Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C([NH:4][C@H:5]([C:10]([NH:12][C@H:13]([C:21]([OH:23])=O)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])[CH2:6][C:7](=[O:9])[OH:8])=O.[OH-].[Na+].[CH3:26]O>>[CH3:26][O:8][C:7](=[O:9])[CH2:6][CH:5]1[C:10](=[O:11])[NH:12][CH:13]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:21](=[O:23])[NH:4]1
Reactant: CO
Reactant: O=CN[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)CC1NC(=O)C(Cc2ccccc2)NC1=O
Temperature: 10 °C

Procedure:
To a solution having 9.6 g of hydrogen chloride dissolved in 400 ml of methanol was fed 61.6 g of N-formyl-α-L-aspartyl-L-phenylalanine and the resulting mixture was reacted at 50°-60° C. for 6 hours. The reaction solution was cooled to 10° C., added dropwise with 105.6 g of a 10% aqueous sodium hydroxide solution and then subjected to reaction at 30°-40° C. for 20 hours. Thereafter, the reaction mixture was cooled to 5° C. and the crystal thereby deposited was filtered, washed with methanol and water and dried to obtain 37.6 g of 5-benzyl-3,6-dioxo-2-piperazine acetic acid methyl ester having a melting point of 216°-217.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15]([S:18][CH3:19])=[N:16]3)=[CH:11][CH:10]=2)=[C:6]([NH2:8])[CH:7]=1.N1C=CC=CC=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].Cl>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15]([S:18][CH3:19])=[N:16]3)=[CH:11][CH:10]=2)=[C:6]([NH:8][S:27]([CH3:26])(=[O:29])=[O:28])[CH:7]=1
Reactant: CSc1ncc2ccc(-c3ccc(C)cc3N)n2n1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CSc1ncc2ccc(-c3ccc(C)cc3NS(C)(=O)=O)n2n1
Reaction time: 2 h

Procedure:
To a mixture of 5-Methyl-2-(2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenylamine (480 mg, 1.8 mmol) in dry pyridine (4 mL, 50 mmol) was added at 0° C. methanesulfonyl chloride (160 uL, 2.1 mmol). The mixture was stirred for 2 h and was thrown to 3N HCl. The mixture was extracted from EtOAc. Combined organic was washed with brine and was dried. After solvent evaporation, the product, N-[5-Methyl-2-(2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-methanesulfonamide, was obtained as a yellow solid (591 mg, 96%). The solid was used directly for the next step.
Reaction SMILES: [CH2:1]([S:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([S:16]([NH:19][C@H:20]([CH3:24])[C:21](O)=[O:22])(=[O:18])=[O:17])[CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(Cl)(=O)C([Cl:28])=O.CN(C=O)C>ClCCl>[CH2:1]([S:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([S:16]([NH:19][C@H:20]([CH3:24])[C:21]([Cl:28])=[O:22])(=[O:18])=[O:17])[CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCSc1nc2ccc(S(=O)(=O)N[C@H](C)C(=O)O)cc2s1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCSc1nc2ccc(S(=O)(=O)N[C@H](C)C(=O)Cl)cc2s1
Temperature: 0 °C

