Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]([CH3:25])[C:8](=[O:24])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([CH2:22]O)=[N:11][CH:10]=1.ClCCl.[H-].[Na+].[CH3:40][C:41]1[NH:42][CH:43]=[CH:44][N:45]=1>CN(C)C=O>[F:1][C:2]([F:33])([F:34])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:31])([F:30])[F:32])[CH:28]=1)[CH2:6][N:7]([CH3:25])[C:8](=[O:24])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([CH2:22][N:42]2[CH:43]=[CH:44][N:45]=[C:41]2[CH3:40])=[N:11][CH:10]=1
Reactant: Cc1ncc[nH]1
Reactant: Cc1ccccc1-c1cc(CO)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccccc1-c1cc(Cn2ccnc2C)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To a solution of 100 mg (0.207 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-hydroxymethyl-N-methyl-4-o-tolyl-nicotinamide (Example 7) in 1 ml dichloromethane 0.03 ml (0.4 mmol) thionyl chloride were added at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The solvent was evaporated and the light yellow residue was dried in high vacuo. The residue was dissolved in 1 ml dry N,N-dimethylformamide and added to a suspension of 2-methylimidazole sodium salt that had previously been prepared by addition of 54 mg (1.2 mmol) sodium hydride (55% dispersion in mineral oil) to a solution of 52 mg (0.62 mmol) 2-methylimidazole in 3 ml dry N,N-dimethylformamide under argon at room temperature. After stirring for 3 h the reaction was quenched by addition of excess water, followed by extraction with three portions of ethyl acetate. The combined organic extracts were dried with sodium sulfate and concentrated. Column chromatography afforded 52 mg (46%) of the title compound as an orange solid.
Reaction SMILES: O.O.[OH-].C[N+](C)(C)C.[C:9]([NH2:17])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[N+:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([O-:20])=[O:19]>C1(C)C(C)=CC=CC=1>[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([NH:17][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: NC(=O)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccccc1
Reaction time: 4 h

Procedure:
A solution of tetramethylammonium hydroxide dihydrate (TMA(H)·2H2O) (1.8 g, 14.0 mmole), benzamide (1.2 g., 9.9 mmole) and 10 ml of xylene was stirred under nitrogen at 70° C. Thewater and xylene was removed by vacuum distillation at 740 mmHg/70° C. Nitrobenzene (1.2 g., 9.7 mmole) was added dropwise and the solution was stirred for 4 hours under nitrogen after which time an aliquot was removed for HPLC analysis. 4'-Nitrobenzanilide, i.e., N-(4-nitrophenyl)benzamide, was produced in 98% yield based on benzamide. Azoxybenzene was also detected as a minor product in this reaction.
Reaction SMILES: [Br:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[C:24](=[O:29])N(OC)C)=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[C:24]([C:9]1[O:10][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[C:7]=2[CH:8]=1)=[O:29])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: Brc1cccc2occc12
Reactant: CON(C)C(=O)C1CCCCN1C(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)c1cc2c(Br)cccc2o1

Procedure:
The title compound (1.45 g) was prepared from 4-bromo-benzofuran (3.65 g, WO0109111) and (RS)-1-(tert-butyloxycarbonyl)-2-(N-methoxy-N-methylcarbamoyl)-piperidine, D1 (5.17 g) according to a procedure similar to that for Description 2.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[CH2:4][NH:5][CH3:6].C1C=CC=CC=1.[CH3:15][C:16]1[CH:32]=[CH:31][C:19]([O:20][CH:21]([C:23]2[S:27][C:26]([N:28]=[C:29]=[O:30])=[N:25][N:24]=2)[CH3:22])=[CH:18][CH:17]=1>C1C=CC=CC=1.CCCCCC>[CH3:15][C:16]1[CH:17]=[CH:18][C:19]([O:20][CH:21]([C:23]2[S:27][C:26]([NH:28][C:29](=[O:30])[N:5]([CH3:6])[CH2:4][CH:3]([O:7][CH3:8])[O:2][CH3:1])=[N:25][N:24]=2)[CH3:22])=[CH:31][CH:32]=1
Reactant: Cc1ccc(OC(C)c2nnc(N=C=O)s2)cc1
Reactant: CNCC(OC)OC
Solvent: c1ccccc1
Solvent: CCCCCC
Product: COC(CN(C)C(=O)Nc1nnc(C(C)Oc2ccc(C)cc2)s1)OC
Reaction time: 8 h

