Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7](=[O:9])[CH3:8])[S:5][CH:6]=1.C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:17][CH2:1][C:2]1[N:3]=[C:4]([C:7](=[O:9])[CH3:8])[S:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1nc(C)cs1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)c1nc(CBr)cs1
Temperature: 25 °C
Yield: 72.6 %

Procedure:
A solution of 2a (4.38 g, 0.031 mol), NBS (5.8 g, 0.033 mol) and 100 mg of AIBN in 40 mL of carbon tetrachloride was heated at 70° C. for 16 h. Cooled to rt and the precipitate was filtered. The solvent was concentrated in vacuo to an oil that was subjected to flash chromatography (5% ethyl acetate/95% hexanes) to give 4.95 g (72%) of the desired product 3a. 1H NMR (CDCl3) δ 7.8 (s, 1H), 4.8 (s, 2H), 2.8 (s, 3H).
Reaction SMILES: C([NH:8][CH2:9][CH:10]([C:15]#[N:16])[CH:11]([OH:14])[CH2:12][CH3:13])C1C=CC=CC=1.[H][H]>N.CO.[Ni]>[NH2:8][CH2:9][CH:10]([CH2:15][NH2:16])[CH:11]([OH:14])[CH2:12][CH3:13]
Reactant: CCC(O)C(C#N)CNCc1ccccc1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: CCC(O)C(CN)CN
Reaction time: 1 h
Yield: 150.3 %

Procedure:
To a solution of 1-benzylamino-2-cyano-3-hydroxypentane (1.0 g) in 5% ammonia-methanol solution (20 ml) was added Raney Nickel (W2, 5g). After stirring under atmospheric pressure of hydrogen at room temperature for 4 hours, the catalyst was filtered off and to the filtrate were added ammonium formate (1.4 g) and 10% palladium on carbon (1 g, 50% wet). After stirring for 1 hour under reflux, the catalyst was filtered off and the filtrate was evaporated to give 1-amino-2-aminomethyl-3-hydroxypentane (0.91 g).
Reaction SMILES: [C:1]([C:4]1[CH:20]=[CH:19][C:7]2[C:8](=[O:18])[C:9]3[CH:16]=[CH:15][CH:14]=[C:13](Br)[C:10]=3[CH2:11][CH2:12][C:6]=2[CH:5]=1)([OH:3])=[O:2].[ClH:21]>CN1CCCC1=O.O>[C:1]([C:4]1[CH:20]=[CH:19][C:7]2[C:8](=[O:18])[C:9]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:21])[C:10]=3[CH2:11][CH2:12][C:6]=2[CH:5]=1)([OH:3])=[O:2]
Reactant: Cl
Reactant: O=C(O)c1ccc2c(c1)CCc1c(Br)cccc1C2=O
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(O)c1ccc2c(c1)CCc1c(Cl)cccc1C2=O