Procedure:
(2R)-2-[(2-n-pentylthiobenzthiazol-6-sulfonyl) amino]propionic acid (190 mg, 0.49 mmol) prepared in Example 29 was dissolved in dichloromethane (2 mL) and cooled down to 0° C. Oxalylchloride (0.17 mL, 4 equi.) and DMF of catalytic amount were added and the reaction solution was refluxed for 3 hours at RT. Then, the solution was distilled under reduced pressure to remove the solvent and dried under reduced pressure to give (2R)-2-[(2-n-pentylthiobenzthiazol-6-sulfonyl)amino]propionic chloride. And then, the compound was dissolved in THF (2 mL) to obtain acid chloride THF solution. Hydroxyamine hydrochloride salt (0.34 g, 10 equi.) and NaHCO3 (0.49 g, 12 equi.) was dissolved in THF/H2O (1 mL/1 mL) and cooled down to 0° C. Acid chloride THF solution was slowly added to hydroxyamine solution at 0° C., and the solvent was removed after 1 hour. Then, the product was extracted with ethylacetate (5 mL), washed with H2O and 0.1N HCl, dried over MgSO4, distilled and vacuum-dried to prepare the titled compound, (2R)-N-hydroxy-2-[(2-n-pentylthiobenzthiazol-6-sulfonyl)amino] propion amide (190 mg, 97%).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10](OC)=[O:11])=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].C(O)C.[BH4-].[Na+].CO>C(OCC)(=O)C.O>[C:1]([O:5][C:6]1[N:7]=[CH:8][C:9]([CH2:10][OH:11])=[CH:14][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(OC(C)(C)C)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)Oc1ccc(CO)cn1
Temperature: 50 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
To a mixed liquid of 1191 mg of methyl 6-tert-butoxynicotinate and 35.7 ml of ethanol was slowly added 2153 mg of sodium borohydride, followed by stirring at 50° C. for 18 hours. After the addition of methanol, water and ethyl acetate were added thereto to carry out an extraction operation. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 0.949 g of (6-tert-butoxypyridin-3-yl)methanol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C[Al](C)C.[CH3:13][C:14]1[N:18]=[C:17]([CH3:19])[N:16]([C:20]2[N:25]=[C:24]([CH3:26])[N:23]=[C:22]([C@@H:27]3[CH2:29][C@H:28]3[C:30](OCC)=O)[CH:21]=2)[N:15]=1>C1(C)C=CC=CC=1>[CH3:13][C:14]1[N:18]=[C:17]([CH3:19])[N:16]([C:20]2[N:25]=[C:24]([CH3:26])[N:23]=[C:22]([C@@H:27]3[CH2:29][C@H:28]3[C:30]3[S:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[N:1]=3)[CH:21]=2)[N:15]=1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1cc(-n2nc(C)nc2C)nc(C)n1
Reactant: Nc1ccccc1S
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1nc([C@@H]2C[C@H]2c2nc3ccccc3s2)cc(-n2nc(C)nc2C)n1
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
To 2-aminobenzenethiol (24.0 mg, 0.19 mmol, 1.1 eq.) dissolved in anhydrous toluene (5.0 mL) was added trimethylaluminium (2.0 M in toluene, 0.25 mL, 0.50 mmol, 3.0 eq.) under nitrogen at 0° C. dropwise. The reaction was stirred at a temperature between 10° C. to 20° C. for 30 minutes followed by the addition of ethyl trans-2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidin-4-yl)cyclopropanecarboxylate (2-1) (50.0 mg, 0.165 mmol, 1.0 eq.) and the reaction was heated to 130° C. for 24 hours. The reaction was cooled to room temperature and quenched with saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrate to dryness. The resulting residue was purified by silica gel column chromatography (10-40% ethyl acetate in toluene) to afford trans-2-(2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidin-4-yl)cyclopropyl)benzo[d]thiazole (2-2) as a yellow glue. 1H NMR (300 MHz, CDCl3) δ 7.92 (br d, 1H, J=8.0 Hz), 7.81 (m, 1H), 7.64 (br s, 1H), 7.45 (m, 1H), 7.34 (m, 1H), 3.11 (ddd, 1H, J=9.7, 5.9, 3.9 Hz), 2.92-2.83 (m, 1H), 2.89 (s, 3H), 2.66 (s, 3H), 2.39 (s, 3H), 2.13-1.97 (m, 2H). LRMS m/z (M+H+) 363 found, 363 required.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19](OCC)([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])[C:13](=[O:18])[CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Cc2cc(OCc3ccccc3)ccc2N1
Reactant: CCOC(OCC)OCC
Product: CCOC(OCC)N1C(=O)Cc2cc(OCc3ccccc3)ccc21
Reaction time: 3 h
Yield: 73 %

