Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20](OC)=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].[CH3:27][CH:28]([O:30][C:31]([O:33][CH:34](Cl)[CH3:35])=[O:32])[CH3:29]>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:25])([CH3:26])[C@@H:11]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:12]([O:14][CH2:35][CH2:34][O:33][C:31]([O:30][CH:28]([CH3:29])[CH3:27])=[O:32])=[O:13])(=[O:6])=[O:7]
Reactant: CC(C)OC(=O)OC(C)Cl
Reactant: COc1ccc(CO[C@@H](C(=O)O)C(C)(C)COS(=O)(=O)CCCCl)cc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)OCCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Yield: 50 %

Procedure:
Following the general procedure for the preparation of acyloxyalkyl/alkoxycarbonyloxyalkyl carboxylic esters from carboxylic acids of Description 22, (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoic acid (11) (34.0 g, 89.7 mmol) dissolved in 300 mL of anhydrous toluene was reacted with 30 g (179.5 mmol) of commercially available 1-chloroethyl methylethoxyformate in the presence of 47 g (179.5 mmol) of silver carbonate (Ag2CO3). After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 23.0 g (50% yield) of the title compound (40a). Rf=0.32 (EtOAc/Hxn=1:4). 1H NMR (400 MHz, CDCl3, both diastereomers): δ=1.06-1.08 (m, 6H), 1.24-1.35 (m, 6H), 1.57 (d, J=5.2 Hz, 3H), 2.24-2.31 (m, 2H), 3.20-3.26 (m, 2H), 3.63-3.66 (m, 2H), 3.85-3.86 (2s, 1H), 3.94-3.97 (2d, J=9.6, 9.6 Hz, 1H), 4.19-4.23 (2d, J=9.2, 9.6 Hz, 1H), 4.33-4.38 (2d, J=11.2, 11.6 Hz, 1H), 4.64 (t, J=11.2 Hz, 1H), 4.81-4.97 (m, 1H), 6.81-6.87 (m, 1H), 7.30-7.37 (m, 5H) ppm. MS (ESI) m/z 531.02 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: C(O)C.[CH3:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH3:11])[C:6]1=O.Cl.[NH2:14][OH:15]>N1C=CC=CC=1>[CH3:4][C@H:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]([CH3:11])[C:6]1=[N:14][OH:15].[CH3:4][C@H:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([CH3:11])[C:6]1=[N:14][OH:15]
Reactant: CC1CCCC(C)C1=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: C[C@@H]1CCC[C@H](C)C1=NO
Product: C[C@H]1CCC[C@H](C)C1=NO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Into 80 ml of ethanol were suspended 5 g of 2,6-dimethylcyclohexanone and 5.51 g of hydroxylamine hydrochloride, 9.4 g of pyridine was added dropwise at 0° C., and the mixture was stirred for 4 hours at room temperature. The reaction mixture was concentrated, water was added to the residue, the mixture was extracted with ethyl acetate three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 3.1 g of cis-2,6-dimethyl cyclohexanone oxime and 1.3 g of trans-2,6-dimethylcyclohexanone oxime.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[CH2:12](O)[CH3:13]>S(=O)(=O)(O)O>[CH2:12]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[OH:11])[CH3:13]
Reactant: O=C(O)c1cc(F)ccc1O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(F)ccc1O
Temperature: 90 °C

Procedure:
To a solution of 5-fluorosalicylic acid (50 g) in absolute ethanol (500 ml), concentrated sulfuric acid (10 ml) was cautiously added. The solution was heated at 90° C. for 72 hours. The solvent was removed in vacuo, and the viscous residue was made basic (final pH=9) by portionwise addition of saturated aqueous sodium bicarbonate. The solution was then extracted with three 200 ml portions of methylene chloride. The combined organic extracts were dried (anhydrous sodium sulfate) and concentrated in vacuo to afford the title compound (quantitative yield) as a viscous colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20](=[O:23])[NH:21][CH3:22])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:24]([O:26]CC)=[O:25])=[CH:5][CH:4]=1.[Li+].[OH-]>CO.C1COCC1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20](=[O:23])[NH:21][CH3:22])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:24]([OH:26])=[O:25])=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cnc2ccc(C(=O)NC)cc2c1Nc1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)c1ccc2ncc(C(=O)O)c(Nc3ccc(OC)cc3)c2c1
Yield: 76.7 %

