Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[C:9]2[S:10][C:11]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:24][CH:23]=3)=[C:12]([C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[O:14])[C:8]=2[CH:7]=[CH:6][CH:5]=1.[CH3:36]I.O>CS(C)=O>[CH3:36][O:3][C:4]1[C:9]2[S:10][C:11]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]4[CH2:32][CH2:33][CH2:34][CH2:35]4)=[CH:24][CH:23]=3)=[C:12]([C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[O:14])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(c1ccc(F)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2c(O)cccc12
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1cccc2c(C(=O)c3ccc(F)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc12
Reaction time: 1.5 h
Yield: 28.7 %

Procedure:
To a suspension of powdered KOH (177 mg, 3.15 mmol) in 1.6 mL of dry DMSO was added 4-fluorophenyl 7-hydroxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl ketone (350370) (Example 75, Part G) (364 mg, 0.788 mmol) at room temperature. The reaction mixture turned orange in color. To the alkoxide was added slowly methyl iodide (49 μL, 0.79 mmol) over a period of 15 min. The reaction mixture was then stirred for 1.5 h. Another portion of MeI (20 μL, 0.32 mmol) was added, stirred for 1.5 h., followed by another addition of 20 μL (0.32 mmol) of MeI and stirring for an additional 30 min at room temperature. The reaction mixture was then poured into 20 mL of H2O. This mixture was extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with H2O (5×10 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was then purified by flash chromatography (silica gel, 4%[10% NH4OH in MeOH]/CH2Cl2) to afford 108 mg (0.226 mmol, 29%) of a white foam.
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)=[C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[CH:16]=[N:17][C:10]=2[N:9]([CH3:40])[C:8]1=[O:41])=O.O[Li].O>C1COCC1>[OH:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=3)=[C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=3)[CH:16]=[N:17][C:10]=2[N:9]([CH3:40])[C:8]1=[O:41]
Reactant: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(C(F)(F)F)cc3)c(Oc3cccc(C(F)(F)F)c3)cnc21
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccc(C(F)(F)F)cc3)c(Oc3cccc(C(F)(F)F)c3)cnc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 14 %

Procedure:
To a solution of 3-(1-methyl-2,4-dioxo-5-(4-(trifluoromethyl)benzyl)-6-(3-(trifluoromethyl) phenoxy)-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (150 mg, 0.258 mmol) in THF (2 mL) was added aq. LiOH.H2O (1 mL, 0.5 M). The reaction was stirred at RT for 10 min then extracted with EA (50 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 3-(3-hydroxypropyl)-1-methyl-5-(4-(trifluoromethyl)benzyl)-6-(3-(trifluoromethyl)phenoxy)pyrido[2,3-d]pyrimidine-2,4 (1H,3H)-dione (20 mg, 8% yield over 3 steps) as a white solid. 1H NMR (CDCl3) δ: 8.37 (s, 1H), 7.42 (m, 3H), 7.35 (m, 1H), 7.31 (m, 2H), 7.02 (m, 2H), 4.83 (s, 2H), 4.24 (t, J=6.1 Hz, 2H), 3.73 (s, 3H), 3.56 (s, 2H), 2.95 (s, 1H), 1.98-1.87 (m, 2H). LCMS: MH+ 554 and TR=3.39 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20](=[N:26][OH:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)Cl>[OH:27][N:26]=[C:20]([CH2:19][C:4]1[C:3]2[C:7](=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=2[Cl:1])[NH:6][CH:5]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: Clc1cc(Cl)c2cc[nH]c2c1
Reactant: CCOC(=O)C(CBr)=NO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)C(Cc1c[nH]c2cc(Cl)cc(Cl)c12)=NO
Yield: 70 %

