Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.O[CH2:15][C:16]1([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1>>[F:11][CH2:15][C:16]1([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1
Reactant: CCOC(=O)C1(CO)CCCCO1
Reactant: COCCN(CCOC)S(F)(F)F
Product: CCOC(=O)C1(CF)CCCCO1
Temperature: 70 °C
Yield: 63 %

Procedure:
Neat Deoxo-Fluor® (342 mg, 1.546 mmol) was added to a cold (0° C.) stirred ethyl 2-(hydroxymethyl)tetrahydro-2H-pyran-2-carboxylate (194 mg, 1.031 mmol) and the mixture was heated at 70° C. overnight. The reaction was quenched with ice and neutralized with sat. aq. NaHCO3 and extracted with DCM (2×). The combined organic layers were washed with water, brine and dried (MgSO4), filtered and dried to give a yellow-orange oil which was purified by silica gel FCC (0-5% EtOAc in DCM) to afford ethyl 2-(fluoromethyl)tetrahydro-2H-pyran-2-carboxylate as a colorless oil (125 mg, 63%) which was saponified (LiOH.H2O, MeOH-THF—H2O, sonicate) to afford Cap P-43 as a viscous oil (82 mg, 77%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.66-4.54 (m, 1H), 4.54-4.41 (m, 1H), 4.02-3.84 (m, 2H), 1.98-1.84 (m, 1H), 1.84-1.72 (m, 2H), 1.69-1.52 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:14]3[N:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]3=[N:12][C:11]=2[CH3:20])=[O:9])=[C:4]([F:21])[CH:3]=1.[CH3:22][N+:23]1([O-])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CC(CC(C)=O)=O.CC(CC(C)=O)=O.O=[V].C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:14]3[N:15]=[C:16]([Cl:19])[CH:17]=[C:18]([CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:13]3=[N:12][C:11]=2[CH3:20])=[O:9])=[C:4]([F:21])[CH:3]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: Cc1nc2ccc(Cl)nn2c1C(=O)c1ccc(Cl)cc1F
Agent: O=[V]
Solvent: CC(=O)CC(C)=O
Solvent: CCO
Product: Cc1nc2c(CN3CCOCC3)cc(Cl)nn2c1C(=O)c1ccc(Cl)cc1F

Procedure:
Add ethanol (12 L), (4-chloro-2-fluorophenyl)(6-chloro-2-methylimidazo[1,2-b]pyridazin-3-yl)methanone (897.70 g, 2.77 mol) and bis(2,4-pentanedionato)oxovanadium (IV) (146.81 g, 553.67 mmol) to a reaction vessel with a nitrogen atmosphere. Add an ethanol (6 L) solution of 4-methylmorpholine 4-oxide (3.89 kg, 33.21 mol) drop-wise over 150 min keeping the reaction temperature at 23-33° C.; then heat the reaction at 40° C. for 48 h. Cool the reaction and concentrate by removal of solvent (13 L). Filter the resulting mixture, rinse the filter cake with hexane (1 L) and then dry. (728 g, 66.25%; mp 145-147° C.; M+=423).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:14][N:13]2[C@H:7]([C:8](=[O:53])[NH:9][C:10]3[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]4[CH:31]=[C:30]([N+:32]([O-])=O)[C:29]([C:35]([N:37]5[CH2:41][CH2:40][CH2:39][C@H:38]5[CH:42](SCC)SCC)=[O:36])=[CH:28][C:27]=4[O:49][CH3:50])[C:17]([O:51][CH3:52])=[CH:16][C:11]=3[C:12]2=[O:15])[CH2:6]1)(=[O:3])[CH3:2].CCOC(C)=O>CC#N.O.Cl[Hg]Cl>[C:1]([O:4][C@H:5]1[CH2:14][N:13]2[C@H:7]([C:8](=[O:53])[NH:9][C:10]3[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]4[C:27]([O:49][CH3:50])=[CH:28][C:29]5[C:35](=[O:36])[N:37]6[CH2:41][CH2:40][CH2:39][C@@H:38]6[CH:42]=[N:32][C:30]=5[CH:31]=4)[C:17]([O:51][CH3:52])=[CH:16][C:11]=3[C:12]2=[O:15])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCSC(SCC)[C@@H]1CCCN1C(=O)c1cc(OC)c(OCCCCOc2cc3c(cc2OC)C(=O)N2C[C@H](OC(C)=O)C[C@H]2C(=O)N3)cc1[N+](=O)[O-]
Agent: Cl[Hg]Cl
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1OCCCCOc1cc3c(cc1OC)C(=O)N1C[C@H](OC(C)=O)C[C@H]1C(=O)N3)N=C[C@H]1CCCN1C2=O

