Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[C:6]([NH2:10])([CH3:9])([CH3:8])[CH3:7].[CH3:11][C:12]1[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[O:14][N:13]=1.Cl.[O:21]1CCC[CH2:22]1>O.CN(C)C=O>[C:6]([NH-:10])([CH3:9])([CH3:8])[CH3:7].[CH:22]([C:16]1[C:12]([CH3:11])=[N:13][O:14][C:15]=1[C:17]([OH:19])=[O:18])=[O:21]
Reactant: CC(C)(C)N
Reactant: Cc1cc(C(=O)O)on1
Reactant: C1CCOC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[NH-]
Product: Cc1noc(C(=O)O)c1C=O
Reaction time: 1 h

Procedure:
56 ml of butyllithium (1.6 molar solution in n-hexane) are added dropwise, at -78° C., to 8 g of the tert-butylamine of 3-methylisoxazole-5-carboxylic acid in 150 ml of tetrahydrofuran. The mixture is stirred for 1 hour, after which 22 ml of dimethylformamide are slowly added dropwise. The mixture is allowed to reach room temperature overnight and is hydrolyzed with water, neutralized with concentrated hydrochloric acid and extracted with ether. The oil which remains after evaporation is chromatographed over silica gel using cyclohexane/ethyl acetate. The tert-butylamide of 4-formyl-3-methylisoxazole-5-carboxylic acid is obtained as the first fraction, in the form of pale yellow crystals of melting point 36°-38° C. (compound No. 2).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](C=O)[CH:3]=1.S1(CCCC1)(=O)=O.C([Br:24])C1C=CC=CC=1.[C:25](OCC)(=[O:27])C>O>[Br-:24].[CH:25]([N+:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)=[O:27]
Reactant: Cc1ccnc(C=O)c1
Reactant: CCOC(C)=O
Reactant: BrCc1ccccc1
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: Cc1cc[n+](C=O)cc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-methyl-2-pyridine carboxaldehyde (1.0 g, 8.26 mmol), sulfolane (10 ml) and benzyl bromide (0.98 ml, 8.3 mmol) was stirred at room temperature for 16 hours, then was heated on a steam bath for 16 hours. Several portions of ethyl acetate were added to the reaction mixture and subsequently decanted to yield a residual gum. The gum was dissolved in water, washed with ether and evaporated to dryness to afford crude formyl-4-methyl pyridinium bromide.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([C:7]1[CH:44]=[CH:43][C:10]([CH2:11][CH:12](/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH2:34][CH2:35][CH2:36][N:37]2[CH2:41][CH2:40][CH2:39][C:38]2=[O:42])[CH2:13][CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)=[O:6]>C1COCC1.O>[C:5]([C:7]1[CH:8]=[CH:9][C:10]([CH2:11][CH:12](/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH2:34][CH2:35][CH2:36][N:37]2[CH2:41][CH2:40][CH2:39][C:38]2=[O:42])[CH2:13][CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=2)=[CH:43][CH:44]=1)([OH:6])=[O:4]
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCN2CCCC2=O)Cc2ccc(C(=O)OC)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(CCC(/C=C/c2ccccc2OCCCN2CCCC2=O)Cc2ccc(C(=O)O)cc2)cc1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
492 mg (20.5 mmol) of lithium hydroxide are added to a solution of 3.90 g (6.8 mmol) of methyl 4-[(4E)-3-[4-(methoxycarbonyl)benzyl]-5-{2-[3-(2-oxopyrrolidin-1-yl)propoxy]phenyl}pent-4-en-1-yl]benzoate (Example 21A) in 20 ml of THF and 20 ml of water, and the mixture is stirred at 50° C. for 12 h. The mixture is then cooled and extracted three times with ethyl acetate. The aqueous phase is then adjusted to pH 2 using 1 M hydrochloric acid and extracted three times with ethyl acetate. The latter organic phases are combined, washed with water and saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is removed to dryness. This gives 2.75 g (content 98%, 4.98 mmol, 73% of theory) of the title compound as a colorless solid.