Procedure:
Methylaminoacetaldehyde dimethylacetal (1.8 grams, 0.015 mole) was added to a benzene solution containing 4.0 grams (0.015 mole) of the 5-[1-(4-methylphenoxy)ethyl]-1,3,4-thiadiazol-2-yl isocyanate dimer (prepared above). The resulting solution was refluxed for 20 minutes, topped on a roto-vac at 70° C. to form a viscous red-orange oil, which was redissolved in benzene-hexane mixture and left to stand overnight. Crystals formed which were removed by suction filtration, and dried in a vacuum oven at 70° C. to 3.2 grams of tan crystals of [5-[1-(4-methylphenoxy)ethyl]-1,3,4-thiadiazol-2-yl]-1-methyl-1-(2,2-dimethoxyethyl)urea, (melting point 94°-100° C.).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[CH2:10][N:11]([CH3:22])[C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)(C)(C)C.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:8][C@@H:9]([CH2:23][CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28]1)[CH2:10][N:11]([CH3:22])[C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CN(C[C@H](CC1CCCC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C[C@@H](N)CC1CCCC1)C(=O)OCc1ccccc1
Yield: 102.7 %

Procedure:
A solution of benzyl (S)-2-(t-butoxycarbonylamino)-3-cyclopentylpropylmethylcarbamate (550 mg) in TFA/CH2Cl2 (10 mL, 20% v/v) was stirred for 2 h at 5° C. The mixture was neutralized with sat'd aq NaHCO3 and extracted with CH2Cl2 (3×30 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4 and evaporated to give benzyl (S)-2-amino-3-cyclopentylpropylmethylcarbamate (420 mg) that was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24](O)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]([O:39][CH3:40])=[O:38])=[N:35][CH:36]=1.CN1C=CN=C1.CCN=C=NCCCN(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([C:37]([O:39][CH3:40])=[O:38])=[N:35][CH:36]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1ccc(N)cn1
Reactant: COc1ccc(Nc2nc(N3CCCC(C(=O)O)C3)nc3scnc23)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)C2CCCN(c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)C2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.2 %

Procedure:
To a solution of 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxylic acid (200 mg, 0.48 mmol) and methyl 5-aminopicolinate (73 mg, 0.48 mmol) in dichloromethane (30 mL) were added the solution of 1-methyl-1H-imidazole (158 mg, 1.92 mmol) and EDCI (368 mg, 1.92 mmol) in dichloromethane (10 mL), the reaction mixture was stirred at room temperature for 15 hours, the solvent was removed in vacuo and methanol (6 mL) was added and stirred for 30 minutes, the solid was collected by filtration and washed with methanol to afford methyl 5-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxamido)picolinate (230 mg, 87.1%) as an orange solid. LC-MS: 550 [M+H]+, tR=1.58 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH3:11].[CH2:12]([O:19][C@@H:20]1[C@@H:32]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@H:31]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:30]([CH2:49][O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[O:29][C@@H:21]1OC(=O)C(F)(F)F)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C(Cl)Cl>[CH2:12]([O:19][C@@H:20]1[C@@H:32]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@H:31]([O:41][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C@@H:30]([CH2:49][O:50][CH2:51][C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[O:29][C@H:21]1[C:6]1[CH:7]=[C:2]([Br:1])[C:3]([O:10][CH3:11])=[CH:4][C:5]=1[O:8][CH3:9])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccc(Br)c(OC)c1
Reactant: O=C(O[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1cc(OC)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Br
Reaction time: 0.17 h

