Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]2)=[CH:17][CH:16]=1.Cl.C(N(CC)CC)C>C(#N)C>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:23]1[CH2:24][CH2:25][CH2:26][CH:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:20][CH:19]=2)[CH2:22]1
Reactant: BrCC1COc2ccccc2O1
Reactant: COc1ccc(C2CCCNC2)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C2CCCN(CC3COc4ccccc4O3)C2)cc1

Procedure:
A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (35 mg, 0.15 mmol), 3-(4-methoxyphenyl)piperidine.HCl (38 mg, 0.17 mmol) and triethylamine (41 mg, 0.39 mmol) in acetonitrile (2 mL) was heated in a microwave reactor at 160° C. for 3 h. The mixture was absorbed on silica and purified by flash chromatography using a gradient of heptane and EtOAc as eluent to give 18 mg of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])=[CH:6][CH:5]=1)([OH:3])=[O:2].C(=O)(O)[O-].[Na+].CN(C)C=O.I[CH2:32][CH3:33]>O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]#[C:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])=[CH:8][CH:9]=1)([O:3][CH2:32][CH3:33])=[O:2]
Reactant: O=C(C#Cc1ccc(C(=O)O)cc1)Nc1ccccc1
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(C#CC(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Yield: 89.4 %

Procedure:
A mixture of 1.00 g (3.77 mmol)3 -(4-carboxyphenyl)-N-phenylpropiolamide, 1.00 g (excess) anhydrous sodium bicarbonate and 25 mL dry N,N-dimethylformamide was stirred at room temperature. Added was 1.95 g (excess) iodoethane and the mixture heated at 70°-80° C. for 3 hrs. The mixture was allowed to cool to room temperature and poured into 75 mL water. The resulting solid was filtered and recrystallized from ethanol/water to provide 0.99 g (3.37 mmol, 90%)3-(4-carbethoxyphenyl)-N-phenylpropiolamide as a pale, yellow powder, mp=114°-115° C. NMR (CDCl3 /TMS): 1.40 (t, 3H), 4.39 (q, 2H), 7.16 (t, 1H), 7.36 (t, 2H), 7.60 (d, 4H), 7.90 (s, 1H), 8.03 (d, 2H)). IR (KBr): 3292, 2210, 1692, 1660. High resolution mass spectrum: Calculated; 294.113019. Measured; 294.112376.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])[C:3]([OH:5])=[O:4].[OH-].[Na+].Cl[C:16]([O:18][CH3:19])=[O:17].Cl>C1COCC1>[F:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH:2]([NH:1][C:16]([O:18][CH3:19])=[O:17])[C:3]([OH:5])=[O:4]
Reactant: NC(C(=O)O)c1ccccc1F
Reactant: COC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)NC(C(=O)O)c1ccccc1F
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Amino-(2-fluoro-phenyl)-acetic acid (0.5 g, 2.44 mmol) was dissolved in THF (7 mL) and cooled to 0° C. in an external ice/brine bath. Aqueous sodium hydroxide (12.5M, 0.47 mL, 5.856 mmol) and methyl chloroformate (0.23 mL, 2.948 mmol) were added at 0° C. Upon completion of the addition, the solution was removed from the ice bath and allowed to warm to room temperature, and stirred. After 18 hours, the crude reaction mixture was adjusted to pH 1 with 1N HCl and extracted twice with diethyl ether. The combined organic layers were washed with brine, dried with magnesium sulfate and concentrated to give (2-Fluoro-phenyl)-methoxycarbonylamino-acetic acid as an off-white solid. LCMS-ESI+: calc'd for C10H10FNO4: 227.06 (M+); Found: 228.17 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:17](=[O:18])[C:16]2[C:19]3[N:8]([N:9]([CH3:22])[CH2:10][O:11][C:12]=3[C:13](F)=[C:14]([F:20])[CH:15]=2)[CH:7]=1)=[O:5])[CH3:2].[F:23][C:24]1[CH:25]=[C:26]([N:36]2[CH2:40][C@H:39]([CH2:41][NH:42][C:43](=[O:45])[CH3:44])[O:38][C:37]2=[O:46])[CH:27]=[CH:28][C:29]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>N1C=CC=CC=1.CS(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:17](=[O:18])[C:16]2[C:19]3[N:8]([N:9]([CH3:22])[CH2:10][O:11][C:12]=3[C:13]([N:33]3[CH2:34][CH2:35][N:30]([C:29]4[CH:28]=[CH:27][C:26]([N:36]5[CH2:40][C@H:39]([CH2:41][NH:42][C:43](=[O:45])[CH3:44])[O:38][C:37]5=[O:46])=[CH:25][C:24]=4[F:23])[CH2:31][CH2:32]3)=[C:14]([F:20])[CH:15]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)OCN2C
