Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][O:9][C:10](=[O:13])[CH2:11][NH2:12])=[CH:6][CH:5]=1.[N:16]1[CH:21]=CC=CC=1.[CH:22]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24]([Cl-]C([O-])=O)[CH:23]=1.CC[O:37]CC>>[CH3:2][O:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][O:9][C:10](=[O:13])[CH2:11][NH:12][C:21](=[O:37])[NH:16][C:24]2[CH:23]=[CH:22][C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=2)=[CH:6][CH:5]=1
Reactant: CCOCC
Reactant: c1ccncc1
Reactant: COc1ccc(COC(=O)CN)cc1
Agent: Cl
Product: COc1ccc(COC(=O)CNC(=O)Nc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The HCl salt of glycine 4-methoxybenzyl ester (1 g, 4.3 mmol) to was cooled to 0° C. and 7 mL of pyridine was added. After 10 minutes at 0° C., 4-nitrophenylchloroformate (980 mg, ~1.15 equivalents) was added over 5 minutes. The reaction mixture was stirred at 0° C. for 5 minutes and then allowed to warm to room temperature. After 1.5 hours at room temperature, the reaction mixture was diluted with ether and washed with cold 0.5N HCl and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure to give 1.5 g of crude product.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[CH2:13]([O:15][C:16](=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1)[CH3:14].C(O)(=O)C>O>[CH2:13]([O:15][C:16](=[O:25])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:2](=[O:4])[C:1]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH2:6])=[CH:22][CH:23]=1)[CH3:14]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)Cc1ccc(NC(=O)c2ccccc2N)cc1
Temperature: 90 °C

Procedure:
A round bottomed flask is charged with isatoic anhydride (5 g, 30.6 mmol) and (4-amino-phenyl)-acetic acid ethyl ester (6.05 g, 33.7 mmol). Acetic acid (11 ml) is added and the reaction is heated at 90° C. for 40 minutes and then allowed to cool to RT. The resulting suspension is diluted with distilled water to give a white precipitate. The precipitate is filtered, washed with water and vacuum dried to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH:20]1[C:32]2[CH:31]([CH2:33][O:34][C:35](Cl)=[O:36])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1.O1CCOCC1>O>[CH:20]1[C:32]2[CH:31]([CH2:33][O:34][C:35]([NH:1][C:2]3[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=3)=[O:36])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccc(C(=O)O)c([N+](=O)[O-])c1)OCC1c2ccccc2-c2ccccc21
Reaction time: 20 h
Yield: 67.2 %

Procedure:
To a solution of 11.4 g 4-amino-2-nitro-benzoic acid in 228 ml of water containing 6.63 g of sodium carbonate were added 17.0 g of 9-fluorenylmethyl-chloroformate and dropwise 20 ml of dioxane. After stirring for 20 hours under nitrogen, the mixture was filtered and the filtrate was washed five times with methyl-tert.-butylether. Residual methyl-tert.-butylether was removed from the aqueous phase by evaporation under vacuum. To the aqueous phase were added 456 g of 0° C. cold water. The mixture was adjusted to pH=3 by addition of 31 ml of 2M aqueous hydrochloric acid. The precipitate was sucked off, washed with 513 ml of water, dried at 40° C. in vacuum to give 17.0 g of 4-(((9H-fluorene-9-yl)methoxy)carbonylamino)-2-nitrobenzoic acid as off-white crystals.
Reaction SMILES: O[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:10](=[O:13])([O-])[O-].[K+].[K+].[CH2:16](I)C.O>CC(C)=O.C(OCC)(=O)C>[CH2:10]([O:13][C:9]1[CH:2]=[C:3]([CH:6]=[CH:7][CH:8]=1)[CH:4]=[O:5])[CH3:16]
Reactant: O=Cc1ccccc1O
Reactant: CCI
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOc1cccc(C=O)c1
Yield: 90.3 %