Procedure:
1-bromo-2,4-dimethoxybenzene (9.1 ml) was added to a solution of 2,3,4,6-tetra-O-benzyl-1-O-(trifluoroacetyl)-α-D-glucopyranose (20.0 g) in methylene chloride (100 ml) and the mixture was stirred for 10 minutes. Boron trifluoride-diethyl ether complex (3.9 ml) was added to the reaction mixture and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-(5-bromo-2,4-dimethoxyphenyl)-D-glucitol (17.0 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][C:14](Br)=[CH:15][CH:16]=3)[N:11]([CH3:22])[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][NH:33][C:32](=[O:36])[CH:31]=2)=[C:26]([O:37][CH3:38])[CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][C:14]([N:33]4[CH:34]=[CH:35][C:30]([C:27]5[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][C:26]=5[O:37][CH3:38])=[CH:31][C:32]4=[O:36])=[CH:15][CH:16]=3)[N:11]([CH3:22])[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(Cl)ccc1-c1cc[nH]c(=O)c1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)C2
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: COc1cc(Cl)ccc1-c1ccn(-c2ccc3c4c(n(C)c3c2)CN(C(=O)OC(C)(C)C)CC4)c(=O)c1
Temperature: 130 °C
Reaction time: 0.25 h
Yield: 54.6 %

Procedure:
tert-Butyl-7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (0.19 g, 0.81 mmol), 4-(4-chloro-2-methoxyphenyl)pyridin-2(1H)-one (0.30 g, 0.81 mmol), Cs2CO3 (0.29 g, 0.89 mmol) were diluted with DMSO (3.3 mL), and argon was bubbled through the suspension for 10 min. 8-Hydroxyquinoline (59 mg, 0.41 mmol) and copper iodide (0.18 g, 0.97 mmol) were added, and the resulting suspension was placed under vacuum for 15 min. The system was flushed with argon, and the degassing/argon flushing process was repeated a total of three times. The reaction mixture was heated at 130° C. for 18 h and stirred under argon. The suspension was cooled. A solution of 20% NH4OH in MeOH (40 mL) was added, and the resulting mixture was stirred for 1 h. The mixture was diluted with CH2Cl2 and filtered through celite. The filtrate was washed with brine (2×50 mL), dried over Na2SO4, and concentrated under reduced pressure. Flash chromatography (40 g ISCO (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 3 column volumnes then increase to 50:50 over 10 column volumnes and hold for 10 column volumes) gave the title compound (0.23 g, 54%) as an olive-green film: 1H NMR (500 MHz, DMSO-d6) δ 7.65 (d, J=7.0 Hz, 1H), 7.54 (d, J=2.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.25 (d, J=1.5 Hz, 1H), 7.13 (dd, J=8.0, 1.5 Hz, 1H), 7.02 (dd, J=8.0, 1.5 Hz, 1H), 6.55 (d, J=2.0 Hz, 1H), 6.54 (dd, J=7.0, 1.5 Hz, 1H), 4.64 (s, 2H), 3.87 (s, 3H), 3.68-3.66 (m, 5H), 2.74-2.72 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:18]([C:27]([O:29][CH3:30])=[O:28])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Pd]>[C:1]1([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:18]([C:27]([O:29][CH3:30])=[O:28])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)[C@@H]1CC[C@H](c2ccc(/C=C/c3ccccc3)cc2)N1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]1CC[C@H](c2ccc(CCc3ccccc3)cc2)N1C(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 91.6 %

