Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OCC[CH:4]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])(C)C)[CH:5]1[CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7][CH2:6]1.O1CCCC1.CC(C)([O-])C.[K+]>C(OCC)(=O)C>[O:9]1[C:8]2([CH2:7][CH2:6][CH:5]([CH:4]3[CH2:21][CH2:18][O:17][C:16](=[O:22])[NH:15]3)[CH2:14][CH2:13]2)[O:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC(CCO)C1CCC2(CC1)OCCO2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1NC(C2CCC3(CC2)OCCO3)CCO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
A 250 mL round bottom flask was charge with tert-butyl (3-hydroxy-1-(1,4-dioxaspiro[4.5]decan-8-yl)propyl)carbamate (2.11 g, 6.69 mmol) and tetrahydrofuran (134 mL). The mixture was cooled to 0° C. and potassium tert-butoxide (900 mg, 8.03 mmol) was added. The mixture was stirred at 0° C. for 2 h. The mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride. Dry organic layer with MgSO4, filter, and concentrate in vacuo to give 4-(1,4-dioxaspiro[4.5]decan-8-yl)-1,3-oxazinan-2-one (1.39 g, 5.76 mmol) as a clear oil.
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])C)CC1.[F:13][C:14]1[CH:21]=[C:20](F)[CH:19]=[C:18]([F:23])[C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[Li+].[Li+]>>[CH2:9]([C@H:5]1[C@:4]([OH:12])([CH3:1])[CH2:8][CH2:7][N:6]1[C:20]1[CH:21]=[C:14]([F:13])[C:15]([C:16]#[N:17])=[C:18]([F:23])[CH:19]=1)[CH3:11]
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Reactant: N#Cc1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@@H]1N(c2cc(F)c(C#N)c(F)c2)CC[C@]1(C)O

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2-ethyl-3-methylpyrrolidin-3-ol 0.5 oxalate (200 mg), 2,4,6-trifluorobenzonitrile (270 mg) and lithium carbonate (187 mg), the title compound was obtained as a colorless solid (yield: 187.5 mg, yield: 61%).
Reaction SMILES: C([Mg]Br)C.Br[C:6]1[N:10]2[N:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1.[N:16]1[CH:17]=[CH:18][N:19]2[CH:24]=[C:23]([CH:25]=[O:26])[CH:22]=[CH:21][C:20]=12>C1COCC1>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]2[N:10]([C:6]([CH:25]([C:23]3[CH:22]=[CH:21][C:20]4[N:19]([CH:18]=[CH:17][N:16]=4)[CH:24]=3)[OH:26])=[CH:7][N:8]=2)[N:11]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: O=Cc1ccc2nccn2c1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: OC(c1ccc2nccn2c1)c1cnc2ccc(Cl)nn12
Reaction time: 0.5 h

Procedure:
Ethyl magnesium bromide (3 M in Et2O, 333 μL, 1 mmol) was added to a solution of 3-bromo-6-chloro-imidazo[1,2-b]pyridazine (116 mg, 0.5 mmol) in THF (5 mL) at rt . The RM was stirred for 30 min and imidazo[1,2-a]pyridine-6-carbaldehyde (154 mg, 2 mmol) in THF (3 mL) was added dropwise. After 1 h the RM was extracted with a solution of NH4Cl and EtOAc. The combined organic phases were dried over Na2SO4, concentrated under reduced pressure, and purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, Hexane/EtOAc=95:5->0:100) to afford the title compound as a yellowish crystalline compound (tR 2.72 min (conditions 3), MH+=300.2).
Reaction SMILES: [CH2:1]([CH:3]([CH2:20][CH3:21])[CH:4]([C:10]1[CH:15]=[CH:14][C:13]([NH:16]C(=O)C)=[CH:12][CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)[CH3:2].[OH-].[Na+]>Cl>[CH2:20]([CH:3]([CH2:1][CH3:2])[CH:4]([C:10]1[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)[CH3:21]
Reactant: CCC(CC)C(c1ccc(NC(C)=O)cc1)n1ccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCC(CC)C(c1ccc(N)cc1)n1ccnc1
Temperature: 25 °C

