Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([OH:20])=[CH:16][C:17]=4[CH2:18][CH2:19][C:8]=3[C:7]1=[CH:6][CH2:5][C@@H:4]2[OH:21])[CH3:2].C.[H][H]>C1C=CC=CC=1>[CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([OH:20])=[CH:16][C:17]=4[CH2:18][CH2:19][C:8]=3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:21])[CH3:2]
Reactant: CC[C@]12CCC3=C(CCc4cc(O)ccc43)C1=CC[C@@H]2O
Reactant: [H][H]
Solvent: c1ccccc1
Product: CC[C@]12CCC3=C(CCc4cc(O)ccc43)[C@@H]1CC[C@@H]2O

Procedure:
Shake 13β-ethylgona-1,3,5(10),8,14-pentaene-3,17β-diol (0.28 g.) in benzene (35 cc.) with 10% palladised charcoal (300 mg.) in an atmosphere of hydrogen until 25 cc. of hydrogen has been absorbed. Filter off the catalyst, evaporate the solvent and recrystallize the residue from methanol to obtain the title product, m.p. 234°-8°; ultraviolet absorption peak at 280 mμ (ε 41,200).
Reaction SMILES: [F:1][C:2]1([C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15])[CH:7]([O:8]C(=O)C)[NH:6][C:5](=[O:12])[NH:4][C:3]1=[O:13].[CH:21](=[N:27]/O)\[C:22]1[O:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>N1C=CC=CC=1>[F:1][C:2]1([C:14]([O:16][CH2:17][CH:18]([CH3:19])[CH3:20])=[O:15])[CH:7]([O:8]/[N:27]=[CH:21]/[C:22]2[O:26][CH:25]=[CH:24][CH:23]=2)[NH:6][C:5](=[O:12])[NH:4][C:3]1=[O:13]
Reactant: CC(=O)OC1NC(=O)NC(=O)C1(F)C(=O)OCC(C)C
Reactant: O/N=C/c1ccco1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(C)COC(=O)C1(F)C(=O)NC(=O)NC1O/N=C/c1ccco1
Temperature: 25 °C
Reaction time: 21 h
Yield: 70 %

Procedure:
In 10 ml of pyridine were dissolved 2.9 g (10 mmol) of isobutyl 5-fluoro-6-acetoxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate and 2.22 g (20 mmol) of (E)-furfuraldoxime, and 1.01 g (10 mmol) of dried triethylamine was added to the solution, followed by stirring at room temperature for 21 hours. The reaction solution was concentrated under reduced pressure, and 50 ml of ethyl acetate was added to the residue. The organic layer was washed three times with 10-ml portions of water, and the solvent was dried and evaporated under reduced pressure. The residue was recrystallized twice from ethyl acetate-hexane to give 2.39 g of isobutyl 5-fluoro-6-(E)-furfurylideneaminooxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate. m.p. 167°-168° C.
Reaction SMILES: [Si]([O:8][CH:9]1[CH:15]2[CH:13]([O:14]2)[CH2:12][N:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[OH:8][CH:9]1[CH:15]2[CH:13]([O:14]2)[CH2:12][N:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10]1
Reactant: CCOC(=O)N1CC2OC2C(O[Si](C)(C)C(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CC(O)C2OC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
To a solution of Compound 239F (13.6 g, 45.1 mmol) in 10 mL of dry THF was added a solution of TBAF (67.6 mL, 67.6 mmol) in THF. The mixture was stirred overnight at room temperature. Water was added and the reaction mixture was extracted with EtOAc (250 mL×3). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. Concentration in vacuo followed by flash chromatography (hexane-EtOAc: 1:1 to 1:2) on silica gel afforded 6.03 g (Yield: 75%) of 239H as an oil. 1H-NMR (400 MHz, CDCl3): 4.15 (m, 1H), 4.13 (q, J=7.08, 2H), 3.95 (m, 1H), 3.75 (m, 1H), 3.52 (m, 1H), 3.32 (m, 1H), 3.25 (m, 2H), 3.10 and 2.55 (partial, 1H), 1.27 (t, J=7.08, 3H).
Reaction SMILES: C[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[O:11]1CCOC[CH2:12]1>CCOC(C)=O>[N+:8]([C:7]1[CH:6]=[CH:5][C:4]([CH:12]=[O:11])=[N:3][CH:2]=1)([O-:10])=[O:9]
Reactant: C1COCCO1
Reactant: Cc1ncccc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: O=Cc1ccc([N+](=O)[O-])cn1
Reaction time: 4 h

