Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:18](=[O:19])[C:17]2([CH2:24][CH2:23][N:22](C(OCC3C=CC=CC=3)=O)[CH2:21][CH2:20]2)[N:16]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:15]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.C(O)C.[Pd]>[O:19]=[C:18]1[C:17]2([CH2:20][CH2:21][NH:22][CH2:23][CH2:24]2)[N:16]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:15][N:14]1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CC(C)(C)OC(=O)c1ccccc1N1CN(c2ccccc2)C2(CCN(C(=O)OCc3ccccc3)CC2)C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccccc1N1CN(c2ccccc2)C2(CCNCC2)C1=O
Reaction time: 16 h
Yield: 102.7 %

Procedure:
A solution of benzyl 3-(2-(tert-butoxycarbonyl)phenyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (1.86 g, 3.44 mmol, 1 equiv) in a mixture of ethyl acetate and ethanol was charged with 10% palladium on carbon (360 mg, 20%/wt) and the resulting mixture was hydrogenated at atmospheric pressure for 16 h. The reaction was filtered over Celite and the filtrate was concentrated and dried in vacuo to afford the title compound as a white foam (1.44 g, 96.4%); 1H NMR (400 MHz, DMSO-d6): δ 1.49 (s, 9H); 1.71 (d, 2H, J=13.2 Hz); 2.41-2.49 (m, 2H); 2.84-2.88 (m, 2H); 3.08-3.13 (m, 2H); 5.07 (s, 2H); 6.78 (t, 1H, J=7.2 and 7.6 Hz); 6.98 (s, 1H); 7.00 (s, 1H); 7.23-7.27 (m, 2H); 7.46-7.49 (m, 1H); 7.60 (dd, 1H, J=1.2 and 1.6 Hz); 7.65-7.69 (m, 1H); 7.77 (dd, 1H, J=1.2 and 1.6 Hz); MS for C24H29N3O3 m/z 408.22 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[C:8]([CH:10]=[CH:11][C:12](O)=[O:13])[CH:7]=[C:6]([CH3:15])[C:5]=1[N:16]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH3:17].[CH3:30][NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>C1COCC1>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[C:8]([CH:10]=[CH:11][C:12](=[O:13])[N:31]([CH3:30])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:7]=[C:6]([CH3:15])[C:5]=1[N:16]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH3:17]
Reactant: COC(=O)c1cc(C=CC(=O)O)cc(C)c1N(C)S(=O)(=O)c1ccc(OC)cc1
Reactant: CCCCCCCCNC
Solvent: C1CCOC1
Product: CCCCCCCCN(C)C(=O)C=Cc1cc(C)c(N(C)S(=O)(=O)c2ccc(OC)cc2)c(C(=O)OC)c1
Reaction time: 1 h
Yield: 84 %

Procedure:
A mixture of 182.6 mg (0.43 mmol) of the product of Example 204, 183 mg of molecular sieves and 105.8 mg (0.65 mmol) of 1,1'-dicyclohexylcarbodiimidazole in 4 ml THF was stirred for 1 h under nitrogen. A solution of N-methyloctylamine in 0.5 ml THF was then added to the reaction and the mixture was stirred for 18 hr at room temperature. The resulting mixture was filtered and the filtrate was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with EtOAc/Hexane (1:1) to provide 200 mg (84%) of the desired product as a colorless oil. Electrospray Mass Spec 545(M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[Br:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1>>[Br:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(Br)cc4)cc23)CC1
Yield: 76.1 %

Procedure:
Beginning with 20.0 mg (0.087 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 52.0 mg (0.131 mMol) 4-bromobenzoic acid, 27.3 mg (75.8%) of the title compound were recovered.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([C:6]1[N:7]([N:12]2C(=O)C3=CC=CC=C3C2=O)[C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:5].CN>C(O)C.O>[NH2:12][N:7]1[C:8]([CH3:11])=[CH:9][CH:10]=[C:6]1[C:4](=[O:5])[C:3]1[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=1[F:1]
Reactant: Cc1ccc(C(=O)c2ccccc2F)n1N1C(=O)c2ccccc2C1=O
Agent: CN
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(=O)c2ccccc2F)n1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.4 %