Procedure:
Ethyl 4-[(4-methoxyphenyl)amino]-6-(methylcarbamoyl)quinoline-3-carboxylate (0.2 g) was stirred with LiOH (85.5 mg) in 6 mL of MeOH:THF:H2O (2:2:2) overnight. The reaction mixture was concentrated and the aqueous layer was washed with ethyl acetate. The aqueous layers were collected and acidified with aqueous HCl and the precipitate formed was filtered and dried to give 0.142 g (60%) of 4-[(4-methoxyphenyl)amino]-6-(methylcarbamoyl)-quinoline-3-carboxylic acid. 1H NMR (300 MHz, CD3OD) δ 9.05 (s, 1H, aromatic), 8.20 (s, 1H, aromatic), 8.12-7.81 (m, 2H, aromatic), 7.27 (d, 2H, J=9.9 Hz, aromatic), 7.06 (d, 2H, J=9.9 Hz, aromatic), 3.88 (s, 1H, —OCH3), 2.82 (s, 3H, —NCH3); LC-MS (m/z) 352.0 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]([C:16]2[CH:17]=[C:18]([S:22]([C:25]3[CH:26]=[C:27]4[C:32](=[C:33]([CH3:35])[CH:34]=3)[N:31]=[CH:30][C:29]([C:36]([NH2:38])=[O:37])=[C:28]4[NH:39][C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[CH:41]=3)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=2)=[O:15])[CH:10]=[CH:11][CH:12]=1.[NH2:48][CH2:49][C@@H:50]([C:59]1[CH:68]=[CH:67][C:66]([OH:69])=[C:65]2[C:60]=1[CH:61]=[CH:62][C:63](=[O:70])[NH:64]2)[O:51][Si:52]([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53].C(N(CC)C(C)C)(C)C.[I-].[K+]>CN(C=O)C>[Si:52]([O:51][C@H:50]([C:59]1[CH:68]=[CH:67][C:66]([OH:69])=[C:65]2[C:60]=1[CH:61]=[CH:62][C:63](=[O:70])[NH:64]2)[CH2:49][NH:48][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]([C:16]2[CH:17]=[C:18]([S:22]([C:25]3[CH:26]=[C:27]4[C:32](=[C:33]([CH3:35])[CH:34]=3)[N:31]=[CH:30][C:29]([C:36]([NH2:38])=[O:37])=[C:28]4[NH:39][C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[CH:41]=3)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=2)=[O:15])[CH:10]=[CH:11][CH:12]=1)([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5cccc(C#CCCCBr)c5)c4)cc23)c1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5cccc(C#CCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c6ccc(O)c7[nH]c(=O)ccc67)c5)c4)cc23)c1
Temperature: 55 °C
Yield: 60.4 %

Procedure:
A mixture of Intermediate 98 (0.35 g, 0.48 mmol) and Intermediate 2 (0.24 g, 0.72 mmol) in DMF (4.5 mL) was treated with N,N-diisopropylethylamine (0.25 mL) and catalytic potassium iodide (50 mg). The mixture was heated for 19 hours in a 55° C. oil bath. The mixture was concentrated under reduced pressure and purified via automated flash silica gel chromatography, using a 25 g Silicycle SiliSep flash column (dichloromethane/methanol/ammonium hydroxide). Concentration of the desired fractions under reduced pressure provided the title compound as a yellow solid (0.28 g, 61%). ES/MS calcd. for C53H57N6O8SSi+ 965.4. Found m/z=965.5 (M+H)+.
Reaction SMILES: [C:1]([O:4][C@@H:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])/[CH:6]=[CH:7]/[C@@H:8]1[C@@H:12]([CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:11](=O)[CH:10]2[O:23][CH:9]12)(=[O:3])[CH3:2].O.NN.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.C(O)(=O)C>[C:1]([O:4][C@@H:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])/[CH:6]=[CH:7]/[C@@H:8]1[C@@H:12]([CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:11]=[CH:10][CH:9]1[OH:23])(=[O:3])[CH3:2]
Reactant: CCCCC[C@@H](/C=C/[C@H]1C2OC2C(=O)[C@@H]1C/C=C\CCCC(=O)O)OC(C)=O
Agent: NN
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CCCCC[C@@H](/C=C/[C@H]1C(O)C=C[C@@H]1C/C=C\CCCC(=O)O)OC(C)=O

