Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][O:12][C:13]([CH2:15]P(OC)(OC)=O)=[O:14].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][NH:32][C:31]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([CH:35]=O)[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(OC(N1CCNC(CC2C=CC(F)=CC=2F)(C=O)C1)=O)(C)(C)C.COC(C1(CC2C=CC=CC=2)C(=NO)CCN(CC2C=CC=CC=2)C1)=O>C(Cl)Cl.CCOC(C)=O.O.C1COCC1>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][NH:32][C:31]([CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)([CH:35]=[CH:15][C:13]([O:12][CH3:11])=[O:14])[CH2:30]1)=[O:28])([CH3:23])([CH3:24])[CH3:25]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CC(C)(C)OC(=O)N1CCNC(C=O)(Cc2ccccc2)C1
Agent: CC(C)(C)OC(=O)N1CCNC(C=O)(Cc2ccc(F)cc2F)C1
Agent: COC(=O)C1(Cc2ccccc2)CN(Cc2ccccc2)CCC1=NO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C=CC1(Cc2ccccc2)CN(C(=O)OC(C)(C)C)CCN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a THF (1 mL) solution of NaHMDS at 0° C. was added trimethyl phosphonoacetate (0.18 mL, 1.1 mmol), dropwise. After stirring for 1 hour, a THF (1 mL) solution of crude 3-benzyl-3-formyl-piperazine-1-carboxylic acid tert-butyl ester (0.34 mg, 0.92 mmol), prepared analogous to the compound of Example 198, Step A, was added and the reaction was allowed to warm to room temperature. After stirring for 16 hours, the product was isolated by extraction from water with EtOAc (2×) and methylene chloride (2×). The combined extracts were washed with brine, dried (MgSO4) and concentrated. The product was then purified by silica gel chromatography using methylene chloride, then 5% MeOH in methylene chloride as eluents to afford a 7:3 E:Z mixture of olefins of the compound of Example 201, Step A (0.38 g, 81%), where the Z isomer had lactamized: +APcl MS (M+1, ester)+ 361, (M-tButyl+1, ester)+ 305, (M-tBu+1, lactam)+ 273, (M-BOC+1, ester)+ 261, (M-BOC+1, lactam)+ 229; 1H NMR (400 MHz, CDCl3) δ: 7.30-7.05 (arom, series of m, 5 H), 6.91 (lactam olefin, d, 0.3H), 6.75 (ester olefin, d, 0.7H), 6.09 (lactam olefin, d, 0.3H), 5.88 (ester olefin, d, 0.7H), 3.71 (ester Me, s 2.1H), 1.47 (BOC, s, 9H).
Reaction SMILES: N[C:2]1[C:14]([Br:15])=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[C:3]=1[Br:16].CCOCC>CN(C=O)C>[Br:16][C:3]1[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]=2[CH:13]=[C:14]([Br:15])[CH:2]=1
Reactant: Nc1c(Br)cc2oc3ccccc3c2c1Br
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Brc1cc(Br)c2c(c1)oc1ccccc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 116.4 %

Procedure:
To a solution of t-butylnitride (0.89 ml, 7.2 mmol) dissolved in 10 ml of DMF at 50° C. was added dropwise a solution of 2-amino-1,3-dibromodibenzofuran 17 (1.0 g, 2.9 mmol) in 10 ml of DMF with nitrogen evolution. After stirring at 50° C. for 1 hour the reaction was diluted into ether and washed successively with H2O and saturated NaCl. Drying over MgSO4 and evaporation gave 1.1 g of a red solid which was purified by flash chromatography through 100 g of silica gel (20% methylene chloride:hexane) yielding 650 mg (68%) of the title compound as a pale orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Br:10]Br.C(N)(C)(C)C>C1(C)C=CC=CC=1>[Br:10][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[OH:9]
Reactant: BrBr
Reactant: Oc1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1
Solvent: CC(C)(C)N
Product: Oc1c(Cl)cc(Cl)cc1Br
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 467.3 %

