Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[CH:12]=[CH:11]2.[OH-].[Na+].CN(C)[CH:22]=[O:23]>>[CH:22]([C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([O:7][CH3:6])[CH:9]=2)[N:13]([CH3:17])[CH:12]=1)=[O:23]
Reactant: CN(C)C=O
Reactant: COc1ccc2c(ccn2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)c(C=O)cn2C
Temperature: 110 °C

Procedure:
While cooling in order to maintain the temperature of the reaction medium below 15° C., phosphorus oxychloride (9 ml) is added dropwise to 35 ml of dimethylformamide (DMF), and 5-methoxy-1-methylindole (14.1 g), dissolved in DMF (25 ml) is added in a single portion. The resulting heterogeneous mixture is heated to 110° C. for 1 minute, and then maintained at 65° C. for 30 minutes while being stirred mechanically. After the mixture has been allowed to cool, it is decomposed by adding 200 ml of ice-cold water, and then treated with 5N sodium hydroxide solution (100 ml). The precipitate formed is filtered off and recrystallized in ethanol, to give 14.53 g (87.7%) of colorless scales, m.p.=134° C.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C:3]1[C:8]([NH:9][C:10](=[O:35])[C:11]2[CH:16]=[C:15]([CH2:17][C:18]3[C:19](=[O:30])[C:20]([O:28][CH3:29])=[C:21]([O:26][CH3:27])[C:22](=[O:25])[C:23]=3[CH3:24])[CH:14]=[CH:13][C:12]=2[O:31]C(=O)C)=[CH:7][CH:6]=[CH:5][N:4]=1.C(=O)([O-])O.[Na+]>CO.O>[CH3:36][N:2]([CH3:1])[C:3]1[C:8]([NH:9][C:10](=[O:35])[C:11]2[CH:16]=[C:15]([CH2:17][C:18]3[C:19](=[O:30])[C:20]([O:28][CH3:29])=[C:21]([O:26][CH3:27])[C:22](=[O:25])[C:23]=3[CH3:24])[CH:14]=[CH:13][C:12]=2[OH:31])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cccnc3N(C)C)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3cccnc3N(C)C)c2)=C(C)C1=O
Yield: 99.7 %

Procedure:
N-(2-Dimethylaminopyridin-3-yl)-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide (0.074 g, 0.0933 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (ethyl acetate:hexane=1:1) to obtain the titled compound (0.042 g, 0.0930 mmol, 99%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[NH:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=2)[C:5]([Cl:24])=[CH:4][N:3]=1.[NH2:25][C:26]1[CH:39]=[CH:38][C:29]2[NH:30][C:31](=[O:37])[CH2:32][CH2:33][C:34]([CH3:36])([CH3:35])[C:28]=2[CH:27]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(O)(C)C>>[Cl:24][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[NH:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=2)=[N:7][C:2]([NH:25][C:26]2[CH:39]=[CH:38][C:29]3[NH:30][C:31](=[O:37])[CH2:32][CH2:33][C:34]([CH3:36])([CH3:35])[C:28]=3[CH:27]=2)=[N:3][CH:4]=1
Reactant: FC(F)(F)c1c[nH]c(-c2ccccc2Nc2nc(Cl)ncc2Cl)n1
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CC1(C)CCC(=O)Nc2ccc(Nc3ncc(Cl)c(Nc4ccccc4-c4nc(C(F)(F)F)c[nH]4)n3)cc21
Yield: 26.5 %

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-[2-(4-trifluoromethyl-1H-imidazol-2-yl)-phenyl]-amine (50.0 mg, 0.134 mmol), 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (27.0 mg, 0.132 mmol) and 10-Camphorsulfonic acid (31.0 mg, 0.133 mmol) were suspended in Isopropyl alcohol (3.0 mL, 0.039 mol) and the reaction was microwaved on 300 watts, 140° C. for 20 minutes. The reaction mixture was then reduced under nitrogen and the crude residue was isolated and purified by prep HPLC to afford 18.95 mg (26%) of the desired product as a TFA salt. LC/MS (ESI): 558.26. 1H NMR (400 MHz, DMSO, d6) δ 9.46 (s, 1H), 9.39 (s, 1H), 8.96 (m, 1H), 8.23 (s, 1H), 8.08 (s, 1H), 7.97 (m, 1H), 7.66 (m, 1H), 7.54 (m, 1H), 7.39 (m, 1H), 7.21 (m, 1H), 6.91 (d, 1H, J=8.59 Hz), 2.16 (m, 2H), 1.98 (m, 2H), 1.29 (s, 6H).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[CH:7]=[CH:6][N+:5]([O-])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:13])=O.P(Cl)(Cl)(Cl)(Cl)Cl>O>[Cl:13][C:6]1[CH:7]=[C:2]([C:1]([OH:10])=[O:9])[CH:3]=[CH:4][N:5]=1
Reactant: O=C(O)c1cc[n+]([O-])cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Product: O=C(O)c1ccnc(Cl)c1
Reaction time: 8 h
Yield: 66 %