Procedure:
To a solution of 2-hydroxybenzaldehyde (20 g, 163 mmol) in acetone (250 mL) was added anhydrous potassium carbonate (33 g, 239 mmol) followed by ethyl iodide (17 mL, 211 mmol). The mixture was heated at reflux for 12 hours. After cooling to room temperature water and ethyl acetate were added. The organic layer was removed, dried over MgSO4 and evaporated to dryness yielding the subtitled compound as a yellow oil (22.10 g). 1H NMR δ (CDCl3) 1.40-1.50 (3H, t), 4.024.15 (2H, q), 7.13-7.22 (1H, m), 7.36-7.48 (3H, m), 9.97 (1H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].C(O)CO>O>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[N:13]=[C:14]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[CH3:2]
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1cccc(F)c1
Solvent: OCCO
Solvent: O
Product: CCOC(=O)Cn1c(-c2cccc(F)c2)nc2cccnc21
Temperature: 195 °C
Yield: 91.2 %

Procedure:
A mixture of N-[3-[(3-fluorobenzoyl)amino]-2-pyridinyl]glycine ethyl ester (20.44 g, 0.065 mole), and ethylene glycol (75 ml) was heated at 195° C. for 40 minutes. Water was added to the cooled reaction mixture and the solid was collected by filtration. The solid was suspended in water (2×100 ml) and collected by filtraion to give 17.75 g of crude 2-(3-fluorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid ethyl ester. A portion of this solid (6.0 g, 0.02 mole) together with sodium hydroxide pellets (0.9 g, 0.0231 mole), and 50 ml of ethanol-water (1:1) was refluxed for 1 hour. The ethanol was evaporated. The residual aqueous mixture was cooled, diluted with water (50 ml) and extracted with diethyl ether (2×25 ml). The aqueous portion was acidified to a pH of 3 with concentrated hydrochloric acid. After precipitation was complete, the solid was collected by filtration. The filter cake was suspended in ethanol and filtered, giving 4.94 g (91%). Recrystallization of a 1.2-g sample from tetrahydrofuran gave 1.1 g of an off-white solid, mp 243°-245° C. with decomposition.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10](O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17].CC(C(O)=O)C1C=CC(CC2C(=O)CCC2)=CC=1>CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-].[Ti+4]>[C:1]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CCCCCCO
Reactant: O=C(O)c1ccccc1
Agent: [Ti+4]
Agent: CC(C(=O)O)c1ccc(CC2CCCC2=O)cc1
Agent: CCCC[O-]
Product: CC(C)CCCCCCOC(=O)c1ccccc1

Procedure:
976 g of benzoic acid (8 mol), 1728 g of isononanol from OXENO Olefinchemie GmbH (12 mol), and 0.59 g of butyl titanate (0.06%, based on the amount of acid) are weighed into a four liter distillation flask on top of which a water separator and reflux condenser have been attached, and which has a sampling port and thermometer, and are heated to boiling under nitrogen. The water of reaction produced during the esterification process was removed sequentially. Once the acid value fell below 0.1 mg KOH/g (after about 3 hours), the mixture was first cooled below 60° C., and a 20 cm multifill column was placed on the apparatus. The pressure was then reduced to 2 mbar, and excess alcohol was first distilled off (about 120° C.). After removal of an intermediate fraction at up to 140° C. it was possible to distill over the isononyl benzoate within a range of 142 to 147° C. (at 2 mbar) measured at the head of the column. Purity >99.7% was determined by gas chromatography.
Reaction SMILES: COC1C=CC(C[N:8]2[C:16]3[C:11](=[CH:12]C=[C:14](C(C4C=CC=CC=4)=O)[CH:15]=3)[C:10]([CH3:25])=[CH:9]2)=CC=1.[BH4-].[Na+].[OH2:30]>>[CH3:14][C:15]1[CH:16]=[N:8][CH:9]=[C:10]([CH3:25])[C:11]=1[CH2:12][OH:30]
Reactant: COc1ccc(Cn2cc(C)c3ccc(C(=O)c4ccccc4)cc32)cc1
Reactant: O
Agent: [BH4-]
Agent: [Na+]
Product: Cc1cncc(C)c1CO
Reaction time: 6 h