Procedure:
Mix 4,6-dichloroindole (5.90 g, 31.72 mmol), potassium carbonate (1.81 g, 47.6 mmol) and anhydrous methylene chloride (200 mL). Stir and add a solution of ethyl 3-bromo-2-hydroxyiminopropanoate (7.00 g, 33.31 mmol) in methylene chloride (75 mL). Stir under a nitrogen atmosphere for 48 hours. Take the solution up in methylene chloride (100 mL) and wash with water (300 mL), saturated sodium hydrogen carbonate (200 mL) and brine (100 mL). Dry (MgSO4) and evaporate the solvent in vacuo to give a tan solid. Purify by silica gel chromatography (1 to 3% acetone in chloroform) to give the title compound as a yellow solid (7.00 g, 99% based on consumed starting material). Recrystallize (diethyl ether/hexane) to give the title compound as white crystals (4.0 g, 56%); mp 175°-176° C.
Reaction SMILES: [CH2:1]([CH:8]1[N:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH:11]=[C:10]([C:21]2[CH:22]=[CH:23][C:24]3[O:35][CH2:34][C:27]4=[N:28][NH:29][C:30](=[O:33])[CH:31]([CH3:32])[N:26]4[C:25]=3[CH:36]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH2:1]([CH:8]1[CH2:9][CH:10]([C:21]2[CH:22]=[CH:23][C:24]3[O:35][CH2:34][C:27]4=[N:28][NH:29][C:30](=[O:33])[CH:31]([CH3:32])[N:26]4[C:25]=3[CH:36]=2)[CH2:11][CH2:12][N:13]1[C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1C(=O)NN=C2COc3ccc(C4=CCN(C(=O)OC(C)(C)C)C(Cc5ccccc5)C4)cc3N21
Agent: [Pd]
Solvent: CO
Product: CC1C(=O)NN=C2COc3ccc(C4CCN(C(=O)OC(C)(C)C)C(Cc5ccccc5)C4)cc3N21
Reaction time: 12 h
Yield: 99.9 %

Procedure:
To a solution of tert-butyl 6-benzyl-4-(1-methyl-2-oxo-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.147 g, 0.3 mmol) in MeOH (30 mL) was added Pd/C (10%, 0.096 g, 0.1 mmol) and the mixture was stirred under an atmosphere of H2 (50 psi) for 12 h. After filtration, the filtrate was concentrated in vacuo to give tert-butyl 2-benzyl-4-(1-methyl-2-oxo-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)piperidine-1-carboxylate (0.147 g), which was used in the next step without further purification. LC/MS (Table 1, Method 2) Rt=2.453 min; MS m/z: 491 [M+H]+.
Reaction SMILES: [C:1]([C:3](=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4](O)=[O:5])#[N:2].S(Cl)([Cl:16])=O>C1C=CC=CC=1>[C:1]([C:3](=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([Cl:16])=[O:5])#[N:2]
Reactant: O=S(Cl)Cl
Reactant: N#CC(=Cc1ccccc1)C(=O)O
Solvent: c1ccccc1
Product: N#CC(=Cc1ccccc1)C(=O)Cl