Procedure:
A solution of N-(4-(2-ethyl-1-(1H-imidazol-1-yl)butyl)phenyl)acetamide (350 mg, 1.23 mmol) in 3N HCl (3.28 mL) was stirred overnight at 60° C. After cooling to room temperature, the solution was poured onto ice and basified with 6N NaOH (pH=12-14). The aqueous phase was extracted three times with DCM and the organic extracts were combined and dried over MgSO4, filtered and then concentrated to afford to 4-(2-ethyl-1-(1H-imidazol-1-yl)butyl)aniline, MS (ES+): m/z 244.31 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([OH:14])=[O:13].[C:15](Cl)(=[O:17])[CH3:16]>C1C=CC=CC=1>[C:15]([O:1][C:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=[O:13])[C:8]=2[CH:9]=[CH:10][CH:11]=1)(=[O:17])[CH3:16]
Reactant: O=C(O)c1cccc2c(O)cccc12
Reactant: CC(=O)Cl
Solvent: c1ccccc1
Product: CC(=O)Oc1cccc2c(C(=O)O)cccc12
Reaction time: 0.25 h

Procedure:
A solution of 20 g. of 5-hydroxy-1-naphthoic acid in 200 ml. of benzene and 40 ml. of acetyl chloride is refluxed for 3 hours. Solvent and excess acetyl chloride are evaporated. The mixture is dissolved in methanol (150 ml.) and water (20 ml.) added. After 15 minutes, addition of more water results in the precipitation of 1-acetoxy-5-naphthoic acid.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:28](=[O:29])[C:27]3[CH:26]=[C:25]([C:30]4[C:31]([O:38][CH3:39])=[N:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=4)[N:24]([CH:40]([CH3:42])[CH3:41])[C:23]=3[CH:22]2[C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[Cl:49][C:46]1[CH:47]=[CH:48][C:43]([CH:22]2[C:23]3[N:24]([CH:40]([CH3:42])[CH3:41])[C:25]([C:30]4[C:31]([O:38][CH3:39])=[N:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=4)=[CH:26][C:27]=3[C:28](=[O:29])[N:21]2[CH:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)=[CH:44][CH:45]=1
Reactant: COc1ncc(-c2cc3c(n2C(C)C)C(c2ccc(Cl)cc2)N(C2CCN(C(=O)OC(C)(C)C)CC2)C3=O)c(OC)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(-c2cc3c(n2C(C)C)C(c2ccc(Cl)cc2)N(C2CCNCC2)C3=O)c(OC)n1
Reaction time: 1 h

Procedure:
TFA (32.4 mmol) was added to a solution of 4-[6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-5-yl]-piperidine-1-carboxylic acid tert-butyl ester (Step I06.1) (0.755 mmol) in CH2Cl2 (4 mL) at 0° C. After 1 h, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3 and diluted with EtOAc, THF and NaCl. The separated aqueous phase was extracted with EtOAc/THF (2×). The combined organic phases were dried (MgSO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a white solid (TFA-salt). tR: 4.34 min (HPLC 4); ESI-MS: tR=0.82 min, [M+H]+ 496/498(LC-MS 1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1.BrN1C(=O)CCC1=O.[CH3:28][O:29][C:30](=[O:43])[CH2:31][NH:32][S:33]([C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=1)(=[O:35])=[O:34]>>[CH3:1][O:2][C:3](=[O:19])[C:4]1[C:9]([CH2:10][N:32]([CH2:31][C:30]([O:29][CH3:28])=[O:43])[S:33]([C:36]2[CH:37]=[CH:38][C:39]([CH3:42])=[CH:40][CH:41]=2)(=[O:35])=[O:34])=[CH:8][CH:7]=[CH:6][C:5]=1[O:11][C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1
Reactant: COC(=O)c1c(C)cccc1Oc1ccc(F)cc1
Reactant: COC(=O)CNS(=O)(=O)c1ccc(C)cc1
Agent: O=C1CCC(=O)N1Br
Product: COC(=O)CN(Cc1cccc(Oc2ccc(F)cc2)c1C(=O)OC)S(=O)(=O)c1ccc(C)cc1

Procedure:
The crude title compound was synthesized from 2-(4-fluoro-phenoxy)-6-methyl-benzoic acid methyl ester, N-bromosuccinimide, and (toluene-4-sulfonylamino)-acetic acid methyl ester in analogy to example 18c and was used in the following step without further purification; MS-(+)-ion: M+23=524.4.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([N+:10]([O-])=O)[CH:3]=1.[C:13](OCC)(=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].N1CCCCC1>[Pd].C(O)C>[CH2:18]([O:17][C:15]([C:14]1[C:13](=[O:20])[NH:10][C:4]2[C:5]([CH:6]=1)=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=2)=[O:16])[CH3:19]
Reactant: O=Cc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Pd]
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2ccc(Cl)cc2[nH]c1=O
Temperature: 23 °C
Reaction time: 1 h