Procedure:
To a solution of 2,4-dichloro-phenol (15 g, 19.02 mmol) in toluene (200 ml) was added bromine (5.1 ml, 184.04 mmol) dropwise at −50° C. Then, tert-butylamine (19.4 ml, 99.02 mmol) was added dropwise and the reaction mixture was stirred at −50° C. for 30 minutes. The reaction was quenched by addition of 38% aqueous NaHSO3 solution, the organic layer was separated and the aqueous layer was extracted two times with EtOAc. The combined organic extracts were dried with Na2SO4, filtered and evaporated to obtain the title compound (21.5 g, 96%) as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH2:17](O)[CH3:18]>>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([O:6][CH2:17][CH3:18])=[O:5]
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(Br)ccc1N

Procedure:
2-Amino-5-bromobenzoic acid (24.7 g, 11.4 mol) was dissolved in 350 mL of ethanol and 2, and 5 mL of concentrated H2SO4 was added. The mixture was refluxed under N2 for 12 h. The solvent was removed and the residue was added with EtOAc. The mixture was extracted with 1N NaOH. The organic solution was washed with brine, dried over MgSO4. It was concentrated and chromatographed with CH2Cl2 to give 3.19 g of 2-amino-5-bromobenzoic acid, ethyl ester. MS (AP+): 243.9, 246, M+H.
Reaction SMILES: [NH2:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[OH-].[Na+].[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](Cl)=[O:19]>C(OCC)(=O)C>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]([NH:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:19]
Reactant: O=C(Cl)c1ccco1
Reactant: NC1(C(=O)O)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C(NC1(C(=O)O)CCCCC1)c1ccco1
Temperature: 80 °C
Reaction time: 2 h
Yield: 237.3 %

Procedure:
71.6 g (0.5 mol) of 1-aminocyclohexanecarboxylic acid was added to 250 ml of an aqueous solution of 20 g (0.5 mol) of sodium hydroxide, and the mixture was stirred at 80° C. for 2 hours. The mixed solution was cooled with ice-water, and 71.8 g (0.2 mol) of 2-furancarbonyl chloride and 100 ml of an aqueous solution of 24 g (0.6 mol) of sodium hydroxide were simultaneously added thereto over approximately 1 hour. The temperature of the reaction solution was slowly returned to room temperature and the solution was stirred overnight. After 80 ml of ethyl acetate was added to the reaction solution and the solution was stirred for 1 hour, the insolubles were removed by filtration. The aqueous layer was separately collected and 49 ml of concentrated hydrochloric acid was added thereto under ice-cooling. The precipitated crystal was collected by filtration and dried under reduced pressure to obtain 112.6 g (95%) of the title compound.
Reaction SMILES: OS(O)(=O)=O.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[OH:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O.CC(C)=O>[O:19]=[C:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(NC1CCCCC1O)OCc1ccccc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: O=C(NC1CCCCC1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79 %

Procedure:
CrO3 (0.70 g) and concentrated H2SO4 (0.61 mL) was diluted with H2O to the volume of 6 mL to make Jones Reagent at a concentration of 1.17 M. To a solution of benzyl 2-hydroxycyclohexylcarbamate (1.60 g, 6.43 mmol) in acetone (5.4 mL), cooled in a water bath, was added Jones Reagent (5.51 mL, 1.17 M, 6.43 mmol) dropwise over 5 min. The reaction mixture was stirred at room temperature for 1.5 hr, quenched with 20% aq. K2CO3 to pH=8. The aqueous layer was extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by ISCO chromatography (40 g column) using hexanes/EtOAc (0-30% over 8 min, 30-45% over 10 min) to give benzyl 2-oxocyclohexylcarbamate as a colorless oil at a retention time of 8.5-11 min (1.26 g, 79% yield) HPLC: RT=2.69 min, Purity 99% (HPLC Method 1) NMR: 400 MHz 1H (CDCl3) 7.33 ppm, 5 H, m; 5.76 ppm, 1 H, s; 5.11 ppm, 2 H, m; 4.27 ppm, 1 H, m; 2.65 ppm, 1 H, dd, J=6.60, 2.75 Hz; 2.52 ppm, 1 H, m; 2.38 ppm, 1 H, m; 2.13 ppm, 1 H, m; 1.89 ppm, 1 H, m; 1.77 ppm, 1 H, m; 1.64 ppm, 1 H, m; 1.42 ppm, 1 H, m.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[I:10]I.[OH-].[K+]>CN(C=O)C>[I:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1
Reactant: c1ccc2[nH]ncc2c1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Ic1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 99.4 %