Procedure:
87 g of isonicotinic acid N-oxide, 350 ml of phosphorus oxychloride and 192 g of phosphorus pentachloride were mixed and refluxed for 3 hours. The reaction mixture was poured into water and left to stand overnight. The resulting precipitate was collected by filtration, and recrystallized from ethanol to give 65 g (66 %) of 2-chloro-4-pyridinecarboxylic acid.
Reaction SMILES: [I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.Br[CH:14]([C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[F:24])[CH3:15]>>[I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[N:9]([CH:14]([C:16]3[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=3[F:24])[CH3:15])[C:4]=2[CH:3]=1
Reactant: CC(Br)c1cc(F)c(F)cc1F
Reactant: O=C1CNc2ncc(I)cc2N1
Product: CC(c1cc(F)c(F)cc1F)N1C(=O)CNc2ncc(I)cc21

Procedure:
7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (297 mg) was alkylated with 1-(1-bromoethyl)-2,4,5-trifluorobenzene as in General Procedure 1 to give the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:20])=[CH:4][C:5]2[C:6]3[C:7]4[CH:19]=[CH:18][CH:17]=[N:16][C:8]=4[O:9][C:10](=[O:15])[C:11]=3[NH:12][C:13]=2[CH:14]=1.Br[CH2:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[F:31])[C:26]#[N:27]>CN(C=O)C.C(OCC)(=O)C>[F:31][C:30]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][C:23]=1[CH2:22][N:12]1[C:11]2[C:10](=[O:15])[O:9][C:8]3[N:16]=[CH:17][CH:18]=[CH:19][C:7]=3[C:6]=2[C:5]2[CH:4]=[C:3]([CH3:20])[C:2]([F:1])=[CH:14][C:13]1=2
Reactant: N#Cc1ccc(F)c(CBr)c1
Reactant: Cc1cc2c(cc1F)[nH]c1c(=O)oc3ncccc3c12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc2c3c4cccnc4oc(=O)c3n(Cc3cc(C#N)ccc3F)c2cc1F
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a solution of 9-Fluoro-10-methyl-7H-5-oxa-4,7-diaza-benzo[c]fluoren-6-one 1G (167 mg, 0.622 mmol) in DMF (3.0 mL) was added 3-Bromomethyl-4-fluoro-benzonitrile (160.0 mg, 0.747 mmol) and CsCO3 (243 mg, 0.747 mmol) at room temperature and the reaction mixture was allowed to stir overnight. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The concentrated crude was purified using chromatography over SiO2 using 0 to 30% ethyl acetate in hexane to provide 4-Fluoro-3-(9-fluoro-10-methyl-6-oxo-6H-5-oxa-4,7-diaza-benzo[c]fluoren-7-ylmethyl)-benzonitrile 1H (200 mg, 80%). M.S. found for C23H13F2N3O2: 402.9 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]([C:10]2[CH:18]=[CH:17][C:13]3=[N:14][O:15][N:16]=[C:12]3[CH:11]=2)=[O:9])[CH2:2]1.[H-].[Na+].[CH3:21]I>CN(C=O)C>[CH3:21][N:7]([CH:3]1[CH2:4][CH2:5][CH2:6][O:1][CH2:2]1)[C:8]([C:10]1[CH:18]=[CH:17][C:13]2=[N:14][O:15][N:16]=[C:12]2[CH:11]=1)=[O:9]
Reactant: O=C(NC1CCCOC1)c1ccc2nonc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc2nonc2c1)C1CCCOC1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
N-(Tetrahydro-2H-pyran-3-yl)-[2,1,3]-benzoxadiazole-5-carboxamide (371 mg, 1.5 mmol) was added to a suspension of sodium hydride (216 mg, 9 mmol) in dry DMF (5 ml), followed by methyl iodide (1.0 ml) and the mixture was stirred at 20° C. for 1 hour. The solvent was evaporated under vacuum, dichloromethane (30 ml) was added and the organic phase was washed with 1N HCl (100 ml) and NaHCO3 solution (100 ml). The aqueous was re-extracted with dichloromethane (100 ml), the organics dried over magnesium sulfate and concentrated under vacuum to give the title compound as a white solid after trituration with diethyl ether (186 mg). Mp: 134-135° C., 1H NMR (300 MHz, CDCl3) δ 7.93 (d, 1H, J=9.0 Hz); 7.83 (s, 1H); 7.40 (d, 1H, J=9.0 Hz); 4.70-3.20 (m, 4H), 3.01 (sb, 3H) and 2.10-1.50 ppm (m, 4H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([NH:15][C:16]1[C:21](I)=[C:20]([CH3:23])[N:19]=[C:18]([NH2:24])[N:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:25]([O:29][CH2:30][CH3:31])(=[O:28])[CH:26]=[CH2:27]>CN(C=O)C.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>[CH2:30]([O:29][C:25](=[O:28])/[CH:26]=[CH:27]/[C:21]1[C:16]([NH:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:17][C:18]([NH2:24])=[N:19][C:20]=1[CH3:23])[CH3:31]
Reactant: Cc1nc(N)nc(NCc2ccccc2)c1I
Reactant: C=CC(=O)OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1c(C)nc(N)nc1NCc1ccccc1
Temperature: 95 °C
Reaction time: 24 h
Yield: 28 %