Procedure:
0.81 G. of 2-carboxy-9-bromo-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene and 0.32 g. of cuprous chloride were refluxed for 8 hours in 10 ml of N-methylpyrrolidinone. The solution was cooled and added to a solution of 4.4 g. of ferric chloride hexahydrate in 6 ml of water and 3 ml of concentrated hydrochloric acid. The mixture was heated to 90° for 1 hour, then was poured into water and filtered. The residue was recrystallized from aqueous dimethylformamide to afford 2-carboxy-9-chloro-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene, m.p. 258.5°-260°.
Reaction SMILES: [CH3:1][C:2]1([OH:26])[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:10]=2)[NH:5][CH2:4][CH2:3]1.O=[CH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[OH:26][C:2]1([CH3:1])[C:11]2=[N:10][C:9]([C:12]3[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=3)=[C:8]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[N:7]=[C:6]2[N:5]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:4][CH2:3]1
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)C(C)(O)CCN3)cc1
Reactant: CCOC(=O)CCCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)CCCCCCN1CCC(C)(O)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 8-methyl-2,3-di-p-tolyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazin-8-ol (Intermediate G)(240 mg, 0.695 mmol) in DCE (10 ml) was added ethyl 7-oxoheptanoate (359 mg, 2.084 mmol) followed by sodium triacetoxyborohydride (442 mg, 2.084 mmol) and the resulting mixture was left to stir overnight at room temperature under an atmosphere of nitrogen. The reaction mixture was diluted with water and extracted with EtOAc (2×20 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give a brown oil. The oil was purified by chromatography on silica eluting with EtOAc in iso-hexane to afford ethyl 7-(8-hydroxy-8-methyl-2,3-di-p-tolyl-7,8-dihydropyrido[3,2-b]pyrazin-5(6H)-yl)heptanoate (Intermediate 15.1). This compound was passed through a 5 g Isolute® SCX-2 SPE cartridge (primed with MeOH—20 ml) and washing with MeOH (30 ml). The product was eluted with 2M NH3 in MeOH (20 ml). The basic eluent was concentrated under reduced pressure to afford a 1:2 mixture of ethyl 7-(8-hydroxy-8-methyl-2,3-di-p-tolyl-7,8-dihydropyrido[3,2-b]pyrazin-5(6H)-yl)heptanoate compound: ethyl 7-(8-methoxy-8-methyl-2,3-d i-p-tolyl-7,8-dihydropyrido[3,2-b]pyrazin-5(6H)-yl)heptanoate;
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@@:7]1([CH2:17][CH2:18][NH2:19])[CH2:16][C:11]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1.C(NCC[C@]1(C2C=CC(F)=CC=2)CC2(CCCC2)OCC1)C1C=CC=CC=1.Br[CH2:48][C:49]1[S:50][CH:51]=[CH:52][C:53]=1[CH2:54]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[S:50]1[C:49]2[CH2:48][N:19]([CH2:18][CH2:17][C@:7]3([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:16][C:11]4([CH2:15][CH2:14][CH2:13][CH2:12]4)[O:10][CH2:9][CH2:8]3)[CH2:54][C:53]=2[CH:52]=[CH:51]1
Reactant: BrCc1ccsc1CBr
Reactant: NCC[C@@]1(c2ccccn2)CCOC2(CCCC2)C1
Agent: Fc1ccc([C@]2(CCNCc3ccccc3)CCOC3(CCCC3)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc([C@]2(CCN3Cc4ccsc4C3)CCOC3(CCCC3)C2)nc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethan-1-amine (0.030 g, 0.115 mmol; prepared by following a sequence described for Compound 81 in dried ACN (5.8 mL) was added 2,3-bis(bromomethyl)thiophene (31.1 mg, 0.115 mmol) followed by addition of K2CO3 (79.62 mg, 0.576 mmol). After 30 min, LCMS showed that the reaction was done and the major peak had the corresponding mass to the desired product. It was then subjected to HPLC purification. HPLC purification method: Luna acid medium column, 10-50% acetonitrile in H2O over 15 min, followed by flashing with 100% acetonitrile, 0.1% TFA modifier was employed. The fractions containing the desired product were pooled, basified with 2N NaOH and extracted with DCM (3×20 mL). The combined organics were concentrated and purified with flash chromatography (10 g silica gel column, eluted by 0-10% MeOH in DCM, based upon TLC measurement: DCM/MeOH (10/1) Rf=0.60) to afford 5 mg of 2-[(9R)-9-(2-{4H,5H,6H-thieno[2,3-c]pyrrol-5-yl}ethyl)-6-oxaspiro[4.5]decan-9-yl]pyridine as a colorless oil in 12% yield. LCMS m/z 369 (M+1) observed.
Reaction SMILES: [C:1]1([C:7]([NH:9][CH:10]2[CH2:15][NH:14][CH2:13][CH:12]([C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)[CH2:11]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:27]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(N(CC)CC)C.O>ClCCl>[N:27]1([C:33]([N:14]2[CH2:15][CH:10]([NH:9][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:8])[CH2:11][CH:12]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=3)[CH2:13]2)=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: CCOC(=O)c1ccc(C2CNCC(NC(=O)c3ccccc3)C2)cc1
Reactant: O=C(Cl)N1CCOCC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C2CC(NC(=O)c3ccccc3)CN(C(=O)N3CCOCC3)C2)cc1
Temperature: 25 °C

