Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][NH:10][C:11]([C@@H:13]2[CH2:21][C:16]3([O:20][CH2:19][CH2:18][O:17]3)[CH2:15][N:14]2[C:22](=[O:32])[C@@H:23]([NH:27][C:28](=[O:31])[O:29][CH3:30])[CH:24]([CH3:26])[CH3:25])=O)=[CH:4][CH:3]=1.O1CCOCC1.C([O-])(=O)C.[NH4+:44]>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:44][C:11]([C@@H:13]3[CH2:21][C:16]4([O:17][CH2:18][CH2:19][O:20]4)[CH2:15][N:14]3[C:22](=[O:32])[C@@H:23]([NH:27][C:28](=[O:31])[O:29][CH3:30])[CH:24]([CH3:26])[CH3:25])=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1C(=O)NCC(=O)c1ccc(Br)cc1)OCCO2)C(C)C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(Br)cc3)[nH]1)OCCO2)C(C)C
Temperature: 110 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
In a 5 mL seal tube, methyl (S)-1-((S)-8-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamate (75 mg, 142 μmol) was combined with 1,4-dioxane (2 ml) to give a light yellow solution. Ammonium acetate (110 mg, 1.42 mmol) was added and it was stirred at 110° C. overnight. It was cooled and diluted with EtOAc(10 ml), filtered and concentrated in vacuo to afford methyl (S)-1-((S)-8-(5-(4-bromophenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamate as a light brownish solid (70 mg, 96.8%). ESI-LRMS m/e calcd for C22H27BrN4O5 [M+] 507. found 508 [M+H+].
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[NH2:11][C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][C:13]=1[OH:21].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CC#N>[N+:18]([C:17]1[C:12]2[N:11]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:2][O:21][C:13]=2[CH:14]=[CH:15][CH:16]=1)([O-:20])=[O:19]
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc2c1N=C(c1ccccc1)CO2
Reaction time: 3 h
Yield: 100.8 %

Procedure:
The 2-bromoacetophenone (3.9 g, 19 mmol) [Aldrich, cat. #115835] was added portion wise to a stirred suspension of 2-amino-3-nitrophenol (2.5 g, 16 mmol) [Aldrich, cat. #297003] and K2CO3 (3.4 g, 24 mmol) in MeCN (100 mL) at room temperature. The reaction was monitored by LC/MS. After stirring for 3 h the reaction was complete and then EtOAc added and solution filtered to remove the solids and the organic layer was washed with water, 1 N HCl, brine, dried over MgSO4, filtered and concentrated to give 5-nitro-3-phenyl-2H-1,4-benzoxazine as a dark oil (4.1 g, 100%). LCMS calc. for C14H11N2O3 (M+H)+: m/z=255.3. found: 255.1.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:8]2[NH:9][C:10]3[C@:15]([CH2:18][C:19]([OH:21])=[O:20])([CH2:16][CH3:17])[O:14][CH2:13][CH2:12][C:11]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1.S(=O)(=O)(O)O.C(O)(=O)C>CO>[CH3:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]3[CH2:12][CH2:13][O:14][C:15]([CH2:18][C:19]([OH:21])=[O:20])([CH2:16][CH3:17])[C:10]=3[NH:9][C:8]=12
Reactant: CCc1cccc2c3c([nH]c12)[C@@](CC)(CC(=O)O)OCC3
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CO
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)O)OCC3
Temperature: 25 °C
Yield: 60 %