Reaction SMILES: [CH2:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.BrC.[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.[CH3:16]C(C)([O-])C.[K+]>C(O)CCC>[CH:2]1([CH2:16][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH2:1][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1
Reactant: CC(C)(C)[O-]
Reactant: c1c[nH]cn1
Reactant: C1=CCCCCCC1
Agent: CBr
Agent: [K+]
Solvent: CCCCO
Product: C1=CC(Cn2ccnc2)CCCCC1

Procedure:
2-Cyclooctene-1-bromomethane (0.7 g, 0.0034 mol) was added dropwise to a boiling solution of imidazole (0.24 g, 0.0035 mol) and potassium t-butoxide (0.39 g, 0.0035 mol) in dry n-butanol, under dry nitrogen. After the addition, the reaction mixture was stirred and heated under reflux for 1 h. The pure product was obtained as described in Example 4, b.p. 108°-110°/0.02 mmHg.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:16][C:17]([OH:19])=O)[C:12]2[C:7](=[CH:8][C:9]([CH3:20])=[CH:10][CH:11]=2)[N:6]=1)=[O:4].FC1C(O)=C(F)C(F)=C(F)C=1F.[OH:33][C@@H:34]1[CH2:38][CH2:37][NH:36][CH2:35]1.C(N1CCOCC1)C>CN(C=O)C.C(Cl)Cl.C(Cl)CCl>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:16][C:17]([N:36]2[CH2:37][CH2:38][C@@H:34]([OH:33])[CH2:35]2)=[O:19])[C:12]2[C:7](=[CH:8][C:9]([CH3:20])=[CH:10][CH:11]=2)[N:6]=1)=[O:4]
Reactant: O[C@@H]1CCNC1
Reactant: COC(=O)c1cc(OCC(=O)O)c2ccc(C)cc2n1
Agent: CCN1CCOCC1
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)c1cc(OCC(=O)N2CC[C@@H](O)C2)c2ccc(C)cc2n1

Procedure:
To a solution of 1000 mg 4-Carboxymethoxy-7-methyl-quinoline-2-carboxylic acid methyl ester in 5 ml DMF were added 956 mg pentafluorophenol and 994 mg EDC. The mixture was stirred under exclusion of moisture until LCMS indicated complete conversion to the corresponding pentafluorophenolester. (R)-3-hydroxypyrrolidine (287 mg) was mixed with 1.3 ml N-ethylmorpholine and 5 ml DMF and this mixture added dropwise to the solution of the pentafluorophenolester. After 12 h the reaction mixture was diluted with DCM and washed with aqueous LiCl (4%) and saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was purified by flash chromatography on silica eluting with ethyl acetate/methanol gradient. Yield: 996 mg.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=O)[CH:4]=[C:2]1C.[NH2:9][CH2:10][CH2:11][CH2:12][Si:13]([O:18][CH3:19])([O:16][CH3:17])[O:14][CH3:15].[CH2:20](N(CC)CC)C.CS(O)(=O)=O>C1(C)C=CC=CC=1>[CH3:20][CH:10]([N:9]1[C:1](=[O:8])[CH:2]=[CH:4][C:5]1=[O:7])[CH2:11][CH2:12][Si:13]([O:18][CH3:19])([O:14][CH3:15])[O:16][CH3:17]
Reactant: CC1=CC(=O)OC1=O
Reactant: CCN(CC)CC
Reactant: CO[Si](CCCN)(OC)OC
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CO[Si](CCC(C)N1C(=O)C=CC1=O)(OC)OC
Yield: 35 %

Procedure:
The experimental procedure described in Example 1 was repeated employing citraconic anhydride (25.0 g, 0.22 mol), aminopropyl trimethoxysilane (36.0 g, 0.20 mol), triethylamine (26.0 g, 0.24 mol), methanesulfonic acid (26.0 g, 0.26 mol), and 200 ml of toluene. The product was a yellow viscous liquid. Yield: 35%.
