Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]=[O:11])=[C:7]([CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[C:6]=2[CH:18]=1.[CH:19]1([Mg]Br)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[Cl-].[NH4+].C[N+]1([O-])CCOCC1>O1CCCC1.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.C(#N)C>[CH:19]1([C:10]([C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:18][C:6]=3[C:7]=2[CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[O:11])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COCCOCc1c(C=O)oc2ccc(F)cc12
Reactant: Br[Mg]C1CCCCC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: C1CCOC1
Solvent: CC#N
Product: COCCOCc1c(C(=O)C2CCCCC2)oc2ccc(F)cc12
Reaction time: 2 h
Yield: 50 %

Procedure:
To a solution (20 mL) of 5-fluoro-3-[(2-methoxyethoxy)methyl]-1-benzofuran-2-carbaldehyde (1.33 g) synthesized above in tetrahydrofuran was added a 1.0M solution (7.91 mL) of cyclohexylmagnesium bromide in tetrahydrofuran at 0° C., and the mixture was stirred for 2 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-40% ethyl acetate/hexane) to give a pale-yellow oil. To a mixture of the obtained oil, 4-methylmorpholine N-oxide (933 mg) and acetonitrile (20 mL) was added tetrapropylammonium perruthenate (140 mg), and the mixture was stirred overnight at room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% ethyl acetate/hexane) to give the title object compound (881 mg, 50%) as a colorless oil.
Reaction SMILES: [CH:1](O)=O.C=O.C([BH3-])#N.[Na+].[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[N:21]=[C:20]([CH:22]3[NH:27][CH2:26][CH2:25][N:24]4[C:28]([C:31]5[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=5)=[N:29][N:30]=[C:23]34)[O:19][N:18]=2)[CH:14]=[CH:15][CH:16]=1>CO.O>[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[N:21]=[C:20]([CH:22]3[N:27]([CH3:1])[CH2:26][CH2:25][N:24]4[C:28]([C:31]5[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=5)=[N:29][N:30]=[C:23]34)[O:19][N:18]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: COc1ccc(-c2nnc3n2CCNC3c2nc(-c3cccc(Cl)c3)no2)cc1
Reactant: O=CO
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2nnc3n2CCN(C)C3c2nc(-c3cccc(Cl)c3)no2)cc1
Reaction time: 0.5 h
Yield: 77 %

Procedure:
Formic acid (0.1 mL), formaldehyde (37 wt. % solution in water, 0.1 mL) and sodium cyanoborohydride (1.0 M in THF, 0.1 mL) were added to a solution of 8-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-3-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (30 mg, 0.071 mmol) in methanol (0.8 mL) at room temperature. After stirring for 30 minutes, the reaction mixture was diluted with water and then extracted with chloroform (4 times), dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel; using 50% ethyl acetate in hexanes, ethyl acetate and 4% 2M ammonia in methanol in dichloromethane afforded the titled compound (23.8 mg, 77%). 1H NMR (CDCl3) δ (ppm): 8.04 (m, 1H), 7.93 (m, 1H), 7.68 (m, 2H), 7.42 (m, 2H), 7.03 (m, 2H), 4.37 (m,1H), 4.07 (m, 2H), 3.89 (m, 3H), 3.82 (m, 2H), 3.11 (m, 1H), 2.88 (m, 1H), 2.56 s, 3H).
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][CH2:8][NH:9][C:10](=[O:42])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]([C:26]2[CH:27]=[N:28][C:29]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=3)=[CH:30][CH:31]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:13][CH:12]=1)(C)(C)C.[OH-].[Na+].Cl>C1COCC1>[F:40][C:38]([F:39])([F:41])[C:35]1[CH:34]=[CH:33][C:32]([C:29]2[N:28]=[CH:27][C:26]([CH:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][O:17][C:14]3[CH:15]=[CH:16][C:11]([C:10]([NH:9][CH2:8][CH2:7][C:6]([OH:43])=[O:5])=[O:42])=[CH:12][CH:13]=3)=[CH:31][CH:30]=2)=[CH:37][CH:36]=1
Reactant: CCCCCCC(COc1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCC(COc1ccc(C(=O)NCCC(=O)O)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1