Procedure:
(R)-Etodolac (1.0 g) is dissolved in methanol (20 ml) and treated with concentrated sulphuric acid (0.06 equiv). The mixture is heated under reflux for 3 days then cooled to ambient temperature. The racemic ester is deposited as a white crystalline solid and collected by filtration (60% yield). The racemic ester is treated with aqueous sodium hydroxide to effect hydrolysis, then acidified with acetic acid to pH 4 to give racemic etodolac as an off-white micro-crystalline powder.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[N:16]=[C:15]3[N:17]([CH2:20][C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[CH:26][CH:25]=[CH:24]5)[N:18]=[N:19][C:14]3=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C1C=CC2N(O)N=[N:37]C=2C=1.CCN=C=NC[CH2:47][CH2:48][N:49]([CH3:51])[CH3:50].Cl.C(N(CC)CC)C>CN(C=O)C.O>[CH3:51][N:49]([CH3:50])[CH2:48][CH2:47][NH:37][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([C:11]2[N:16]=[C:15]3[N:17]([CH2:20][C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[CH:26][CH:25]=[CH:24]5)[N:18]=[N:19][C:14]3=[CH:13][CH:12]=2)=[CH:10][C:2]=1[F:1]
Reactant: On1nnc2ccccc21
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)CCNC(=O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1F
Reaction time: 0.08 h
Yield: 16.5 %

Procedure:
To a solution of example 13 (0.150 g, 0.375 mmol) in DMF (1.5 ml), HOBT (0.068 g, 0.454 mmol), EDC-HCl (0.180 g, 0.941 mmol) and triethylamine (0.15 ml, 1.09 mmol) were added and stirred for 5 min. 2-N,N-Dimethylethylamine (0.123 g, 1.39 mmol) was added at RT and the reaction mixture was stirred for 12 h. To the reaction mixture water was added and extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as a yellow solid (0.029 g, 17%). M.P.: 122-125° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.88 (d, J=2.8 Hz, 1H), 8.72 (d, J=8.7 Hz, 1H), 8.37 (d, J=8.3 Hz, 1H), 8.29 (br s, 1H), 8.23 (d, J=8.8 Hz, 1H), 8.18 (m, 2H), 8.04 (s, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.84 (m, 2H), 7.53 (dd, J=8.3, 4.1 Hz, 1H), 6.23 (s, 2H), 3.39 (m, 4H), 2.49 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]=[C:35]=[O:36])[CH:29]=1>>[ClH:27].[ClH:27].[Cl:27][C:28]1[CH:29]=[C:30]([NH:34][C:35]([NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:20]([CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][N:12]([C:8]4[CH:7]=[CH:6][CH:5]=[C:4]5[C:9]=4[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]5)[CH2:17][CH2:16]3)[CH:21]=2)=[O:36])[CH:31]=[CH:32][CH:33]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: O=C=Nc1cccc(Cl)c1
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)Nc5cccc(Cl)c5)c4)CC3)cccc2n1
Product: Cl
Yield: 52 %

Procedure:
The title compound was prepared in 52% yield according to the general procedure for the preparation of ureas (Method E) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 1-chloro-3-isocyanatobenzene.
Reaction SMILES: CS([Cl:5])(=O)=O.[N+:6]1([O-])[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.C(=O)(O)[O-].[Na+]>>[Cl:5][CH:14]1[C:15]2[N:6]=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:11][CH2:12][CH2:13]1
Reactant: CS(=O)(=O)Cl
Reactant: [O-][n+]1cccc2c1CCCC2
Agent: O=C([O-])O
Agent: [Na+]
Product: ClC1CCCc2cccnc21
Temperature: 20 °C