Procedure:
5-Nitropyridine-2-carboxaldehyde was prepared from the nitro derivative, 2-methyl-3-nitropyridine, by the procedure employed for the synthesis of Example I, except that anhydrous dioxane was used as the solvent and the reaction time was 4 h. Yield: 2.0 g (42%); mp 66°-67° C. (lit. 66.5°-67.5° C.); TLC, Rf 0.85 (EtOAc); 1H NMR (90 MHz, CDCl3) δ 8.0 (d, 1H, 3-H, J3,4 =4.5 Hz), 8.30 (d, 1H, 4-H, J3,4 =4.5 Hz), 9.25 (s, 1H, 6-H), 10.45 (s, 1H, 2-CHO).
Reaction SMILES: CN([CH:4]=[O:5])C.P(Cl)(Cl)(Cl)=O.[Br:11][C:12]1[CH:20]=[CH:19][C:18]([C:21]([NH2:23])=O)=[C:17]2[C:13]=1[CH:14]=[CH:15][NH:16]2.C([O-])(O)=O.[Na+].[OH-].[Na+]>C(Cl)Cl>[Br:11][C:12]1[CH:20]=[CH:19][C:18]([C:21]#[N:23])=[C:17]2[C:13]=1[C:14]([CH:4]=[O:5])=[CH:15][NH:16]2
Reactant: NC(=O)c1ccc(Br)c2cc[nH]c12
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: N#Cc1ccc(Br)c2c(C=O)c[nH]c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.2 %

Procedure:
A solution of DMF (8.42 mL, 109 mmol) in CH2Cl2(105 mL) stirred on a salt-ice bath was treated dropwise with phosphorus oxychloride (2.57 mL, 27.6 mmol). After 15 min, 4-bromo-1H-indole-7-carboxamide (2 g, 8.37 mmol) was added in one portion while maintaining the temperature below −10° C. After addition, the mixture was stirred at room temperature overnight. After 16 h, ice was added, followed by NaHCO3 and 1 M aqueous NaOH added in portions to make the mixture basic. The mixture was extracted with dichloromethane (3 times), and the combined organic phases were washed with brine, dried and concentrated. The residue was subjected to column chromatography on silica gel (80 g), eluting with a gradient from 100% CH2Cl2 to 15% Methanol-85% CH2Cl2, to provide the desired product as a pale solid (1.36 g, 65% yield). LCMS (M+H)+ m/z 248.9, 250.9.
Reaction SMILES: [Cl:1][C@H:2]1[C:28](=[O:29])[N:4]2[C:5]([C:12]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[C:6]([CH3:11])[CH2:7][S:8](=[O:10])(=[O:9])[C@H:3]12.Cl.[CH3:31]NC.C=O.C(O)(C)(C)C>C(Cl)Cl>[Cl:1][C@H:2]1[C:28](=[O:29])[N:4]2[C:5]([C:12]([O:14][CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:13])=[C:6]([CH3:11])[C:7](=[CH2:31])[S:8](=[O:9])(=[O:10])[C@H:3]12
Reactant: CNC
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@H](Cl)[C@H]2S(=O)(=O)C1
Agent: C=O
Agent: Cl
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: C=C1C(C)=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@H](Cl)[C@H]2S1(=O)=O
Temperature: 95 °C
Yield: 37.7 %