Procedure:
A rapidly stirred suspension of 2-(2-fluorobenzoyl)-5-methyl-1-phthalimidopyrrole (137 g, 0.39 mol) in 500 ml of 95% ethanol was treated with 230 ml of 40% w/w solution of methylamine and the mixture was further stirred at ambient temperature for 5 hours. The mixture was diluted with 300 ml of H2O and extracted with three 400 ml portions of dichloromethane. The combined extracts were dried (MgSO4), filtered, and evaporated to an oil which was purified by HPLC (silica gel, DCM) to give 71 g (83%) of an oil which solidified upon seeding. A three gram portion of this material was distilled at 120° (0.1 mmHg) to give 2.9 g of solid, m.p. 45°-48°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.[NH2:32][C:33]1[N:38]=[CH:37][C:36](B(O)O)=[CH:35][N:34]=1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10]([C:36]3[CH:35]=[N:34][C:33]([NH2:32])=[N:38][CH:37]=3)[C:3]=12
Reactant: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(I)c2c(N)ncnc21
Reactant: Nc1ncc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2cnc(N)nc2)c2c(N)ncnc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 13.7 %

Procedure:
To a solution of Example 57c (0.350 g, 0.663 mmoles) in DMF (4 ml), ethanol (2 ml) and water (2 ml), 2-aminopyrimidine-5-boronic acid (0.184 g, 1.327 mmoles) and sodium carbonate (0.351 g, 3.318 mmoles) were added and the system is degassed for 30 min. Tetrakistriphenylphosphine Palladium (0.151 g, 0.130 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as brown solid (0.045 g, 14% yield). MP: 264-268° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.38 (s, 2H), 8.05 (s, 1H), 8.03 (d, J=7.9, Hz, 1H), 7.85 (m, 1H), 7.68 (d, J=8.3 Hz, 1H), 7.52 (t, J=7.3 Hz, 1H), 7.29 (br s, 1H), 7.07-6.93 (m, 5H), 5.99 (q, J=7.0 Hz, 1H), 1.88 (d, J=7.0 Hz, 3H). Mass: 494.86 (M+).
Reaction SMILES: BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[F:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[CH:29]([OH:37])[C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][N:31]=1.S([O-])([O-])(=O)=S.[Na+].[Na+].[C:45]([O-:48])(=[O:47])[CH3:46].[Na+]>C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C>[C:45]([O:48][CH2:36][C:33]1[CH:32]=[N:31][C:30]([C:29]([C:23]2[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:22]=2[F:21])=[O:37])=[CH:35][CH:34]=1)(=[O:47])[CH3:46]
Reactant: Cc1ccc(C(O)c2cc(F)ccc2F)nc1
Reactant: CC(=O)[O-]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)OCc1ccc(C(=O)c2cc(F)ccc2F)nc1
Temperature: 25 °C
Yield: 18.4 %

Procedure:
While heating under reflux, N-bromosuccinimide (6.0 g, 33.6 mmol) and a catalytic amount of 2,2′-azobis(2-methylpropionitrile) were added to a solution of the 2-[(2,5-difluorophenyl)-hydroxymethyl]-5-methylpyridine (2.64 g, 11.2 mmol), which had been obtained in Referential Example 15, in carbon tetrachloride (60 ml). The resulting mixture was then, stirred. After reflux for 7 hours, the reaction mixture was cooled to room temperature and added to an aqueous solution of sodium thiosulfate. The mixture was extracted with ether. The solution was washed with water and brine, and then dried over sodium sulfate. The residue obtained by concentrating the solution under reduced pressure was dissolved in toluene and the resulting solution was concentrated again. The residue was dissolved in N,N-dimethylformamide (20 ml). Sodium acetate (4.59 g, 56 mmol) was added to the resulting solution and the mixture was stirred at 70° C. for 17 hours. After cooling, the reaction mixture was dissolved in ethyl acetate (100 ml), followed by washing with water and brine. The solution was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=5:1) to yield the title compound (600 mg, 18%) as an oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[CH2:17]([N:24]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[CH2:17]([N:24]1[CH2:30][CH2:29][CH2:28][N:27]([C:6]2[CH:5]=[CH:4][C:3]([N+:8]([O-:10])=[O:9])=[CH:2][CH:7]=2)[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: c1ccc(CN2CCCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCCN(Cc3ccccc3)CC2)cc1
Temperature: 90 °C