Procedure:
In a 50 mL round-bottomed flask, indazole (0.80 g, 6.8 mmol) was dissolved in DMF (14 mL). Iodine (3.4 g, 13.5 mmol) was added followed by potassium hydroxide (1.47 g, 26.2 mmol). The dark reaction mixture was stirred at room temperature for 1.25 h then was quenched with 10% aq NaHSO3 and extracted with diethyl ether (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated to give 1.65 g (95%) of 3-iodo-1H-indazole as a light yellow solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 10.56 (br. s, 1H), 7.47-7.57 (m, 3H), 7.23-7.30 (m, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:15]C(C)([O-])C.[K+].[I-].C[S+](C)(C)=O>C(O)CCC>[O:1]1[C:2]2([CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (5 g, 25 mmol) in BuOH (20 mL) was added potassium tert-butoxide (4.125 g, 18.75 mmol). The mixture was stirred at 50° C. for 1 h. Then trimethyl sulfoxonium iodide (11 g, 50 mmol) was added to the mixture, and the resulting reaction mixture was stirred at 50° C. overnight. When TLC showed that s.m. was consumed, the mixture was cooled and filtered. The filtrate was concentrated to give the crude product which was used in the next step without further purification.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:8]([O:12][CH3:13])(=[O:11])[CH:9]=[O:10]>C(=O)([O-])O.[Na+]>[OH:10][C@@H:9]([CH2:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1)[C:8]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C=O
Reactant: C=C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)[C@@H](O)CC1=CCCCC1
Temperature: -10 °C
Yield: 70.6 %