Procedure:
At ambient temperature, 3 ml of methane sulfonyl chloride were added slowly to 1.49 g of 5,6,7,8-tetrahydroquinoline-N-oxide with stirring under an insert atmosphere. The mixture was heated for 4 hours at 80° to 82° C., then cooled to 20° C. and poured into 20 ml of a saturated solution of sodium bicarbonate. Then, sodium bicarbonate was added until an alkaline pH was obtained and after extracting with methylene chloride, washing with water, drying the re-united organic solutions and distillation to dryness under reduced pressure, 1.53 g of 8-chloro-5,6,7,8-tetrahydroquinoline were obtained in the form of an oil.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:16]=[C:15]([CH3:17])[C:14]([O:18][CH3:19])=[C:13]2[C:5]=1[CH:6]1[CH:11]([C:12]2=[O:20])[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:21]I.O>CN(C)C=O>[CH3:3][C:4]1[CH:16]=[C:15]([CH3:17])[C:14]([O:18][CH3:19])=[C:13]2[C:5]=1[CH:6]1[C:11]([CH3:21])([C:12]2=[O:20])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COc1c(C)cc(C)c2c1C(=O)C1CCCCC21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C)cc(C)c2c1C(=O)C1(C)CCCCC21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3.42 Grams of 60% sodium hydride was gradually added to a solution prepared by dissolving 17.7 g of 5,7-dimethyl-8-methoxy-1,2,3,4,4a,9a-hexahydro-9-fluorenone in 100 ml of dimethylformamide under ice-cooling, followed by stirring at room temperature for 30 minutes. Then, 5.4 ml of methyl iodide was added thereto under ice-cooling, followed by stirring at room temperature for 1 hour. The reaction mixture was poured into 3 liters of water and extracted with chloroform. The organic layer was dried with magnesium sulfate and then the solvent was distilled off. The residue was purified by a silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:20) to obtain 9.6 g of 5,7,9a-trimethyl-8-methoxy-1,2,3,4,4a,9a-hexahydro-9fluorenone. fluorenone.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:25](OCC)(OCC)OCC>>[N:12]1([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[CH:25]1
Reactant: CCOC(OCC)OCC
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2ccccc12
Product: CC(C)(C)OC(=O)NCCCCn1cnc2cnc3ccccc3c21

Procedure:
Using the general method of Example 1 Part C, tert-butyl N-(4-[(3-aminoquinolin-4-yl)amino]butyl)carbamate (149 g, 0.451 mol) was reacted with triethyl orthoformate to provide crude product. This material was recrystallized from isopropyl alcohol to provide 84 g of tert-butyl N-[4-(1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate as a crystalline solid.
Reaction SMILES: CO.[C:3]([NH:10][C:11]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[N:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:28]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:28][N:12]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C:11]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[N:10][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)C(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A solution of anhydrous methanol (0.04 ml, 1.0 mmol), N-,N'-,N"-tri-Boc-guanidine (1.80 g, 5.0 mmol), and triphenylphoshine (393 mg, 1.5 mmol) in anhydrous THF (50 ml) is cooled to -5° C. under an atmosphere of argon. Diethylazodicarboxylate (DEAD, 0.22 ml, 1.5 mmol) is added dropwise at a rate such that the reaction mixture is completely colorless before addition of the next drop. After the addition is completed, the reaction mixture is refluxed for 15 h. The solution is then cooled to room temperature, and hexanes (50 ml) is added. A precipitate of excess N-,N'-,N"-tri-Boc-guanidine forms which is collected by filtration on a Buechner-funnel and washed with a mixture of THF/hexanes 1:1. The filtrate is concentrated under reduced pressure and the product (colorless oil, 182 mg, 49%) isolated by flash chromatography on silica gel (eluent: dichloromethane-ethyl ether 98:2): 1H NMR (360 MHz, DMSO-d6) δ 10.17 (s, 1H), 2.94 (s, 3H), 1.43-1.36 (27H); FAB-MS m/e (relative intensity) 396 (100, M+Na+)0.374 (91, M+H+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH:9]([CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.[H-].[Na+].[CH3:29]I>O1CCCC1>[CH3:29][O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH:9]([CH2:16][O:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: CI
Reactant: COc1ccc(COCC(Cn2ccnc2)OCCCCCCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCCCCCOC(COCc1ccc(OC)cc1)Cn1ccnc1
Reaction time: 1 h