Procedure:
At 0° C., 500 mg (1.42 mmol) of ethyl 4-{5-[(phenylcarbonyl)amino]piperidin-3-yl}benzoate were initially charged in 8 ml of dichloromethane, and 424 mg (2.84 mmol) of morpholine-4-carbonyl chloride and 300 μl (2.13 mmol) of triethylamine were added. The mixture was slowly warmed to RT overnight. Water was added, and the reaction mixture was extracted. The organic phase was dried over magnesium sulphate and concentrated under reduced pressure. The residue was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 551 mg (83% of theory)
Reaction SMILES: [CH2:1]([CH:8]1[O:12][C:11](=[O:13])[CH:10]=[C:9]1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[C:27]2[CH2:33][CH2:34][NH:35][C:36](=[O:38])[CH3:37]>>[CH2:1]([CH:8]1[O:12][C:11](=[O:13])[C:10]([CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:28]2[NH:29][C:30]3[C:26]([C:27]=2[CH2:33][CH2:34][NH:35][C:36](=[O:38])[CH3:37])=[CH:25][C:24]([F:23])=[CH:32][CH:31]=3)=[C:9]1[OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)NCCc1c[nH]c2ccc(F)cc12
Reactant: O=Cc1ccccc1
Reactant: O=C1C=C(O)C(Cc2ccccc2)O1
Product: CC(=O)NCCc1c(C(C2=C(O)C(Cc3ccccc3)OC2=O)c2ccccc2)[nH]c2ccc(F)cc12

Procedure:
Using general procedure C, 5-benzyl-4-hydroxy-5H-furan-2-one (Lit. 13) was reacted with benzaldehyde and N-[2-(5-fluoro-1H-indol-3-yl)-ethyl]-acetamide (Lit. 5) to give the title compound as pale yellow solid. MS: 497.4 ([M−H]−).
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:23][F:24])[CH:8]=[CH:7][C:6]2[CH:9]=[C:10]([C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])[CH:11]=[CH:12][C:5]=2[O:4]1.ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)Cl>[O:33]1[CH:7]2[CH:8]1[C:3]([CH2:2][F:1])([CH2:23][F:24])[O:4][C:5]1[CH:12]=[CH:11][C:10]([C:13]([F:22])([F:21])[C:14]([F:19])([F:20])[C:15]([F:16])([F:17])[F:18])=[CH:9][C:6]=12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FCC1(CF)C=Cc2cc(C(F)(F)C(F)(F)C(F)(F)F)ccc2O1
Solvent: ClCCl
Product: FCC1(CF)Oc2ccc(C(F)(F)C(F)(F)C(F)(F)F)cc2C2OC21
Temperature: 25 °C
Reaction time: 27 h
Yield: 44.5 %

Procedure:
A mixture of 3.1 g of 2,2-bisfluoromethyl-6-heptafluoropropyl-2H-1-benzopyran, 4.20 g of m-chloroperbenzoic acid (70%) and 50 ml of methylene chloride was stirred at room temperature for 27 hours. After removal of the separated crystal by filtration, the filtrate was washed with saturated sodium hydrogen carbonate solution and saturated saline solution, and dried with sodium sulfate. The solvent was distilled off and the resultant residue was purified using silica gel column chromatography (developing solution, hexane:CH2Cl2 =5:1) to obtain 1.44 g of oily 3,4-epoxy-2,2-bisfluoromethyl-6-heptafluoropropyl-3,4-dihydro-2H-1-benzopyran represented by the following formula.
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](=[S:19])=[S:18].[OH-].[K+].Cl/[CH:23]=[CH:24]\Cl>CS(C)=O.O>[S:18]1[CH:24]=[CH:23][S:19][C:17]1=[C:11]([C:9](=[O:10])[NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Cl/C=C\Cl
Reactant: S=C=S
Reactant: CCOC(=O)CC(=O)NCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C(C(=O)NCc1ccccc1)=C1SC=CS1
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
Ethyl (N-benzylcarbamoyl)acetate (39.00 g) and carbon disulfide (14.03 g) are dissolved in dimethylsulfoxide (390 ml). A solution of potassium hydroxide (21.52 g) in water (39 ml) is added dropwise to the mixture at 20° to 40° C. The mixture is stirred at the same temperature for 30 minutes, and then cis-1,2-dichloroethylene (17.84 g) is added dropwise thereto. The mixture is stirred at 50° C. for 5 hours. Cis-1,2-dichloroethylene (3.24 g) is further added to the mixture 3 hours after the commencement of the reaction. After cooling, the mixture is poured into water, and the aqueous solution is extracted with ethyl acetate. The extract is washed with water, dried and then evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate=2:1), and then recrystallized from a mixture of n-hexane and ethyl acetate, whereby ethyl 2-(1,3-dithiol-2-ylidene)-2-(N-benzylcarbamoyl)acetate (33.77 g) is obtained as pale yellow prisms. Yield: 62.8%.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4](=[O:20])[CH2:5][C:6]([OH:19])([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1.N1C=CN=C1.Cl[Si:27]([CH3:30])([CH3:29])[CH3:28]>CN(C)C=O>[CH3:1][S:2][C:3]1[C:4](=[O:20])[CH2:5][C:6]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)([O:19][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:7]=1
Reactant: C[Si](C)(C)Cl
Reactant: CSC1=CC(O)(CCCCOc2ccccc2)CC1=O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CSC1=CC(CCCCOc2ccccc2)(O[Si](C)(C)C)CC1=O
Yield: 89 %