Procedure:
A stirred solution of 3,5-dimethyl-pyridyl-4-carbaldehyde (2.3 g, Reference Example 24) in methylated spirit (50 ml), at room temperature and under nitrogen, was treated with powdered sodium borohydride (1.28 g). After stirring for 6 hours the resulting homogeneous solution was allowed to stand at room temperature for a further 12 hours then treated with water (10 ml). The reaction mixture was evaporated, then azeotroped with toluene. The residue was extracted three times with hot dichloromethane (100 ml). The combined extracts were evaporated to afford a white solid which was subjected to flash chromatography on silica, eluting with a mixture of ethyl acetate and pentane (1:1, v/v) to afford the title compound (1.2 g) as a white solid, map. 93-95° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH2:18][CH3:19])=[O:11])=[CH:7][CH:8]=1
Reactant: CSc1ccc(CC(=O)O)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 4-methylthiophenylacetic acid (1.0 g, 5.48 mmol) in 55 mL of ethanol was slowly added a catalytic amount of concentrated sulfuric acid. The mixture was stirred at room temperature overnight and then concentrated at reduced pressure. The residue was partitioned between methylene chloride and sodium bicarbonate. The organic layer was washed with brine, dried with magnesium sulfate, filtered, and concentrated to yield 1.1 g of a colorless oil (96%). 1H NMR (300 MHz, CDCl3) δ7.22 (s, 4H), 4.15 (q, J=6 Hz, 2H), 3.57 (s, 2H), 2.47 (s, 3H), 1.25 (t, J=6 Hz, 3H).
Reaction SMILES: C([O:8][C:9](=[O:21])[NH:10][C:11]1C=CC2OCC[O:18][C:13]=2[CH:12]=1)C1C=CC=CC=1.[Li][CH2:23]CCC.[C:27]([O:32][CH2:33][C@@H:34]1[O:36][CH2:35]1)(=O)[CH2:28][CH2:29][CH3:30].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.CC(=O)OCC>[O:32]1[C:27]2[CH:28]=[CH:29][C:30]([N:10]3[CH2:11][C@H:12]([CH2:13][OH:18])[O:8][C:9]3=[O:21])=[CH:23][C:35]=2[O:36][CH2:34][CH2:33]1
Reactant: [Li]CCCC
Reactant: CCCC(=O)OC[C@H]1CO1
Reactant: O=C(Nc1ccc2c(c1)OCCO2)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1O[C@@H](CO)CN1c1ccc2c(c1)OCCO2
Temperature: -78 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
A solution of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-carbamic acid benzyl ester (3.0 g, 10.5 mmol, prepared according to method C) in THF (60 mL) was cooled to −78° C. before the dropwise addition of n-BuLi (5.1 mL of a 2.5M solution in hexanes, 1.2 eq.). The mixture was stirred at −78° C. for 1 h and then warmed to −15° C. At this temperature (R)-glycidyl butyrate (1.98 g, 1.2 eq.) was added dropwise. The mixture was stirred at rt overnight. Cs2CO3 (tip of a spatula) was added and the mixture heated at 40° C. until complete conversion. The mixture was diluted with EA and washed with sat. NH4Cl solution and water. The org. layer was dried over MgSO4 and concentrated. Chromatography on SiO2 (Hex/EA 2:1, 1:1) gave the desired intermediate as a beige solid (1.09 g, 41% yield).
Reaction SMILES: [CH3:1][C:2](=[CH:8][C:9]1[CH:14]=[CH:13][C:12](SC)=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[OH:17][S:18]([OH:21])(=O)=O.OO.S([O-])([O-])=O.[Na+].[Na+].[CH3:30]O>O>[CH3:1][C:2](=[CH:8][C:9]1[CH:10]=[CH:11][C:12]([S:18]([CH3:30])(=[O:21])=[O:17])=[CH:13][CH:14]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)=Cc1ccc(SC)cc1
Reactant: O=S(=O)(O)O
Reactant: CO
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(C)=Cc1ccc(S(C)(=O)=O)cc1
Reaction time: 3 h