Procedure:
Triethylamine (7.60 mL, 54.5 mmol) was added to a suspension of N4-benzyl-5-iodo-6-methylpyrimidine-2,4-diamine (3.14 g, 10.9 mmol), ethyl acrylate (3.55 mL, 32.7 mmol) and Pd(PPh3)4 (629 mg, 0.545 mmol) in anhydrous DMF (20 mL). The reaction was heated to 95° C. under nitrogen. After 24 h, the reaction was allowed to cool to room temperature and concentrated in vacuo. The residue was poured into a 10% solution of LiCl and washed with ethyl acetate (100 mL). The organic phase was separated and washed with brine, separated and dried over Na2SO4. The filtrate was concentrated in vacuo and purified on SiO2 (3:2 methylene chloride:ethyl acetate) to afford (E)-ethyl-3-(2-amino-4-(benzylamino)-6-methylpyrimidin-5-yl)acrylate (0.954 g, 28% yield) as a light yellow solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)(=[O:3])[CH3:2].C(N(CC)CC)C.C(OC(Cl)=O)C.[Cl:27][C:28]1[CH:41]=[CH:40][C:31]([CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1>CN(C=O)C.C(Cl)Cl>[Cl:27][C:28]1[CH:41]=[CH:40][C:31]([CH2:32][CH2:33][N:34]2[CH2:35][CH2:36][N:37]([C:8](=[O:10])[C:7]3[CH:11]=[CH:12][CH:13]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=3)[CH2:38][CH2:39]2)=[CH:30][CH:29]=1
Reactant: CC(=O)Nc1cccc(C(=O)O)c1
Reactant: Clc1ccc(CCN2CCNCC2)cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c1