Reaction SMILES: N(C(OCC1C=CC=CC=1)=O)[C@H](C(N[C@H](C(N)=O)C)=O)CC1C=CC=CC=1.[NH:28]([C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])[C@H:29]([C:40]([OH:42])=O)[CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1.[CH2:53]([NH2:60])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>C1COCC1>[NH:28]([C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])[C@H:29]([C:40]([NH:60][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:42])[CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1
Reactant: NCc1ccccc1
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Agent: C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(N)=O
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCc1ccccc1)OCc1ccccc1
Yield: 89 %

Procedure:
The coupling procedure described above for the preparation of Cbz-Phe-Ala-NH2 was employed using 10.0 g of Cbz-Trp-OH (Sigma Chemical Company) and 4.84 mL of freshly distilled BnNH2 in dry THF to give 11.3 g (89% yield) of crystalline Cbz-Trp-NHBn. Characteristic analytical data are as follows: mp 104°-105° C.; 1H NMR (300 MHz, CDCl3) δ8.00-6.88 (m, 16H, Ar), 5.85 (br, 1H, H-α), 5.45 (br, 1H, H--N), 5.10 (s, 2H, CH2 --O), 4.57-4.45 (br, H--), 4.27 (t, 6H, CH2 --N), 3.38 (dd, J=4, 14 Hz, 1H, H-β), 3.16 (dd, J=8, 14 Hz, 1H, H-β); mass spectrum (EI), m/e 427 (M+), 336 (M+ -Bn), 277 (M+ -Cbz-NH), 130 (M30 -Cbz-NH--CH--CONH-Bn), 91 (Bn+); [α]D25 +7.0° (c=0.20, EtOAc).
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12]([NH2:15])(=[O:14])=[O:13]>C(OCC)(=O)C.[Pd]>[OH:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12]([NH2:15])(=[O:14])=[O:13]
Reactant: NS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 91 %

Procedure:
To a solution of 2-hydroxy-3-nitro-6-chlorobenzenesulfonamide (1.1 g, 4.36 mmol) in ethyl acetate, was added 10% Pd/C (500 mg). The mixture was flushed with hydrogen, and then stirred under a hydrogen atmosphere at balloon pressure for 4 hours at room temperature. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated to give the desired product (91%). EI-MS (m/z) 221.1, 223.1 (M−).
Reaction SMILES: ClC[C:3]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[N:5](CC2C=CC(F)=CC=2F)[CH:4]=1.[CH3:25][C:26]1([CH3:33])[O:30][C@H:29]([CH2:31][OH:32])[CH2:28][O:27]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:25][C:26]1([CH3:33])[O:30][C@H:29]([CH2:31][O:32][CH2:15][O:14][C:12]([C:9]2[CH:10]=[C:11]3[CH:3]=[CH:4][NH:5][C:6]3=[CH:7][N:8]=2)=[O:13])[CH2:28][O:27]1
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: COC(=O)c1cc2c(CCl)cn(Cc3ccc(F)cc3F)c2cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)OC[C@@H](COCOC(=O)c2cc3cc[nH]c3cn2)O1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
To a solution of methyl 3-(chloromethyl)-1-(2,4-difluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (3 mL, 0.197M in CH2Cl2, 0.591 mmol)) [prepared as described in step 2 of example 40] in anhydrous DMF (5 mL) was added (R)-(−)-2,2-Dimethyl-1,3-dioxolane-4-methanol (0.37 ml, 2.955 mmol, 5.0 eq.) followed by i-Pr2NEt (0.4079, 3.14 mmol, 0.55 mL, 4 eq.). The mixture, under nitrogen, was placed in an oil bath and the bath was warmed to 40° C. After stirring for 24 hours (40° C.) the reaction was judged to by complete by HPLC-MS analysis and the volatiles were removed in vacuo (ca. 2 torr) to give a golden yellow oil. The crude material was purified by chromatography on a column of silica gel (40 mm OD, 100 g, 230-400 mesh, packed with CH2Cl2, eluted with CH2Cl2-EtOAc 50:50 v/v, 1.0 L, 25 mL fractions) using the flash technique. Fractions 30-54 were combined to afford 0.224 g (85%) of Methyl 1-(2,4-difluorobenzyl)-3-({([(4R)-2,2-dimethyl -1,3-dioxolan-4-yl]methoxy}methyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate as a colorless oil.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:11]([O:13][C:14]([CH:16]([CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:31][CH:30]=1)[CH2:17][CH2:18][P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])=[O:15])[CH3:12].I[CH3:44]>O1CCCC1.C(OCC)(=O)C>[CH2:11]([O:13][C:14]([C:16]([CH3:44])([CH2:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:33][CH:34]=1)[CH2:17][CH2:18][P:19](=[O:26])([O:20][CH2:21][CH3:22])[O:23][CH2:24][CH3:25])=[O:15])[CH3:12]