Procedure:
To a solution of 1-(1,1-dimethylethyl) 2-methyl (2S,5R)-5-{4-[(E)-2-phenylethenyl]phenyl}-1,2-pyrrolidinedicarboxylate (D79, 50 mg, 0.12 mmol) in methanol was added palladium (10 mg, 10 wt. % dry basis on activated carbon) and the mixture was stirred under hydrogen atmosphere (1 atm) for 4 h. A further addition of catalyst (20 mg) was required before the reaction was complete (as shown by HPLC). The catalyst was filtered off, the solvent removed under reduced pressure affording the title compound as a colourless oil (45 mg, 92%). Rt (HPLC): 7.04 min; MS: (ES/+) m/z: 432 [M+Na] C25H31NO4 requires 409.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([C@@H:21]4[CH2:26][CH2:25][C@H:24]([CH2:27][C:28]#[N:29])[CH2:23][CH2:22]4)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.C(O)(C(F)(F)F)=O.C(Cl)Cl.CO.[OH-].[NH4+]>>[N:12]1[C:11]2[NH:7][CH:8]=[CH:9][C:10]=2[C:15]([C:16]2[CH:17]=[N:18][N:19]([C@@H:21]3[CH2:22][CH2:23][C@H:24]([CH2:27][C:28]#[N:29])[CH2:25][CH2:26]3)[CH:20]=2)=[N:14][CH:13]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H]4CC[C@@H](CC#N)CC4)c3)ncnc21
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC[C@H]1CC[C@@H](n2cc(-c3ncnc4[nH]ccc34)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylacetonitrile (0.080 g, 0.00018 mol) and TFA (0.50 mL, 0.0065 mol) were added to DCM (3.00 mL, 0.0468 mol) and the mixture was stirred at 25° C. for 16 hours. The reaction was concentrated by roto-evaporation and the concentrate was dissolved in methanol (3.0 mL, 0.074 mol) and ammonium hydroxide (0.5 mL, 0.01 mol) was added This reaction was stirred at 25° C. for 6 hours at which time LCMS analysis showed no starting material present. The reaction was chromatographed on silica gel using 5% MeOH/EtOAc to give the product.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1([OH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1CCCCC1.[H][H].[H][H].C1(O)C=CC=CC=1.C1(=O)CCCCC1>[Pd].C1CCCCC1>[CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1([OH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [H][H]
Agent: [Pd]
Solvent: O=C1CCCCC1
Solvent: Oc1ccccc1
Solvent: C1CCCCC1
Product: OC1CCCCC1
Yield: 2 %

Procedure:
In the case of hydrogenating phenol through a phenol hydrogenation process of prior art, for example by using an alumina-supported palladium catalyst, and introducing a mixed solution of phenol and cyclohexane with a phenol/cyclohexane molar ratio of ½ at a phenol flow rate of 0.0135 mol/hr into a hydrogen gas stream (hydrogen/phenol molar ratio=5.4) and carrying out reaction at 230° C., at the start of the flow reaction 98% cyclohexanone and 2% cyclohexanol were produced at a phenol conversion ratio of 77%. However, with this method, there is a drawback that a drop in activity and hence a drop in the conversion ratio occurs due to carbonaceous matter accumulating on the catalyst, and hence the conversion ratio became 63% thirty minutes after the start of the reaction, 55% after 1 hour, 44% after 2 hours, and 42% after 8 hours. Moreover, with this method, experimental operation using only phenol was difficult, and hence the phenol had to be used with harmful cyclohexane as a solvent (N. Mahata and V. Vishwanathan, Journal of Catalysis, 196, 262-270 (2000)).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:16]([O:18]CC)=[O:17])[CH:6]([C:12]([F:15])([F:14])[F:13])[O:7]2.[OH-].[Li+].Cl>C1COCC1.CO.O>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:16]([OH:18])=[O:17])[CH:6]([C:12]([F:15])([F:14])[F:13])[O:7]2
Reactant: CCOC(=O)C1=Cc2c(F)cccc2OC1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C1=Cc2c(F)cccc2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 80104.6 %