Procedure:
A mixture of 4-chloro-2-nitrobenzaldehyde (9-1, 495 mg, 2.64 mmol, 1 equiv) and 10% palladium on carbon (0.280 g, 0.264 mmol, 0.100 equiv) in ethanol (20 mL) was stirred under a hydrogen balloon for 1 h at 23° C. The catalyst was filtered onto a pad of celite and washed with ethanol (20 mL). The combined filtrate was concentrated to 20 mL, then diethyl malonate (0.801 mL, 5.28 mmol, 2.00 equiv) and piperidine (0.130 mL, 1.32 mmol, 0.500 equiv) were added. The resulting mixture was heated at reflux for 5 h. The mixture was allowed to cool to 23° C., and the precipitate was filtered and washed with cold ethanol (10 mL) to give 7-chloro-2-oxo-1,2-dihydro-quinoline-3-carboxylic acid ethyl ester (9-2) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[CH:11][N:10]=[C:9]2[CH:15]([NH:17][CH3:18])[CH3:16])=[CH:4][CH:3]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([N:27]=[C:28]=[O:29])[CH:24]=[CH:25][CH:26]=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[CH:11][N:10]=[C:9]2[CH:15]([N:17]([CH3:18])[C:28]([NH:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:30])([F:31])[F:19])[CH:22]=2)=[O:29])[CH3:16])=[CH:6][CH:7]=1
Reactant: CNC(C)c1nccc(=O)n1-c1ccc(F)cc1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: ClC(Cl)Cl
Product: CC(c1nccc(=O)n1-c1ccc(F)cc1)N(C)C(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 64.5 %

Procedure:
The amine (26) (12 mg, 0.05 mmol) and 3-trifluoromethylphenyl isocyanate (7.5 L, 0.05 mmol) were dissolved in chloroform (0.2 mL) and stirred at ambient temperature. After complete conversion of the starting material by TLC analysis, the solvent was removed and the resulting residue was subjected to silica-gel column chromatography [eluent: Dichloromethane] to give the title urea (27) (14 mg, quant.) as a solid:
Reaction SMILES: [Na].[CH3:2][N:3]([CH3:8])[CH2:4][CH2:5][CH2:6][SH:7].Cl[C:10]1[C:11]2[CH2:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[O:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:15]=1>C(O)C>[CH3:2][N:3]([CH3:8])[CH2:4][CH2:5][CH2:6][S:7][C:10]1[C:11]2[CH2:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[O:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:15]=1
Reactant: Clc1nc(-c2ccccc2)nc2c1Cc1ccccc1O2
Reactant: CN(C)CCCS
Agent: [Na]
Solvent: CCO
Product: CN(C)CCCSc1nc(-c2ccccc2)nc2c1Cc1ccccc1O2
Yield: 52 %

Procedure:
Eight and one tenth (8.1) gram 4-hydroxy-2-phenyl[1]benzopyrano[2,3-d]pyrimidine, 9.0 g phosphoruspentachloride and 36 ml phosphorusoxychloride are heated for two hours under reflux. Excess phosphorusoxychloride is then distilled off under a vacuum and the residue is partitioned to chloroform and water, a pH 6 value being adjusted by the addition of 10% sodium hydroxide. The organic phase is separated and the chloroform removed by distillation in a rotary evaporator. The residue obtained is separated by chromatography using cyclohexane/chloroform 1:1 as an eluting agent. There are obtained 4.0 g 4-chloro-2-phenyl[1]benzopyrano[2,3-d]pyrimidine, mp 168°-170° C. as colorless crystals. Thereafter 0.05 g sodium are dissolved in 10 ml anhydrous ethanol and 0.25 g 3-dimethylamino-1-propane-thiol added to the solution. The mixture obtained is added dropwise to a solution of 0.6 g 4-chloro-2-phenyl[1]benzopyrano[2,3-d]pyrimidine at reflux temperature. The reaction mixture is then kept under reflux for another two hours. After cooling the reaction mixture is filtered and the filtrate is evaporated to dryness and the residue partitioned to chloroform and water. The organic phase is separated off, the chloroform is evaporated and the residue recrystallized from ethanol. There are obtained 0.4 g colorless crystals, mp 93° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:21]=[C:22](/[CH:24]=[CH:25]/[C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)[N:23]=3)[C:10]([C:13]3[CH:14]=[C:15]([NH2:20])[C:16]([NH2:19])=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1.C1N=CN([C:41](N2C=NC=C2)=[O:42])C=1>C1COCC1>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:21]=[C:22](/[CH:24]=[CH:25]/[C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)[N:23]=3)[C:10]([C:13]3[CH:14]=[C:15]4[N:20]=[C:41]([OH:42])[NH:19][C:16]4=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1
Reactant: Nc1cc(-c2cnc(N3CCOCC3)c3nc(/C=C/c4ccc5ccccc5n4)cn23)cnc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Oc1nc2cc(-c3cnc(N4CCOCC4)c4nc(/C=C/c5ccc6ccccc6n5)cn34)cnc2[nH]1
Yield: 25 %