Procedure:
To a solution of sulfide 6a (2.36 g, 10 mmol), Na2WO4 ·2 H2O (49.5 mg, 0.15 mmol), and H2SO4 (1 M, 68 μL) in methanol (10 mL) was added dropwise 30% H2O2 (2.6 mL) at room temperature under nitrogen maintaining the temperature at 38-45° C. The mixture was aged at ambient temperature for 3 h and cooled ~18° C. Sodium sulfite (20% aqueous solution, 2.6 mL) was added slowly with an external cooling to maintain the temperature below 20° C. After aged for 0.5 h the mixture was diluted with water (20 mL) and filtered. The solid was washed with water (2×10 mL) and dried in vacuo to give 2.55 g of 6b as a light yellow solid: IR (thin film) 1700 cm-1 ; 1H NMR (CDCl3, 300 MHz) δ 7.92 (2 H), 7.64 (1 H), 7.52 (2 H), 4.24 (2 H), 3.04 (3 H), 2.05 (3 H), and 1.30 (3 H); 13C NMR (CDCl3, 75.5 MHz) δ 167.88, 141.50, 139.76, 136.29, 131.87, 130.21, 127.45, 61.24, 44.45, 14.28, and 14.14.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.Cl.[CH2:17]([NH:19][O:20][CH:21]([CH3:23])[CH3:22])[CH3:18]>>[CH2:13]([NH:12][C:4]1[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:7]=[C:2]([N:19]([CH2:17][CH3:18])[O:20][CH:21]([CH3:23])[CH3:22])[N:3]=1)[CH2:14][CH3:15]
Reactant: CCNOC(C)C
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Agent: Cl
Product: CCCNc1nc(NCCC)nc(N(CC)OC(C)C)n1
Yield: 88 %

Procedure:
2-Chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) was reacted with N-ethyl-O-isopropyl-hydroxylamine hydrochloride (LXXV) as described in Example 13, yielding N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-O-isopropyl-hydroxylamine (LXXVI) (88% yield). ESI-MS (m/z): 297 [M+H]+.
Reaction SMILES: [F:1][C:2]1([F:23])[C:15]([F:17])([F:16])[C:14]2[CH2:13][CH:12](Br)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][C:5]([CH2:19][CH2:20][CH2:21][CH3:22])=[CH:6][CH:7]=2.[CH2:24]([O:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>[Pd]>[CH2:24]([O:34][C:35]1[CH:36]=[CH:37][C:38]([C:12]2[CH:11]=[CH:10][C:9]3[C:8]4[C:3](=[CH:4][C:5]([CH2:19][CH2:20][CH2:21][CH3:22])=[CH:6][CH:7]=4)[C:2]([F:23])([F:1])[C:15]([F:17])([F:16])[C:14]=3[CH:13]=2)=[CH:39][CH:40]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCc1ccc2c(c1)C(F)(F)C(F)(F)C1=C2C=CC(Br)C1
Reactant: CCCCCCCCCCOc1ccc(B(O)O)cc1
Agent: [Pd]
Product: CCCCCCCCCCOc1ccc(-c2ccc3c(c2)C(F)(F)C(F)(F)c2cc(CCCC)ccc2-3)cc1

