Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:12]1[CH:20]=[CH:19][C:15]([N:16]([CH3:18])[CH3:17])=[CH:14][C:13]=1Br)[C:2]1[CH:10]=[CH:9][C:5]([N:6]([CH3:8])[CH3:7])=[CH:4][C:3]=1Br.[Li]C(CC)C.[Ge:27](Cl)(Cl)([CH3:29])[CH3:28].C1C[O:35]CC1>>[CH3:17][N:16]([CH3:18])[C:15]1[CH:19]=[CH:20][C:12]2[C:1](=[O:35])[C:2]3[CH:10]=[CH:9][C:5]([N:6]([CH3:8])[CH3:7])=[CH:4][C:3]=3[Ge:27]([CH3:29])([CH3:28])[C:13]=2[CH:14]=1
Reactant: C[Ge](C)(Cl)Cl
Reactant: C1CCOC1
Reactant: CN(C)c1ccc(Cc2ccc(N(C)C)cc2Br)c(Br)c1
Agent: [Li]C(C)CC
Product: CN(C)c1ccc2c(c1)[Ge](C)(C)c1cc(N(C)C)ccc1C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the solution of 4,4′-methylene-bis(3-bromo-N,N-dimethylaniline) (2.0 g, 4.85 mmol) in anhydrous THF (50 mL), 1.4 M sec-BuLi (12.13 mmol) at −78° C. was added, and the mixture stirred for 30 min. At the same temperature, a solution of GeMe2Cl2 (1.26 g, 7.28 mmol) in anhydrous THF (15 mL) was slowly added. The mixture was warmed to room temperature and stirred for 1 h. The reaction was quenched by addition of 2 N HCl (7 ml), and the mixture neutralized with NaHCO3 and extracted with CH2Cl2. The organic layer was washed with brine and dried over Na2SO4. To this solution, the sufficient chlorinil (5 eq.) was added, and the resultant mixture stirred for 2 hours. Acetone/saturated NaHCO3 (50 mL/100 ml) were added, and the mixture stirred overnight. The mixture was then diluted with CH2Cl2 (200 mL), filtered through glass wool, and the filtrate extracted three times with methylene chloride and evaporated to dryness. The residue was purified by silica column chromatography using heptane/methylene chloride/ethyl acetate as eluent to give light yellow compound. 1HNMR (300 MHz, CD2Cl2): δ 8.32 (d, 2H), 6.7-6.90 (m, 4H), 3.20 (s, 12H, NCH3), 0.6 (d, 6H, CH3); MS (m/e): calculated 370.11. found 371.0 for [M+H]+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[O:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[CH2:39][S:40][CH2:41][C:42](=[N:44]O)[NH2:43]>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:16]2[O:18][N:43]=[C:42]([CH2:41][S:40][CH2:39][C:35]3[O:34][CH:38]=[CH:37][CH:36]=3)[N:44]=2)[N:8]([C:6]([C:31]2[CH:30]=[CH:29][C:28]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:33][CH:32]=2)=[O:7])[CH2:12]1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NC(CSCc1ccco1)=NO
Product: CON=C1C[C@@H](c2nc(CSCc3ccco3)no2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 59, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylic acid (Intermediate 2), [1,1′-biphenyl]-4-carbonyl chloride, and 2-[(2-furylmethyl)sulfanyl]-N′-hydroxyethanimidamide, the title compound was obtained in 53% purity by HPLC. MS(ESI+): m/z=489.6.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([OH:17])=[C:12]([F:18])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][N:22]=1.[H-].[Na+].O>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][N:22]=2)=[C:12]([F:18])[CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)NCCc1cc(F)c(O)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCc1cc(F)c(Oc2ccc(C#N)cn2)c(F)c1
Yield: 51 %

Procedure:
A solution of phenol obtained in step 3 above (1.31 g, 4.8 mmol), 6-chloronicotinonitrile (700 mg, 5.04 mmol) and sodium hydride (290 mg, 7.2 mmol) in DMSO (25 mL) is stirred at room temperature for 18 h. Pour the mixture into iced water and extract the aqueous layer with EtOAc. Dry the organic layer over Na2SO4, filtrate and eliminate the solvent. Purify by flash chromatography (EtOAc/hexane 20/80 and 34/66) to get the title compound (950 mg, 51%). 1H-NMR (CDCl3, 200 MHz): 8.41 (dd, 1H, J=0.8 and 2.1 Hz), 7.97 (dd, 1H, J=2.4 and 8.6 Hz), 7.18 (dd, 1H, J=0.8 and 8.6 Hz), 6.92-6.81 (m, 2H), 3.39 (q, 2H, J=6.9 Hz), 2.81 (t, 2H, J=6.7 Hz), 1.45 (s, 9H).