Procedure:
A solution of compound 6b (220 mg, 0.470 mmol) and CDI (200 mg, 1.23 mmol) in THF (8 mL) was stirred at rt for 18 h. The reaction was quenched with H2O (10 mL). The resulting solids were collected by filtration and washed with Et2O to obtain the title compound 94 as a light yellow solid (57.6 mg, 25% yield). 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 11.62 (s, 1H), 11.08 (s, 1H), 8.33 (d, J=8.4 Hz, 1H), 8.21 (s, 1H), 8.11 (s, 1H), 7.97-7.92 (m, 2H), 7.86-7.80 (m, 2H), 7.74 (t, J=7.8 Hz, 1H), 7.66 (s, 1H), 7.60-7.51 (m, 2H), 7.39 (s, 1H), 4.40-4.25 (m, 4H), 3.95-3.75 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C27H22N8O2: 491.2 (M+H). Found 491.0.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1.[CH3:20][C:21]1[C:29]2[CH2:28][O:27][C:26](=[O:30])[C:25]=2[CH:24]=[CH:23][C:22]=1[CH2:31][CH:32]=O>>[CH3:20][C:21]1[C:29]2[CH2:28][O:27][C:26](=[O:30])[C:25]=2[CH:24]=[CH:23][C:22]=1[CH2:31][CH2:32][N:6]1[CH2:5][CH2:4][N:3]([CH:8]2[CH2:17][CH2:16][C:15]3[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=3[CH2:9]2)[C:2](=[O:1])[CH2:7]1
Reactant: N#Cc1ccc2c(c1)CCC(N1CCNCC1=O)C2
Reactant: Cc1c(CC=O)ccc2c1COC2=O
Product: Cc1c(CCN2CCN(C3CCc4cc(C#N)ccc4C3)C(=O)C2)ccc2c1COC2=O

Procedure:
The title compound was prepared from 6-(2-Oxopiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile and (4-Methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde following essentially the same procedure as Example 6. The product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 430 [M+1]+.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:30]=[CH:29][C:28](CO)=[CH:27][CH:26]=1>ClCCl>[Br:5][CH2:1][C:36]1[CH:37]=[CH:38][C:33]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:34][CH:35]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1ccc(-c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1ccc(-c2ccccc2)cc1
Reaction time: 1.5 h
Yield: 95.1 %

Procedure:
Carbon tetrabromide (8.99 g, 27.1 mmol) and triphenyl phosphine (7.11 g, 27.1 mmol) were added to a stirred solution of biphenyl-4-yl methanol (5.00 g, 27.1 mmol) in dichloromethane (100 mL) at room temperature. Stirring was continued at room temperature for 1.5 hours then the solvent removed by evaporation under reduced pressure. The residue was purified by column chromatography on silica gel (1:20 diethyl ether:cyclohexane) to give the title compound (6.37 g, 95%) as a white solid. 1H NMR (400 MHz: CDCl3): 7.6 (4H), 7.45 (4H), 7.35 (1H), 4.55 (2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][CH:12]2[CH2:17][CH2:16][Si:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:6][CH:5]=1)[CH3:2].[H][H]>C(OCC)(=O)C.[C].[Pd]>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH:12]2[CH2:13][CH2:14][Si:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:16][CH2:17]2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCCCC[Si]1(c2ccccc2)CCC(C=Cc2ccc(OCC)cc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCC[Si]1(c2ccccc2)CCC(CCc2ccc(OCC)cc2)CC1