Procedure:
10 g of 3-acetamidobenzoic acid are dissolved in 100 ml of DMF. At a temperature of from -5° to 0° there are added dropwise, while stirring, firstly 5.65 g of triethylamine and then 6.05 g of chloroformic acid ethyl ester dissolved in 40 ml of CH2Cl2. The whole is stirred for a further 30 minutes at from 0° to +5° and then, at the same temperature, 12.54 g of 1-(p-chlorophenethyl)piperazine in 75 ml of DMF are added dropwise. The whole is stirred overnight at room temperature and then concentrated to dryness by evaporation. The residue is taken up in 350 ml of CH2Cl2 and the whole is washed with 150 ml of 2N NaOH and with 50 ml of H2O and dried over Na2SO4. After filtration and concentration by evaporation, a brown oil is obtained, which is caused to crystallise with ether. Recrystallisation is effected from ethanol/ether. 1-[2-(p-chlorophenyl)-ethyl]-4-(3-acetamidobenzoyl)-piperazine having a melting point of 101°-107° is thus obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:21]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][N:22]=1>C1COCC1>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:21]2[N:22]=[CH:23][C:24]([C:27]#[N:28])=[CH:25][CH:26]=2)[CH2:3]1
Reactant: CC1(C)CCCC(O)C1
Reactant: N#Cc1ccc(Cl)nc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)CCCC(Oc2ccc(C#N)cn2)C1
Temperature: -78 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
Dissolve 3,3-dimethylcyclohexanol (6 g, 47 mmoles) in anhydrous THF (70 mL) under nitrogen atmosphere and cool at −78° C. Add sodium bis(trimethylsilyl)amide (23.4 mL, 47 mmol, 2M solution in THF) to this solution and stir at −78° C. for 30 min before raising to room temperature. Cool down again to −78° C. and add a solution of 2-chloro-5-cyanopyridine (7.1 g, 51.7 mmoles) in anhydrous THF (20 mL) and stir overnight while warming to room temperature. Add saturated aqueous NaHCO3 (100 mL) and extract the aqueous layer with DCM (3×100 mL). Wash the combined organic extracts with brine (200 mL). Dry over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with cyclohexane/EtOAc (1:0 to 9:1 gradient) to afford the desired intermediate as a solid (9.14 g, 84%). MS (ES+) m/z: 231.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH2:15][CH2:14][O:13][N:12]=2)=[C:9]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[OH:27][C:28]1[N:32]([CH3:33])[N:31]=[CH:30][CH:29]=1>O1CCOCC1>[Cl:1][C:2]1[C:10]([C:11]2[CH2:15][CH2:14][O:13][N:12]=2)=[C:9]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:8]=[CH:7][C:3]=1[C:4]([C:29]1[CH:30]=[N:31][N:32]([CH3:33])[C:28]=1[OH:27])=[O:5]
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)c(Cl)c1C1=NOCC1
Reactant: Cn1nccc1O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(C3=NOCC3)c2Cl)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
At room temperature and under an atmosphere of protective gas, 43.60 g (0.13 mol) of 2-chloro-3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoyl chloride in 375 ml of anhydrous dioxane and 13.56 g (0.134 mol) of triethylamine in 375 ml of anhydrous dioxane were simultaneously added dropwise to a solution of 12.74 g (0.13 mol) of 5-hydroxy-1-methylpyrazole and 300 ml of anhydrous dioxane. The reaction mixture was stirred at room temperature for 2 hours and then filtered off through silica gel, which was rinsed with dioxane. The eluate was concentrated under reduced pressure to about 500 ml and admixed with 17.94 g (0.13 mol) of dried, finely powdered potassium carbonate. After 6 hours under reflux, the solvent was distilled off under reduced pressure and the residue was taken up in about 700 ml of water. Insoluble components were filtered off and the pH of the filtrate was adjusted to 2-3 by slowly adding 10% strength hydrochloric acid. The precipitate that formed was filtered off with suction. 46.16 g (92% of theory) of 4-[2-chloro-3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoyl]-5-hydroxy-1-methyl-1H-pyrazole were obtained.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]([O:23][CH3:24])=[C:15]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:14]=2)=[CH:7][C:6]=1[F:29].[OH-].[Na+].C(O)C.O>C(#N)C>[C:19]([C:17]1[CH:18]=[C:13]([C:12]#[C:11][C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:30])=[O:2])=[C:6]([F:29])[CH:7]=2)[CH:14]=[C:15]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:16]=1[O:23][CH3:24])([CH3:20])([CH3:21])[CH3:22]
Reactant: COC(=O)Cc1ccc(C#Cc2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCO
Solvent: O
Product: COc1c(C(C)(C)C)cc(C#Cc2ccc(CC(=O)O)c(F)c2)cc1C(C)(C)C