Reaction SMILES: C[O:2][C:3](=[O:46])[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][CH2:17][CH2:18][N:19]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[C:36]=2[Cl:45])[CH2:20][CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:10]=1)([CH2:7][CH3:8])[CH2:5][CH3:6].[Li+].[Cl-]>CN(C=O)C>[ClH:45].[Cl:45][C:36]1[C:37]([C:41]([F:42])([F:43])[F:44])=[CH:38][CH:39]=[CH:40][C:35]=1[CH2:34][N:19]([CH2:20][CH:21]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:18][CH2:17][CH2:16][O:15][C:11]1[CH:10]=[C:9]([C:4]([CH2:5][CH3:6])([CH2:7][CH3:8])[C:3]([OH:46])=[O:2])[CH:14]=[CH:13][CH:12]=1
Reactant: CCC(CC)(C(=O)OC)c1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCC(CC)(C(=O)O)c1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Product: Cl
Reaction time: 0.17 h

Procedure:
A solution of 2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-2-ethyl-butyric acid methyl ester (30 mg, 0.05 mmol) in DMF (9 mL) was treated with LiCl (20 mg, 0.46 mmol). The resulting reaction mixture was heated to reflux overnight and concentrated. The crude product was purified by HPLC (YMC CombiPrep ODS-A, 50×20 mm, 20 mL/min, A:acetonitrile B:water, A: 60 to 100% during 10 min, UV detection at 254 nm) to give the title compound, the free amine as an oil (15 mg, 45%). To a solution of the free amine in diethyl ether was added HCl in diethyl ether (1.0 M) to precipitate the amine salt. The suspension was filtered and dried to give the title compound as a white solid. MS m/e 638.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[N:13]([CH3:14])[N:12]=[CH:11][CH:10]=1.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.[Li]CCCC.[OH-].[Na+]>O.C(OCC)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([B:15]([OH:20])[OH:16])=[C:3]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][CH:10]=2)[CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cn1nccc1-c1cc(Cl)ccc1Br
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: Cn1nccc1-c1cc(Cl)ccc1B(O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
A 50-mL round-bottom flask was charged with 5-(2-bromo-5-chlorophenyl)-1-methyl-1H-pyrazole (992.0 mg, 3.65 mmol), diethyl ether (18 mL), and triisopropyl borate (1 mL, 4.38 mmol). The flask was cooled in a dry ice-acetone bath for 10 min, then n-BuLi (1.91 mL, 4.38 mmol) was added dropwise over a couple of minutes. Following the addition, the cooling bath was removed, and the mixture was warmed to room temperature. An aq. 2N NaOH solution (20 mL, 40 mmol) was added, and the resulting mixture was stirred vigorously for 2 h. The mixture was diluted with water and diethyl ether. The layers were separated, and the ethereal layer was extracted with water (twice). The aq. layers were combined, and the combined aq. mixture as washed with diethyl ether. The etheral layer was back-extracted once more, and the aq. layers were all combined. The combined aq. solution was acidified to about pH 1 with 3N aq. HCl to give a clear solution. The aq. solution was extracted with EtOAc (three times), and the combined organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was taken up in DCM and concentrated under a vacuum to give (4-chloro-2-(1-methyl-1H-pyrazol-5-yl)phenyl)boronic acid (660 mg, 2.79 mmol) as a light-yellow foam. m/z (ESI) 237.0 (M+H)+.