Procedure:
36.0 g of the thus obtained 4-(2-(4-ethoxyphenyl)ethenyl)-1-n-pentyl-1-phenyl- 1-silacyclohexane was dissolved in 100 ml of ethyl acetate, followed by hydrogenation at a pressure of 5 kg/cm2 of hydrogen at room temperature in the presence of 200 mg of palladium-carbon used as a catalyst. After the hydrogen had been consumed theoretically, the catalyst was removed by filtration and the resultant flitrate was concentrated to obtain 36.2 g (quantitative yield) of 4-(2-(4-ethoxyphenyl)ethyl)-1-n-pentyl-1-phenyl-1-silacyclohexane.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:12]OC(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:12])=[O:6]
Reactant: COC(OC)OC
Reactant: O=C(O)c1cccc(Br)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)c1cccc(Br)c1F
Reaction time: 16 h
Yield: 84 %

Procedure:
A solution of 3-bromo-2-fluorobenzoic acid (0.219 g, 1 mmol) in dry methanol (5 mL) under nitrogen was treated with trimethylorthoformate (0.22 mL, 2 mmol) and p-toluenesulfonic acid (catalytic amount), and then heated under reflux. After 16 h, the mixture was evaporated and the residue partitioned between water and Et2O. the organic layer was washed with sat. sodium hydrogen carbonate solution, water, brine, dried (MgSO4) and evaporated to give methyl 3-bromo-2-fluorobenzoate (0.195 g, 0.84 mmol, 84%): 1H-NMR (CDCl3) δ7.90-7.85 (m, 1H), 7.71-7.65 (m, 1H), 7.10 (dt, 1H, J=8.0, 1.0 Hz), 3.94 (s, 3H): MS (EI) 232 (M+).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:10][CH2:11][CH3:12])[C:5]([O:7]CC)=O)[CH3:2].[Si:13]([O:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[CH2:24][Mg]Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[Cl-].[NH4+]>C1COCC1>[Si:13]([O:20][C:21]1[CH:22]=[C:23]([CH2:24][C:5](=[O:7])[CH:4]([O:3][CH2:1][CH3:2])[O:10][CH2:11][CH3:12])[CH:27]=[CH:28][CH:29]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15]
Reactant: CCOC(=O)C(OCC)OCC
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C[Mg]Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(OCC)C(=O)Cc1cccc(O[Si](C)(C)C(C)(C)C)c1
Temperature: -78 °C

Procedure:
Under an argon atmosphere, to a solution of ethyl diethoxyacetate (1.80 mL, 10.1 mmol) in THF (20 mL) was added slowly a THF solution of (103) prepared above at −78° C. After stirring at −78° C. for an hour, to this was added 20% aqueous solution of ammonium chloride (30 mL) and the product was extracted with ethyl acetate (×3). The organic layer was sequentially washed with water (×1) and saturated brine (×1), and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure and the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate═10/1) to give 3-[3-(tert-butyldimethylsilyloxy]phenyl]-1,1-diethoxypropan-2-one (104) as a colorless oily substance (1.90 g, 5.39 mmol, 53.9%).
Reaction SMILES: [C:1]([C:9]1[NH:13][CH:12]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CC[CH2:21][CH2:20]1.[H-].[Na+].C(I)C>O>[CH2:20]([N:13]1[C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12]1)[CH3:21]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1c[nH]c(C(=O)c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCI
Product: CCOC(=O)c1cc(C(=O)c2ccccc2)n(CC)c1
Reaction time: 0.5 h