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCNCC3)c(F)c2)C(=O)O1
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)c1cn2c3c(c(N4CCN(c5ccc(N6C[C@H](CNC(C)=O)OC6=O)cc5F)CC4)c(F)cc3c1=O)OCN2C

Procedure:
A solution of 100 mg 8,9-difluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid ethyl ester (0.32 mmol) and 216 mg of N-[{(5S)-3[3-fluoro-4-(1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl}-methyl]-acetamide (0.64 mmol) were dissolved in a mixture of 1 ml pyridine and 1 ml DMSO. The reaction was monitored by TLC. The DMSO was evaporated, the residue digested in water and the solid collected. The solid was purified by chromatography, using a 9/1 dichloromethane/methanol mixture as eluent.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8](=[N:10][S:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])[CH3:9])[CH:5]=[C:4]([F:17])[C:3]=1[NH:18][S:19]([CH3:22])(=[O:21])=[O:20].[BH4-].[Na+].CO>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([NH:10][S:11]([C:13]([CH3:16])([CH3:14])[CH3:15])=[O:12])[CH3:9])[CH:5]=[C:4]([F:17])[C:3]=1[NH:18][S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CC(=NS(=O)C(C)(C)C)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(NS(=O)C(C)(C)C)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Temperature: -48 °C
Reaction time: 10 h
Yield: 85.5 %

Procedure:
To a solution of N-(4-acetyl-2,6-difluoro-phenyl)-methanesulfonamide (1.84 g, 7.38 mmol) and (R)-(+)-2-methyl-2-propanesulfinamide (1.07 g, 8.86 mL) in THF (15 mL) was added dropwise Ti(OEt)4 (2.61 mL, 12.6 mmol) at room temperature. The mixture was stirred overnight at 90° C. The mixture cooled to room temperature and then was added brine. After the mixture was extracted three times with EtOAc, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by chromatography to yield N-{2,6-difluoro-4-[1-(2-methyl-propane-2-sulfinylimino)-ethyl]-phenyl}-methanesulfonamide (2.2 g, 85%). To a solution of N-{2,6-difluoro-4-[1-(2-methyl-propane-2-sulfinylimino)-ethyl]-phenyl}-methanesulfonamide (2.2 g, 6.24 mmol) in THF (20 mL) was added portionwise NaBH4 (944 mg, 24.9 mmol) dissolved in THF (2 mL) at −48° C. The mixture was stirred for 10 hours at −48° C. room temperature, and then CH3OH was added dropwise until gas was no longer evolved. The mixture was concentrated under reduced pressure, and then was purified by chromatography to afford N-{2,6-difluoro-4-[1-(2-methyl-propane-2-sulfinylamino)-ethyl]-phenyl}-methanesulfonamide (1.89 g, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](/[CH:13]=[CH:14]/[C:15]([F:18])([F:17])[F:16])[C:11](=[O:19])[N:10]([CH2:20][C:21](O)=[O:22])[N:9]=2)=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:38](=[O:52])([O:40][CH2:41][CH:42]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[Cl:51])[CH2:43][NH2:44])[NH2:39]>CN(C=O)C>[C:38](=[O:52])([O:40][CH2:41][CH:42]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[Cl:51])[CH2:43][NH:44][C:21](=[O:22])[CH2:20][N:10]1[C:11](=[O:19])[N:12](/[CH:13]=[CH:14]/[C:15]([F:18])([F:17])[F:16])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:9]1)[NH2:39]
Reactant: NCC(COC(N)=O)c1ccccc1Cl
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(/C=C/C(F)(F)F)c1=O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: NC(=O)OCC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(/C=C/C(F)(F)F)c1=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 47 mg (135 μmol) of the compound of Example 33A, 34 mg (176 μmol) of EDC and 24 mg (176 μmol) of HOBt in 1 ml of DMF was stirred at RT for 1 h, and 34 mg (149 μmol) of the compound of Example 15A were then added. The mixture was stirred at RT for 16 h and then separated directly by preparative HPLC [Method 9] into its components. This gave 28 mg (37% of theory) of the title compound.