Procedure:
To a solution of 290 mg (1.0 mmole) of ethyl 5-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate in 7 mLs of THF and 2 mL of methanol was added a solution of 85 mg of lithium hydroxide monohydate in 1.0 mL of water. The mixture was heated to reflux for 30 min and allowed to cool to rt. After stirring overnight, the mixture was treated with 75 mL of 1N HCl and extracted three times with diethyl ether. The combined extracts were washed with brine, dried and concd in vacuo to afford 210 g (80%) of a white solid: 1H NMR (d6-acetone/400 MHz) 5.86 (q, 1H, J=7.1 Hz), 6.88 (m, 2H), 7.44 (q, 1H, J=6.7 Hz), 7.93 (s, 1H); 19F NMR (d6-acetone/400 MHz) −120.9 (t, 1F, J=7.7 Hz), −79.4 (d, 3F, J=7.7 Hz); MS (ES+) 263 (M+l, 100); MS (ES−) 261 (M−1, 100); HRMS (ES−) m/z calcd for (C11H6F4O3) 261.0175, found 261.0193.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([OH:18])=O)=[CH:10][CH:9]=1.[CH3:19][N:20](C=O)C.CN>C(Cl)Cl.C1COCC1.O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([NH:20][CH3:19])=[O:18])=[CH:10][CH:9]=1
Reactant: CN(C)C=O
Reactant: O=C(O)CCc1ccc(Br)cc1
Agent: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)CCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
Add oxalyl chloride (1.75 mL, 2.54 g, 4 eq.) to a solution of 3-(4-bromo-phenyl)-propionic acid in methylene chloride (100 mL), which contains 0.1 mL DMF at 0° C. and allow the reaction mixture to warm to room temperature and stir 1 hour. Evaporate solvent and dissolve it in 10 mL THF. Add half of the THF solution to 20 mL of methylamine (2M) and stir another hour. Add water to the solution to dissolve solid and wash organic layer with 2N HCl, water and saturated aq. sodium chloride and dry it over MgSO4. Evaporate solvent to afford the title compound 500 mg, 41%. MS 246.0.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:9]2.[F:30][CH:31]([F:34])[CH2:32]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[F:30][CH:31]([F:34])[CH2:32][N:15]([S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)(=[O:17])=[O:18])[C:13]1[CH:14]=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:9]2
Reactant: OCC(F)F
Reactant: CCOC(=O)c1cc2cc(OCCOC)cc(NS(=O)(=O)c3ccccn3)c2[nH]1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cc(OCCOC)cc(N(CC(F)F)S(=O)(=O)c3ccccn3)c2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
To a mixture of ethyl 5-(2-methoxyethoxy)-7-[(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxylate (500 mg), 2,2-difluoroethanol (0.09 mL), tributylphosphine (0.59 mL) and toluene (30 mL) was added 1,1′-(azodicarbonyl)dipiperidine (600 mg), and the mixture was stirred at room temperature overnight. The insoluble substance was filtered off, and the filtrate was diluted with ethyl acetate and 1N aqueous hydrochloric acid solution. The organic layer was washed with aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography to give the title compound (211 mg, yield 37%) as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: [OH:1][CH:2]1[C:3](=[O:34])[NH:4][C:5]2[CH:6]=[C:7]([NH:29][C:30]([O:32][CH3:33])=[O:31])[CH:8]=[CH:9][C:10]=2[C:11]2[CH:28]=[C:15]([C@@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:17][CH:18]=[CH:19]1)[N:14]=[CH:13][CH:12]=2.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.O>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:33][O:32][C:30]([NH:29][C:7]1[CH:6]=[C:5]2[C:10]([C:11]3[CH:12]=[CH:13][N:14]=[C:15]([CH:28]=3)[C@@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[CH2:17][CH2:18][CH2:19][C:2](=[O:1])[C:3](=[O:34])[NH:4]2)=[CH:9][CH:8]=1)=[O:31]
Reactant: COC(=O)Nc1ccc2c(c1)NC(=O)C(O)C=CC[C@H](NC(=O)OC(C)(C)C)c1cc-2ccn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: COC(=O)Nc1ccc2c(c1)NC(=O)C(O)/C=C/C[C@H](NC(=O)OC(C)(C)C)c1cc-2ccn1
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Product: COC(=O)Nc1ccc2c(c1)NC(=O)C(=O)CCC[C@H](NC(=O)OC(C)(C)C)c1cc-2ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 123B (360 mg, 0.765 mmol) in DCM (7.5 mL) was added Dess-MartinPeriodinane (357 mg, 0.842 mmol) and stirred at rt. After 1 hr, the reaction mixture was diluted with a small amount of sat. NaHCO3 and some water was added. The reaction mixture was extracted with DCM (3×). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. This material was used in the next step without purification. MS (ESI) m/z: 487.2 (M+H2O+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([NH:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27])=[O:15])=[CH:6][CH:7]=1
Reactant: NCCOCCO
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(Cl)cc1
Product: COc1ccc(C(=O)NCCOCCO)cc1/C=C/c1ccc(Cl)cc1

Procedure:
The captioned compound was synthesized from 3-[(E)-2-(4-chlorophenyl)vinyl]-4-methoxy-benzoic acid and 2-(2-aminoethoxy)-ethanol in accordance with the same procedure as in the manufacturing method described in step C of Example 1-2-3.