Procedure:
Following General Procedure I and using [4-(3,5-di-tert-butyl-4-methoxy-phenylethynyl)-2-fluoro-phenyl]-acetic acid methyl ester (Compound 144, 0.122 g, 0.29 mmol), 5M aqueous sodium hydroxide solution (1 mL) and ethanol (4 mL), followed preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase, the title compound was obtained as a white solid (0.077 g, 65%).
Reaction SMILES: [CH3:1][CH:2]([CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=[O:13])[CH3:3].N1C2C(=CC=CC=2)CC1=O.[CH3:24][S:25]C1(CC2C=CC=CC=2)C2C(=CC=CC=2)NC1=O>CC(C)=O>[CH3:3][CH:2]([C:4]1([S:25][CH3:24])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=[O:13])[CH3:1]
Reactant: CSC1(Cc2ccccc2)C(=O)Nc2ccccc21
Reactant: CC(C)C1C(=O)Nc2ccccc21
Agent: O=C1Cc2ccccc2N1
Solvent: CC(C)=O
Product: CSC1(C(C)C)C(=O)Nc2ccccc21

Procedure:
Prepared from 3-(1-methylethyl)-1,3-dihydro-2H-indol-2-one (prepared from 1,3-dihydro-2H-indol-2-one and acetone by the method of Daisley and Walker, J. Chem. Soc. (C) (1971) page 1373) by the method described above for 3-methylthio-3-phenylmethyl-1,3-dihydro-2H-indol-2-one.
Reaction SMILES: [CH2:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:13])[C:5]=1[OH:14])[CH:2]=[CH2:3].[OH-].[Na+].[C:17](OC(=O)C)(=[O:19])[CH3:18].Cl>O>[C:17]([O:14][C:5]1[C:6]([CH3:13])=[C:7]([CH:11]=[CH:12][C:4]=1[CH2:1][CH:2]=[CH2:3])[C:8]([OH:10])=[O:9])(=[O:19])[CH3:18]
Reactant: C=CCc1ccc(C(=O)O)c(C)c1O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCc1ccc(C(=O)O)c(C)c1OC(C)=O

Procedure:
4-Allyl-3-hydroxy-2-methylbenzoic acid (2.0 g, 10.4 mmol) was slurried in 6 ml water in a 500 ml round bottom flask, cooled in an ice bath, and stirred. Aqueous NaOH solution (4.2 g of 50% NaOH in 6 ml water) was added slowly. The mixture was stirred for few minutes until the solution was clear. Acetic anhydride was added drop wise until pH 6 was obtained, by that time the reaction mixture become a thick slurry with an off white color. The mixture was stirred overnight at room temperature. The reaction mixture became a thick white slurry. The pH was adjusted to 2 with conc. HCl. A precipitate formed, and was filtered under vacuum and dried. The combined dried product was dissolved in DCM and purified on an ISCO system using 40 g silica column and hexane/EtOAc solvent gradient. The product eluted ˜30% EtOAc in hexane, and the fractions were collected and dried under vacuum to give (2.4 g, 98%) SKC-01-116. 1H NMR (400 MHz, CDCl3) δ 12.0 (br s, 1H), 7.92 (d, J=8.1 Hz, 1H), 7.18 (d, J=8.1 Hz, 1H), 6.03-5.67 (m, 1H), 5.26-4.89 (m, 2H), 3.31 (d, J=6.6 Hz, 2H), 2.44 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH2:42][OH:43])[C:38]2=[N:44][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:50][CH2:49][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:47])=[C:28]([F:46])[C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=C(Cl)N2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(C)=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH2:42][OH:43])[C:38]2=[N:44][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:47])=[C:28]([F:46])[C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:49][CH2:50]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(CO)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)c(F)c1-c1cccc-3c1
Agent: Cc1ccc2c(c1)-c1cccc(c1)-c1nc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3c1Cl)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Product: Cc1c([C@H](OC(C)(C)C)C(=O)O)c2n3cc(nc3c1CO)-c1cccc(c1)-c1c(ccc(F)c1F)O[C@@H](C)CCCCOC1(C)CCN2CC1
Yield: 80 %