Procedure:
Ethyl 5-benzoylpyrrole-3-carboxylate (0.973 g., 4 mmoles) was dissolved in 40 ml. of dry tetrahydrofuran. To the stirred solution, under nitrogen, there was added sodium hydride dispersion in oil (57%, 0.173 g., 4 mmoles), and the mixture was stirred for 0.5 hour. Ethyl iodide (1.25 g., 8 mmoles) was added and stirring continued for 6 hours. Additional sodium hydride (0.17 g.) and ethyl iodide (1.25 g.) was added and reflux continued for an additional 104 hours. Like quantities of sodium hydride and ethyl iodide were added after 16 hours reflux and a like quantity of ethyl iodide after 24 hours reflux. The reaction was cooled and excess sodium hydride decomposed by cautious addition of 40 ml. of water. The product was extracted into 40 ml. of ether, the ether back-washed with 10 ml. of water, and evaporated to dryness to yield ethyl 1-ethyl-5-benzoylpyrrole-3-carboxylate (1 g.), used directly in the next step.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[C:14](F)[C:13]([F:17])=[CH:12][C:11]=3[N+:18]([O-:20])=[O:19])[CH:5]=2)[CH2:3][CH2:2]1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]([NH2:30])[CH3:29])=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>CCCCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:11]([N+:18]([O-:20])=[O:19])=[CH:12][C:13]([F:17])=[C:14]([NH:30][C@H:28]([C:25]4[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=4)[CH3:29])[CH:15]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1Nc1cc(C2CC2)[nH]n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1cc(Nc2cc(C3CC3)[nH]n2)c([N+](=O)[O-])cc1F)c1ccc(F)cc1
Temperature: 160 °C
Yield: 84.2 %

Procedure:
A mixture of 5-cyclopropyl-N-(4,5-difluoro-2-nitrophenyl)-1H-pyrazol-3-amine (Method 86; 0.300 g, 1.07 mmol), (S)-1-(4-fluoro-phenyl)ethylamine (0.164 g, 1.18 mmol), and DIEA (0.280 ml, 1.61 mmol) in n-BuOH (2 ml) was heated in a sealed tube at 160° C. for 16 hrs. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane:EtOAc=3:1) to give the title compound as an orange solid (0.360 g, 84%). NMR (400 MHz) 12.29 (s, 1H), 10.14 (s, 1H), 7.75 (d, J=12.8 Hz, 1H), 7.63 (d, J=6.4 Hz, 1H), 7.41 (m, 2H), 7.14 (t, J=8.8 Hz, 2H), 7.00 (d, J=8.0 Hz, 1H), 5.63 (s, 1H), 4.55 (m, 1H), 1.90 (m, 1H), 1.52 (d, J=6.8 Hz, 3H), 0.98 (m, 2H), 0.71 (m, 2H). MS: Calcd.: 399; Found: [M+H]+ 400.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH:15]([C:18](=[O:26])[CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])[CH2:14][CH2:13]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>CCO>[CH2:3]([O:10][CH2:11][CH:12]1[CH2:13][CH2:14][CH:15]([C:18](=[O:26])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:16][CH2:17]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)CCC(=O)C1CCC(COCc2ccccc2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCC(=O)C1CCC(COCc2ccccc2)CC1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
Potassium hydroxide (17.0 g, 0.30 mol) is added to EtOH (300 mL) solution of ethyl 4-[4-(benzyloxymethyl)cyclohexyl]-4-oxobutyrate (cis/trans=1/1, 33.0 g, 0.10 mol), and the mixture is stirred at 85° C. for 2 hours. After cooling to 0° C., 5N HCl is added to the mixture (to reach pH 2-3), the mixture is concentrated to remove ethanol. The crude mixture is extracted with EtOAc. The water layer is extracted with EtOAc, and the combined organic layer is washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure to afford crude 4-[4-(benzyloxymethyl)cyclohexyl]-4-oxobutyric acid (cis/trans=ca. ⅙). The mixture of ether-hexane (ca. 1:4, 120 mL) is added to the resulting solid and sonicated. The crystal is collected by filtration, washed with small amount of ether-hexane (1:4) and dried to give trans-4-[4-(benzyloxymethyl)cyclohexyl]-4-oxobutyric acid as a pale yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10](=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.[OH-].[Na+]>O1CCOCC1>[C:10]([N:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]1[CH2:3][CH2:2][O:1][S:35]([C:32]1[CH:33]=[CH:34][C:29]([CH3:39])=[CH:30][CH:31]=1)(=[O:37])=[O:36])(=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCCCCCCCCCCCCC(=O)N1CCCCC1CCO
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCCCCC(=O)N1CCCCC1CCOS(=O)(=O)c1ccc(C)cc1

Procedure:
1,4-Dioxane solution of 1-[2-(2-hydroxyethyl)piperidino]octadecan- 1-one and p-toluenesulfonyl chloride is added to sodium hydroxide solution and the mixture is reacted at room temperature to obtain 1-octadecanoyl-2-[2-(tosyloxy)ethyl]piperidine.