]([C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]=3[OH:26])=[O:15])[CH2:10][C@H:9]2[C:27]([OH:29])=[O:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.[CH2:35](O)[CH3:36]>>[CH2:35]([O:28][C:27]([C@@H:9]1[CH2:10][C@H:11]([NH:13][C:14]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[OH:26])=[O:15])[CH2:12][N:8]1[CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:29])[CH3:36]
Reactant: CCO
Reactant: O=C(N[C@H]1C[C@@H](C(=O)O)N(CC2CCCCC2)C1)c1ccc2ccccc2c1O
Agent: O=S(=O)(O)O
Product: CCOC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1CC1CCCCC1
Temperature: 95 °C
Reaction time: 14 h
Yield: 52.3 %

Procedure:
To a stirred solution of (2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid (50 mg, 0.13 mmol) in ethanol (3 mL) was added conc. sulfuric acid (0.1 mL) and the reaction mixture was stirred at 95° C. for 14 h. The reaction mixture was then concentrated under vacuum, diluted with water, extracted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (using 5% EtOAc in hexane as eluent) to give (2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid ethyl ester (28 mg, 52.3% yield) as a blue sticky liquid. MS calcd. for C25H33N2O4 [(M+H)+] 425.0, obsd. 425.2.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3]1.F[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][N:7]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:28])([F:30])[F:29])[CH:20]=2)[CH:2]([CH3:1])[CH2:3]1)=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: CC1CN(C(=O)OCc2ccccc2)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CN(C(=O)OCc2ccccc2)CCN1c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A 1.01 g portion of benzyl 3-methylpiperazine-1-carboxylate synthesized in Reference Example 10, 814 mg of 4-fluoro-2-trifluoromethylbenzonitrile and 2.38 g of potassium carbonate were added to 20 ml of DMF and stirred at 100° C. for 20 hours. This was mixed with water, extracted with ethyl acetate and dried, and then the solvent was evaporated. The resulting residue was purified by a silica gel column chromatography to obtain 440 mg of the title compound from ethyl acetate-hexane (3:1, v/v) eluate.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH3:14])[CH2:12][OH:13])=[N:8][C:7]([SH:15])=[N:6][C:5]=2[N:16]=1.[Cl:17][C:18]1[S:22][N:21]=[N:20][C:19]=1[CH2:23]Cl>>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH3:14])[CH2:12][OH:13])=[N:8][C:7]([S:15][CH2:23][C:19]3[N:20]=[N:21][S:22][C:18]=3[Cl:17])=[N:6][C:5]=2[N:16]=1
Reactant: C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Reactant: ClCc1nnsc1Cl
Product: C[C@H](CO)Nc1nc(SCc2nnsc2Cl)nc2nc(N)sc12

Procedure:
The titled compound was prepared from the product of example 4, step (b), and 5-chloro-4-(chloromethyl)-1,2,3-thiadiazole, using the method of example 4, step (c).