Reaction SMILES: C(OC(N1C[CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[CH2:31]([S:37]CCN)[C:32]1[O:36][CH:35]=[CH:34][CH:33]=1.C(N1CCC(N)C1)(OC(C)(C)C)=O>>[O:36]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH2:31][S:37][CH2:11][CH2:10][NH:13][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: NCCSCc1ccco1
Agent: CC(C)(C)OC(=O)N1CCC(N)C1
Product: O=C(NCCSCc1ccco1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 2-(furfurylthio)ethylamine of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 399 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.92 (1H, br. s.) 10.46 (1H, s) 8.29 (1H, t, J=5.71 Hz) 8.06 (1H, d, J=6.05 Hz) 7.84 (1H, d, J=5.37 Hz) 7.56 (1H, td, J=1.10, 0.54 Hz) 7.44 (1H, d, J=5.37 Hz) 7.38 (1H, dd, J=3.51, 1.76 Hz) 6.80 (1H, d, J=6.15 Hz) 6.57 (1H, d, J=3.32 Hz) 6.36 (1H, dd, J=3.17, 1.90 Hz) 6.28 (1H, dd, J=3.22, 0.59 Hz) 3.78 (2H, s) 3.36-3.44 (2H, m) 2.59 (2H, dd, J=7.96, 6.20 Hz)
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH3:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH3:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH:40][C:28]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]2[C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:31])[F:32])=[CH:8][CH:7]=4)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:27]=3)=[O:30])=[CH:37][CH:36]=1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: COc1ccc(CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CNC(=O)c2cnc3cc(NC(=O)c4ccccc4-c4ccc(C(F)(F)F)cc4)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.6 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (40 mg, 0.092 mmol) was combined with 4-methoxybenzylamine (15 mg, 0.14 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21 mg, 0.11 mmol), 1-hydroxybenzotriazole (14 mg, 0.10 mmol), and triethylamine (0.051 ml, 0.37 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide a residue. This material was purified by preparative thin-layer-chromatography on silica eluting with 4% methanol in dichloromethane. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 9 mg of the title compound as a colorless solid.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6])=[CH2:2].C(=O)(O)[O-:12].[Na+].ClCCl.C1C=C(Cl)C=C(C(OO)=O)C=1>O>[O:12]1[CH2:2][CH:1]1[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: C=Cc1ccccc1C#N
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccccc1C1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.1 %

Procedure:
Into a 100-mL round-bottom flask was placed 2-ethenylbenzonitrile (2.73 g, 21.14 mmol, 1.00 equiv), sodium bicarbonate (1.77 g, 21.07 mmol, 4.61 equiv), dichloromethane (20 mL) and water (20 mL). Then m-CPBA (10.9 g, 63.16 mmol, 2.25 equiv) was added at 0° C. in several batches. The resulting solution was stirred overnight at room temperature and then concentrated under vacuum. The residue was applied onto a silica gel column with PE/EA (50:1). Purification afforded 400 mg (13%) of 2-(oxiran-2-yl)benzonitrile as a yellow oil.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[C:11]([CH2:19][CH2:20][NH:21][CH3:22])=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23](O)(C(F)(F)F)=O.C=O>C(#N)C>[CH:1]1([CH2:7][CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[C:11]3[CH2:19][CH2:20][N:21]([CH3:23])[CH2:22][C:10]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNCCc1cn(CCC2CCCCC2)c2ccc(C)cc12