Procedure:
Benzhydryl 7α-chloro-3-methyl-3-cephem-4-carboxylate 1,1-dioxide (9.3 g, 0.0215 mol) was dissolved in methylene chloride (35 ml), dimethylamine hydrochloride (4.9 g, 0.0645 mol), formaldehyde solution (2.25 g, 0.075 mol) and t-butyl alcohol (300 ml) were added and the mixture was heated to reflux at 95° C. for 4 hours. After removing the solvent under reduced pressure the residue was redissolved in methylene chloride, washed successively with water, dried over sodium sulfate and concentrated. The product was purified over a silica column using hexane-ethyl acetate mixture as the eluant to yield benzhydryl 7α-chloro-2-methylene-3-methyl-3-cephem-4-carboxylate 1,1-dioxide (3.6 g, 40%) as a white foam. IR (Nujol) ν max 1723, 1800 cm-1.
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:48]=[CH:47][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:40]=[CH:39][C:38]([CH2:41][C:42]([O:44]CC)=[O:43])=[CH:37][CH:36]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:49][CH3:50])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:48]=[CH:47][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:36]=[CH:37][C:38]([CH2:41][C:42]([OH:44])=[O:43])=[CH:39][CH:40]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:49][CH3:50])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:14]=2)[N:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4csc(CC)n4)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4ccc(CC(=O)O)cc4)oc3C)c(OC)c2)cs1
Yield: 91.7 %

Procedure:
A mixture of ethyl {4-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (800 mg), 1N aqueous sodium hydroxide solution (5 mL), tetrahydrofuran (10 mL) and ethanol (10 mL) was heated under reflux for 30 min. After cooling, the reaction mixture was neutralized with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. Recrystallization of the obtained crystal from ethyl acetate-hexane gave {4-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetic acid as colorless crystals (704 mg, yield 92%). melting point: 123-124° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([OH:9])[N:3]=1.[H-].[Na+].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: ClCc1ccccc1
Reactant: Cc1cc(O)nc(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccccc2)nc(N)n1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
2-Amino-4-methyl-6-hydroxypyrimidine (62.5 g, 0.50 mole) is dissolved in 500 ml of dimethylformamide and sodium hydride (0.5 mole) is added over a 1 hour period under a nitrogen atmosphere. The mixture is heated at 75° C. for 11/2 hours. Benzyl chloride (69.3 g, 0.55 moles) is then added over 15 minutes and the mixture is heated at 90° C. and stirred for 11/2 hours. After cooling, the reaction mixture is filtered and concentrated under vacuum to an oil from which 2-amino-4-methyl-6-benzyloxypyrimidine melting at 108°-109.5° C. is obtained by crystallization from n-butyl chloride.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:20]=O)[C:9]([N:12]3[CH2:17][C@H:16]([CH3:18])[O:15][C@H:14]([CH3:19])[CH2:13]3)=[C:10]([F:11])[C:5]=2[O:4][N:3]=1.[NH:22]1[C:29](=[O:30])[CH2:28][C:26](=[O:27])[NH:25][C:23]1=[O:24]>CC(O)C>[NH2:1][C:2]1[C:6]2[CH:7]=[C:8]3[C:9](=[C:10]([F:11])[C:5]=2[O:4][N:3]=1)[N:12]1[CH2:13][C@@H:14]([CH3:19])[O:15][C@@H:16]([CH3:18])[C@@H:17]1[C:28]1([C:26](=[O:27])[NH:25][C:23](=[O:24])[NH:22][C:29]1=[O:30])[CH2:20]3
Reactant: C[C@@H]1CN(c2c(C=O)cc3c(N)noc3c2F)C[C@H](C)O1
Reactant: O=C1CC(=O)NC(=O)N1
Solvent: CC(C)O
Product: C[C@@H]1CN2c3c(cc4c(N)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Temperature: 85 °C