Procedure:
3-(4-{2-[6-(4-Trifluoromethyl-phenyl)-pyridin-3-yl]-octyloxy}-benzoylamino)-propionic acid tert-butyl ester (50 mg) is taken into THF (1.0 mL) and treated with NaOH (1.0 mL, 5.0 N), then refluxed under nitrogen. The reaction mixture is neutralized with HCl (1.0 mL, 5.0 N), extracted with ethyl ether, dried over sodium sulfate. Concentration gives the title compound. MS (ES): 541.19 [M+H]−, the structure is also confirmed by proton NMR.
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[C:52]([F:53])=[CH:51][C:35]3[N:36]=[C:37]([C:39]4[C:43]([NH2:44])=[CH:42][N:41]([CH:45]5[CH2:50][CH2:49][CH2:48][CH2:47][O:46]5)[N:40]=4)[NH:38][C:34]=3[CH:33]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(=O)(O)[O-].[Na+]>C1COCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[C:52]([F:53])=[CH:51][C:35]3[N:36]=[C:37]([C:39]4[C:43]([NH:44][C:7]([N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)=[O:8])=[CH:42][N:41]([CH:45]5[CH2:50][CH2:49][CH2:48][CH2:47][O:46]5)[N:40]=4)[NH:38][C:34]=3[CH:33]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3[nH]c(-c4nn(C5CCCCO5)cc4N)nc3cc2F)CC1
Reactant: O=C(Cl)N1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2cc3[nH]c(-c4nn(C5CCCCO5)cc4NC(=O)N4CCCCC4)nc3cc2F)CC1
Temperature: 80 °C

Procedure:
1.2 mL of 1-piperidinecarbonyl chloride and 1.7 mL of N,N-diisopropylethylamine are added to a solution of 480 mg of 4-{2-[4-amino-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-6-fluoro-3H-benzimidazol-5-yl}piperazine-1-carboxylic acid tert-butyl ester in 10 mL of THF. The reaction mixture is heated at 80° C. for 16 hours. The reaction medium is cooled to ambient temperature and 20 mL of a saturated solution of sodium bicarbonate are added. The aqueous phases are extracted with 3 times 10 mL of EtOAc. The organic phases are dried over MgSO4, filtered and concentrated under vacuum in a rotary evaporator. The reaction crude is purified by flash chromatography, elution being carried out with a mixture of cyclohexane/ethyl acetate. 350 mg of 4-{6-fluoro-2-[4-[(piperidine-1-carbonyl)amino]-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-3H-benzimidazol-5-yl}piperazine-1-carboxylic acid tert-butyl ester are obtained in the form of a brown foam. 1H NMR (400 MHz, DMSO-d6, δ in ppm): from 1.37 to 2.22 (m, 12H); 1.42 (s, 9H); 3.04 (m, 4H); 3.44 (m, 4H); 3.53 (m, 4H); 3.67 (m, 1H); 3.96 (m, 1H); 5.52 (dd, J=2.0 and 10.0 Hz, 1H); 7.29 (d, J=7.5 Hz, 1H); 7.56 (d, J=11.5 Hz, 1H); 8.15 (s, 1H). ES mass spectrum: m/z=597 MH+ (base peak).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]1[CH:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:6]=[C:5]([NH:17][C:18](=O)[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:27][N:2]([CH3:1])[C:3]1[CH:8]=[C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:6]=[C:5]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:4]=1
Reactant: Cc1ccc(Nc2cc(N(C)C)nc(NC(=O)Cc3ccccc3)n2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(Nc2cc(N(C)C)nc(NCCc3ccccc3)n2)cc1