Procedure:
A mixture of 5-benzyloxyoxindole (1.88 g, 7.9 mmol), (EP 0636608 A1), and triethyl orthoformate (180 ml) was heated at reflux with stirring for 3 hours. The volatiles were removed by evaporation and the residue was purified by column flash chromatography using petroleum ether/ether (7/3) as eluent. Evaporation of the solvents lead to a crystalline material which was collected by filtration and dried under vacuum to give 5-benzyloxy-1-diethoxymethyloxindole (1.96 g, 73%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:6]([CH3:27])=[CH:7][C:8]([CH2:14][C:15]2[C:16]([CH3:26])=[N:17][N:18]([CH2:21][CH2:22][C:23]([NH2:25])=[O:24])[C:19]=2[CH3:20])=[C:9]2[C:13]=1[CH2:12][CH2:11][CH2:10]2.[CH:28]([S:31](Cl)(=[O:33])=[O:32])([CH3:30])[CH3:29]>O1CCCC1>[CH3:3][O:4][C:5]1[C:6]([CH3:27])=[CH:7][C:8]([CH2:14][C:15]2[C:16]([CH3:26])=[N:17][N:18]([CH2:21][CH2:22][C:23]([NH:25][S:31]([CH:28]([CH3:30])[CH3:29])(=[O:33])=[O:32])=[O:24])[C:19]=2[CH3:20])=[C:9]2[C:13]=1[CH2:12][CH2:11][CH2:10]2
Reactant: COc1c(C)cc(Cc2c(C)nn(CCC(N)=O)c2C)c2c1CCC2
Reactant: CC(C)S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1c(C)cc(Cc2c(C)nn(CCC(=O)NS(=O)(=O)C(C)C)c2C)c2c1CCC2
Reaction time: 0.33 h
Yield: 12.2 %

Procedure:
To the suspension of 60% Sodium hydride (76 mg, 0.0019 mole) in Tetrahydrofuran (2 ml), the solution of 3-[4-(7-Methoxy-6-methyl-indan-4-ylmethyl)-3,5-dimethyl-pyrazol-1-yl]-propionamide (500 mg, 0.00146 mole) in Tetrahydrofuran (5 ml) was added at room temperature and stirred for 20 minutes. A solution of Isopropyl sulfonyl chloride (0.18 ml, 0.0016 moles) in Tetrahydrofuran (3 ml) was added at 0-5° C. and stirred at 15-25° C. for 3 hours. Tetrahydrofuran was distilled under vacuum, dilute hydrochloric acid (20 ml) was added to the reaction mixture and extracted with Ethyl Acetate (50 ml). The Ethyl acetate layer was dried over Sodium sulphate and distilled under vacuum to give a crude product which was purified by column chromatography using Ethylacetate as a mobile phase. The fractions were distilled to give 80 mg of desired compound as a solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([NH:13][C:14]3[CH:15]=[N:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:18]([CH3:20])[CH:19]=3)=[C:8]([CH:12]=2)[C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:35])C=1>ClCCl>[C:9]([C:8]1[CH:12]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[CH:5]=[CH:6][C:7]=1[NH:13][C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N+:16]([O-:35])[CH:15]=1)([OH:11])=[O:10]
Reactant: Cc1cc(Nc2ccc(C3CC3)cc2C(=O)O)cnc1-c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(Nc2ccc(C3CC3)cc2C(=O)O)c[n+]([O-])c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5-cyclopropyl-2-(5-methyl-6-phenylpyridin-3-ylamino)benzoic acid (0.29 mmol, 0.1 g) in 4 ml of dichloromethane was added mCPBA in portions, at 0° and under argon atmosphere. After the addition the mixture was stirred overnight at room temperature. The solvent was evaporated and the solid residue was triturated with a water/ethyl acetate mixture. The solid was filtered off affording 0.035 g (33% of yield) of the expected product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[CH:24][CH:23]=[C:22]3Cl)=[CH:4][N:3]=1.O.[CH3:31][O:32][C:33]1[C:38](B(O)O)=[CH:37][CH:36]=[CH:35][N:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].O1CCOCC1>[Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([C:19]2[CH:28]=[C:27]3[C:26](=[CH:21][CH:20]=2)[N:25]=[CH:24][CH:23]=[C:22]3[C:38]2[C:33]([O:32][CH3:31])=[N:34][CH:35]=[CH:36][CH:37]=2)=[CH:4][N:3]=1
Reactant: O=S(=O)(Nc1cc(-c2ccc3nccc(Cl)c3c2)cnc1Cl)c1ccc(F)cc1
Reactant: COc1ncccc1B(O)O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ncccc1-c1ccnc2ccc(-c3cnc(Cl)c(NS(=O)(=O)c4ccc(F)cc4)c3)cc12
Reaction time: 0.33 h