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Solvent: CC#N
Product: Cc1ccc2c(c1)c1c(n2CCC2CCCCC2)CN(C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound was prepared by General Method 4. 2-(1-(2-cyclohexylethyl)-5-methyl-1H-indol-3-yl)-N-methylethanamine (72 mg) was dissolved in acetonitrile (2 mL) containing 5% TFA and the reaction mixture was heated to reflux. 37% aqueous formaldehyde (0.02 mL) was added and the reflux was continued for additional 2 h. The reaction mixture was cooled to 25° C., concentrated under reduced pressure and partitioned between ethyl acetate and satd. Aqueous NaHCO3. The organic layer was dried over sodium sulfate, evaporated under reduced pressure and the residue was purified by silica gel chromatography (eluent EtOAc/EtOH/NH3: 9/1/0.1) to obtain 52 mg of product. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF. 1H NMR (DMSO) δ 7.5 (d, 1H), 7.4 (s, 1H), 6.9 (d, 1H), 4.3 (bs, 2H), 4.0 (t, 2H), 3.6 (bs, 2H), 2.8 (m, 5H), 2.3 (s, 3H), 1.8-0.7 (m, 13H). MS m/z observed 311. HPLC RT 5.93 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH3:19])[CH:12]=[CH:11][C:10]=1[C:20]([CH3:23])(O)[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>O1CCCC1.Cl>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH3:19])[CH:12]=[CH:11][C:10]=1[C:20]([CH3:23])=[CH2:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc2ccc(C(C)(C)O)c(OCc3ccccc3)c12
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)c1ccc2cccc(C)c2c1OCc1ccccc1
Yield: 59 %

Procedure:
1.8 g of 1-(1-benzyloxy-8-methyl-2-naphthyl)-1-methyl-1-ethanol was dissolved in 20 ml of tetrahydrofuran, to which 30 ml of 3N hydrochloric acid was added, followed by refluxing for 2 hours. The reaction solution was returned to room temperature, to which water was added, followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated saline solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (4% ethyl acetate/hexane) to obtain 1.0 g of the captioned compound as a yellowish green oily substance.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:3].[S:15]1[CH:19]=[C:18]([C:20]2[NH:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)[N:17]=[CH:16]1>N1C=CC=CC=1>[CH2:11]([O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][C:2]([N:24]1[C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[N:21]=[C:20]1[C:18]1[N:17]=[CH:16][S:15][CH:19]=1)=[O:3])[CH2:12][CH2:13][CH3:14]
Reactant: c1ccc2[nH]c(-c3cscn3)nc2c1
Reactant: CCCCOCCOCCOC(=O)Cl
Solvent: c1ccncc1
Product: CCCCOCCOCCOC(=O)n1c(-c2cscn2)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