Procedure:
A mixture of N-[4-(dimethylamino)-6-(4-toluidino)-2-pyrimidinyl]-2-phenylacetamide (60 mg, 0.166 mmol), and LAH (1 mL, 1M in THF) in THF (10 mL) was refluxed for 3 h.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].B.[Na].C(O)C>O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:13]2[CH:14]=[CH:15][C:16]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:17][CH:18]=2)[OH:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2nccc(Oc3ccc(C(=O)c4ccc(C(C)(C)C)cc4)cc3)c2cc1OC
Agent: B
Agent: [Na]
Solvent: CCO
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C(O)c4ccc(C(C)(C)C)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
[4-(Tert-butyl)phenyl]{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-methanone (111 mg) and sodium boron hydride (76 mg) were added to ethanol (15 ml), and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. Chloroform was removed by evaporation under the reduced pressure to give a crude which was then purified by thin-layer chromatography on silica gel using chloroform/ethyl acetate for development to give (4-tert-butylphenyl)-[4-(6,7-dimethoxy-4-quinolyloxy)phenyl]methanol (108 mg, yield 97%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=O.[ClH:8].[NH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH:19][C:20]([C:22]3[C:23]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=4)=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=3)=[O:21])[CH:16]=2)[CH2:11]1.C(N(CC)CC)C.[BH4-]>CO>[ClH:8].[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[CH2:6][NH:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH:19][C:20]([C:22]3[C:23]([C:29]4[CH:30]=[CH:31][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:34]=4)=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=3)=[O:21])[CH:16]=2)[CH2:11]1
Reactant: O=Cc1ncc[nH]1
Reactant: Cc1cccc(C(=O)Nc2ccc3c(c2)CC(N)C3)c1-c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [BH4-]
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cccc(C(=O)Nc2ccc3c(c2)CC(NCc2ncc[nH]2)C3)c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Imidazole-2-carboxaldehyde (2.45 g, 25.5 mmol) is added to a solution of 6-methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid (2-amino-indan-5-yl)-amide hydrochloride (11.1 g, 24.9 mmol) and triethylamine (5.05 mL, 50.0 mmol) in methanol (500 mL). The mixture is stirred at room temperature for 16 hours. Polymer supported borohydride (Aldrich, borohydride on Ambelite IR-400, 2.5 mmol/g, 10.0 g, 25.0 mmol) is added, the mixture stirred for 2 hours, filtered and concentrated under reduced pressure. The residue is taken up in ethanol (100 mL) and a saturated solution of hydrochloric acid gas in diethyl ether (10 mL) is added. The white precipitate is collected to yield 6-methyl-4′-trifluoromethylbiphenyl-2-carboxylic acid [2-(2-imidazolylmethylamino)-indan-5-yl] amide hydrochloride m.p. 240-242° C. Free base has m.p. 169-170° C.
Reaction SMILES: Cl[C:2]1[C:3]([C:11]#[N:12])=[CH:4][C:5]([S:8][CH2:9][CH3:10])=[N:6][CH:7]=1.[Cl:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=1[Cl:20].CC([O-])(C)C.[K+]>C1COCC1.CS(C)=O>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:21][C:2]1[C:3]([C:11]#[N:12])=[CH:4][C:5]([S:8][CH2:9][CH3:10])=[N:6][CH:7]=1
Reactant: CCSc1cc(C#N)c(Cl)cn1
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCSc1cc(C#N)c(Oc2ccc(Cl)c(Cl)c2)cn1
Yield: 36.2 %

Procedure:
5-Chloro-2-ethylthio-4-pyridinecarbonitrile (5.4 g) was mixed with 5.4 g of 3,4-dichlorophenol in the presence of 3.7 g of t-BuOK in 30 ml of THF and 30 ml of DMSO. The mixture was heated at boiling temperature for about 70 hours to give 3.2 g (36%) of the desired 5-(3,4-dichlorophenoxy)-2-ethylthio-4-pyridinecarbonitrile, m.p. 79°-81° C.
Reaction SMILES: [F:1][C:2]1[C:8]([Cl:9])=[C:7]([O:10][CH:11]([CH3:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[C:6]([Cl:20])=[CH:5][C:3]=1[NH2:4].[F:21][C:22]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:23]=1[C:24]([N:26]=[C:27]=[O:28])=[O:25]>ClCCCl>[F:21][C:22]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:23]=1[C:24]([NH:26][C:27]([NH:4][C:3]1[CH:5]=[C:6]([Cl:20])[C:7]([O:10][CH:11]([CH3:19])[C:12]([F:18])([F:17])[C:13]([F:15])([F:16])[F:14])=[C:8]([Cl:9])[C:2]=1[F:1])=[O:28])=[O:25]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: CC(Oc1c(Cl)cc(N)c(F)c1Cl)C(F)(F)C(F)(F)F
Solvent: ClCCCl
Product: CC(Oc1c(Cl)cc(NC(=O)NC(=O)c2c(F)cccc2F)c(F)c1Cl)C(F)(F)C(F)(F)F
Reaction time: 8 h
Yield: 39.1 %