Procedure:
1-[2-[(6-Hydroxyhexyl)oxy]-3-[(4-methoxyphenyl)methoxy]propyl]-1H-imidazole (Example 23) (0.3 g, 0.00086 mol) was added to a suspension of sodium hydride (0.006 g of an 80% dispersion in oil, 0.002 mol) in dry tetrahydrofuran (5 ml) at 25° C. and the resulting slurry stirred for 1 hour at this temperature. Methyl iodide (0.284 g, 0.002 mol) was then added and the resulting suspension stirred at 25° C. overnight. The suspension was then evaporated under reduced pressure and the residue poured into dilute hydrochloric acid (6N, 20 ml) and washed with ethyl acetate (2×5 ml), the aqueous phase was then basified with solid potassium carbonate and the liberated oil extracted into ethyl acetate (10 ml), the organic phase was then dried and evaporated under reduced pressure to give the product which was purified by column chromatography (silica gel, 10% methanol in ethyl acetate) to give the title compound as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11](OC)=[O:12])[CH:8]=[C:7]([F:15])[C:5]=2[N:6]=1.CC(C[Al]CC(C)C)C>C1(C)C=CC=CC=1.C1COCC1>[Br:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[C:7]([F:15])[C:5]=2[N:6]=1
Reactant: COC(=O)c1cc(F)c2nc(Br)sc2c1
Agent: CC(C)C[Al]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCc1cc(F)c2nc(Br)sc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.2 %

Procedure:
To a solution of methyl 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylate (0.335 g, 1.15 mmol) in toluene (10 mL) and THF (5 mL) was added Dibal-H (4.8 mL, 4.8 mmol) at −78° C. over 10 min. The resulting mixture was allowed to warm to rt and stirred at rt for 3 hr before it was poured into ice cold water (100 mL). The mixture was stirred at rt for 30 min and then filtered through Celite® 545. The organic layer was separated and the aqueous layer was extracted twice with AcOEt. The combined organic phase was dried over anhydrous MgSO4 and concentrated under vacuum. Evaporation of solvent under vacuum gave the title compound (0.269 g, 89% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[NH:14][CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31].P([O-])([O-])([O-])=O>CN(C=O)C.O>[CH3:1][C:2]1([CH3:18])[O:7][C:6]2[CH:8]=[CH:9][C:10]([CH:12]3[O:16][C:15](=[O:17])[N:14]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31])[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: OCCOCCCCCCBr
Reactant: CC1(C)OCc2cc([C@@H]3CNC(=O)O3)ccc2O1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc(C3CN(CCCCCCOCCO)C(=O)O3)ccc2O1
Reaction time: 0.25 h
Yield: 84.3 %

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (1.067 g) in DMF (10 ml) under nitrogen was treated with sodium hydride (60% dispersion in mineral oil, 222 mg) and the mixture was stirred at 20° for 15 min. A solution of 2-[(6-bromohexyl)oxy]ethanol (1.157 g) in DMF (1 ml) was added and the mixture was stirred at 20° for 3.5 h. Phosphate buffer solution (pH 6.5, 20 ml) and water (30 ml) were added. The mixture was extracted with EtOAc (2×20 ml) and the combined extracts were washed with water (30 ml) and dried (Na2SO4). Solvent evaporation in vacuo gave a residue which was purified by flash chromatography on silica gel. Elution with MeOH-EtOAc (1:9) gave the title compound (1.42 g). LCMS RT=2.90 min, ES+ve 394 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(CC#N)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-:14].[K+].Cl.[CH2:17]([OH:20])[CH2:18]O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:18][C:17]([OH:20])=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: [OH-]
Reactant: N#CCC1(c2ccc(Br)cc2)CC1
Agent: Cl
Agent: [K+]
Product: O=C(O)CC1(c2ccc(Br)cc2)CC1
Temperature: 180 °C
Reaction time: 8 h