Procedure:
To a solution of 400 mg of 2-methylthio-4-hydroxy-4-(4-phenoxybutyl)-2-cyclopentenone obtained in Example 52 or Example 551 dissolved in 4 ml of dimethylformamide were added 279 mg of imidazole and 260 μl of chlorotrimethylsilane, under ice-cooling and stirring, and the mixture was stirred at 0° C. for 3 hours. The reaction mixture was extracted with an addition of water and hexane. The organic layer was washed with saturated aqueous sodium chloride, and the product dried over anhydrous sodium sulfate, filtered and concentrated, followed by silica gel column chromatography, to give 445 mg (yield 89%) of 2-methylthio-4-(4-phenoxybutyl)-4-trimethylsilyloxy-2-cyclopentenone.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[NH:11]1[C:15]2[CH:16]=[CH:17][C:18]([CH:20]=O)=[CH:19][C:14]=2[N:13]=[N:12]1.N1CCCCC1>CCO>[NH:11]1[C:15]2[CH:16]=[CH:17][C:18](/[CH:20]=[C:3]3/[C:2](=[O:10])[NH:1][C:9]4[C:4]/3=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:19][C:14]=2[N:13]=[N:12]1
Reactant: O=Cc1ccc2[nH]nnc2c1
Reactant: O=C1Cc2ccccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ccccc2/C1=C\c1ccc2[nH]nnc2c1
Temperature: 90 °C
Yield: 74.8 %

Procedure:
A scintillation vial was charged with indolin-2-one (101 mg, 0.760 mmol), 1H-benzo[d][1,2,3]triazole-5-carbaldehyde (123 mg, 0.836 mmol), piperidine (7.5 uL, 0.076 mmol) and EtOH (4 mL). The reaction was then heated to 90° C. for 2 hrs. A yellow precipitate formed which was further precipitated by cooling to room temperature and adding more EtOH (5 mL). The yellow solid was then filtered and washed with EtOH (20 mL) giving 149 mg, 75% of the title compound. 1H NMR (400 MHz, d6-DMSO) δ 15.94 (s, 1H), 10.65 (s, 1H), 8.27 (bs, 1H), 8.05 (bs, 1H), 7.80 (s, 1H), 7.77 (bs, 1H), 7.51 (d, J=7.6 Hz, 1H), 7.24 (t, J=7.6 Hz, 1H), 6.88 (d, J=7.6 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H); MS ESI 263.0 [M+H]+, calcd for [C15H10N4O+H]+ 263.09.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:30][C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1[CH:33]=[CH:34][NH:35]2>CC(N(C)C)=O>[NH:35]1[C:36]2[C:32](=[C:31]([O:30][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)[CH:39]=[CH:38][CH:37]=2)[CH:33]=[CH:34]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Reactant: Oc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3cccc4[nH]ccc34)ncnc2cc1OCCCN1CCCCC1
Temperature: 85 °C
Reaction time: 3 h
Yield: 50.9 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (200 mg, 0.595 mmol), (prepared as described for the starting material in Example 67), potassium carbonate (411 mg, 2.98 mmol) and 4-hydroxyindole (103 mg, 0.774 mmol) in DMA (2.0 ml) was stirred at 85° C. for 3 hours and allowed to cool to ambient temperature. The reaction mixture was filtered and the filtrate evaporated to give a solid residue. The residue was purified by silica column chromatography, with gradient elution using dichloromethane with 0%, 2%, 4%, 10% methanolic ammonia to give 4-(indol-4-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline (131 mg, 51%).
Reaction SMILES: [N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([CH3:5])=[CH:3][CH:2]=1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]>>[Br-:12].[C:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N+:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([CH3:5])=[CH:3][CH:2]=1)([OH:20])=[O:19]
Reactant: Cc1ccnc2ccccc12
Reactant: O=C(O)CCCCCBr
Product: Cc1cc[n+](CCCCCC(=O)O)c2ccccc12
Product: [Br-]
Temperature: 130 °C
Yield: 88.9 %