Procedure:
200 mg of 2-Fluoro-3,5-dichloro-4-(1-methyl-2,2,3,3,3-pentafluoropropoxy)aniline was stirred in 15 mL 1,2-dichloroethane as 118 mg 2,6-difluorobenzoyl isocyanate in 5 mL 1,2-dichloroethane was added. The mixture was heated under reflux for 30 minutes before lowering heat and stirring overnight. The mixture was then concentrated to half volume and chilled to give 120 mg of 1-(2,6-Difluorobenzoyl)-3-[2-fluoro-3,5-dichloro-4-(1-methyl-2,2,3,3,3-pentafluoropropoxy)phenyl]urea as a white solid. 1H NMR: 10.60 (s, 1H), 9.46 (s, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.54 (m, 1H), 7.08 (t, J=8.7 Hz, 2H), 5.11 (m, 1H), 1.43 (d, J=6.7 Hz, 3H). MS: 524 m/z. IR: 1699(s), 1469(s).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH2:19][C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.CN(C)CCCN=C=NCC.[C:35]([O:39][C:40](=[O:52])[N:41]([CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[NH2:51])[CH3:42])([CH3:38])([CH3:37])[CH3:36]>ClCCl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16](=[O:17])[NH:18][CH2:19][C:20](=[O:21])[NH:51][C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=3[CH2:44][CH2:43][N:41]([C:40]([O:39][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:52])[CH3:42])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CN(CCc1ccccc1N)C(=O)OC(C)(C)C
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CN(CCc1ccccc1NC(=O)CNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-(((9-Fluorenyl)methoxycarbonyl)amino)acetic acid (2.49 g, 2.79 mmol) was suspended in dichloromethane (40 ml). The suspension was cooled to 0° C. N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (802 mg, 4.19 mmol) was added. The reaction mixture was stirred for 30 min at 0° C. A solution of N-(2-(2-aminophenyl)ethyl)-N-methylcarbamic acid tert-butyl ester (698 mg, 2.79 mmol) in dichloromethane (15 ml) was added. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was diluted with dichloromethane (100 ml) and washed with brine (100 ml). The aqueous solution was extracted with dichloromethane (2×30 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (80 g), using ethyl acetatelheptane (1:1) as eluent, to give 1.412 9 of ({2-[2-(N-(tert-butoxycarbonyl)-N-methylamino)ethyl]phenylcarbamoyl}methyl)carbamic acid ((9-fluorenyl)methyl) ester.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[CH2:4][CH2:5][CH:6]1OCC[O:7]1.Cl.O>C1COCC1>[CH3:1][O:2][CH:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[CH2:4][CH2:5][CH:6]=[O:7]
Reactant: COC(CCC1OCCO1)c1ccccc1C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COC(CCC=O)c1ccccc1C
Reaction time: 12 h