32.9 G. (146 mmoles) of 2(2-n-Butoxyethoxy)-ethyl chloroformate is added dropwise to a stirred suspension of 24.9 g. (124 mmoles) of 2-(4-thiazolyl)-benzimidazole in 200 ml. of pyridine. The addition is complete in 40 minutes whereupon all of the starting material had dissolved. The reaction mixture is stirred for 16 hours at room temperature and filtered to remove pyridine hydrochloride which is washed with additional pyridine. The combined filtrate and washing are evaporated to dryness in vacuo affording a residual oil which is triturated with 300 ml. portions of ice water. The water is decanted and the residue extracted with 300 ml. of methylene chloride, filtered and the methylene chloride filtrates washed with 300 ml. of ice water, 250 ml. of 0.25 N HCl containing ice and 200 ml. of saturated sodium bicarbonate solution containing 50 ml. of ice. The organic fraction is dried, filtered and evaporated to dryness in vacuo affording 51.7 g. of a residual oil. The oil is extracted with petroleum ether whereupon a dark oil remains. The petroleum ether solution is decanted and the product separates therefrom as an oil. The petroleum ether is decanted and the remaining solvent is removed in vacuo affording 17.4 g. of a light yellow residual oil. Thin layer chromatography revealed a single spot which is confirmed by elemental analysis.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][O-:11].[Na+]>CO.O1CCOCC1.CO>[CH3:10][O:11][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1ccnc(Cl)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: COc1cc(C#N)ccn1
Yield: 110.8 %

Procedure:
2-Chloro-4-cyanopyridine (115.53 g) in methanol/dioxan (1:1, 850 ml) was added to a solution of sodium methoxide (prepared from 20.8 g sodium) in methanol (285 ml) and the mixture was boiled under reflux for 2.5 hours and was allowed to cool. The mixture was filtered and the volume of the filtrate was reduced by evaporation to 200 ml and water (400 ml) was added. The solid which precipitated out was filtered off to give 2-methoxy-4-cyanopyridine (57.2 g, 51%) m.p. 93°-95.5°.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:21][CH2:22][CH3:23])[CH2:5][O:6][C:7]1[CH:20]=[CH:19][C:10]([CH:11]=[C:12]2[S:16][C:15](=S)[NH:14][C:13]2=[O:18])=[CH:9][CH:8]=1)[CH3:2].S1CC(=O)NC1=S.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C(O)C>[CH2:1]([O:3][CH:4]([O:21][CH2:22][CH3:23])[CH2:5][O:6][C:7]1[CH:20]=[CH:19][C:10]([CH:11]=[C:12]2[S:16][C:15]([N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[N:14][C:13]2=[O:18])=[CH:9][CH:8]=1)[CH3:2]
Reactant: C1CCNCC1
Reactant: CCOC(COc1ccc(C=C2SC(=S)NC2=O)cc1)OCC
Agent: O=C1CSC(=S)N1
Solvent: CCO
Product: CCOC(COc1ccc(C=C2SC(N3CCCCC3)=NC2=O)cc1)OCC
Yield: 69.2 %

Procedure:
A mixture of 5-[4-(2,2-diethoxy-ethoxy)-benzylidene]-2-thioxo-thiazolidin-4-one (which was obtained in Intermediate 37)(1.19 g, 5 mmol), rhodanine (0.67 g, 5 mmol) and piperidine (1.72 g, 20.2 mmol) in ethanol (50 mL) was refluxed for 2 hours. After cooling to room temperature hexanes (70 mL) were added and the solid which was formed was collected to give the title compound as a yellowish solid (1.4 g, 69%); 1H NMR (300 MHz, DMSO-d6) δ 1.14(t, J=7.1 Hz, 6 H), 1.55-1.75(m, 6 H), 3.40-3.80 (m, 6 H), 3.85-3.95(m, 2 H), 4.02(d, J=5.2 Hz, 2 H), 4.82 (t, J=5.2 Hz, 1 H), 7.11 (d, J=7.6 Hz, 2 H), 7.57 (d, J=7.6 Hz, 2 H), 7.58(s, 1 H); MS (ES) m/z: 404.9 (MH+, 100%); HRMS Calcd. for C21H28N2O4S (M+): 404.1770. Found: 404.1780.