Procedure:
From 9,9,10,10-tetrafluoro-2-bromo-7-butyldihydrophenanthrene and 4-decyloxyphenylboronic acid by means of palladium-catalyzed Suzuki coupling (in analogy to Acc. Chem. Res. 1982, 15, 178). The crude product is purified by column chromatography.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:33][C:32]([CH3:34])=[CH:31][C@@H:30]([CH2:35][CH:36]=[CH2:37])[C:28](=[O:29])[CH2:27][C@H:26]([OH:38])[C@@H:25]([CH3:39])[C@@H:24](/[C:40](/[CH3:51])=[CH:41]/[C@H:42]2[CH2:47][C@@H:46]([O:48][CH3:49])[C@H:45]([OH:50])[CH2:44][CH2:43]2)[O:23][C:21](=[O:22])[C@H:20]2[N:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[C:13](=[O:14])[C:11](=[O:12])[C@:9]2([OH:52])[O:10][C@@H:5]([C@@H:6]([O:54][CH3:55])[CH2:7][C@H:8]2[CH3:53])[C@@H:4]([O:56][CH3:57])[CH2:3]1.[C:58]1(=[O:64])[O:63][C:61](=[O:62])[CH2:60][CH2:59]1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH2:35]([CH:30]1[CH:31]=[C:32]([CH3:34])[CH2:33][CH:2]([CH3:1])[CH2:3][CH:4]([O:56][CH3:57])[CH:5]2[O:10][C:9]([OH:52])([CH:8]([CH3:53])[CH2:7][CH:6]2[O:54][CH3:55])[C:11](=[O:12])[C:13](=[O:14])[N:15]2[CH:20]([CH2:19][CH2:18][CH2:17][CH2:16]2)[C:21](=[O:22])[O:23][CH:24]([C:40]([CH3:51])=[CH:41][CH:42]2[CH2:43][CH2:44][CH:45]([O:50][C:58](=[O:64])[CH2:59][CH2:60][C:61]([OH:63])=[O:62])[CH:46]([O:48][CH3:49])[CH2:47]2)[CH:25]([CH3:39])[CH:26]([OH:38])[CH2:27][C:28]1=[O:29])[CH:36]=[CH2:37]
Reactant: C=CC[C@@H]1C=C(C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Reactant: O=C1CCC(=O)O1
Agent: C=CC[C@@H]1/C=C(\C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OC(=O)CCC(=O)O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of the FR-900506 substance (248 mg) in pyridine (7 ml) were added succinic anhydride (145 mg) and 4-(N,N-dimethylamino)pyridine (7 mg), and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue was subjected to chromatography on silica gel (20 g) with ethyl acetate to give 17-allyl-12-[2-[4-(3-carboxypropionyloxy)-3-methoxycyclohexyl]-1-methylvinyl]-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (90 mg).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].[Na].Cl[C:9](=[CH2:14])[C:10](OC)=[O:11]>CO>[OH:11][C:10]1[CH:9]=[CH:14][S:3][C:2]=1[C:1]([O:5][CH3:6])=[O:4]
Reactant: C=C(Cl)C(=O)OC
Reactant: COC(=O)CS
Agent: [Na]
Solvent: CO
Product: COC(=O)c1sccc1O
Reaction time: 1 h
Yield: 74.4 %