Reactant: CI
Reactant: CCCCCCCCc1ccc(CCC(CCP(=O)(OCC)OCC)C(=O)OCC)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc(CCC(C)(CCP(=O)(OCC)OCC)C(=O)OCC)cc1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 82 %

Procedure:
To a solution potassium bis(trimethylsilyl)amide (0.213 g, 1.068 mmol) in tetrahydrofuran (1 ml) at −78° C. was added (±)-diethyl 3-ethoxycarbonyl-5-(4-(octyl)phenyl)pentylphosphonate (0.250 g, 0.533 mmol) as a solution in 1 ml of tetrahydrofuran. After stirring for 40 minutes at −78° C., iodomethane (0.083 ml, 1.33 mmol) was added. The reaction was stirred for 1 h at −78° C. then allowed to warm to room temperature. The solution was diluted with ethyl acetate (25 ml) and washed with 2N HCl (10 ml) 5% aqueous sodium thiosulfate (10 ml), saturated aqueous sodium chloride (10 ml), dried over magnesium sulfate and concentrated to give a colorless oil (0.211 g): MS m/e 483.4 (M+).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].C(OC(=O)[NH:37][C:38]([CH3:51])([CH3:50])[CH2:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([CH:47]=O)=[CH:43][C:42]=1[F:49])(C)(C)C>>[NH2:37][C:38]([CH3:51])([CH3:50])[CH2:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=2[C@@H:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=3[CH2:15]2)=[CH:43][C:42]=1[F:49]
Reactant: CC(C)(COc1ccc(C=O)cc1F)NC(=O)OC(C)(C)C
Reactant: CCNc1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1cc(NCCCc2ccc(OCC(C)(C)N)c(F)c2)c([C@@H]2CCc3cc(O)ccc3C2)cc1OC
Yield: 51.2 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and tert-butyl[2-(2-fluoro-4-formylphenoxy)-1,1-dimethylethyl]carbamate (72 mg) according to an analogous synthetic method to Example 238 and purified by LC-MS, the title compound (13 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][CH3:13])=[O:11].[CH3:15][O:16][C:17](=[O:28])[C@H:18]1[CH2:22][C@@H:21]([OH:23])[CH2:20][N:19]1[C:24]([O:26][CH3:27])=[O:25]>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[CH3:1][O:2][C:3](=[O:14])[C@@H:4]1[CH2:8][C@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][CH3:13])=[O:11].[CH3:15][O:16][C:17](=[O:28])[C@H:18]1[CH2:22][C@H:21]([OH:23])[CH2:20][N:19]1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC
Product: COC(=O)[C@H]1C[C@H](O)CN1C(=O)OC
Reaction time: 24 h
Yield: 3 %
Yield: 82.7 %

Procedure:
A 5.0 mL aqueous solution containing 51 mM N-(methoxycarbonyl)-trans-4-hydroxy-L-proline methyl ester and 51 mM N-(methoxycarbonyl)-cis-4-hydroxy-D-proline methyl ester in 0.100M potassium phosphate (pH 7.0) was mixed with 50 mg/mL of Candida antartica lipase fraction B at 25° C. The reaction was analyzed by removal of a 0.200 mL sample and mixing with an equivalent volume of 0.100M propionic acid (HPLC internal standard) in water. The resulting solution was filtered through a 10K molecular weight cut-off filter to remove the enzyme and the filtrate analyzed by high pressure liquid chromatography on a HPX-87H column (Bio-Rad, 30 cm×7.8 mm) to determine the percent conversion of each isomer of the diastereomeric mixture, and the diastereomeric excess of the N-(methoxycarbonyl)-trans-4-hydroxy-D-proline methyl ester. After 24 h, a 93% diastereomeric excess of N-(methoxycarbonyl)-trans-4-hydroxy-D-proline methyl ester was obtained at 57% conversion of the diastereomeric mixture (3.0% N-(methoxycarbonyl)-cis-4-hydroxy-L-proline methyl ester and 82.7% N-(methoxycarbonyl)-trans-4-hydroxy-D-proline methyl ester remained).