Reaction SMILES: [CH:1]([C:3]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:23]=[N:24][N:25]([CH3:27])[CH:26]=3)=[CH:18][CH:17]=2)=[CH:9][C:4]=1[C:5](OC)=[O:6])=[O:2].[O:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[CH2:33][NH2:34].S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1.C(OCC)(=O)C>[OH:2][CH:1]1[C:3]2[C:4](=[CH:9][C:10]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[N:23]=[N:24][N:25]([CH3:27])[CH:26]=4)=[CH:18][CH:17]=3)=[C:11]([CH3:14])[C:12]=2[CH3:13])[C:5](=[O:6])[N:34]1[CH2:33][C@@H:29]1[CH2:30][CH2:31][CH2:32][O:28]1
Reactant: NC[C@@H]1CCCO1
Reactant: COC(=O)c1cc(Cc2ccc(-c3cn(C)nn3)cc2)c(C)c(C)c1C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(-c3cn(C)nn3)cc2)cc2c(c1C)C(O)N(C[C@@H]1CCCO1)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-formyl-3,4-dimethyl-5-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)benzoate (0.13 g) in THF (3.00 mL) were added 1-((2S)-tetrahydrofuran-2-yl)methanamine (0.04 mL) and anhydrous magnesium sulfate (0.04 g), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.11 g).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C[Al](C)C.[CH3:15][C:16]1([S:22]([CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)(=[O:24])=[O:23])[CH2:20][CH2:19][O:18][C:17]1=[O:21]>C(Cl)Cl.C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:17](=[O:21])[C:16]([CH3:15])([S:22]([CH:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)(=[O:24])=[O:23])[CH2:20][CH2:19][OH:18])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(S(=O)(=O)C2CCOCC2)CCOC1=O
Reactant: CC(C)(C)c1cc(N)on1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(NC(=O)C(C)(CCO)S(=O)(=O)C2CCOCC2)on1
Temperature: 45 °C
Reaction time: 0.25 h
Yield: 69.3 %

Procedure:
To a solution of 3-tert-butyl-isoxazol-5-ylamine (0.421 g; 3.00 mmol) in methylene chloride (10 mL) was added dropwise the trimethylaluminum (1.50 mL of a 2.0 M solution in toluene; 3.0 mmol). The mixture was stirred 15 minutes and 3-methyl-3-(tetrahydro-pyran-4-sulfonyl)-dihydro-furan-2-one (0.596 g; 2.40 mmol) was added. The mixture was heated to 45° C. overnight, cooled to room temperature, carefully quenched with 0.5 mL methanol, applied to a plug of silica gel and eluted with ethyl acetate. Removal of the volatiles in vacuo provided a residue which was purified by silica gel chromatography using ethyl acetate and hexanes as the eluent. The product-rich fractions were concentrated in vacuo to provide 0.646 g of the desired product. 1H NMR (CDCl3) δ 9.92 (bs, 1H), 6.29 (s, 1H), 4.11-3.92 (m, 4H), 3.86 (m, 1H), 3.60 (m, 1H), 3.40 (m, 2H), 2.57 (m, 1H), 2.36 (m, 1H), 2.12-1.90 (m, 4H), 1.80 (s, 3H), 1.32 (s, 9H). MS (ESI): m/e 389 (M+H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].I[CH2:6][CH2:7][O:8][C:9]([C@:11]1([F:31])[C@@H:16]2[C@H:12]1[CH2:13][C@@H:14]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C@@:15]2([NH2:20])[C:17]([OH:19])=[O:18])=[O:10]>CN(C)C=O.O>[N:1]([CH2:6][CH2:7][O:8][C:9]([C@:11]1([F:31])[C@@H:16]2[C@H:12]1[CH2:13][C@@H:14]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C@@:15]2([NH2:20])[C:17]([OH:19])=[O:18])=[O:10])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@H]1OCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)OCCI
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](OCc3ccc(Cl)c(Cl)c3)[C@@](N)(C(=O)O)[C@@H]21
Temperature: 60 °C
Reaction time: 12 h
Yield: 46.3 %

Procedure:
6 mg of sodium azide was added to 18 mg of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6-(2-iodoethyl)ester dissolved in a mixture of 0.2 mL of N,N-dimethylformamide and 0.02 mL of water at room temperature, and the mixture was stirred for 12 hours at 60° C. After standing to cool, the solvent was distilled under reduced pressure, and the residue was purified by reverse phase column chromatography (Wako gel 50C18, eluent: water to a 70% aqueous solution of acetonitrile), thereby yielding 7 mg of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6-(2-azidoethyl)ester