Procedure:
to a solution of 30 parts of (5Z,13E,15S)-15-acetyloxy-10ξ,11ξ-epoxy-9-oxoprosta-5,13-dien-1-oic acid in 1200 parts of methanol at 5° is added a solution of 12 parts of 100% hydrazine hydrate in 96 parts of methanol followed by a solution of 1 part of acetic acid in 5 parts of methanol. The resultant mixture is stirred at 5° for 30 minutes, then acidified with aqueous 2% citric acid. The mixture thus obtained is extracted with dichloromethane. The extract is washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. The residual red oil is taken up in benzene; and the benzene solution is chromatographed on silica gel, using benzene and mixtures thereof with increasing amounts of ethyl acetate as developing solvents. From an eluate comprising 20% ethyl acetate in benzene, on evaporation of solvent, (5Z,13E,15S)-15-acetyloxy-11ξ-hydroxyprosta-5,9,13-trien-1-oic acid is obtained as a colorless oil which gradually darkens upon standing.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[C:16][CH2:17][Cl:18])[CH2:10][C@H:9]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([CH3:27])[CH:21]=1)=[O:7].[ClH:37].[CH2:38]([C@H:40]1[CH2:45][O:44][CH2:43][CH2:42][NH:41]1)[CH3:39].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[ClH:18].[ClH:37].[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[C:16][CH2:17][N:41]2[CH2:42][CH2:43][O:44][CH2:45][C@@H:40]2[CH2:38][CH3:39])[CH2:10][C@H:9]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([CH3:27])[CH:21]=1)=[O:7]
Reactant: CC[C@H]1COCCN1
Reactant: Cc1ccc(C[C@@H]2CN(CC#CCCl)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@H]1COCCN1CC#CCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccc(C)c(C)c2)C1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 91.8 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(4-chloro-2-butynyl)-2-(3,4-dimethylbenzyl)piperazine (150 mg), (3S)-3-ethylmorpholine hydrochloride (47 mg) and powdered potassium carbonate (117 mg) in dry N,N-dimethylformamide (1 ml) was stirred at 50° C. for 1.5 hours. The reaction mixture was poured into water (10 ml) and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the obtained residue was purified by column chromatography on silica gel using ethyl acetate as eluent. The obtained product was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-((3S)-3-ethylmorpholino)-2-butynyl]-2-(3,4-dimethylbenzyl)piperazine dihydrochloride (177 mg).
Reaction SMILES: [C:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:9](O)(=[O:13])[C:10]([CH3:12])=[CH2:11].C1(C)C=CC(S(O)(=O)=O)=CC=1.COC1C=CC(O)=CC=1>C1(C)C=CC=CC=1>[C:9]([O:8][CH2:7][C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1)(=[O:13])[C:10]([CH3:12])=[CH2:11]
Reactant: OCC1=CCCCC1
Reactant: C=C(C)C(=O)O
Agent: COc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OCC1=CCCCC1
Yield: 78 %