Reaction SMILES: C[O-].[Na+].I.[NH:5]=[C:6]1[N:10]([CH3:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[N:7]1[CH3:16].[C:17]1([N:23]=[C:24]=[S:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C.C1(C)C=CC=CC=1>[CH3:11][N:10]1[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[N:7]([CH3:16])[C:6]1=[N:5][C:24]([NH:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[S:25]
Reactant: Cn1c(=N)n(C)c2ccccc21
Reactant: S=C=Nc1ccccc1
Agent: C[O-]
Agent: I
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cn1c(=NC(=S)Nc2ccccc2)n(C)c2ccccc21

Procedure:
Sodium methoxide (0.54 g) was added to a mixture of 2-imino-1,3-dimethylbenzimidazole hydroiodide (3.135 g) in ethanol (10 ml) and brought to reflux, with stirring. Phenylisothiocyanate (1.635 g) in toluene (5 ml) was added to the mixture over 10 minutes and the resulting mixture heated under reflux, with stirring, for 1 hour then cooled in ice. Filtration, washing with ethanol and water and drying gave analytically pure product, mpt 245° C.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[O:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[N:32][CH:33]=1>C(#N)C.O>[CH3:18][O:17][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:2]=1[O:1][CH2:27][C:28]1[CH:33]=[N:32][C:31]([CH3:34])=[CH:30][CH:29]=1)[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: COc1cc(CNC(=O)OC(C)(C)C)ccc1O
Reactant: Cc1ccc(CCl)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc(CNC(=O)OC(C)(C)C)ccc1OCc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 63 h
Yield: 106.2 %

Procedure:
To a stirred solution of tert-butyl 4-hydroxy-3-methoxybenzylcarbamate (21.02 g, 82.99 mmol) in acetonitrile (250 mL) was added potassium carbonate (30.61 g, 221.5 mmol) and 5-(chloromethyl)-2-methylpyridine hydrochloride (16.25 g, 91.29 mmol). The resulting mixture was heated to reflux. After 63 h, the brown suspension was allowed to cool to room temperature and was diluted with water (1000 mL). The mixture was extracted with dichloromethane (3×250 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to provide 31.59 g (>100%) of tert-butyl 3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzylcarbamate as a brown oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH:7]1[CH2:10][NH:9][CH2:8]1.C(N1CC(OC2C=CC=C(C(F)(F)F)C=2)C1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:44][N:45]=[C:46]=[S:47]>C(Cl)Cl>[CH3:44][NH:45][C:46]([N:9]1[CH2:10][CH:7]([O:6][C:5]2[CH:11]=[CH:12][CH:13]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:4]=2)[CH2:8]1)=[S:47]
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Reactant: CN=C=S
Agent: FC(F)(F)c1cccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)c1
Solvent: ClCCl
Product: CNC(=S)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Crude 3-[3-(trifluoromethyl)phenoxy]azetidine from catalytic debenzylation of 26.0 g (0.078 mole) of 1-benzhydryl-3-[3-(trifluoromethyl)phenoxy]azetidine was dissolved in 100 ml of methylene chloride and treated dropwise under a nitrogen atmosphere with a solution of 5.0 g (0.0678 mole) of methylisothiocyanate in 15 ml of methylene chloride. The reaction mixture was stirred for 16 hr at ambient temperature and let stand over the weekend. The solution was filtered through a celite filter pad to remove a fine crystalline precipitate and the filtrate was evaporated under reduced pressure. The residual oil was crystallized from isopropyl ether to give 12.6 g of product, m.p. 78°-86° C. A 5.0 g sample was recrystallized from isopropyl ether (charcoal) to give 3.2 g, m.p. 89°-93° C., which was shown by TLC on silica gel (10% methanol-toluene) to be contaminated by a lower Rf material. The filtrate was evaporated under reduced pressure, combined with the 3.2 g of solid and dissolved in 100 ml of methylene chloride. The solution was stirred with 25 g of silica gel for 0.5 hr and filtered through a sintered glass filter. The silica gel was washed with a small volume of methylene chloride and the filtrate evaporated under reduced pressure. The residual solid was recrystallized from isopropyl ether to give 1.3 g of pure product, m.p. 96°-98° C.