Procedure:
100 ml of benzene was added to 17.3 grams of α-cyanocinnamic acid. 12 ml of thionyl chloride was added dropwise slowly thereto at ambient temperature. The temperature was elevated to 70° C. and the heating was continued until foaming ceased. Benzene and thionyl chloride were distilled off and the residue was dried thoroughly under reduced pressure.
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:6][C:5]=2[O:4]1.[CH:18](OC)=[O:19]>C1COCC1>[CH:18]([CH:13]([CH2:12][C:7]1[CH:8]=[CH:9][C:10]2[O:11][CH2:3][O:4][C:5]=2[CH:6]=1)[C:14]([O:16][CH3:17])=[O:15])=[O:19]
Reactant: COC(=O)CCc1ccc2c(c1)OCO2
Reactant: COC=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C=O)Cc1ccc2c(c1)OCO2
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
First, 1.38 g of 60% NaH was suspended in 12 ml of THF. Then, 2.4 g of methyl 3-(3,4-methylenedioxyphenyl)-propionate was dissolved in 12 ml of THF and added dropwise to the suspension solution prepared above at room temperature. After the suspension solution was raised in temperature to 40° C. and stirred for 15 minutes, 3.46 g of methyl formate was added dropwise for 1 hour. Further, 0.7 g of 60% NaH and 0.9 g of methyl formate were divided into four parts and each part was added separately. Afterwards, the solution mixture was stirred at 40° C. for 3 hours.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:12]=[CH:13][C:14]3[N:20]([CH3:21])[C:19](=[O:22])[CH:18]([CH3:23])[CH2:17][N:16]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:15]=3[N:30]=2)=[C:6]([O:31][CH3:32])[CH:5]=1.I[CH3:35].[H-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([C:11]2[N:12]=[CH:13][C:14]3[N:20]([CH3:21])[C:19](=[O:22])[CH:18]([CH3:23])[CH2:17][N:16]([CH:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]4)[C:15]=3[N:30]=2)[CH3:35])=[C:6]([O:31][CH3:32])[CH:5]=1
Reactant: CI
Reactant: COC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCCC2)CC(C)C(=O)N3C)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N(C)c2ncc3c(n2)N(C2CCCCC2)CC(C)C(=O)N3C)c(OC)c1
Reaction time: 2 h
Yield: 98.3 %

Procedure:
To a mixture of 0.170 g (0.00037 mole) of (rac)-4-(9-cyclohexyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl amino)-3-methoxy-benzoic acid methyl ester, 0.35 mL (0.00056 mole) of iodomethane and 10 mL of N,N-dimethylformamide at 0 degrees, was added 0.024 g of sodium hydride (60% dispersion in mineral oil). The mixture was stirred at 0 degrees for 2 hours and then partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica chromatography, eluting with hexanes-ethyl acetate (30:70) to give 0.170 g of (rac)-4-[(9-cyclohexyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)-methyl-amino]-3-methoxy-benzoic acid methyl ester as white powder.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[CH3:16].[H+].[B-:18]([F:22])([F:21])([F:20])[F:19]>O>[F:19][B-:18]([F:22])([F:21])[F:20].[CH3:13][O:12][C:10]([C:9]1[CH:14]=[CH:15][C:6]([N+:5]#[N:1])=[C:7]([CH3:16])[CH:8]=1)=[O:11]
Reactant: COC(=O)c1ccc(N)c(C)c1
Reactant: O=N[O-]
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc([N+]#N)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
To an aqueous solution of NaNO2 (12.54 g, 2.0 eq) in 75 mL H2O at 0° C. was added dropwise cooled solution of methyl 4-amino-3-methylbenzoate (15 g, 1.0 eq) in HBF4(aq)(40% in water). After addition, the mixture was stirred for 15 min at ambient temperature. The precipitate was filtered, washed with ice-cold water, and dried, to give the desired product as a white solid (16 g, 90%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH2:21]([O:28][C:29]1[C:34]([C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:36])=[CH:33][CH:32]=[CH:31][C:30]=1[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:21]([O:28][C:29]1[C:34]([C:35]([C:2]2[CH:3]=[C:4]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=2)([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[OH:36])=[CH:33][CH:32]=[CH:31][C:30]=1[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COc1ccccc1-c1cccc(Br)c1
Reactant: O=C(c1ccccc1)c1cccc(-c2ccccc2)c1OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccccc1-c1cccc(C(O)(c2ccccc2)c2cccc(-c3ccccc3)c2OCc2ccccc2)c1
Reaction time: 1 h
Yield: 16.9 %