Procedure:
A solution of the 8-(4-(4-(2-di(ethylsulfanyl)methyl-(2S)-tetrahydro-1H-1-pyrrolylcarbonyl)-2-methoxy-5-aminophenoxy)butoxy)-7-methoxy-5,11-dioxo-(2R,11aS)-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-2-yl acetate of formula V (744 mg, 1 mmol), HgCl2 (794 mg, 2.93 mmol) and HgO (687 mg, 3.18 mmol) in CH3CN/H2O (3:1, 15 ml) was stirred at room temperature for 12 h until TLC (EtOAc) indicated complete loss of starting material. Then the organic layer was evaporated in a vacuum and the residue was diluted with EtOAc. To this, saturated NaHCO3 was added slowly at room temperature and the mixture was filtered through celite and washed with ethylacetate. The filtrate was evaporated in a vacuum to obtain crude 7-methoxy-8-(4-(7-methoxy-5-oxo-(11aR)-2,3,5,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-8-yloxy)butoxy)-5,11-dioxo-(2R,11aS)-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-2-yl acetate of formula VI, which was further purified by column chromatography on silica gel by eluting first with ethylacetate to remove traces of mercuric salts and then with MeOH:CHCl3 (2:8).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:10]O)[CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N(CC)CC)C.O>COCCOC>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:8]=[C:4]2[CH:3]=1
Reactant: ON=C(Cc1cc(Cl)ccn1)c1ccc(F)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: COCCOC
Product: Fc1ccc(-c2cc3cc(Cl)ccn3n2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56.8 %

Procedure:
To a solution of 2-(4-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone oxime (8.0 g, 30 mmol) in 1,2-dimethoxyethane (50 mL) at 0° C. was added trifluoroacetic anhydride (6.3 g, 30 mmol), keeping the temperature below 10° C. during the addition. After the addition was complete, the reaction was warmed to room temperature. The solution was then cooled to 4° C. and a solution of triethylamine (8.4 mL, 60 mmol) in 1,2-dimethoxyethane (20 mL) was added over a period of 0.5 hours. The mixture was allowed to warm to room temperature and was stirred for 1.5 hours. To this mixture was added iron(ll) chloride (40 mg) and the reaction was heated at 75° C. for 15 hours. The reaction mixture was poured into water (300 mL). The resulting suspension was extracted with ethyl acetate. The combined organics were dried (magnesium sulfate), filtered and concentrated to a solid residue. This residue was purified by flash chromatography (1:1 ethyl acetate-hexane) to give 5-chloro-2-(4 fluorophenyl)pyrazolo[1,5-α]pyridine (4.2 g, 57%) as a white solid. 1H-NMR (CDCl3): δ 8.36 (d, 1H), 7.93 (q, 2H), 7.49 (d, 1H), 7.15 (t, 2H), 6.70 (dd, 1H), 6.69 (s, 1H); 19F-MNR (CDCl3): δ 113.30; MS m/z 247 (M+1).
Reaction SMILES: [H][H].[C:3]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4]1>>[C:3]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4]1.[CH:3]([OH:8])([OH:7])[CH2:4][CH2:5][CH3:6]
Reactant: [H][H]
Solvent: O=C1CCCO1
Product: CCCC(O)O
Temperature: 160 °C
Reaction time: 6 h