Reaction SMILES: [C:1]12[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:8][C:7]1[C:2]2=[C:3](O)[N:4]=[CH:5][N:6]=1.O=P(Cl)(Cl)[Cl:17]>O1CCOCC1>[Cl:17][C:3]1[N:4]=[CH:5][N:6]=[C:7]2[C:2]=1[C:1]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:8]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2sc3ccccc3c12
Solvent: C1COCCO1
Product: Clc1ncnc2sc3ccccc3c12
Temperature: 90 °C
Reaction time: 4 h
Yield: 41.2 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2,4,6,10,12-hexaen-3-ol (2.0 g, 9.89 mmol, 1.00 equiv) in 1,4-dioxane (15 mL) and POCl3 (4.5 g, 29.35 mmol, 2.97 equiv) under nitrogen. The resulting solution was stirred for 4 h at 90° C. The excess amount of POCl3 was removed under reduced pressure and the residue was diluted with DCM. The resulting mixture was poured into a cooled saturated aqueous sodium bicarbonate, extracted with DCM, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:10) to afford 3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2,4,6,10,12-hexaene (0.9 g, 41%) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2].C(O)(=[O:17])C>C1COCC1.O>[CH2:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH:9]=[O:17])[NH:5][C:4]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2]
Reactant: CC(=O)O
Reactant: CCOC(=O)c1[nH]c(C)c(C)c1CC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c(C=O)c(C)c1CC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl 3-ethyl-4,5-dimethyl-1H-pyrrole-2-carboxylate (Salor-Aldrich) (0.0147 g, 0.077 mmol) in acetic acid (5 mL), THF (4 mL) and water (4 mL) was added ceric ammonium nitrate (0.169 g, 0.31 mmol) and the reaction was stirred at ambient temperature. After 1.5 h, the reaction was poured into water (10 mL) and extracted with CH2Cl2 (3×5 mL). The combined organic layers were washed with saturated NaHCO3, dried over Na2SO4, filtered, and concentrated. The resultant residue was purified by normal phase chromatography. Proton NMR for the product was consistent with the title compound. 1H NMR (500 MHz, CDCl3) δ 9.78 (s, 1H); 4.36 (q, J=7.1 Hz, 2H); 2.76 (q, J=7.6 Hz, 2H); 1.62 (s, 3H); 1.38 (t, J=7.1 Hz, 3H); 1.13 (t, J=7.6 Hz, 3H). HRMS (ES) exact mass calculated for C11H16NO3 (M+H+): 209.1052. Found 209.1050.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([CH2:14][CH3:15])[CH2:7][NH:8][C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[O:5])[CH3:2].C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>CC(C)=O>[CH2:1]([O:3][C:4]([CH:6]([CH2:14][CH3:15])[CH2:7][N:8]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)C(CC)CN[C@@H](C)C(=O)O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCOC(=O)C(CC)CN(C(=O)OCC)[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of N-[2-(ethoxycarbonyl)butyl]alanine (21.7 g, 100 mmol) in acetone (250 mL) was added a solution of triethylamine (27.7 mL, 20.2 g, 200 mmol) in acetone (50 mL) followed by ethyl chloroformate (24.8 mL, 28.2 g, 260 mmol) at 0-5° C. After stirring for 2 h at ambient temperature the solvent was evaporated and the residue was stirred with a mixture of water (200 mL) and concentrated hydrochloric acid (2 mL) for 8 h at ambient temperature. The mixture was extracted with ethyl acetate (200 mL) and the solution in ethyl acetate was extracted with cold aqueous sodium hydroxide solution [prepared from ice (100 g) and aqueous sodium hydroxide solution (1N, 200 mL)]. Concentrated hydrochloric acid (15 mL) was added to the aqueous layer and the mixture was extracted with ethyl acetate (200 mL). After drying and evaporation N-[2-(ethoxycarbonyl)butyl]-N-ethoxycarbonylalanine (23.8 g, 82%) was obtained as a yellow oil which can be used in the next reaction without further purification.