Procedure:
CHMA was prepared by the above procedure from cyclohexenyl methanol (200 grams, 1.79 mole), methacrylic acid (137.6 grams, 1.60 mole), p-toluenesulfonic acid (15.2 grams, 80 mmole), MEHQ (8 grams, 5.7 mmole), and toluene (1000 ml) in a 2 liter reaction flask. The aqueous washes were performed with 400 ml portions for each wash. The CHMA was obtained in an amount of 225.9 grams (78% yield). The CHMA was determined to have a boiling point in the range of 64-66° C. at a reduced pressure of 0.3 Torr.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[C:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]3[C:22](=[O:23])[N:21]4[CH:24]=[CH:25][S:26][C:20]4=[N:19][C:18]=3[CH3:27])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:35][CH:36]([CH:40]([OH:44])[C:41]([OH:43])=[O:42])[C:37]([OH:39])=[O:38]>CC(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[C:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]3[C:22](=[O:23])[N:21]4[CH:24]=[CH:25][S:26][C:20]4=[N:19][C:18]=3[CH3:27])[CH2:11][CH2:10]2)=[CH:6][CH:7]=1.[OH:35][CH:36]([CH:40]([OH:44])[C:41]([O-:43])=[O:42])[C:37]([O-:39])=[O:38]
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: Cc1nc2sccn2c(=O)c1CCN1CCC(=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Solvent: CC(C)O
Product: O=C([O-])C(O)C(O)C(=O)[O-]

Procedure:
A mixture of 4 parts of 6-[2-[4-[bis(4-fluorophenyl)methylene]-1-piperidinyl]ethyl]-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one, 1.3 parts of (+)-[R-(R*,R*)]-2,3-dihydroxybutanedioic acid and 96 parts of 2-propanol was stirred and heated till all solid entered solution. The whole was cooled while stirring. The product was filtered off and dried, yielding 5.1 parts (98%) of (+)-6-[2-[4-[bis(4-fluorophenyl)methylene]-1-piperidinyl]ethyl]-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one [R-(R*,R*)]-2,3-dihydroxybutanedioate(1:1).; mp. 198.7° C. (compound 147).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15].[F-].[Cs+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:15]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1)[CH:14]=[CH2:13]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ccc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: C=CCc1ccc(C(=O)OC)c(F)c1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
Methyl 4-bromo-2-fluorobenzoate (424 mg, 1.82 mmol), allyl tributyl tin (0.846 mL, 2.73 mmol), tetrakis(triphenylphosphine)palladium (0) (105 mg, 0.091 mmol) and cesium fluoride (415 mg, 2.73 mmol) were heated to reflux in 1,4-dioxane (10 mL) for 7 hours under argon atmosphere. The mixture was cooled to room temperature, and then filtered through diatomaceous earth by ethyl acetate and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=2%→10%) to give methyl 4-allyl-2-fluorobenzoate (333 mg, 94%) as a pale yellow viscous material.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(=O)(O)[O-].[Na+].[OH:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[C:28]2[C:34]1[CH2:35][CH2:36][NH:37][CH2:38][CH:39]=1>CN(C)C=O.O1CCCC1>[OH:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[C:28]2[C:34]1[CH2:35][CH2:36][N:37]([CH2:2][CH2:3][CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=34)[S:6]2(=[O:18])=[O:17])[CH2:38][CH:39]=1
Reactant: Oc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CC=C(c2c[nH]c3ccc(O)cc23)CC1
Temperature: 20 °C

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (7 g), sodium bicarbonate (4.2 g) and 4-(5-hydroxy-3-indolyl)-1,2,3,6-tetrahydropyridine (5.3 g) in dimethylformamide (50 cc) and tetrahydrofuran (50 cc). The mixture is heated for 5 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is maintained for 7 hours at this temperature. After purification by crystallization from water (100 cc), then recrystallization from a boiling acetoneethanol mixture (50-50 vol) (80 cc), 2-(3-[4-(5-hydroxy 3-indolyl)-1,2,3,6-tetrahydro-1-pyridyl]propyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (5.1 ) is obtained, m.p. 214° C.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:30])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH3:28])=[CH:22][C:21]=1[Cl:29])[CH2:16][CH:17]=C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:31]1CCCC1.C(O)(C)(C)C.I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.O>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:30])[CH:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH3:28])=[CH:22][C:21]=1[Cl:29])[CH2:16][CH:17]=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: C=CC[C@@H](Cc1c(Cl)cc(OC)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1cc(Cl)c(CC(CC=O)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c(Cl)c1
Yield: 49 %