Procedure:
A stainless steel tubular reaction with an O.D. of 1 inch and I.D. 0.93 inches was packed with 70 ml (27 g.) of the catalyst from Example 1 to provide a 7 inch bed length. The catalyst was reduced over a six hour period 150°-300° C. using hydrogen in nitrogen in increasing concentration of from about 3% to about 10% H2. The hydrogen mixture was introduced intermittently until there was little exotherm, after which the hydrogen concentration was increased to 100%. A feed of γ-Butyrolactone was pumped to a vaporizer from which the vapor was carried by a hydrogen stream to the reaction. The ratio of hydrogen to butyrolactone feed (99% pure) was 150:1. The reactor was maintained at 160° C. temperature, 600 psig. pressure and an LHSV of 0.05 (g. of feed/hour/volume of catalyst). The product vapors were collected and condensed. A conversion of 90% butyrolactone with 95% selectivity to butanediol was obtained.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C@:9]23[CH2:14][C@H:13]2[CH2:12][NH:11][CH2:10]3)=[CH:5][CH:4]=1.Br[CH2:18][CH2:19][CH2:20][Cl:21]>C1COCC1.CCN(C(C)C)C(C)C.CCOC(C)=O>[Cl:21][CH2:20][CH2:19][CH2:18][N:11]1[CH2:12][C@H:13]2[C@:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=3)([CH2:14]2)[CH2:10]1
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Reactant: ClCCCBr
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc([C@]23C[C@H]2CN(CCCCl)C3)cc1
Temperature: 25 °C

Procedure:
To a solution of (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (P4, 1.00 g) in dry THF (5 mL), DIPEA (2.4 mL) and 1-bromo-3-chloropropane (3.7 mL) were added and the resulting mixture was heated at reflux for 3 hours. After cooling at room temperature it was diluted with EtOAc (30 mL) washed twice with a saturated solution of NH4Cl in water (20 mL) and once with a saturated aqueous NaHCO3 solution (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with cyclohexane/EtOAc 7:3 to give the title compound as a colourless oil (1.26 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[CH2:20]([NH:27][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)C1(Cc2ccc(F)c(Br)c2)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C1(Cc2ccc(F)c(NCc3ccccc3)c2)CC1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
Under argon and under dry conditions, 174.0 g (528.5 mmol) of tert-butyl 1-(3-bromo-4-fluorobenzyl)cyclopropanecarboxylate, 69.2 ml (634.2 mmol) of benzylamine, 4.84 g (5.29 mmol) of tris(dibenzylideneacetone)dipalladium, 60.95 g (634.2 mmol) of sodium tert-butoxide and 3.29 g (5.29 mmol) of (+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl were suspended in 1218 ml of toluene. The reaction mixture was then stirred at 110° C. for 2.0 h. After cooling, 2.1 liters of ethyl acetate and 1.7 liters of semisaturated aqueous ammonium chloride solution were added to the reaction mixture. After phase separation, the organic phase was washed with a saturated ammonium chloride solution and saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on 3.7 kg of silica gel (mobile phase petroleum ether/ethyl acetate 20:1). 145.0 g (68.7% of theory) of the title compound were thus obtained.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([N:16]1[C:25](=[O:26])[C:24]2[NH:23][C:22]([C:27]3[N:31]([CH3:32])[N:30]=[C:29]([O:33][CH2:34][C:35](O)=[O:36])[CH:28]=3)=[N:21][C:20]=2[N:19]([CH2:38][CH2:39][CH3:40])[C:17]1=[O:18])[CH2:14][CH3:15]>>[CH3:40][CH2:39][CH2:38][N:19]1[C:17](=[O:18])[N:16]([CH2:13][CH2:14][CH3:15])[C:25](=[O:26])[C:24]2[C:20]1=[N:21][C:22]([N:23]=2)=[C:27]1[N:31]([CH3:32])[NH:30][C:29]([O:33][CH2:34][C:35]([N:10]2[CH2:11][CH2:12][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]2)=[O:36])=[CH:28]1
Reactant: CCCn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)nn3C)nc2n(CCC)c1=O
Reactant: c1ccc(N2CCNCC2)cc1
Product: CCCn1c(=O)c2c(n(CCC)c1=O)=NC(=C1C=C(OCC(=O)N3CCN(c4ccccc4)CC3)NN1C)N=2