Procedure:
A solution of an (S)-binaphthol-dichlorotitanium complex (0.1 mmole) which had been prepared in the same manner as in Example 1 was cooled to -10° C. and there was added thereto 96 mg (1 mmole) of methylenecyclohexane and 88 mg (1 mmole) of methyl glyoxylate, followed by reaction for 8 hours. Then, 10 ml of an aqueous sodium hydrogen carbonate solution was added to terminate the reaction. The reaction mixture was filtered through Celite and extracted with two 20 ml portions of diethyl ether and two 20 ml portions of ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. Thereafter, the solvents were distilled off, and hexane was added to the residue to crystallize binaphthol. The remaining solution was purified by mean of silica gel column chromatography to obtain 0.13 g of methyl (S)-2-hydroxy-3-(1-cyclohexenyl)propanoate. The yield was 73%.
Reaction SMILES: Br[C:2]1([CH3:19])[O:6][C:5]([CH3:17])([C:7]23[CH2:16][CH:11]4[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]4)[CH2:8]2)[CH2:14]3)[O:4][C:3]1=[O:18].CN(C)C=O.C(OC(C)C)(C)C>>[CH2:19]=[C:2]1[O:6][C:5]([C:7]23[CH2:14][CH:13]4[CH2:15][CH:9]([CH2:10][CH:11]([CH2:12]4)[CH2:16]2)[CH2:8]3)([CH3:17])[O:4][C:3]1=[O:18]
Reactant: CC1(Br)OC(C)(C23CC4CC(CC(C4)C2)C3)OC1=O
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Product: C=C1OC(C)(C23CC4CC(CC(C4)C2)C3)OC1=O
Temperature: 40 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
16.5 g (0.05 mol) of the obtained 5-bromo-2,5-dimethyl-2-(1-adamantyl)-1,3-dioxolan-4-one was placed in a 100 ml egg-plant type flask, and 73.1 g (1.0 mol) of N,N-dimethylformamide was added thereto, followed by intensively stirring at 40° C. for 2 hours. After completion of the stirring, the mixture was transferred into a 500 ml separatory funnel, and 200 g of isopropyl ether was added thereto, followed by fully shaking. Thereafter, the obtained mixture was left at rest, so as to separate the mixture into two layers. And then, the N,N-dimethylformamide phase that was a lower layer was removed. The isopropyl ether phase that was a upper layer washed with water to remove N,N-dimethylformamide dissolved therein. Thereafter, isopropyl ether was removed, so as to obtain white crystals. The obtained white crystals were recrystallized from hexane, so as to obtain 10.9 g of 5-methylene-2-(1-adamantyl)-2-methyl-1,3-dioxolan-4-one at a purity of 99.8% (Formula (19), yield: 88%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[C:34]3[C:29](=[C:30]([Cl:36])[CH:31]=[C:32]([Cl:35])[CH:33]=3)[CH2:28][N:27]([CH3:37])[CH2:26]2)[CH:20]=1)(=[O:18])=[O:17])=[N+]=[N-].O.P(C)(C)C>C1COCC1>[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[C:34]3[C:29](=[C:30]([Cl:36])[CH:31]=[C:32]([Cl:35])[CH:33]=3)[CH2:28][N:27]([CH3:37])[CH2:26]2)[CH:20]=1)(=[O:18])=[O:17]
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN=[N+]=[N-])c2)C1
Agent: CP(C)C
Solvent: O
Solvent: C1CCOC1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN)c2)C1
Reaction time: 8 h
Yield: 57.9 %

Procedure:
N-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (intermediate 28.1) (1.035 g, assume 1.41 mmol) was dissolved in a 10:1 THF:water solution (26.5 mL) and placed under N2. PMe3 (165 mg, 2.18 mmol) was added and the reaction stirred overnight. The solvent was removed and the resulting residue brought up in EtOAc (100 mL) and washed with NaHCO3 (100 mL) and brine (100 mL). After drying the organic layer over Na2SO4, the solvent was removed to give 446 mg of the title compound (58% over two steps) as an oil. A portion of the crude product was purified by preparative HPLC to give the title compound as a TFA salt. 1H-NMR (400 mHz, CD3OD) δ 7.87 (m, 1H), 7.73 (m, 1H), 7.67 (t, j=7.7 Hz, 1H), 7.54 (m, 2H), 6.82 (s, 1H), 4.8-4.6 (m, 4H), 4.46 (m, 1H), 3.86 (m, 1H), 3.69 (m, 2H), 3.66 (s, 3H), 3.61 (m, 2H), 3.55 (m, 2H), 3.12 (m, 4H), 3.03 (t, j=5.4 Hz, 1H). MS (m/z): 546.18 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([CH2:11][C@H:12]([CH3:23])[C:13]([O:15]CC2C=CC=CC=2)=[O:14])(=[O:10])=[O:9])[CH2:4][CH2:3]1>CO.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([S:8]([CH2:11][C@H:12]([CH3:23])[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])[CH2:6][CH2:7]1
Reactant: C[C@@H](CS(=O)(=O)N1CCN(C)CC1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@@H](CS(=O)(=O)N1CCN(C)CC1)C(=O)O