Procedure:
[1-(4-Bromo-phenyl)-cyclopropyl]-acetonitrile (3.95 g, 16.73 mmol) and potassium hydroxide (3.75 g, 66.92 mmol) were combined in ethylene glycol (24 mL) and stirred at 180° C. overnight. The mixture was acidified with 6 N aqueous HCl and extracted three times with EtOAc. The combined organic layers were dried and concentrated to yield the title compound.
Reaction SMILES: [CH3:1][C:2]([CH2:13][CH2:14][CH2:15][CH:16]([CH3:28])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[OH:12].[H][H]>C(O)C.[Ni]>[CH3:1][CH:2]([CH2:13][CH2:14][CH2:15][CH:16]([CH3:28])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[OH:12]
Reactant: [H][H]
Reactant: CC(=CCc1ccc(O)cc1O)CCCC(C)CCCC(C)CCCC(C)C
Agent: [Ni]
Solvent: CCO
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCc1ccc(O)cc1O
Yield: 65 %

Procedure:
4-(3,7,11,15-Tetramethyl-2-hexadecenyl)-1,3-benzenediol (2.00 g: 5.14 mmole) was dissolved in ethanol (10 ml), a suspension of Raney's nickel W4 in ethanol (15 ml), was added thereto and then the mixture was reciprocatively shaken at 70° to 85° C. and a hydrogen pressure of 70 to 80 atm. for 2 days. After removing Raney's nickel by filtration, the filtrate was concentrated and the concentrate was chromatographed through a silica gel column. Thus, 1.30 g of the title compound was recovered from the fractions eluted with hexane-ethyl acetate (5:1). Yield=65%.
Reaction SMILES: [CH2:1]([NH:8][C:9](=O)[CH2:10][CH2:11][C:12]([CH3:17])([N+:14]([O-:16])=[O:15])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCCC1>[CH2:1]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:17])([N+:14]([O-:16])=[O:15])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(CCC(=O)NCc1ccccc1)[N+](=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(CCCNCc1ccccc1)[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
The N-benzyl-4-methyl-4-nitropentanoic acid amide (2.5 g) obtained above was dissolved in tetrahydrofuran (20 ml) and cooled to 0° C. 1 N Borane tetrahydrofuran complex (13 ml) was added dropwise thereto and then stirred overnight at room temperature. The reaction mixture was cooled again to 0° C., and 2 N hydrochloric acid (30 ml) was added thereto, followed by heating to 50° C. The reaction solution was extracted with ethyl acetate. The aqueous phase was alkalinized by 50% sodium hydroxide solution, extracted with chloroform. The extract was washed with a saturated saline solution, and dried over sodium sulfate anhydrous. The product was concentrated under reduced pressure to give benzyl-4-methyl-4-nitropentylamine (1.7 g, Y.: 73%) as a colorless oil.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:17][C:16]3[CH2:15][CH2:14][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12][C:11]=3[C:9]=2[CH:10]=1)(=[O:4])=[O:3].[CH3:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1>>[CH3:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]([S:2]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][C:16]4[CH2:15][CH2:14][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12][C:11]=4[C:9]=3[CH:10]=2)(=[O:4])=[O:3])[CH:27]=1
Reactant: Cc1c[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCc2oc3ccc(S(=O)(=O)Cl)cc3c2C1
Product: Cc1cn(S(=O)(=O)c2ccc3oc4c(c3c2)CN(C(=O)OC(C)(C)C)CC4)c2ccccc12
Yield: 32 %

Procedure:
The product of Example 41, step B was reacted with 3-methylindole following the procedure of Example 41, step C providing tert-butyl 8-(3-methyl-1H-indol-1-ylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (36 mg, 32%) as a clear oil: 1H NMR (CDCl3, 300 MHz) δ 8.02 (m, 2H), 7.74 (d, J=8.7 Hz, 1H), 7.42 (t, J=8.4 Hz, 2H), 7.34 (s, 1H), 7.30 (dd, J=8.4, 1.3 Hz, 1H), 7.21 (dt, J=3.7, 1.0 Hz, 1H), 4.53 (br s, 2H), 3.80 (br s, 2H), 2.84 (br s, 2H), 2.22 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: [OH-].[Na+:2].[CH3:3][C:4]1[N:8]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:13][CH:12]=2)[C:7]([C:29]2[CH:46]=[CH:45][C:32]([O:33][C@H:34]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:35]([OH:37])=[O:36])=[CH:31][CH:30]=2)=[CH:6][CH:5]=1>C(O)C>[CH3:3][C:4]1[N:8]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:15][CH:16]=2)[C:7]([C:29]2[CH:46]=[CH:45][C:32]([O:33][C@H:34]([CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)=[CH:6][CH:5]=1.[Na+:2]
Reactant: CCCCCCCCCCCOc1ccc(CCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCOc1ccc(CCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)[O-])cc2)cc1
Yield: 83.9 %