Procedure:
To a solution of 2-(3-Methoxy-3-o-tolyl-propyl)-[1,3]dioxolane (285.0 mg, 1.2 mmol) in 14 mL THF was added 7 mL 1M aqueous HCl at room temperature. After stirring the mixture for 12 h, water was added and the solution extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (2×10 mL) and dried over Na2SO4. Evaporation of solvent provided the desired product as an oil which was used directly in the next experiment without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][CH:10]=2)[O:5]1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.5 g) and ethyl bromoacetate (0.91 mL) in DMF (10 mL) was added potassium carbonate (1.41 g), and the mixture was stirred at 80° C. for 5 hr. The reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.77 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([N:14]([CH2:22][C:23]2[C:31]3[O:30][CH:29]=[CH:28][C:27]=3[CH:26]=[C:25](Br)[CH:24]=2)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:9]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:44]1[CH:45]=[N:46][CH:47]=[N:48][CH:49]=1)CCC>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([N:14]([CH2:22][C:23]2[C:31]3[O:30][CH:29]=[CH:28][C:27]=3[CH:26]=[C:25]([C:44]3[CH:45]=[N:46][CH:47]=[N:48][CH:49]=3)[CH:24]=2)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:9]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncnc1
Reactant: CC(C)(C)OC(=O)N(Cc1cc(Br)cc2ccoc12)[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Product: CC(C)(C)OC(=O)N(Cc1cc(-c2cncnc2)cc2ccoc12)[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1

Procedure:
From cis-3-[(5-bromobenzofuran-7-ylmethyl)tert-butoxycarbonyl-amino]-2-phenyl-piperidine-1-carboxylic acid tert-butyl ester (600 mg) and 5-tributylstannanyl-pyrimidine (458 mg)
Reaction SMILES: [CH3:1][CH:2]([CH:4]1[C:8]2=[N:9][C:10]3[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:12][CH:13]=[CH:14][C:15]=3[C:16]([OH:17])=[C:7]2[C:6](=[N:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[O:5]1)[CH3:3].[C:29]([OH:32])(=[O:31])[CH3:30]>>[C:29]([O:32][CH:4]([C:8]1[C:7]([C:6]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[O:5])=[C:16]([OH:17])[C:15]2[C:10](=[C:11]([C:18]([F:21])([F:19])[F:20])[CH:12]=[CH:13][CH:14]=2)[N:9]=1)[CH:2]([CH3:3])[CH3:1])(=[O:31])[CH3:30]
Reactant: CC(=O)O
Reactant: CC(C)C1OC(=Nc2ccccn2)c2c1nc1c(C(F)(F)F)cccc1c2O
Product: CC(=O)OC(c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1ccccn1)C(C)C

Procedure:
Using the procedure of Example 23, 6 g of 1,3-dihydro-3-(1-methylethyl)-1-[(2-pyridinyl)-imino]-5-trifluoromethyl furo-[3,4-b]-quinolin-9-ol and 120 ml of acetic acid were reacted to obtain 3.5 g of 1-[4-hydroxy-3-[(2-pyridinyl)-aminocarbonyl]-8-trifluoromethyl-2-quinolinyl]-2-methylpropyl acetate melting at 230° C.
Reaction SMILES: [OH-].[Na+].N1CCC[C@H]1C(O)=O.I[C:12]1[CH:13]=[C:14]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:15]2[O:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]=2[CH:22]=1.[CH3:28][S:29]([O-:31])=[O:30]>CS(C)=O.[Cu]I.O>[CH3:20][C:18]1([CH3:21])[CH2:17][C:16]2[CH:22]=[C:12]([S:29]([CH3:28])(=[O:31])=[O:30])[CH:13]=[C:14]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:15]=2[O:19]1
Reactant: CS(=O)[O-]
Reactant: CCOC(=O)c1cc(I)cc2c1OC(C)(C)C2
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cc(S(C)(=O)=O)cc2c1OC(C)(C)C2
Reaction time: 0.5 h
Yield: 43.5 %

Procedure:
Sodium hydroxide (11.5 mg, 0.288 mmol) was added to a solution of L-proline (33.1 mg, 0.288 mmol) in DMSO (3 mL) and stirred for 30 minutes. To this solution was added ethyl 5-iodo-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylate (829) (500 mg, 1.44 mmol), methane sulfinate (176.6 mg, 1.73 mmol), and copper (I) iodide (27.4 mg, 0.144 mmol) and the reaction was stirred for 18 hours at 80° C. Water (20 mL) was added and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over sodium sulfate, filtered, concentrated in vacuo, and purified by silica gel chromatography (eluting with 0-60% ethyl acetate in hexane) to provide ethyl 2,2-dimethyl-5-(methylsulfonyl)-2,3-dihydrobenzofuran-7-carboxylate (830) (186.9 mg, 44%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][N:12]=1.ClC1C=CC(C(NC2C=CC(I)=C(C)C=2)=O)=CN=1>>[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:16])=[CH:13][N:12]=1
Reactant: COc1cccc(N)c1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: Cc1cc(NC(=O)c2ccc(Cl)nc2)ccc1I
Product: COc1cccc(NC(=O)c2ccc(Cl)nc2)c1