Procedure:
(Some starting materials may be obtained from Frontier Scientific, Inc., Logan, Utah) To a 5 mL CEM microwave tube was added N-(2-chloro-5-(4-chloroquinolin-6-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (0.07 g, 0.2 mmol), 2-methoxypyridine-3-boronic acid hydrate (0.07 g, 0.5 mmol), sodium carbonate (0.2 mL, 0.5 mmol), Pd fibrecat PPh (20% wt, 15 mg), and dioxane (3 mL). The vial was sealed and placed into CEM microwave for 20 min. at 120° C., with 100 watts of power. LC/MS showed a desired product mass as a major peak. The reaction mixture was partitioned between DCM/water. The aqueous layer was extracted with DCM (2×10 mL). The combined organic layers were washed with water, brine, dried over MgSO4 and concentrated. The crude product was purified using SiO2 (12 g) chromatography with hexanes:acetone=80%:20% as the solvent system to afford the desired product as light yellow solid (25 mg). MS (ESI pos. ion) m/z: calc'd for C26H18ClFN4O3S: 520.1; found: 521.3 (M+1). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.95 (s, 3 H) 7.06-7.19 (m, 3 H) 7.42 (d, J=4.53 Hz, 1 H) 7.67 (dd, J=7.31, 1.90 Hz, 1 H) 7.72 (d, J=1.90 Hz, 1 H) 7.75-7.82 (m, 2 H) 7.90 (dd, J=8.77, 2.05 Hz, 1 H) 8.20 (d, J=2.34 Hz, 1 H) 8.31 (d, J=8.77 Hz, 1 H) 8.34 (d, J=2.19 Hz, 1 H) 8.40 (dd, J=5.04, 1.97 Hz, 1 H) 9.03 (d, J=4.38 Hz, 1 H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][CH2:10][CH2:9][CH:8]2[C:13]([OH:15])=O)#[N:2].[CH2:16]([N:18]1[CH:22]=[C:21]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)[CH:20]=[N:19]1)[CH3:17]>>[C:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][CH2:10][CH2:9][CH:8]2[C:13]([N:24]([CH2:23][C:21]1[CH:20]=[N:19][N:18]([CH2:16][CH3:17])[CH:22]=1)[C:25]1[CH:30]=[CH:29][C:28]([CH:31]([CH3:32])[CH3:33])=[CH:27][CH:26]=1)=[O:15])#[N:2]
Reactant: CCn1cc(CNc2ccc(C(C)C)cc2)cn1
Reactant: N#Cc1cccc2c1OCCC2C(=O)O
Product: CCn1cc(CN(C(=O)C2CCOc3c(C#N)cccc32)c2ccc(C(C)C)cc2)cn1
Yield: 81.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 8-cyanochroman-4-carboxylic acid (0.7 g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.84 g) as starting materials, 8-cyano-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)chroman-4-carboxamide (1.2 g) was obtained.
Reaction SMILES: [C:1]([C:4]12[CH2:14][C:8]3([OH:15])[CH2:9][C:10]([OH:13])([CH2:12][C:6]([OH:16])([CH2:7]3)[CH2:5]1)[CH2:11]2)([OH:3])=[O:2].[C:17]([O:21][CH2:22][CH2:23]O)(=[O:20])[CH:18]=[CH2:19]>C1(C)C=CC=CC=1>[C:17]([O:21][CH:22]([O:2][C:1]([C:4]12[CH2:5][C:6]3([OH:16])[CH2:7][C:8]([OH:15])([CH2:9][C:10]([OH:13])([CH2:12]3)[CH2:11]1)[CH2:14]2)=[O:3])[CH3:23])(=[O:20])[CH:18]=[CH2:19]
Reactant: C=CC(=O)OCCO
Reactant: O=C(O)C12CC3(O)CC(O)(CC(O)(C3)C1)C2
Solvent: Cc1ccccc1
Product: C=CC(=O)OC(C)OC(=O)C12CC3(O)CC(O)(CC(O)(C3)C1)C2