Procedure:
Treat a mixture of (R)-4-benzyl-3-[(S)-2-(4-methoxy-2,6-dichloro-benzyl)-pent-4-enoyl]-oxazolidin-2-one (6.65 g, 14.87 mmol), tetrahydrofuran (140 mL) and water (45 mL) with 2.5% osmium tetroxide in t-butanol (378 mL, 1.487 mmol). Add sodium periodate (9.55 g, 44.63 mmol) and stir the reaction 4 hr at room temperature. Quench the reaction with water and extract with ethyl acetate. Wash the organic phase with aqueous 1N sodium thiosulfate then brine. Dry the organic layer over magnesium sulfate, filter, and concentrate under vacuum. Purify the crude material by silica gel chromatography using hexanes:ethyl acetate to elute the pure product. Concentrate the fractions containing product under vacuum to afford 3.35 g (49%) of desired product. MS (m/z): 451 (M+).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([N:22]3[CH2:27][CH2:26][N:25]([C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])[CH2:24][CH2:23]3)[CH:15]=2)(=[O:13])=[O:12])=[CH:6][CH:5]=1.[OH-:34].[Na+]>>[F:30][C:29]([F:32])([F:31])[C:28]([OH:33])=[O:34].[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([N:22]3[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]3)[CH:15]=2)(=[O:12])=[O:13])=[CH:6][CH:5]=1
Reactant: [OH-]
Reactant: COCc1ccc(NS(=O)(=O)c2ccc(OC)c(N3CCN(C(=O)C(F)(F)F)CC3)c2)cc1
Agent: [Na+]
Product: COCc1ccc(NS(=O)(=O)c2ccc(OC)c(N3CCNCC3)c2)cc1
Product: O=C(O)C(F)(F)F

Procedure:
The product was obtained as described in Example 1 by reaction of N-(4-methoxymethyl-phenyl)-4-methoxy-3-[4-(2,2,2-trifluoro-acetyl)piperazin-1-yl]-benzenesulfonamide with aqueous sodium hydroxide.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[CH3:12][S:13](Cl)(=[O:15])=[O:14].C(N(CC)CC)C>>[Br:1][C:2]1[CH:10]=[C:9]([NH:11][S:13]([CH3:12])(=[O:15])=[O:14])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(Br)c2cn[nH]c2c1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cc(Br)c2cn[nH]c2c1
Yield: 61.5 %

Procedure:
4-Bromo-1H-indazol-6-amine (500 mg, 2.36 mmol) was treated with methanesulfonyl chloride (130 μl, 1.68 mmol) and triethylamine (49 μl, 3.55 mmol) according to the method described in Preparation 15b. The residue was purified using SP1® Purification System to give 300 mg (49% yield) of the title compound. Purity 80%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:26](OC)(OC)(OC)[CH2:27][CH2:28][CH2:29][CH3:30]>C1(C)C=CC=CC=1>[CH2:27]([C:26]1[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:28][CH2:29][CH3:30]
Reactant: Nc1cnc2ccccc2c1NCCCCCC(=O)c1ccccc1
Reactant: CCCCC(OC)(OC)OC
Solvent: Cc1ccccc1
Product: CCCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)c1ccccc1
Yield: 87.7 %

Procedure:
A solution of 6-(3-aminoquinolin-4-ylamino)-1-phenylhexan-1-one (2.09 g, 6.25 mmol) and trimethyl orthovalerate (1.52 g, 9.37 mmol) in toluene (50 mL) was heated at reflux under a Dean-Stark trap for 2 hours, then concentrated under reduced pressure to provide 6-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylhexan-1-one (2.19 g) as a dark red oil that was used directly in the next step without further purification.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C@H:19]2[CH2:24][CH2:23][C@H:22]([CH2:25][OH:26])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1>ClCCl.C(OCC)C>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C@H:19]2[CH2:20][CH2:21][C@H:22]([CH:25]=[O:26])[CH2:23][CH2:24]2)=[CH:17][CH:18]=1
Reactant: OC[C@H]1CC[C@H](c2ccc(F)cc2)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C[C@H]1CC[C@H](c2ccc(F)cc2)CC1
Reaction time: 4 h