Procedure:
6-Chloro-N-(3-methoxy-phenyl)-nicotinamide was prepared from 3-methoxyaniline and 6-chloronicotinoyl chloride following a procedure similar to the one described in the synthesis of 6-chloro-N-(4-iodo-3-methyl-phenyl)-nicotinamide, above. The product was isolated after precipitation out of small volume of CH2Cl2 with hexanes. HRMS m/z calcd for C13H11N2OCl [M+H]+: 263.0582. Found: 263.0581.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][P:13](=[O:18])([O:16][CH3:17])[O:14][CH3:15].[CH3:19][CH2:20][CH2:21][O:22][CH2:23][C:24]([C:27](OC)=[O:28])([CH3:26])[CH3:25]>C1COCC1.C(OCC)(=O)C.C1CCCCC1.O.C(O)(=O)C>[CH3:25][C:24]([CH3:26])([CH2:23][O:22][CH2:21][CH2:20][CH3:19])[C:27](=[O:28])[CH2:12][P:13](=[O:18])([O:16][CH3:17])[O:14][CH3:15]
Reactant: CCCOCC(C)(C)C(=O)OC
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: O
Solvent: CC(=O)O
Product: CCCOCC(C)(C)C(=O)CP(=O)(OC)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
n-Butyl lithium in hexane (1.59N, 63.3 ml, 0.1 mol) was added dropwise under argon atmosphere with stirring to a solution of dimethyl methylphosphonate (12.4 g, 0.1 mol) in anhydrous THF (80 ml) at -78° C., and stirred for 30 min. To the reaction mixture was added dropwise a solution of methyl 2,2-dimethyl-4-oxaheptylate (7.0 g, 0.04 mol) in anhydrous THF (10 ml). The mixture was stirred for 30 min. and allowed to warm to 0° C. To the resulting mixture were added acetic acid (6.2 ml) and water (10 ml), and the mixture was concentrated. Water (20 ml) was added to the residue and the mixture was extracted with ethyl acetate (50 ml×2). The ethyl acetate layers were washed with water (20 ml) and with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated to afford the residue. Column chromatography (silica gel; 200 g, ethyl acetate/cyclohexane: 2/1) of the residue gave a colourless and transparent oil of dimethyl 3,3-dimethyl-2-oxo-5-oxaoctylphosphonate (6.15 g, 0.023 mol, yield: 57.5%). The product was assigned the structure by the following data.
Reaction SMILES: [CH:1](=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]1[CH2:16][CH:15]=[C:14]([CH2:17][C:18]#[N:19])[CH2:13][CH2:12]1.[OH-].[Na+]>C(O)C>[C:14]1([C:17](=[CH:1][CH:2]=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:18]#[N:19])[CH2:13][CH2:12][CH2:11][CH2:16][CH:15]=1
Reactant: O=CC=Cc1ccccc1
Reactant: N#CCC1=CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#CC(=CC=Cc1ccccc1)C1=CCCCC1

Procedure:
In a 50 ml 3-necked round bottom flask equipped with a nitrogen inlet, condensor and magnetic stir bar is placed cinnamaldehyde (2.64 g, 0.02 mol), 1-cyclohexenylacetonitrile (2.42 g, 0.02 mol) and sodium hydroxide (0.2 g, 0.005 mol) in absolute ethanol (25 ml). The reaction is stirred at room temperature until completion, during which time the crude product precipitates from solution. The precipitate is filtered, washed with water and dried. Recrystallization from ethanol yields a yellowish solid with maximum absorption at 338 nm and extinction coefficient of 45,825.