Procedure:
Fluoronitrobenzene (3.09 g, 21.9 mmol) is dissolved in water (14 ml), and then potassium carbonate (3.64 g, 26.28 mmol) and 1-benzylhomopiperazine (5 g, 26.28 mmol) are added. The medium is heated at 90° C. for 4 h 20 min and then cooled to room temperature. The precipitate formed is filtered, and a yellow solid is obtained. 6.30 g (92.5%) of product are recovered.
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[C:8]([S:24][CH3:25])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([O:18]C)=[O:17])[C:10](=[O:12])[CH:11]=1.O1CCOCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[OH-].[Na+].O>[F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[C:8]([S:24][CH3:25])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([OH:18])=[O:17])[C:10](=[O:12])[CH:11]=1
Reactant: COC(=O)c1ccc(C)c(-n2c(SC)nc(OCc3ccc(F)cc3F)cc2=O)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CSc1nc(OCc2ccc(F)cc2F)cc(=O)n1-c1cc(C(=O)O)ccc1C
Yield: 100.9 %

Procedure:
A mixture of the ester (0.4 g, 0.0009 mol) obtained from step 3, in 2N NaOH (0.9 mL) and dioxane (0.5 mL) was stirred at room temperature for 1.5 h. The resulting clear solution was diluted with water (5.0 mL), acidified with 5% citric acid and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (2×15 mL), dried (Na2SO4), and concentrated to afford the title compound (0.38 g) as a white powder: 1H NMR (CD3OD/400 MHz) δ 8.06 (d, 1H, J=8.0 Hz), 7.81 (s, 1H ), 7.51 (m, 2H), 6.99 (m 2H), 5.64 (s, 1H), 5.48 (s, 2H), 2.50 (s, 3H), and 2.15 (s, 3H); ES-HRMS m/z 419.0892 (M+H calcd for C20H17N2O4SF2 requires 419.0872).
Reaction SMILES: [C:1]([C:3](=[CH:10][CH:11]([CH3:13])[CH3:12])[CH2:4][C:5]([O:7]CC)=[O:6])#[N:2].O.[OH-].[Li+].Cl>O1CCCC1.O>[C:1]([C:3](=[CH:10][CH:11]([CH3:13])[CH3:12])[CH2:4][C:5]([OH:7])=[O:6])#[N:2]
Reactant: CCOC(=O)CC(C#N)=CC(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C=C(C#N)CC(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethyl 3-cyano-5-methylhex-3-enoate (mixture of E and Z isomers) and lithium hydroxide hydrate are suspended in a mixture of tetrahydrofuran and water. The slurry is vigorously stirred for 4 hours at room temperature. The mixture is acidified to pH 2 (3N HCl) and extracted into ethyl acetate (3×150 mL). The combined organic layers are dried (MgSO4), and the solvent is removed in vacuo to give crude 3-cyano-5-methylhex-3-enoic acid. The crude acid is dissolved in ethyl acetate (400 mL), and a solution of tert-butylamine in ethyl acetate (20 mL) is added. The temperature of the solution rises approximately 10° C. as a mass of white crystalline solid precipitates. The product is collected by filtration and dried in vacuo. Yield 22.15 g, 97.9 mmol, 89%.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[C:16]2[C:11](=[C:12]([O:20][CH3:21])[C:13]([O:18][CH3:19])=[C:14]([Cl:17])[CH:15]=2)[N:10]=[C:9]([N:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][C:32](=[CH2:34])[CH3:33])=[O:29])[CH2:24][CH2:23]2)[N:8]=1.[OH-:35].[Na+]>O>[NH2:6][C:7]1[C:16]2[C:11](=[C:12]([O:20][CH3:21])[C:13]([O:18][CH3:19])=[C:14]([Cl:17])[CH:15]=2)[N:10]=[C:9]([N:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][C:32]([CH3:33])([OH:35])[CH3:34])=[O:29])[CH2:24][CH2:23]2)[N:8]=1
Reactant: C=C(C)COC(=O)N1CCN(c2nc(N)c3cc(Cl)c(OC)c(OC)c3n2)CC1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1c(Cl)cc2c(N)nc(N3CCN(C(=O)OCC(C)(C)O)CC3)nc2c1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A stirred solution of 24 ml. of concentrated sulfuric acid dissolved in an equal volume of water was cooled to 10°-12° C. and 0.015 mole of methallyl 4-(4-amino-6-chloro-7,8-dimethoxyquinazolin-2-yl)piperazine-1-carboxylate is added in small portions with stirring. The addition is carried out at a rate sufficient to keep the reaction temperature below 20° C. The resulting mixture is stirred for 15 minutes at 15°-20° C., then for two hours at 10°-15° C. The reaction mixture is diluted with 150 ml. of ice-water and adjusted to pH 10 with sodium hydroxide while maintaining the temperature below 12° C. After extraction with chloroform, the combined extracts are washed with water and dried over anhydrous sodium sulfate. The solvent is evaporated in vacuo and the residue recrystallized to afford 2-methyl-2-hydroxypropyl 4-(4-amino-6-chloro-7,8-dimethoxyquinazolin-2-yl)piperazine-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([OH:21])[C:19]4[C:14](=[CH:15][C:16]([C:22]([F:25])([F:24])[F:23])=[CH:17][CH:18]=4)[C:13]3=[O:26])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl[C:29]([N:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1)=[O:30].C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([O:21][C:29]([N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)=[O:30])[C:19]4[C:14](=[CH:15][C:16]([C:22]([F:24])([F:25])[F:23])=[CH:17][CH:18]=4)[C:13]3=[O:26])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: O=C1c2cc(C(F)(F)F)ccc2C(O)N1c1ccc2ccc(Cl)nc2n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CN1CCN(C(=O)OC2c3ccc(C(F)(F)F)cc3C(=O)N2c2ccc3ccc(Cl)nc3n2)CC1
Yield: 73.5 %