Procedure:
A 100 mL Fisher/Porter vessel was charged with benzyl 3-[(4-methylpiperizin-1-yl)sulfonyl]-2(R)-methylpropionate in 15 mL MeOH with a catalytic amount of 10% Pd—C. Hydrogenation at 50 psi for 48 hours afforded, after filtration through Celite and concentration in vacuo to yield 3-[(4-methylpiperizin-1-yl)sulfonyl]-2(R)-methylpropionic acid as a hygroscopic foam suitable for use without further purification.
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([C:19]1[C:24]([OH:25])=[C:23]([O:26][CH3:27])[C:22]([O:28][CH3:29])=[CH:21][C:20]=1[CH3:30])=[O:18])(=O)C>CO>[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([C:19]1[C:24]([OH:25])=[C:23]([O:26][CH3:27])[C:22]([O:28][CH3:29])=[CH:21][C:20]=1[CH3:30])=[O:18]
Reactant: COc1cc(C)c(C(=O)CCCCCCCCCCOC(C)=O)c(O)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C)c(C(=O)CCCCCCCCCCO)c(O)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
Sodium hydroxide (7 g) is added to a solution of 6-(11-acetoxy-1-oxoundecyl)-2,3-dimethoxy-5-methylphenol (34 g) in methanol (300 ml) and the mixture is stirred at room temperature for 2 hours. To the reaction mixture is neutralized with 5N--HCl and the solvent is distilled off, whereupon crude crystals are obtained. These crystals are rinsed with water and recrystallized from ether-hexane (1:1). The above procedure yields colorless needles of 6-(11-hydroxy-1-oxoundecyl)-2,3-dimethoxy-5-methylphenol (30 g), m.p. 81° C.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][C:8]=1[C:14]([F:17])([F:16])[F:15].N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][C:3]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([Cl:6])=[C:8]([C:14]([F:17])([F:15])[F:16])[CH:9]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCl)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
Chloroacetic acid chloride (0.69 ml; 8.44 mmol) is dropped slowly into a stirred solution of 4-chloro-3-trifluoro methyl aniline (1.5 g; 7.67 mmol) in pyridine (0.81 ml; 9.97 mmol) and dichloromethane (15 ml), cooled to 0° C. Stirring is continued for 2 h at room temperature. The reaction mixture is diluted with dichloromethane, washed twice with 1N aqueous hydrochloric acid and with water. The reaction mixture is then dried over Na2SO4, filtered and evaporated to yield 2.05 g (98%) brownish solid of 9.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=[O:24])[CH:18]=2)=[C:12]([CH3:25])[CH:11]=1.N1C=CN=C1>CN(C=O)C>[Si:1]([O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=[O:24])[CH:18]=2)=[C:12]([CH3:25])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cc(O)cc(C)c1-c1cccc(C=O)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cc(O[Si](C)(C)C(C)(C)C)cc(C)c1-c1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
By adding tert-butyl(dimethyl)silyl chloride to a DMF solution of 4′-hydroxy-2′,6′-dimethylbiphenyl-3-carbaldehyde and imidazole, and stirring at room temperature for 10 hours, 4′-{[tert-butyl(dimethyl)silyl]oxy}-2′,6′-dimethylbiphenyl-3-carbaldehyde was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[OH-:15].[Na+].Cl>CO>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[OH:15])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1O
Reaction time: 0.17 h

Procedure:
45 g of 4-chloro-3-nitro-benzotrifluoride, dissolved in 150 ml of methanol, are initially introduced. 80 g of an ion exchanger resin containing quaternary ammonium groups are then introduced, the mixture is stirred for 10 minutes, 100 g of 50% strength sodium hydroxide solution are added dropwise, up to a maximum temperature of 70° C., and the mixture is stirred at 65° C. for 8 hours. After cooling the mixture, it is acidified with concentrated hydrochloric acid, the ion exchanger is filtered off and the crude product is distilled with steam. 27 g of 2-nitro-4-trifluoromethylphenol are obtained. nD20 : 1.5003.
Reaction SMILES: [OH-:1].[Na+].[N+:3]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1Cl)([O-:5])=[O:4].Cl>CS(C)=O>[N+:3]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1[OH:1])([O-:5])=[O:4]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1O