Procedure:
Ethanol (5 ml) and a solution of 1N sodium hydroxide in ethanol (0.724 ml) were added to (2R)-2-{4-[5-methyl-1-(4-undecyloxyphenethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoic acid (480 mg, 0.804 mmol) and the mixture was concentrated. To the residue was added hexane to give the object compound as a solid. 375 mg (yield: 83.9%)
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].Cl[C:13]1[N:18]([CH3:19])[C:17](=[O:20])[CH:16]=[C:15]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:14]=1.C(N(CC)CC)C.O>CN(C)C1C=CN=CC=1.CS(C)=O>[CH3:19][N:18]1[C:17](=[O:20])[CH:16]=[C:15]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:14]=[C:13]1[NH:2][CH2:3][C:4](=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Reactant: NCC(=O)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cn1c(NCC(=O)c2ccccc2)nc(-c2ccncc2)cc1=O
Yield: 57.9 %

Procedure:
A solution of 2-amino-1-phenyl-ethanone hydrochloride (1.03 g, 6.00 mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (0.665 g, 3.00 mmol), 4-dimethylaminopiridine (36.0 mg, 0.30 mmol) and triethylamine (0.80 ml, 6.00 mmol) in dimethylsulfoxide (15 ml) was stirred at room temperature. After stirring for several hours, water was added to the reaction mixture. The precipitate was filtered and washed with refluxing diethyl ether to give the title compound (0.556 g, 68%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][CH:8]([F:18])[C:9]1[C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]([CH3:17])[N:10]=1.Br[C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]1[C:30](=[C:31]([Cl:33])[Cl:32])[CH:25]2[CH2:24][CH2:23]1.CNCCNC>>[Cl:32][C:31]([Cl:33])=[C:30]1[CH:22]2[C:21]3[C:26]([CH:25]1[CH2:24][CH2:23]2)=[CH:27][CH:28]=[CH:29][C:20]=3[NH:16][C:14]([C:13]1[C:9]([CH:8]([F:7])[F:18])=[N:10][N:11]([CH3:17])[CH:12]=1)=[O:15]
Reactant: Cn1cc(C(N)=O)c(C(F)F)n1
Reactant: ClC(Cl)=C1C2CCC1c1c(Br)cccc12
Agent: CNCCNC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cn1cc(C(=O)Nc2cccc3c2C2CCC3C2=C(Cl)Cl)c(C(F)F)n1
Reaction time: 24 h

Procedure:
A 20 ml screw-cap vial was filled with the following solids: CuO (0.05 mmol, 4.0 mg), anhydrous CuCl2 (0.05 mmol, 6.7 mg), K2CO3 (2.0 mmol, 277 mg), 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid amide (1.1 mmol, 193 mg) and 5-bromo-9-dichloromethylene-1,2,3,4-tetrahydro-1,4-methano-naphthalene (1.0 mmol, 304 mg). A magnetic stir bar was added, and the open vial was gently flushed with N2. Dioxane (2 mL) was added, followed by N,N′-dimethylethylenediamine (0.45 mmol, 48 μl). The vial was sealed and placed into a preheated screening block at 130° C. Conversion was complete after 24 hours. The yield (HPLC-analysis) of the compound of formula I was 70%.