Procedure:
To a solution of 3-amino-6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-7-fluoro-1,2-benzisoxazole-5-carbaldehyde (Intermediate 8, 100 mg, 0.34 mmol) in IPA was added barbituric acid (48 mg, 0.34 mmol) and the mixture heated at 85° C. for 12 hours. Solvents were evaporated and the residue was purified over neutral alumina using a gradient of methanol in CH2Cl2 to give the title compound as a racemic mixture in the form of a pale yellow solid. Yield: 18 mg, (13%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]1[CH:22]=[C:23](B2OCC(C)(C)CO2)[CH:24]=[CH:25][CH:26]=1>>[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]1[CH:22]=[C:23]([C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]3)[CH:24]=[CH:25][CH:26]=1
Reactant: CC1(C)COB(c2cccc(-c3ccco3)c2)OC1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Product: FC(F)(F)c1ccc2c(-c3cccc(-c4ccco4)c3)ccnc2n1
Yield: 48.1 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 2-(3-furan-2-ylphenyl)-5,5-dimethyl[1,3,2]-dioxaborinane (72 mg, 0.28 mmol) as described in Example 7 part g), affording 5-(3-furan-2-ylphenyl)-2-trifluoromethyl[1,8]naphthyridine (36 mg, 49%). δH (360 MHz, CDCl3) 6.53 (1H, q, J 1.8), 6.75 (1H, d, J 3.2), 7.35-7.38 (1H, m), 7.51 (1H, d, J 1.1), 7.55-7.62 (2H, m), 7.79-7.86 (3H, m), 8.57 (1H, d, J 8.4), 9.29 (1H, d, J 4.2). m/z (ES+) 341 [MH]+.
Reaction SMILES: [CH3:1][CH:2]([CH:9]=[CH2:10])[CH2:3][CH2:4][CH2:5][C@H:6]([OH:8])[CH3:7].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O:8][C@@H:6]([CH2:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH:9]=[CH2:10])[CH3:7])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CC(C)CCC[C@@H](C)O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: C=CC(C)CCC[C@@H](C)OS(=O)(=O)c1ccc(C)cc1
Reaction time: 0.17 h
Yield: 58.2 %

Procedure:
To a solution of (2R)-6-methyloct-7-en-2-ol (12 g, 84 mmol) in pyridine (16 mL) was added DMAP (0.51 g, 4.22 mmol) and the solution was stirred for 10 min. P-Toluenesulfonyl chloride (18.5 g, 97 mmol) was added to the reaction mass at 0° C. The reaction mass was allowed to come to room temperature and stirred overnight. Pyridine was removed under reduced pressure and the residue was diluted with ethyl acetate (200 mL). The organic solution was washed with aqueous 1.5 N HCl solution, saturated bicarbonate solution, brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure to get crude compound (14.5 g, 32%). The crude compound was taken to the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[CH2:22]([S:24](Cl)(=[O:26])=[O:25])[CH3:23]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]([S:24]([CH2:22][CH3:23])(=[O:26])=[O:25])[S:10]([CH2:13][CH3:14])(=[O:11])=[O:12])[CH:5]=[N:6][CH:7]=1
Reactant: CCS(=O)(=O)Cl
Reactant: CCS(=O)(=O)NCc1cncc(Br)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N(Cc1cncc(Br)c1)S(=O)(=O)CC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of N-((5-bromopyridin-3-yl)methyl)ethanesulfonamide (1.8 g, 5.55 mmol) and triethylamine (1.683 g, 16.64 mmol) in DCM (20 mL) at 0° C. is added ethanesulfonyl chloride (1.426 g, 11.09 mmol), and the mixture is stirred at 0° C. for 1 h. Silica gel (10 g) is added and the mixture is concentrated in vacuo. The residue is purified by silica chromatography eluting with 0 to 2% MeOH-DCM to give N-((5-bromopyridin-3-yl)methyl)-N-(ethylsulfonyl)ethanesulfonamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (t, J=7.3 Hz, 6H), 3.48 (q, J=7.3 Hz, 4H), 4.92 (s, 2H), 8.0 (t, J=2.1 Hz, 1H), 8.59 (d, J=2.0 Hz, 1H), 8.72 (d, J=2.3 Hz, 1H).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([Cl:32])=[C:24]3[C:28]=2[N:27]([CH3:29])[C:26]([CH3:30])=[C:25]3[CH3:31])[C:11]1=[O:33])[CH2:7][CH2:8][CH3:9])C.O.[OH-].[Li+]>C1COCC1.O>[Cl:32][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:10]([CH:6]([CH2:7][CH2:8][CH3:9])[CH2:5][C:4]([OH:34])=[O:3])[C:11]2=[O:33])=[C:28]2[C:24]=1[C:25]([CH3:31])=[C:26]([CH3:30])[N:27]2[CH3:29]
Reactant: CCCC(CC(=O)OCC)n1c(=O)n(Cc2ccc(Cl)c3c(C)c(C)n(C)c23)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCC(CC(=O)O)n1c(=O)n(Cc2ccc(Cl)c3c(C)c(C)n(C)c23)c2ccccc21
Temperature: 25 °C
Yield: 44.1 %