Procedure:
Using N-phenyl-piperazine and 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methyl-pyrazol-3-yl)oxyacetic acid (Example 36), according to the method described in Example 36.
Reaction SMILES: [CH2:1]([C:3]1([CH3:23])[CH:8]([CH3:9])[C:7](=O)[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[N:4]1[O:14][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[CH3:2].[NH2:24][OH:25]>CO.[OH-].[K+]>[CH2:1]([C:3]1([CH3:23])[CH:8]([CH3:9])[C:7](=[N:24][OH:25])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[N:4]1[O:14][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[CH3:2]
Reactant: NO
Reactant: CCC1(C)CC(=O)C(C)C(C)(CC)N1OC(C)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCC1(C)CC(=NO)C(C)C(C)(CC)N1OC(C)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.1 %

Procedure:
2,6-diethyl-2,3,6-trimethyl-1-(1-phenyl-ethoxy)-4-oxopiperidine prepared according to DE 199 09 767 A1 is dissolved in methanol containing 10% by weight of KOH and stirred for 5 hours at room temperature. Methanol is evaporated, the residue is washed with water and dried in vacuo. A solution of 95.24 g (0.3 mol) of 2,6-diethyl-2,3,6-trimethyl-1-(1-phenyl-ethoxy)-4-oxopiperidine and 29.7 g (0.45 mol) 50% aqueous hydroxylamine solution in 150 ml of methanol is stirred under reflux during 5 h. The suspension is then cooled to −8° C. and filtered. The solid is washed with 100 ml of a cold (−20° C.) methanol and dried to afford 64 g (64.1%) of the title compound as a white, microcrystalline powder, mp 130-145 oC. C20H32N2O2 (332.49) calculated C 72.25%, H 9.70%, N 8.43%; found 72.19% C, 9.54% H, 8.43% N.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:17]([CH2:18][CH2:19][CH3:20])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][CH2:29][C:30]4[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:31]=4[CH3:38])[CH:23]=3)[CH:14]=2)[N:9]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:18]([N:17]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][CH2:29][C:30]4[C:31]([CH3:38])=[CH:32][C:33]([CH3:37])=[CH:34][C:35]=4[CH3:36])[CH:23]=3)[CH:14]=2)[N:9]=[C:8]1[NH2:7])[CH2:19][CH3:20]
Reactant: CCCN1Cc2cc(Oc3cccc(NCc4c(C)cc(C)cc4C)c3)ccc2N=C1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN1Cc2cc(Oc3cccc(NCc4c(C)cc(C)cc4C)c3)ccc2N=C1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of {3-propyl-6-[3-(2,4,6-trimethyl-benzylamino)-phenoxy]-3,4-dihydro-quinazolin-2-yl}-carbamic acid tert-butyl ester (0.0001 mol) in 10% TFA in DCM (6 mL) was stirred in a reaction vial for 1 hour at room temperature and then the solvent was evaporated. The obtained residue was crystallized from CH3CN, and then the desired product was filtered off, washed with diisopropyl ether and dried under vaccum to yield the title compound as a solid.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)[CH:6]=[O:7].[BH4-].[Na+]>CO>[F:1][C:2]([F:22])([F:23])[C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=1
Reactant: O=Cc1ccc(Oc2cccc(C(F)(F)F)c2)c(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(Oc2cccc(C(F)(F)F)c2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.6 %