Procedure:
A solution of 3′-bromo-2-methoxybiphenyl (1.08 g, 4.1 mmol) in anhydrous tetrahydrofuran (10 mL) was stirred at −78° C. and 2.5M n-butyllithium in hexanes (1.64 mL, 4.1 mmol) was added at such a rate that the temperature did nor exceed −70° C. Stirring was continued at −78° C. for 1 hr. A solution of 25 (1.5 g, 4.1 mmol) in tetrahydrofuran (6 mL) was added at such a rate that the temperature did not exceed −65° C. Stirring was continued at −78° C. for 20 min and at room temperature for 2 hr. The reaction mixture was poured onto saturated ammonium chloride (150 mL) and extracted with ethyl acetate (150 mL). The organic extract was washed with water (2×80 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed on a rotary evaporator. The crude product was purified by chromatography on silica (80 g) with 2% ethyl acetate in heptane (4 L). Pure 26 (0.87 g) and slightly impure 26 (0.38 g) were isolated (total yield 55%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH2:13][OH:14])[N:7]=[CH:6]2>CC(=O)OCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH:13]=[O:14])[N:7]=[CH:6]2
Reactant: COc1ccc2nc(CO)ncc2c1
Solvent: CCOC(C)=O
Product: COc1ccc2nc(C=O)ncc2c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 9.6 %

Procedure:
To the solution of (6-methoxyquinazolin-2-yl)methanol (4 g, 0.21 mol) in EA (30 mL) was added IBX (11.6 g, 4.2 mol, 2 eq). The reaction was stirred at 80° C. for 16 h. After filtration, the solution was evaporated in vacuum to give 6-methoxyquinazoline-2-carbaldehyde (3.8 g, yield: 95%) as a white solid. ESI-MS: m/z 189.2 ([M+1]+).
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].IC.[O:9]=[C:10]1[CH:24]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:23]2[N:22]=[CH:21][N:14]3[CH2:15][C:16](=[O:20])[CH2:17][CH2:18][NH:19][C:12]([C:13]=23)=[CH:11]1>CN(C=O)C>[CH3:1][CH:15]1[N:14]2[CH:21]=[N:22][C:23]3[CH:24]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:10](=[O:9])[CH:11]=[C:12]([C:13]=32)[NH:19][CH2:18][CH2:17][C:16]1=[O:20]
Reactant: CC(C)(C)OC(=O)CC1C(=O)C=C2NCCC(=O)Cn3cnc1c32
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC1C(=O)CCNC2=CC(=O)C(CC(=O)OC(C)(C)C)c3ncn1c32
Reaction time: 18 h

Procedure:
Cesium carbonate (214 mg, 0.66 mmol) and iodomethane (93 mg, 0.66 mmol) were added to a solution of tert-butyl (2,7-dioxo-5,6,7,8-tetrahydro-4H-imidazo[1,5,4-fg][1,6]benzodiazocin-1(2H)-yl)acetate (109 mg, 0.33 mmol, described in Intermediate 13) in DMF (5 mL). After 18 h, the mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=346 (M+1).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[NH2:14].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Cl:10][C:11]1[CH:12]=[C:13]([NH:14][C:3]([CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[O:5])[CH:15]=[C:16]([Cl:18])[CH:17]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)CC(=O)Nc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 63 %

Procedure:
In 200 ml of dichloromethane were dissolved 5.0 g of monoethyl malonate and 6.12 g of 3,5-dichloroaniline. Under cooling with ice, to the solution was added 8.57 g of N,N'-dicyclohexylcarbodiimide, followed by stirring at room temperature for 5 hours. Insoluble materials was removed by filtration. The filtrate was diluted with ethyl acetate and washed with 1N hydrochloric acid and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography using 250 g of silica gel and using chloroform-acetone (20:1 by volume) as an eluent to obtain 6.57 g of the oily titled compound.
Reaction SMILES: [CH2:1]([O:5][CH2:6][C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].C(O)(=O)C.[Br:16]N1C(=O)CCC1=O>C(Cl)Cl>[Br:16][C:8]1[S:9][CH:10]=[CH:11][C:7]=1[CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCOCc1ccsc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCOCc1ccsc1Br