Procedure:
1 mmol of 1-carboxy-3,5,7-adamantanetriol and 2.5 mmol of 2-hydroxyethyl acrylate were reacted in toluene to give 1-acryloyloxyethoxycarbonyl-3,5,7-adamantanetriol. To 30 ml of tetrahydrofuran were added 5 mmol of 1-acryloyloxyethoxycarbonyl-3,5,7-adamantanetriol, 25 mmol of acetoaldehyde, and 1 mmol of p-toluenesulfonic acid, and the mixture was acetalized in the same manner as in Example 1 to give the object compound 1-acryloyloxyethoxycarbonyl-3,5,7-tri(1-hydroxyethoxy)adamantane (actalilzed compound) shown by the following formula.
Reaction SMILES: C([O:5][C:6](=[O:15])[C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([CH3:14])[CH:8]=1)(C)(C)C.[ClH:16]>C(O)(C)C>[ClH:16].[CH3:13][C:11]1[CH:12]=[C:7]([CH:8]=[C:9]([CH3:14])[N:10]=1)[C:6]([OH:15])=[O:5]
Reactant: Cc1cc(C(=O)OC(C)(C)C)cc(C)n1
Agent: Cl
Solvent: CC(C)O
Product: Cc1cc(C(=O)O)cc(C)n1

Procedure:
A solution of 2,6-dimethylisonicotinic acid tert.-butyl ester (2.37 g, 11.44 mmol) in 5 N HCl in isopropanol (40 mL) is stirred at 80° C. for 3 h. The solvent is evaporated and the crude product is purified by MPLC on silica gel (heptane:EA gradient) to give 2,6-dimethylisonicotinic acid hydrochloride as a beige resin; 1H NMR (CD3OD): δ 8.16 (s, 2H), 2.84 (s, 6H).
Reaction SMILES: [C:1](=[O:3])=[O:2].[NH:4]([CH2:8][CH2:9][OH:10])[CH2:5][CH2:6][OH:7].O>>[C:1](=[O:7])([OH:3])[OH:2].[NH:4]([CH2:8][CH2:9][OH:10])[CH2:5][CH2:6][OH:7]
Reactant: O=C=O
Solvent: OCCNCCO
Solvent: O
Product: O=C(O)O

Procedure:
Carbon dioxide was introduced into a mixture of diethanolamine (900 g=8.57 mol) and 80 g of water (4.44 mol) until saturation. In the course of 75 minutes, 73 l of CO2 (3.26 mol) were introduced into one sample and 72 l (3.21 mol) into another sample. The reaction temperature rose to 63° C. without cooling.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([F:14])[CH:3]=1.[Mg].II.[CH2:18]([C@H:21]1[CH2:26][CH2:25][C@H:24](CC(Cl)=O)[CH2:23][CH2:22]1)[CH2:19][CH3:20]>O1CCCC1.O>[F:14][C:4]1[CH:3]=[C:2]([C@H:24]2[CH2:25][CH2:26][C@H:21]([CH2:18][CH2:19][CH3:20])[CH2:22][CH2:23]2)[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Fc1cc(Br)ccc1-c1ccccc1
Reactant: CCC[C@H]1CC[C@H](CC(=O)Cl)CC1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CCC[C@H]1CC[C@H](c2ccc(-c3ccccc3)c(F)c2)CC1
Temperature: -60 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-bromo-2-fluorobiphenyl (38.1 gram) in tetrahydrofuran (60 ml) was added over 20 minutes to magnesium turnings (4 gram) suspended in tetrahydrofuran (20 ml), reaction being initiated by adding a crystal of iodine and warming as usual. This Grignard reagent was now added to a solution of trans-4-propylcyclohexylacetyl chloride (40 gram) and cuprous chloride (0.4 gram) in tetrahydrofuran (200 ml) with stirring at -60° C. over 90 minutes. After allowing to warm to room temperature over two hours, the mixture was decomposed with water and the product extracted with petroleum ether (bpt. 60°-80°). The crude material was recrystallized twice from ethanol at 5° C. to give the product (20.6 gram, 40% theory), m.p. 96.5°-97.3° C., which was found to be 99.6 pure by glc.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:16][C:17]1[C:18]([CH2:23][N:24]([CH2:31][C:32]2[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][N:33]=2)[CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:19][CH:20]=[CH:21][CH:22]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.C1COCC1.[OH-].[Na+].CCOC(C)=O.CN(C=O)C>[CH3:16][C:17]1[C:18]([CH2:23][N:24]([CH2:31][C:32]2[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][N:33]=2)[CH:25]2[CH2:30][CH2:29][N:28]([C:1]([C:2]3[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=3)=[O:9])[CH2:27][CH2:26]2)=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Reactant: O=C(O)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C(=O)c2ccncc2)CC1
Temperature: 0 °C
Yield: 41.8 %