Procedure:
To a stirred solution of 3-[3-(4-Chloro-1,2,3-trimethyl-1H-indol-7-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester (25 mg, 0.05 mmol) in THF (5 ml) and water (1 ml) was added lithium hydroxide monohydrate (20 mg, 0.48 mmol). The resulting mixture was stirred at ambient temperature until all of the starting material was consumed. After this time the reaction was concentrated to low volume and diluted with water (5 ml) and acetic acid (0.2 ml). The resulting solid was collected via filtration and suspended in acetonitrile/water. The solid was collected once more via filtration and dried on house vacuum at 70° C. to give 10 mg (43%) of the desired product. LCMS (ESMS): m/z 454.96 (M+H+).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CCN(C(C)C)C(C)C.Br[C:21]1[N:26]=[C:25](/[CH:27]=[C:28]2/[C:29](=[O:34])[NH:30][C:31](=[O:33])[S:32]/2)[CH:24]=[CH:23][CH:22]=1>CS(C)=O>[CH3:1][N:2]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:21]1[N:26]=[C:25](/[CH:27]=[C:28]2/[C:29](=[O:34])[NH:30][C:31](=[O:33])[S:32]/2)[CH:24]=[CH:23][CH:22]=1
Reactant: CNCCc1ccccc1
Reactant: O=C1NC(=O)/C(=C/c2cccc(Br)n2)S1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CN(CCc1ccccc1)c1cccc(/C=C2\SC(=O)NC2=O)n1
Temperature: 110 °C
Reaction time: 48 h

Procedure:
An 8 mL round-bottomed vial was charged with N-methyl-2-phenylethanamine (43 mg, 0.318 mmol, 1 equiv.) and DMSO (1 mL, 0.3 M), DiPEA (105 μL, 0.636 mmol, 2 equiv.), (Z)-5-((6-bromopyridin-2-yl)methylene)thiazolidine-2,4-dione (91 mg, 0.318 mmol, 1 equiv.), and the vial was purged with argon. The mixture was shaken for 48 h at 110° C. The reaction mixture was then partitioned between CH2Cl2 (10 mL) and sat. NaCl (20 mL). The aqueous layer was back extracted with CH2Cl2 (2×15 mL) and the combined organic layer was dried over xxx and concentrated under reduced pressure to provide an orange residue. The orange residue was triturated with ether (3×15 mL) to provide (Z)-5-((6-(methyl(phenethyl)amino)pyridin-2-yl)methylene)thiazolidine-2,4-dione as an orange film (2.6 mg, 175 mg theoretical, 5%). LC-MS m/z: 340 (M+1).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][C:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[O:53])[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([O:64][Si](C(C)(C)C)(C)C)[CH2:5][C:4]1=[O:72])[CH3:2].C1C=CN=CC=1.F>C1COCC1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][C:52]([C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)=[O:53])[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([OH:64])[CH2:5][C:4]1=[O:72])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(=O)c4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(=O)c4ccccc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.1 %