Procedure:
3-Butoxymethylthiophene (6.17 grams, 36.24 mmol) was dissolved in 100 milliliters of CH2Cl2, and then 100 milliliters of acetic acid (AcOH) were added. N-Bromosuccinimide (NBS) (6.45 grams, 36.24 mmol) was then added in portions to the resulting mixture under stirring. The mixture resulting was then stirred at room temperature, about 23° C. to about 27° C., for 24 hours. Reaction completion was determined by 1H NMR. The solvents were then removed by evacuation. The residue remaining was dissolved in hexane, and the soluble part was passed through a short silica gel column (10 centimeters×3 centimeters). After removing the solvent, the resulting colorless liquid was purified by column chromatography using hexane/CH2CI2 (3/2, v/v) then by distillation under reduced pressure.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=O)[CH2:3][CH2:2]1.[CH:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([OH:15])[CH:9]=1>CN(C)C=O.O>[OH:15][C:10]1[CH:11]=[CH:12][C:13]([N:14]2[C:1](=[O:7])[CH2:2][CH2:3][C:4]2=[O:6])=[CH:8][CH:9]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=C1CCC(=O)O1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCC(=O)N1c1ccc(O)cc1
Temperature: 170 °C
Yield: 94 %

Procedure:
A solution of succinic anhydride (100 g, 1 mol) in dimethylformamide (50 g) was added slowly to a stirred solution of p-aminophenol (109 g, 1 mol) in dimethylformamide (150 g) at a temperature between 25° and 30° C. After 1.5 h the reaction mixture was transferred to a film evaporator in which dimethylformamide (160 g) was separated off at a pressure of 0.05 bar and a temperature of 130° C. A solution of p-toluenesulphonic acid (2 g) in methanol (18 g) was added to the residue obtained, the temperature was increased to 170° C. and dimethylformamide and water were evaporated at a pressure of 13 mbar. The brown solid material thus obtained was dissolved in dimethylformamide having a temperature of 90° C., water was added to the solution until it became turbid, the turbid solution was allowed to adopt ambient temperature and the crystals obtained were filtered off. The N-(4-hydroxyphenyl)succinimide was obtained in a yield of 94 % and with a purity of more than 99%.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.[C:10]1([C:16](Cl)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1>[C:16]([O:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCC1CCC(O)CC1
Solvent: c1ccncc1
Product: OC1CCC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
4-(Hydroxymethyl)cyclohexanol (2.0 g, 0.015 mol) was dissolved in pyridine (15.0 mL) and the mixture was cooled to 0° C. To the reaction was added triphenylmethyl chloride (4.7 g, 0.017 mol) and the resulting mixture was stirred at 0° C. for 2 hours and at 25° C. for 16 hours. The reaction was then concentrated using a rotory evaporator, and the concentrate was extracted with ethyl acetate. The organic extracts were washed with water, saturated NaCl, dried (MgSO4) and then concentrated in vacuo. The reaction was chromatographed on silica gel using 30% EtOAc/hexanes to give the cis isomer (0.74 g) 1H NMR(CDCl3): δ 7.52 (m, 6H), 7.27 (m, 9H), 3.98 (m, 1H), 2.93 (m, 2H), 1.21-1.68 (m, 9H); and the trans isomer (2.72 g) 1H NMR(CDCl3): δ 7.44 (m, 6H), 7.20-7.31 (m, 9H), 3.54 (m, 1H), 2.88 (m, 2H), 1.98 (m, 2H), 1.88 (m, 2H), 1.60 (m, 1H), 0.99-1.37 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH:9]=[CH:8][CH2:7][C@@H:6]1[C:11](N1CCOC1=O)=[O:12])=[O:4].[CH3:19][O:20][Mg]OC.CO.[Cl-].[NH4+]>CO>[CH3:19][O:20][C:11]([C@@H:6]1[C@@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH:9]=[CH:8][CH2:7]1)=[O:12]
Reactant: CO[Mg]OC
Reactant: COC(=O)[C@H]1CC=CC[C@@H]1C(=O)N1CCOC1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)[C@H]1CC=CC[C@@H]1C(=O)OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 28.4 %