Procedure:
To a cold (0° C.), stirred, mixture of isonicotinic acid (130 mg, 1.05 mmol) in CH2Cl2 (10 mL) was added DMF (1 mL) followed by oxalyl chloride (0.46 mL, 5.27 mmol). The mixture was warmed to room temperature. After 15 minutes the mixture was concentrated under reduced pressure and provided a white solid. To a solution of COMPOUND 249 (60 mg, 0.19 mmol) in THF (7 mL) was added the white solid from above followed by DIPEA (1.20 mL, 6.88 mmol). The resultant mixture was stirred at room temperature for 2.5 hours then diluted with 1.0 N NaOH (10 mL) and EtOAc (50 mL). The phases were separated and the organic phase was washed with 1.0 N NaOH (3×10 mL) and brine (10 mL), dried (Na2SO4), and concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 50:1:1 CH2Cl2-MeOH—NH4OH) provided 33 mg (42%) of COMPOUND 266 as a white solid. 1H NMR (CDCl3) δ 1.50-1.76 (m, 2H), 1.80-2.04 (m, 2H), 2.09 (s, 6H), 2.57-3.02 (m, 3H), 3.65-3.91 (m, 5H), 4.76-4.84 (m, 1H), 7.09 (dd, 2H, J=7.5, 4.8 Hz), 7.27 (d, 2H, J=5.7 Hz), 7.38 (d, 2H, J=7.5 Hz), 8.35 (d, 2H, J=4.8 Hz), 8.69 (d, 2H, J=5.7 Hz); ES-MS m/z 416 (M+H).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([Mg]Br)=[CH:3][CH:2]=1.C1(C)C=CC(Br)=CC=1.[Mg].[CH:19]12[O:25][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24]2>O1CCCC1>[C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]2[OH:25])=[CH:3][CH:2]=1
Reactant: C1CCC2OC2C1
Reactant: Cc1ccc([Mg]Br)cc1
Agent: Cc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc(C2CCCCC2O)cc1
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
A solution of p-tolyl-magnesium bromide, prepared from 17.1 g (100 mmol) p-tolyl bromide and 2.43 g (100 mmol) magnesium, in 100 ml abs. tetrahydrofuran was cooled to −20° C. and 1 g CuBr-dimethylsulfid complex was added and the mixture stirred at −20° C. for 10 min. To this a solution of 10 ml (9.80 g, 100 mmol) cyclohexene oxide in 10 ml abs. tetrahydrofuran was added drop-wise and the reaction warmed to 0° C. at which an exothermic reaction starts. With cooling the temperature was maintained below 25° C. The reaction mixture was stirred at 0 to 5° C. for additional 2h, then quenched with saturated aqueous ammonium chloride solution and extracted with tert.-butyl methyl ether. The organic extract was washed with water, dried over Na2SO4, filtered and evaporated. The residue, 18.25 g slightly yellow crystals was re-crystallizes from n-hexane: 9.91 g rac-2-p-tolyl-cyclohexanol as colorless crystals: m.p. 72.5–73° C., MS (EI): 190.1 M+.
Reaction SMILES: [CH3:1][C:2]12[CH2:31][CH:5]([C:6]3([CH3:30])[C:10]1([CH3:11])[C:9]1[CH:12]=[C:13]([C:16](=[O:29])[C:17]#[C:18][C:19]4[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=4)[CH:14]=[CH:15][C:8]=1[O:7]3)[CH2:4][CH2:3]2.O.[OH-].[Li+]>O1CCCC1>[CH3:1][C:2]12[CH2:31][CH:5]([C:6]3([CH3:30])[C:10]1([CH3:11])[C:9]1[CH:12]=[C:13]([C:16](=[O:29])[C:17]#[C:18][C:19]4[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=4)[CH:14]=[CH:15][C:8]=1[O:7]3)[CH2:4][CH2:3]2
Reactant: COC(=O)c1ccc(C#CC(=O)c2ccc3c(c2)C2(C)C4(C)CCC(C4)C2(C)O3)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC12CCC(C1)C1(C)Oc3ccc(C(=O)C#Cc4ccc(C(=O)O)cc4)cc3C21C