Procedure:
To a solution of the product from Step A (188 mg) in THF (2.8 ml) was added hydrogen fluoride/pyridine and the reaction mixture stirred at room temperature for 24 hours. The reaction was then quenched by the addition of saturated aqueous sodium bicarbonate and extracted into ethyl acetate. The organic phase was dried with magnesium sulphate and concentrated. The crude material was purified by column chromatography on silica gel eluting with 50% hexane:50% ethyl acetate to give the title compound (102 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=1.[CH3:33][C:34]([Si:37](Cl)([CH3:39])[CH3:38])([CH3:36])[CH3:35]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Si:37]([O:18][CH2:17][C@H:10]1[O:9][C@:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:30])[F:31])=[CH:24][CH:23]=3)[CH:4]=2)([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@@H:11]1[OH:16])([C:34]([CH3:36])([CH3:35])[CH3:33])([CH3:39])[CH3:38]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OC(F)(F)F)cc3)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OC(F)(F)F)cc3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 16 h
Yield: 97 %

Procedure:
(2S,3R,4S,5S,6R)-2-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 61 (1.33 g, 2.78 mmol) was dissolved in 12 mL pyridine, followed by addition of 4-dimethylamino pyridine (67.93 mg, 0.55 mmol) and TBSCl (0.50 g, 3.34 mmol) in turn. The reaction mixture was stirred for 16 hours. Thereafter, the reaction mixture was concentrated under reduced pressure and partitioned after 75 mL ethyl acetate and 75 mL water were added. The aqueous phase was extracted with ethyl acetate (50 mL×2) and the organic extracts were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3R,4S,5S,6R)-6-[(tert-butyl(dimethyl)silyl)oxymethyl]-2-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 6j (1.60 g, white solid), yield: 97.6%. 1H NMR (400 MHz, CD3OD): δ 7.55 (d, 1H), 7.46 (d, 1H), 7.41 (d, 1H), 7.26 (d, 2H), 7.17 (d, 2H), 4.17 (s, 2H), 4.04 (d, 1H), 3.92-3.88 (m, 1H), 3.77 (t, 1H), 3.61-3.59 (m, 1H), 3.09 (s, 3H).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:17][CH2:18][C:19](Br)([CH3:21])[CH3:20])=[C:14]([OH:16])[CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-:24].[K+].[K+]>CN(C=O)C.Cl>[C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]3[NH:17][C:18](=[O:24])[C:19]([CH3:21])([CH3:20])[O:16][C:14]=3[CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(Br)CNc1ccc(S(=O)(=O)c2ccccc2)cc1O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)Oc2cc(S(=O)(=O)c3ccccc3)ccc2NC1=O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
The crude 5-benzenesulfonyl-2-(2-bromo-2-methyl-propylamino)-phenol from step 1 was dissolved in 10 mL DMF and potassium carbonate (0.565 g., 4.096 mmol) was added. The reaction mixture was heated to 80° C. with stirring for 2 hours, then cooled to room temperature and poured onto 100 g of ice in 150 mL 10% aqueous hydrogen chloride. The resulting solid was filtered and dried under vacuum for 18 hours to give 0.570 g (1.79 mmol) of 7-benzenesulfonyl-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one. MS: 316 (M−H)−.
Reaction SMILES: F[B-](F)(F)F.[CH2:6]([N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[NH:18])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:19][S:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>>[CH2:6]([N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[N:18][C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([S:20][CH3:19])=[CH:22][CH:23]=1)=[O:29])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CSc1ccc(N=C=O)cc1
Reactant: N=C1CCCN1Cc1ccccc1
Agent: F[B-](F)(F)F
Product: CSc1ccc(NC(=O)N=C2CCCN2Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The fluoroborate salt of 1-benzyl-2-iminopyrrolidine (6.55 g; 0.025 mole) is converted to the free base (4.36 g.; 0.025 mole) in the usual manner. After drying over K2CO3, the benzene solution is filtered through diatomaceous earth and 4.13 g. (0.025 mole) of 4-methylthiophenylisocyanate is added. The reaction mixture is stirred at room temperature for 1 hour and then evaporated to dryness in vacuo to give an oil which crystallizes. Recrystallizations from acetone-ether yields the pure product, 1-(1-benzyl-2-pyrrolidylidene)-3-(4-methylthiophenyl)urea, m.p. = 113°-115° C.