Procedure:
To a solution of 3-(trifluoromethyl)-4-{[3-(trifluoromethyl)phenyl]oxy}benzaldehyde (400 mg, 1.197 mmol) in methanol (10 mL) was added sodium borohydride (47.5 mg, 1.257 mmol) at 0° C. The mixture was stirred at room temperature for 15 min. The result mixture was quenched by acetone, concentrated, and purified via flash chromatography to afford the title compound (350 mg, 0.989 mmol, 83% yield).
Reaction SMILES: FC1C=CC=CC=1C(Cl)=O.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([N:20]=[C:21]=[S:22])=[O:19].[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][CH:29]=[C:28]2[O:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[C:40]([CH3:45])[CH:39]=1.C1(C)C=CC=CC=1>C(O)C>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([N:20]=[C:21]=[S:22])=[O:19].[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][CH:29]=[C:28]2[O:37][C:38]1[CH:44]=[CH:43][C:41]([NH:42][C:21]([NH:20][C:18](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[F:11])=[S:22])=[C:40]([CH3:45])[CH:39]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Agent: O=C(Cl)c1ccccc1F
Agent: O=C(N=C=S)c1ccccc1F
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4F)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
2-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2-Fluoro-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (41 mg, yield 52%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[CH:3]=1.C1C[O:13][CH2:12]C1.C([Li])CCC.CCCCCC.CN(C=O)C>CCOC(C)=O.O>[CH3:8][C:6]1[CH:7]=[C:2]([CH2:12][OH:13])[CH:3]=[C:4]([CH3:9])[N:5]=1
Reactant: C1CCOC1
Reactant: Cc1cc(Br)cc(C)n1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Cc1cc(CO)cc(C)n1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
4-Bromo-2,6-dimethylpyridine (2 g) was mixed with THF (30 ml) and cooled to −78° C. under argon atmosphere. A 1.65 M n-butyl lithium/hexane solution (8.5 ml) was added dropwise thereto, followed by stirring at −78° C. for 10 minutes, and DMF (1.3 ml) was added thereto. The reaction mixture was warmed to 0° C. over 1 hour, followed by stirring at 0° C. for 1 hour. Water and EtOAc were added to the reaction mixture, and the organic layer was dried over Na2SO4, and the reaction mixture was concentrated under reduced pressure. The obtained residue was mixed with MeOH (30 ml), and NaBH4 (610 mg) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and CHCl3 and water were added to the obtained residue. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain (2,6-dimethylpyridin-4-yl)methanol (457 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)(F)[CH2:4][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[OH:16]S(O)(=O)=O>>[Cl:1][C:2]1[C:3](=[O:16])[CH2:4][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1
Reactant: COc1ccc(C2=C(Cl)C(F)(F)C2)cc1
Reactant: O=S(=O)(O)O
Product: COc1ccc(C2=C(Cl)C(=O)C2)cc1
Reaction time: 0.33 h

Procedure:
2Chloro-1,1-difluoro-3-(p-methoxyphenyl)-2-cyclobutene (215 g., 0.93 mole) is poured gradually into 272 ml. of concentrated H2SO4 with stirring. The rate of addition is adjusted to maintain the reaction temperature below 40° C. When the reaction subsides, the cooling bath is removed, but stirring is continued for 20 min. The mixture is poured into 3 l. of water. A precipitate forms, and is collected on a filter, washed with water, and air-dried. recrystallization of this material twice from i-PrOH yields 128.8 g. (66%) of the desired intermediate, m.p. 96°-98° C. An analytical sample was prepared by chromatography an alumina (benzene) and recrystallized from heptane, m.p. 98-100° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:6](=[O:7])[O:5][CH:4]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([CH3:24])[CH2:13][C:14]([CH3:23])=[CH:15][C:16]([CH3:22])=[CH:17][C:18]([O:20][CH3:21])=[O:19].[H][H]>CCOC(C)=O.O=[Pt]=O>[OH:1][CH2:2][CH:3]1[C:6](=[O:7])[O:5][CH:4]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([CH3:24])[CH2:13][CH:14]([CH3:23])[CH2:15][C:16]([CH3:22])=[CH:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: [H][H]
Reactant: COC(=O)C=C(C)C=C(C)CC(C)CCCCC1OC(=O)C1CO
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: COC(=O)C=C(C)CC(C)CC(C)CCCCC1OC(=O)C1CO