Procedure:
A solution of methyl thioglycolate (19.2 g, 181 mmoles) in methanol (100 mL) is added to a solution of sodium (8.0 g, 348 mmoles) in methanol (100 mL) with stirring, and cooling with an ice bath. A solution of methyl α-chloroacrylate (22.1 g, 183 mmoles) in methanol (25 mL) is then added at such a rate that the temperature does not exceed 30° C. After 1 hour at ambient temperature, the methanol is removed under reduced pressure. The residue is dissolved in water, acidified with HCl and steam distilled until the distillate is clear. The distillate is cooled and shaken, and the resulting precipitate filtered off, rinsed with water and dried to afford the product (21.3 g); mp 43°-45° C.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:35]([NH2:38])(=[O:37])=[O:36])[CH:31]=[CH:32][C:33]=1[Cl:34]>>[Cl:34][C:33]1[CH:32]=[CH:31][C:30]([S:35](=[O:36])(=[O:37])[NH2:38])=[CH:29][C:28]=1[NH:27][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([C:2]([F:26])([F:1])[F:25])=[CH:4][C:5]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][CH:16]=3)=[N:6][C:7]=12)=[O:13]
Reactant: Nc1cc(S(N)(=O)=O)ccc1Cl
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1ccc(Cl)c(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-4-chloro-benzenesulfonamide [CAS-No. 29092-34-0; commercially available] according to general procedure II. Light yellow solid. MS (ISP) 563.1 [(M−H−]; mp 300° C.
Reaction SMILES: CO[C:3](=[O:37])[N:4]=[C:5](SC)[C:6]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28](=[O:31])[NH:29][CH3:30])=[C:22]([O:32][CH2:33][CH3:34])[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=C(C)O[N:15]=2)=[CH:10][CH:9]=1.[CH3:38][O:39][C:40]1[C:41]([NH:46][NH2:47])=[N:42][CH:43]=[CH:44][CH:45]=1>>[C:33]([OH:39])(=[O:32])[CH3:34].[C:14]([C:11]1[CH:12]=[CH:13][C:8]([NH:7][CH:6]([C:5]2[NH:4][C:3](=[O:37])[N:46]([C:41]3[C:40]([O:39][CH3:38])=[CH:45][CH:44]=[CH:43][N:42]=3)[N:47]=2)[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([NH:29][CH3:30])=[O:31])=[C:22]([O:32][CH2:33][CH3:34])[CH:21]=2)=[CH:9][CH:10]=1)(=[NH:18])[NH2:15]
Reactant: COc1cccnc1NN
Reactant: CCOc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)ccc1OCC(=O)NC
Product: CC(=O)O
Product: CCOc1cc(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccc3OC)c(=O)[nH]2)ccc1OCC(=O)NC

Procedure:
The same procedure was carried out as in Examples (21i)-(21j), except that {2-(3-ethoxy-4-methylcarbamoylmethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester was used instead of the {2-(8-methoxy-4H-benzo[1,3]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in Example (21i), and (3-methoxy-pyridin-2-yl)hydrazine was used instead of 2-hydrazinopyrimidine in Example (21i), to give the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[C:14]3[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]([CH3:19])=[CH:18][C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:33](Cl)(=[O:35])[CH3:34]>ClCCl>[C:33]([C:18]1[C:13]2[O:12][CH2:11][C@H:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=3)[C:14]=2[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]=1[CH3:19])(=[O:35])[CH3:34]
Reactant: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)[C@@H](c1ccc(C(C)C)cc1)CO2
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OC[C@@H]2c1ccc(C(C)C)cc1
Temperature: 10 °C
Reaction time: 0.33 h
Yield: 84.2 %

Procedure:
To a solution of (+)-N-((3R)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (933 mg, 2.46 mmol) obtained in Example 37 in dichloromethane (20 mL) was added aluminum chloride (721 mg, 5.40 mmol) at −70° C. under an argon atmosphere and the mixture was stirred for 20 minutes. To the reaction solution was added dropwise acetyl chloride (424 mg, 5.40 mmol) at the same temperature and the reaction mixture was gradually warmed to 10° C. The reaction solution was added to ice, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, an aqueous saturated sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to synthesize 873 mg (yield: 84%) of the title compound. Melting point: 176-177° C. (ethyl acetate-hexane). [α]D20=+6.2° (c=0.53, chloroform).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[OH-].[K+].[CH:12](=[O:15])[CH2:13][CH3:14].C(O)(=O)C>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:13]([CH3:14])[CH:12]=[O:15])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CCC=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C=O)=Cc1ccc(F)cc1
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a solution of 124 g (1 mole) of 4-fluorobenzaldehyde and 8 g (0.143 mole) of potassium hydroxide in 500 ml ethanol at room temperature was added dropwise a solution of 52.2 g (0.9 mole) of propionaldehyde in 100 ml ethanol. After stirring for 0.5 hour, the mixture was acidified with acetic acid and concentrated by rotary evaporation. The residue was partitioned between methylene chloride and water. The aqueous layer was extracted three times with additional methylene chloride. The combined organic layers were dried and concentrated. Distillation through a 12-inch vacuum jacketed column gave 113.5 g (77%) of pale yellow low-melting crystalline product, b.p. 70°-72° C. (0.4-0.7 mm).