Procedure:
Following the procedure of Example 28, but starting from 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxy-6-trifluoromethyl-1-isoindolinone (4.8 g.), 1-chlorocarbonyl-4-methyl-piperazine hydrochloride (15.1 g.), triethylamine (14.2 cc., equivalent to 10.2 g.) and pyridine (66 cc.) in methylene chloride (250 cc.), a crude product (7.8 g.) is obtained, which is triturated with water (50 cc.). The solid obtained is filtered off and washed with water (30 cc.). After recrystallisation from isopropanol (240 cc.), 2-(7-chloro1,8-naphthyridin-2-yl)-3-(4-methyl-piperazinyl)carbonyloxy-6-trifluoromethyl-1-isoindolinone (4.7 g.) melting at 219° C is obtained.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].O=C[C@H]([C@H]([C@@H]([C@H](CO)O)O)O)O.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[OH:12][CH2:11][C@@H:9]([C@H:7]([C@@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])[OH:10]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
A method for producing L-sugars including L-idose and L-gulose from D-glucose. The method comprises hydrogenating D-glucose to provide sorbitol, oxydizing the D-sorbitol to provide L-sorbose, racemizing the L-sorbose to provide a mixture of L-sorbose, L-idose and L-gulose, and precipitating the L-sorbose with lime from a dilute solution. The unconverted L-sorbose is recovered by carbonation and recycled. The hydrogenation of glucose is done in a fixed catalyst bed.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.[Cl:38][C:39]1[CH:47]=[C:46]([F:48])[C:45]([S:49](=[O:52])(=[O:51])[NH2:50])=[CH:44][C:40]=1[C:41](O)=[O:42]>>[Cl:38][C:39]1[CH:47]=[C:46]([F:48])[C:45]([S:49](=[O:51])(=[O:52])[NH2:50])=[CH:44][C:40]=1[C:41]([N:29]1[CH2:28][CH2:27][C:26]([CH2:25][NH:24][C:22](=[O:23])[C:3]2[C:2]([F:1])=[C:7]([S:8][C:9]3[S:13][C:12]([NH:14][C:15]4[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=4)=[N:11][CH:10]=3)[CH:6]=[CH:5][N:4]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:31][CH2:30]1)=[O:42]
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5)CCNCC4)c3F)s2)c1
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1F
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5)CCN(C(=O)c5cc(S(N)(=O)=O)c(F)cc5Cl)CC4)c3F)s2)c1

Procedure:
Following the procedure given for example 92, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)-N-((4-phenylpiperidin-4-yl)methyl)picolinamide (compound example 11) was reacted with 2-chloro-4-fluoro-5-sulfamoylbenzoic acid to give the title compound. LC/MS (M+H)+: 770. Ret. time: 2.17 min. (Condition J); analytical HPLC Ret. time: 12.91 min (Condition K).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([Cl:13])=[CH:8][N:7]=1.CS[C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[CH:18][N:17]=1>N1C=CC=CC=1>[Cl:13][C:9]1[CH:10]=[C:11]([CH3:12])[C:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:16]2[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[CH:18][N:17]=2)=[N:7][CH:8]=1
Reactant: Cc1cc(Cl)cnc1NCCCN
Reactant: CSc1ncc(Cc2ccncc2)c(=O)[nH]1
Solvent: c1ccncc1
Product: Cc1cc(Cl)cnc1NCCCNc1ncc(Cc2ccncc2)c(=O)[nH]1
Yield: 64 %