Procedure:
In an atmosphere of argon gas, a solution of (4S,5S)-5-methoxycarbonyl-4-(oxazolidin-2-on-3-yl)carbonyl-1-cyclohexene (8.50 g, 33.6 mmoles) disclosed in literature [N. Narasaka et al, J. Am. Chem. Soc., 111, 5340 (1989)] in methanol (50 ml) was added to 1M dimethoxymagnesium/methanol (168 ml, 168 mmoles), and the mixture was stirred at 0° C. for 15 minutes. Saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the resulting mixture was extracted with toluene. The toluene extract solution was washed with saturated aqueous solution of sodium chloride and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:9, v/v) to obtain (4S,5S)-4,5-bis(methoxycarbonyl)-1-cyclohexene (1.89 g, Yield 30%).
Reaction SMILES: CO[CH:3](OC)[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1>ClCCCl>[CH3:13][O:12][C:10]([C:9]1[CH:14]=[CH:15][C:6]2[O:5][CH:4]=[CH:3][C:7]=2[CH:8]=1)=[O:11]
Reactant: COC(=O)c1ccc(OCC(OC)OC)cc1
Solvent: ClCCCl
Product: COC(=O)c1ccc2occc2c1
Yield: 11.7 %

Procedure:
Methyl 4-((2,2-dimethoxy)ethoxy)benzoate (10.00 g) and polyphosphoric acid (20.00 g) were refluxed in 1,2-dichloroethane (50 ml) for 1 hr. After cooling, ice was added, and the separated organic layer was washed with 10% hydrochloric acid. The mixture was dried over magnesium sulfate, concentrated and purified by column chromatography to give the objective compound (0.86 g).
Reaction SMILES: [BH4-].[Li+].[C:3]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][CH:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14](OCC)=[O:15])[CH2:8][CH2:7]1)(=[O:5])[CH3:4].[H][H].O>O1CCCC1>[C:3]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][CH:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][OH:15])[CH2:8][CH2:7]1)(=[O:5])[CH3:4]
Reactant: CCOC(=O)C(OC1CCN(C(C)=O)CC1)c1ccccc1
Reactant: [H][H]
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N1CCC(OC(CO)c2ccccc2)CC1
Yield: 98.4 %

Procedure:
Lithium borohydride (3.24 g.) was added portionwise to a solution of α-(N-acetyl-4-piperidinoxy) phenylacetic acid, ethyl ester (11.2 g.) in dry tetrahydrofuran (200 ml.). When the hydrogen evolution had subsided the reaction mixture was heated under reflux for 4 hours. Water was added to the cooled solution, the solvent evaporated in vacuo, then the residue taken up in chloroform (200 ml.) and washed with dilute hydrochloric acid, water and brine. The chloroform extract was dried (MgSO4) and the solvent evaporated in vacuo. Thin layer chromatography analysis of the product indicated that reduction was incomplete, therefore the product in tetrahydrofuran (100 ml.) was treated with a further quantity of lithium borohydride (3.24 g.) and heated under reflux for 4 hours. The reaction mixture was treated as above to give N-acetyl-4-(2-hydroxy-1-phenyl-ethoxy) piperidine (9.5 g.) as an oil which solidified on standing. A sample crystallized from ether and had an m.p. of 92°-94° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][N+:11]([O-])=O)[CH:6]=[CH:5][C:4]=1[OH:14].O.NN>C(O)C.[Ni]>[NH2:11][CH2:10][CH2:9][C:7]1[CH:6]=[CH:5][C:4]([OH:14])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(CC[N+](=O)[O-])ccc1O
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1cc(CCN)ccc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2-methoxy-4-(2-nitro-ethyl)-phenol (2.0 g) and Raney-nickel (3.7 g) in ethanol (30 ml) is added hydrazine hydrate (3.8 g) during 30 minutes. The reaction mixture is stirred for 1 hour at room temperature. After filtration the reaction mixture is poured into water (350 ml). It is extracted with ethyl acetate (2×400 ml) washed with brine (2×50 ml) dried (Na2SO4) and evaporated. 4-(2-amino-ethyl)-2-methoxy-phenol is obtained as colorless crystals.