Procedure:
See FIG. 3B. A mixture of lepidine (5 g) and 6-bromohexanoic acid (10 g) was heated to 130° C. for 6 h. The solid was washed with acetone and filtered to provide an off-white solid (10.5 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19].O[CH2:23][C:24]1[CH:25]=[C:26]([CH2:30][CH2:31][CH2:32][OH:33])[CH:27]=[CH:28][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:23][C:24]2[CH:25]=[C:26]([CH2:30][CH2:31][CH2:32][OH:33])[CH:27]=[CH:28][CH:29]=2)=[CH:12][C:11]=1[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: OCCCc1cccc(CO)c1
Reactant: COc1ccc(F)c(-c2ccc(O)cc2CC(C)(C)C)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc(F)c(-c2ccc(OCc3cccc(CCCO)c3)cc2CC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 58.6 %

Procedure:
To a solution of 2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-ol (312 mg), 3-(3-(hydroxymethyl)phenyl)propan-1-ol (199 mg) and triphenylphosphine (522 mg) in THF (10 mL) was added a 40% solution of diethyl azodicarboxylate in toluene (790 μL) at 0° C., and the mixture was stirred at 0° C. for 5 min and at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (277 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[C:12]([CH2:17][CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13]>C1COCC1>[CH2:15]([O:14][C:12](=[O:13])/[C:17](/[CH3:18])=[CH:5]/[C:4]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([F:1])[CH:3]=1)[CH3:16]
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C=O)cc1F
Solvent: C1CCOC1
Product: CCOC(=O)/C(C)=C/c1ccc(OC)c(F)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
After 3-fluoro-4-methoxy-benzaldehyde (0.50 g, 3.24 mmol) was dissolved in anhydrous THF (10 mL), carbethoxyethylidene triphenylphosphorane (1.75 g, 4.86 mmol) was added thereto at 0° C., and the mixture was stirred at room temperature for 3 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure and purified by column chromatography (eluent, EtOAc/Hex=1/2) to obtain the title compound (0.768 g, 99%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]2C=CC=CC=2)=[CH:3][CH:2]=1.C1C=CC([O:19]C2C=CC=CC=2)=CC=1.[OH2:26]>>[C:7]([OH:19])(=[O:26])[C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: O
Reactant: c1ccc(-c2ccccc2)cc1
Product: O=C(O)c1ccccc1