Procedure:
A suspension of 11.35 g of pyridinium chlorochromate in 80 ml of dichloromethane was treated dropwise with a solution of 6.06 g of (trans-4-(4-fluorophenyl)cyclohexyl]methanol in 18 ml of diethyl ether. The reaction mixture was stirred for 4 hours, then diluted with 50 ml of diethyl ether, decanted off from the dark residue and filtered. Concentration of the filtrate gave 4.86 g of trans-4-(4-fluorophenyl)cyclohexanecarboxaldehyde as a yellowish oil which solidified at room temperature; m.p. <30° C.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].O=[C:12]([CH2:19][CH2:20][CH3:21])[CH2:13][C:14](OCC)=[O:15]>>[OH:15][C:14]1[N:1]([C:3]2[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=2)[N:2]=[C:12]([CH2:19][CH2:20][CH3:21])[CH:13]=1
Reactant: N#Cc1ccnc(NN)c1
Reactant: CCCC(=O)CC(=O)OCC
Product: CCCc1cc(O)n(-c2cc(C#N)ccn2)n1
Yield: 44 %

Procedure:
The title compound was prepared in 44% yield from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl 3-oxohexanoate according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C12H12N4O, 229. Found, 229.
Reaction SMILES: [O:1]=[C:2]([NH:18][CH:19]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)[C:20]([F:23])([F:22])[F:21])/[CH:3]=[CH:4]/[C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([C:14]([F:17])([F:16])[F:15])[CH:6]=1.ClC1C=C(O)C2N=NNC=2C=1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)C(C)C)C.Cl.[F:67][CH2:68][CH:69]([NH2:71])[CH3:70]>ClCCl>[F:67][CH2:68][CH:69]([NH:71][C:9](=[O:10])[C:8]1[CH:12]=[CH:13][C:5](/[CH:4]=[CH:3]/[C:2](=[O:1])[NH:18][CH:19]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=2)[C:20]([F:22])([F:23])[F:21])=[CH:6][C:7]=1[C:14]([F:16])([F:17])[F:15])[CH3:70]
Reactant: CC(N)CF
Reactant: O=C(/C=C/c1ccc(C(=O)O)c(C(F)(F)F)c1)NC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cc(Cl)cc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(CF)NC(=O)c1ccc(/C=C/C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
49 mg (1 eq, 0.1 mmol) of 4-[(1E)-3-oxo-3-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-amino)prop-1-en-1-yl]-2-(trifluoromethyl)benzoic acid from Example 2, Stage 2 were dissolved in 1 ml of dichloromethane. Then 17 mg (1.0 eq, 0.10 mmol) of 6-chlorohydroxybenzotriazole, 23 mg (1.2 eq, 0.12 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 26 mg (2 eq, 0.20 mmol) of N-ethyldiisopropylamine were added thereto, and the mixture was stirred at RT for 20 min. Subsequently, 11 mg (1.0 eq, 0.10 mmol) of 1-fluoropropan-2-amine hydrochloride were added and the reaction mixture was stirred at room temperature for 12 h. After this time, the reaction mixture was concentrated and the resulting crude product was purified by means of preparative HPLC (phenomenex Gemini C18 5 μm; 110A; AXIA 50×21.2 mm; gradient: 0-2 min 70% water, 30% MeOH, 2.5-6.0 min linear gradient to 5% water, 95% MeOH, 6.0-20.00 min 5% water, 95% MeOH; modifier: 20% HCOOH added at 2 ml/min). This gives 27 mg (37%) of N-(1-fluoropropan-2-yl)-4-[(1E)-3-oxo-3-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}amino)-prop-1-en-1-yl]-2-(trifluoromethyl)benzamide as a solid.