Procedure:
49 mg (0.144 mmole) of Methyl 11-(3-hydroxymethyl-4-oxo-2-oxetanyl)-3,5,7-trimethyl-2,4-undecadienoate in 5 ml of EtOAc was added 3 mg of platinium oxide. This mixture was hydrogenated at room temperature and 1 atmosphere for 30 minutes (0.144 mmole (1 eq) of hydrogen was consumed). The solution was filtered and the filtrate was concentrated to dryness afforded methyl 11-(3-hydroxymethyl-4-oxo-2-oxetanyl)-3,5,7-trimethyl-2-undecenoate.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:23][C:24]#[N:25]>CN(C=O)C>[C:24]([CH2:23][N:7]1[C:8]2[C:4](=[C:3]([C:2]([F:14])([F:1])[F:15])[C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)#[N:25]
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#CCn1ccc2c(C(F)(F)F)c(C#N)ccc21
Temperature: 75 °C
Yield: 84.7 %

Procedure:
To 4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.210 g, 1.00 mmol) in DMF (20 mL), was added Cs2CO3 (0.489 g, 1.50 mmol) and bromoacetonitrile (0.180 g, 1.50 mmol). The reaction mixture was heated at 75° C. under an N2 atmosphere for 1 hr. Dilution with water was followed by extraction with Et2O. The combined organic portions were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification (SiO2, EtOAc/hexanes) afforded 0.211 g of the title compound: MS (ESI): m/z 250 (M+1).
Reaction SMILES: [C:1]1([C@@H:7]([NH:10][C:11]([CH2:13][C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=O)[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([C:13]1[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16](=[O:17])[O:18][C:11]=1[NH:10][C@H:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:8][CH3:9])(=[O:25])[CH3:24]
Reactant: CC[C@H](NC(=O)Cc1ccccc1C(=O)O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Product: CC[C@H](Nc1oc(=O)c2ccccc2c1C(C)=O)c1ccccc1

Procedure:
A mixture of 2-[((S)-1-phenyl-propylcarbamoyl)-methyl]benzoic acid (10 g), acetic anhydride (50 ml), and N,N-dimethylaminopyridine (100 mg) was heated at gentle reflux (Tmax=+124° C.) for 7 min and evaporated in vacuo at +50° C. to give the title compound as a yellow-brown solid (11.1 g, purity 98% by NMR). LC-MS (m/z) 322.3 (MH+); tR=1.72. 1H NMR (500 MHz, DMSO-d6): 0.89 (t, J=7.2 Hz, 3H), 1.86-1.97 (m, 2H), 2.56 (s, 3H), 4.95 (q, J=7.1 Hz, 1H, CH—NH), 7.26 (t, J=7.5 Hz, 1H), 7.29 (unres. m, 1H), 7.36-7.41 (unres m., 3H), 7.71 (t, J=7.5 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.98 (d, J=7.8 Hz, 1H), 11.53 (d, J=7.6 Hz, 1H, NH). 13C APT NMR (125 MHz, DMSO-d6, δ(DMSO-d6)=39.87 ppm): 10.68 (CH3), 30.0 (CH2), 31.57 (CH3), 57.01 (CH), 92.44 (C), 114.88 (C), 124.2 (CH), (CH), 124.26 (CH), 126.65 (CH), 127.8 (CH), 129.05 (CH), 129.93 (CH), 135.71 (CH), 138.68 (C), 141.86 (C), 158.51 (C), 160.55 (C), 194.82 (C, MeCO).
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:36])=[C:5]([C:27]([O:34]C)=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C(=O)([O-])O.[Na+]>C(#N)C.O>[CH3:31][O:30][C:29]1[C:3](=[O:2])[C:4]([CH3:36])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[C:11]([CH:20]=2)[C:12]([N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[O:13])[C:27](=[O:34])[C:28]=1[O:32][CH3:33]
Reactant: COc1c(C)c(Cc2ccc(-c3cccnc3)c(C(=O)N3CCCCC3)c2)c(OC)c(OC)c1OC
Agent: O=C([O-])O
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3cccnc3)c(C(=O)N3CCCCC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(3-pyridyl)benzoyl]piperidine (33 mg, 0.0673 mmol) was dissolved in a mixed solvent of acetonitrile (6 ml) and water (2 ml), then CAN (92 mg, 0.1678 mmol) was added thereto at room temperature and the mixture was stirred for 1 hour. The reaction solution was poured into water, neutralized with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer silica gel (methylene chloride:methanol=95:5) to give the title compound (20 mg, 0.0434 mmol, 64%).