Procedure:
The activity and selectivity of the catalyst in Example I for producing phenol from benzoic acid were measured in a fixed bed reactor. The reactorwas a jacketed 1'×1" dia. 316 stainless steel tube. Boiling Dowtherm was used in the jacket for temperature control. The feed was prepared by metering water through a heater at reactor pressure, passing the steam so produced through a benzoic acid saturator maintained at a temperature required to give the desired benzoic acid/water ratio, and then mixing thestream with the desired amount of air. The reactor contained 60 g of catalyst. Operating conditions and results are given in Table I.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14]>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C:10]([N:15]([CH2:16][CH3:17])[CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNCC
Reactant: O=C(Cl)COCc1ccccc1
Solvent: ClCCl
Product: CCN(CC)C(=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 0° C., 1.54 ml (9.7 mmol) of benzyloxyacetyl chloride and 0.92 ml (8.9 mmol) of diethylamine were dissolved in 35 ml of CH2Cl2. The reaction mixture was stirred at room temperature (RT) for 2 hours and then washed with dilute HCl solution and saturated NaCl solution. The organic phase was dried over Na2SO4 and evaporated to dryness. 2-(Benzyloxy)-N,N-diethylacetamide was obtained as a colorless residue.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[CH2:14][C:15](=O)[CH2:16][CH2:17][CH3:18])[C:7]([O:9][CH3:10])=[O:8])([O-])=O.C(O)C.O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O1CCCC1>[CH2:16]([C:15]1[NH:1][C:4]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=2)[CH2:17][CH3:18]
Reactant: CCCC(=O)Cc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCCc1cc2ccc(C(=O)OC)cc2[nH]1
Yield: 58.5 %

Procedure:
To a solution of methyl 3-nitro-4-(2-oxopentyl)benzoate (114 mg) in a mixture of tetrahydrofuran (1.5 ml), ethanol (1.5 ml) and water (2.1 ml) was added sodium hydrosulfite (3.0 g), and the mixture was stirred under reflux for 30 minutes. The resulting mixture was evaporated in vacuo, and the residue was diluted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by thin layer chromatography with a mixture of hexane and ethyl acetate (2:1) to give methyl 2-propylindole-6-carboxylate (54.6 mg).
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[N:7]12[CH2:15][CH:11]([CH2:12][CH2:13][CH2:14]1)[C:10](=[O:16])[CH2:9][CH2:8]2>ClCCl.[I-].[Zn+2].[I-]>[NH2:6][CH2:5][C:10]1([OH:16])[CH:11]2[CH2:15][N:7]([CH2:14][CH2:13][CH2:12]2)[CH2:8][CH2:9]1
Reactant: C[Si](C)(C)C#N
Reactant: O=C1CCN2CCCC1C2
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Product: NCC1(O)CCN2CCCC1C2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Trimethylsilyl cyanide (3 ml) was added dropwise to a stirred solution of 1-azabicyclo[3.3.1]nonan-4-one (2.5 g) and zinc iodide (0.15 g) in dry dichloromethane (20 ml) and the resulting mixture was heated at reflux for 4 hours. The mixture was cooled and the solvent removed at reduced pressure; the residue was dissolved in dry tetrahydrofuran (20 ml) and cooled to 0° C. A solution of lithium aluminium hydride in tetrahydrofuran (18 ml of 1.0M soln) was then added and the resulting solution stirred overnight at room temperature. Water (0.7 ml), followed by 15% sodium hydroxide (aq) (0.7 ml) and water (2.1 ml) were then added and the precipitate removed by filtration. Evaporation of the filtrate yielded the title compound (2.2 g); δH (360 MHz, CDCl3) 1.2-1.3 (2H, m, CH2), 1.34 (1H, m, CHH), 1.41 (1H, m, CHH), 1.6 (2H, m, CH2), 1.7-1.74 (1H, m, CHH), 1.76-1.91 (2H, m, CH2), 2.11-2.16 (1H, m, CHH), 2.67-3.18 (8H, m); m/z 170 (M+).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]4=[O:28])=[CH:18][C:17]=3F)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[CH2:30]([CH2:32][NH2:33])[OH:31]>CS(C)=O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]4=[O:28])=[CH:18][C:17]=3[NH:33][CH2:32][CH2:30][OH:31])[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: O=C(NCc1cn(-c2ccc(-n3ccccc3=O)cc2F)cn1)c1ccc(Cl)s1
Solvent: CS(C)=O
Product: O=C(NCc1cn(-c2ccc(-n3ccccc3=O)cc2NCCO)cn1)c1ccc(Cl)s1

Procedure:
A solution of 5-chloro-N-((1-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide prepared in Example 11 (75 mg, 0.17 mmol) and ethanolamine (1.5 mL) in DMSO (1 mL) in a sealed tube was heated at 150° C. overnight. The mixture was purified by HPLC to give the title compound (13 mg). MS 470.0 and 472.0 (M+H, Cl pattern).