Procedure:
Prepared in 80.0% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-16,17-difluoro-5-(hydroxymethyl)-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-8-chloro-4,17,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid. 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J=7.8 Hz, 1H), 7.94 (s, 1H), 7.89 (s, 1H), 7.52 (t, J=7.7 Hz, 1H), 7.39 (q, J=9.6 Hz, 1H), 7.30 (d, J=7.5 Hz, 1H), 7.01 (d, J=7.0 Hz, 1H), 5.51 (s, 1H), 5.03 (br. s., 1H), 4.98 (d, J=11.3 Hz, 1H), 4.83 (d, J=11.3 Hz, 1H), 4.65 (br. s., 1H), 3.93-3.83 (m, 1H), 3.76 (br. s., 1H), 3.52-3.43 (m, 3H), 2.40 (s, 3H), 1.92 (d, J=12.0 Hz, 1H), 1.82-1.51 (m, 9H), 1.19 (s, 3H), 1.12 (s, 9H), 1.09 (d, J=6.0 Hz, 3H); LCMS (ESI, M+1): 692.20.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([CH3:24])=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=2)=[O:12])=[CH:4][C:3]=1[CH3:25].[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>CC(O)C.[OH-].[Na+].O>[CH3:25][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([CH3:24])=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=2)=[O:12])[CH:6]=[C:7]([CH3:8])[C:2]=1[O:1][CH2:26][CH:28]1[CH2:29][O:30]1
Reactant: ClCC1CO1
Reactant: Cc1cc(CCC(=O)c2cc(-c3ccccc3)c(C)s2)cc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Cc1cc(CCC(=O)c2cc(-c3ccccc3)c(C)s2)cc(C)c1OCC1CO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 26.3 %

Procedure:
A solution of 3-(4-hydroxy-3,5-dimethyl-phenyl)-1-(5-methyl-4-phenyl-thiophen-2-yl)-propan-1-one (300 mg, 0.86 mmol) in 2-propanol (7.5 mL) and 3 N aq. NaOH (2.5 mL) is treated with epichlorohydrine (158 mg, 1.72 mmol) and the mixture is stirred at rt for 24 h, then diluted with water and extracted with EA. The solvent of the organic extract is evaporated and the residue is purified by CC on silica gel eluting with hepaten:EA 5:1 to give 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-1-(5-methyl-4-phenyl-thiophen-2-yl)-propan-1-one (92 mg) as an oil; LC-MS: tR=1.13 min, [M+1]+=407.24.
Reaction SMILES: [Cl:1][C:2]([F:15])([F:14])[C:3](=[O:13])[CH2:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6].[CH:16]([O-])([O-])[O:17][CH2:18][CH3:19].C(OC(=O)C)(=O)C>>[Cl:1][C:2]([F:14])([F:15])[C:3](=[O:13])[C:4](=[CH:16][O:17][CH2:18][CH3:19])[C:5]([CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)=[O:6]
Reactant: CCOC([O-])[O-]
Reactant: O=C(CC(=O)C(F)(F)Cl)C1CCCCC1
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)C1CCCCC1)C(=O)C(F)(F)Cl
Yield: 96.2 %

Procedure:
A mixture of 235.9 g of 1-chloro-4-cyclohexyl-1,1-difluoro-2,4-butanedione, 266.4 g of ethyl orthoformate and 367.2 g of acetic anhydride was refluxed under heating for 12 hours. The solvent was distilled off under reduced pressure to obtain 280.3 g of the desired product (crude product), which was directly used for the next reaction. A part of the crude product was further purified for measurement of the refractive index. nD20.6 1.4787
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[C:5]([C@@H:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH3:16])=[O:14])[C@@H:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8]2)[O:4][NH:3]1>CCCCCCC.CCO>[O:1]=[C:2]1[CH:6]=[C:5]([C@H:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH3:16])=[O:14])[C@H:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8]2)[O:4][NH:3]1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccccc1
Solvent: CCCCCCC
Solvent: CCO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@H]1c1ccccc1
Yield: 32.3 %

Procedure:
Racemic trans-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-phenylpiperidine-1-carboxylate (772 mg, 2.55 mmol) was subjected to chiral preparative HPLC (Column: Chiralpak AD (250×20), 5 μm particle size, mobile phase: Heptane/EtOH 75/25, flow rate 15 mL/min) to yield (2S,4S)-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-phenylpiperidine-1-carboxylate (249 mg, 32%). Optical rotation [α]D20=+23.0 (acetonitrile, c=1), Chiral purity 99.7% ee.