Procedure:
0.66 g of methyl ester obtained in Example 10 dissolved in 10 ml of tetrahydrofuran was treated with 200 mg of lithium hydroxide monohydrate.
Reaction SMILES: C[O:2][C:3](=[O:45])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:32][C:33]2[CH:41]=[C:40]3[C:36]([C:37]([C:42](=[O:44])[CH3:43])=[CH:38][NH:39]3)=[CH:35][CH:34]=2)[CH2:11][C:12]([N:14]2[CH2:18][C@H:17]([F:19])[CH2:16][C@H:15]2[C:20](=[O:31])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=2[F:30])=[O:13])=[CH:6][CH:5]=1.[OH-].[Na+]>C1COCC1.O>[C:42]([C:37]1[C:36]2[C:40](=[CH:41][C:33]([O:32][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:45])=[O:2])=[CH:9][CH:8]=3)[CH2:11][C:12]([N:14]3[CH2:18][C@H:17]([F:19])[CH2:16][C@H:15]3[C:20](=[O:31])[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[F:30])=[O:13])=[CH:34][CH:35]=2)[NH:39][CH:38]=1)(=[O:44])[CH3:43]
Reactant: COC(=O)c1ccc(C(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)Oc2ccc3c(C(C)=O)c[nH]c3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1c[nH]c2cc(OC(CC(=O)N3C[C@H](F)C[C@H]3C(=O)NCc3cccc(Cl)c3F)c3ccc(C(=O)O)cc3)ccc12

Procedure:
The title compound was prepared in a similar manner as described for Example 595 from 4-(3-acetyl-1-{2-[(2S,4R)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-pyrrolidin-1-yl]-2-oxo-ethyl}-1H-indol-6-yloxymethyl)-benzoic acid methyl ester (37.0 mg, 0.058 mmol) and 1N NaOH (0.928 mL, 0.928 mmol) in THF (5 mL) and water (0.5 mL). Solid. MS (LC/MS): 624/626 [M+H]+; tR (HPLC conditions k): 3.48 min.
Reaction SMILES: C(O)[C:2](N)([CH2:5][OH:6])[CH2:3][OH:4].[O:9]=[CH:10][C@@H:11]([C@H:13]([C@@H:15]([C@@H:17]([CH2:19][OH:20])[OH:18])[OH:16])[OH:14])[OH:12]>>[CH2:19]([OH:20])[C@H:17]1[O:18][C@H:10]([O:9][C@:2]2([CH2:3][OH:4])[O:12][C@H:11]([CH2:13][OH:14])[C@@H:10]([OH:9])[C@@H:5]2[OH:6])[C@H:11]([OH:12])[C@@H:13]([OH:14])[C@@H:15]1[OH:16]
Reactant: NC(CO)(CO)CO
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O

Procedure:
NAC and THAM were first granulated separately in mixtures with gum arabic and dextrose. The granulates were dried and then mixed together with saccharin, saccharose and flavour and then distributed into the bags.