Procedure:
2-(3-Aminopropylamino)-5-chloro-3-methylpyridine (0.92 g) and 2-methylthio-5-(4-pyridylmethyl)-4-pyrimidone (0.90 g) were heated together under reflux in pyridine (5 ml) for 46 hr. After stripping to dryness the residue was triturated with wet ether to give a white solid. Repeated recrystallisation from isopropanol/water gave 2-[3-(5-chloro-3-methylpyrid-2-ylamino)propylamino]-5-(4-pyridylmethyl)-4-pyrimidone (0.95 g; 64%) m.p. 90°-92° C.
Reaction SMILES: [CH2:1]([N:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=2)[CH:8]=1)[C:4](=[O:6])[CH3:5])[CH3:2].[CH2:20]([NH:22][C:23](=S)[NH:24][NH2:25])[CH3:21]>C(O)C>[CH2:1]([N:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]3[N:15]([C:23]([NH:22][CH2:20][CH3:21])=[N:24][N:25]=3)[N:14]=2)[CH:8]=1)[C:4](=[O:6])[CH3:5])[CH3:2]
Reactant: CCNC(=S)NN
Reactant: CCN(C(C)=O)c1cccc(-c2ccc(Cl)nn2)c1
Solvent: CCO
Product: CCNc1nnc2ccc(-c3cccc(N(CC)C(C)=O)c3)nn12

Procedure:
A solution of 7.0 g N-ethyl-N-[3-(6-chloro-3-pyridazinyl) phenyl]acetamide and 6.0 g 4-ethyl-3-thiosemicarbazide in 200 ml ethanol was refluxed for 18 hours. The mixture was then worked up and the product chromatographed as described in Example 70. Recrystalization of the product from dichloromethane-hexane afforded 2.1 g yellow flakes mp 171°-172° C.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11](OCC)=[O:12])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[S:4][CH:3]1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1.[NH3:27]>CO>[NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([NH2:27])=[O:12])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[S:4][CH:3]1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1
Reactant: CCOC(=O)CN1C(=O)C(N)C(c2ccc(Cl)cc2)Sc2ccccc21
Reactant: N
Solvent: CO
Product: NC(=O)CN1C(=O)C(N)C(c2ccc(Cl)cc2)Sc2ccccc21
Reaction time: 8 h

Procedure:
In 200 ml of methanol is dissolved 1.5 g of ethyl 3-amino-2-(p-chlorophenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, and ammonia gas is blown into the solution under ice-cooling up to the saturated state. The reaction temperature is slowly elevated to room temperature, and the reaction mixture is left standing overnight. Then, the reaction mixture is concentrated under reduced pressure. Ethyl acetate is added to the obtained residue, and the resulting crystals are collected by filtration to give 0.9 g of 3-amino-2-(p-chlorophenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide, m.p. 217-220° C. (decomposition).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=[C:11]2[C:31]2[CH:32]=[N:33][C:34]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:35][C:36]=2[O:37][CH2:38][CH3:39])=[O:9])[CH2:4][CH2:3]1.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>ClCCl>[C:40]([C:34]1[N:33]=[CH:32][C:31]([C:11]2[N:10]([C:8]([N:5]3[CH2:4][CH2:3][CH:2]([NH:1][S:45]([CH3:44])(=[O:47])=[O:46])[CH2:7][CH2:6]3)=[O:9])[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=2)=[C:36]([O:37][CH2:38][CH3:39])[CH:35]=1)([CH3:42])([CH3:41])[CH3:43]
Reactant: CS(=O)(=O)Cl
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N)CC1
Solvent: ClCCl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(NS(C)(=O)=O)CC1
Reaction time: 1 h
Yield: 86 %

Procedure:
A solution of (4-amino-piperidin-1-yl)-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-methanone (87 mg, 0.139 mmole, example 204) in dichloromethane (5 mL) was treated with methanesulfonyl chloride (31.8 mg, 0.277 mmole, Aldrich) at 0° C. and allowed to stir for 1 h before diluted with dichloromethane (60 mL), washed with aqueous sodium carbonate (15 mL), water (15 mL) and concentrated. The residue was purified by flash column chromatography (silica gel, eluting with a gradient of 1% to 10% methanol in dichloromethane) to give the title compound (83.8 mg). HR-MS (ES, m/z) calculated for C35H44Cl2N5O4S [(M+H)+] 700.2486, observed 700.2482.