Procedure:
87.6 g of finely powdered sodium hydroxide was added in portions over an 8-hour period to a stirred solution of 164.0 g of 2-nitro-4-(trifluoromethyl)chlorobenzene in 220 ml of dimethyl sulfoxide at room temperature. The mixture was acidified to pH 1 with concentrated hydrochloric acid. An oil formed; it was separated and dissolved in ether. The solution was dried (MgSO4) and stripped of solvent under reduced pressure. The residue was mixed with cold sodium hydroxide solution. The mixture was extracted with petroleum ether. The water layer was acidified with concentrated hydrochloric acid. An oil that formed was separated and dissolved in ether. The solution was dried (MgSO4) and stripped of solvent to give 2-nitro-4-(trifluoromethyl)phenol (A).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.[CH2:14](Br)[CH2:15][CH3:16].[Mg].Cl>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ni]Cl.O>[CH3:13][O:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH2:14][CH2:15][CH3:16])[CH:3]=2)[CH:8]=1
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: CCCBr
Agent: Cl[Ni]Cl
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1ccc2cc(OC)ccc2c1
Reaction time: 1 h
Yield: 101.8 %

Procedure:
To a solution of 200 g of 2-bromo-6-methoxynaphthalene and 2.5 g of dichloro[1,2-bis(diphenylphosphino)ethane]nickel (II) in 200 ml of tetrahydrofuran (THF) was added dropwise a Grignard reagent prepared from 125 g of propyl bromide and 27 g of magnesium under nitrogen atomsphere. The reaction mixture was further stirred for 1 hour, and then poured into water. To the reaction mixture was then added diluted hydrochloric acid. The resulting organic phase was then separated. The resulting aqueous phase was extracted with toluene. The organic phase and the material thus extracted were together washed sequentially with water, saturated aqueous solution of sodium bicarbonate, water and saturated brine, and then dehydrated and dried over anhydrous sodium sulfate. The solvent was then distilled off to obtain 172 g of 2-methoxy-6-propylnaphthalene.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[OH:17][C:18]1[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[C:24]2[C:19]=1[C:20](=[O:38])[N:21](COC(=O)C(C)(C)C)[CH:22]=[N:23]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:59]1[CH2:64][CH2:63][N:62]([CH3:65])[CH2:61][CH2:60]1.N>C(Cl)Cl>[CH3:29][O:28][C:27]1[C:18]([O:17][CH:59]2[CH2:64][CH2:63][N:62]([CH3:65])[CH2:61][CH2:60]2)=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][NH:21][C:20]2=[O:38]
Reactant: COc1ccc2ncn(COC(=O)C(C)(C)C)c(=O)c2c1O
Reactant: CN1CCC(O)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc2nc[nH]c(=O)c2c1OC1CCN(C)CC1
Temperature: 5 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
A solution of di-tert-butyl azodicarboxylate (1.75 g ) in methylene chloride (3 ml) was added to a stirred mixture of 5-hydroxy-6-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one (1.55 g), triphenylphosphine (1.99 g), 4-hydroxy-1-methylpiperidine (0.75 g) and methylene chloride (12 ml) which had been cooled to 5° C. The mixture was stirred at ambient temperature for 1 hour. The mixture was evaporated and the residue was purified by column chromatography on silica using a 9:10:1 mixture of methylene chloride, ethyl acetate and a saturated methanolic ammonia solution as eluent. The material so obtained was stirred in a saturated methanolic ammonia solution for 48 hours. The mixture was evaporated and the residue was triturated under diethyl ether. The resultant solid was washed with diethyl ether and dried under vacuum to give 6-methoxy-5-(N-methylpiperidin-4-yloxy)-3,4-dihydroquinazolin-4-one (0.92 g); NMR Spectrum: (DMSOd6) 1.7–1.9 (m, 4H), 1.95 (t, 2H), 2.15 (s, 3H), 2.7 (m, 2H), 3.85 (s, 3H), 4.08 (m, 1H), 7.4 (d, 1H), 7.6 (d, 1H), 7.85 (s, 1H), 11.8 (br s, 1H); Mass Spectrum: M+H+ 290.