Reaction SMILES: CC(OC(C)=O)=O.OS(O)(=O)=O.[I:13]I.[F:15][C:16]1[C:24]([F:25])=[C:23]([F:26])[CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]>O=[Mn]=O.C(Cl)Cl.CC(O)=O>[F:15][C:16]1[C:24]([F:25])=[C:23]([F:26])[C:22]([I:13])=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]
Reactant: O=C(O)c1ccc(F)c(F)c1F
Reactant: II
Agent: O=[Mn]=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: O=C(O)c1cc(I)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 232.1 %

Procedure:
AcOH (1.2 L) and Ac2O (0.63 L) were added to a 5 L flask. H2SO4 (1.6 L) was then added to the same flask while cooling with ice to prevent the temperature from exceeding 40° C. Next, I2 (70 g), activated MnO2 (70 g) and 2,3,4-trifluorobenzoic acid (120 g, 0.68 mol) were added in solid form while stirring at room temperature. While stirring the resulting dark purple suspension at 50° C., I2 (70 g) and activated MnO2 (70 g) were added after 2 to 3 hours, and I2 (33 g) and activated MnO2 (37 g) were further added after 4 to 6 hours. After 24 hours, the reaction mixture was added to ice water (2 L). The purple organic layer obtained by extraction three times with CH2Cl2 (1.6 L, 1.0 L, 1.0 L) was washed twice with 0.2N Na2S2O3 aqueous solution (2.0 L, 1.0 L), resulting in alteration of the organic layer color to pale yellow. The organic layer was washed four times with 1.0 L of water to remove the AcOH, yielding a non-cloudy transparent organic layer. After removing water in the organic layer with Na2SO4 (1.3 kg), the solvent was removed by distillation to yield 192 g of 2,3,4-trifluoro-5-iodobenzoic acid (0.64 mol, 94%, purity: 99 LC area % (UV peak area % in LC)) as white powders. If necessary, rinsing may be performed with a mixed solvent of ethanol and hexane (EtOAc: hexane=1:9 (v/v)).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[SH:27].C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([S:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][CH3:19])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1Cl
Reactant: COc1ccccc1S
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1Sc1ccc(C=O)c(Cl)c1Cl
Yield: 84.5 %

Procedure:
2,3-Dichloro-4-trifluoromethanesufonyloxy-benzaldehyde (2.50 g) was dissolved in 6 mL acetonitrile. 2-Methoxybenzenethiol (2.55 g of 70% pure material, 50% excess) was added. With cooling 2.50 g diisopropylethylamine was added slowly. The solution was removed from the ice bath, whereon a solid formed. The solution was warmed in a 50 C waterbath for 5 minutes. More acetonitrile (5 mL) was added and the mixture was cooled in ice, and then filtered to get 2.047 g of product, m.p. 137-139C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:21])[CH2:9][N:10]([CH3:20])[S:11]([C:14]2[CH:18]=[C:17]([Cl:19])[S:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:31][O:32][CH2:33]Cl.[I-].[Na+]>ClCCl.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:21][CH2:31][O:32][CH3:33])[CH2:9][N:10]([CH3:20])[S:11]([C:14]2[CH:18]=[C:17]([Cl:19])[S:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1csc(Cl)c1
Reactant: COCCl
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCOC(CN(C)S(=O)(=O)c1csc(Cl)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5-chlorothiophene-3-sulfonic acid [2-(4-fluorophenyl)-2-hydroxyethyl]-methyl-amide (the compound of Preparation Example 83) (1.33 g) in dichloromethane (7 mL) was added dropwise diisopropylethylamine (1.2 mL) and 0.34 mL of chloromethyl methyl ether (0.34 mL) on an ice bath. Sodium iodide (25 mg) was added, and the solution was stirred at room temperature for 4 hours at room temperature. In addition, diisopropylethylamine (1.2 mL) and chloromethyl methyl ether (0.34 mL) were added to this solution, and the solution was further stirred for 17 hours. After the solution was diluted with ethyl acetate, and was washed with water and saturated sodium chloride water. After drying the organic layer with anhydrous sodium sulfate, the residue that was obtained upon removing the solvent by evaporation was purified by silica gel column chromatography (hexane/ethyl acetate), and the title compound (646 mg) was obtained as a colorless solid. Recovery of raw materials was 557 mg.
Reaction SMILES: [NH2:1][C@H:2]([C:14]([NH:16][C:17]1[CH:18]=[N:19][N:20]([CH3:23])[C:21]=1[NH2:22])=[O:15])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C.[C:31]([O:35][C:36]([NH:38][CH2:39][CH2:40][C:41](ON1C(=O)CCC1=O)=[O:42])=[O:37])([CH3:34])([CH3:33])[CH3:32]>C(Cl)(Cl)Cl>[NH2:22][C:21]1[N:20]([CH3:23])[N:19]=[CH:18][C:17]=1[NH:16][C:14](=[O:15])[C@@H:2]([NH:1][C:41](=[O:42])[CH2:40][CH2:39][NH:38][C:36]([O:35][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:37])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:11])([CH3:12])[CH3:10]
Reactant: Cn1ncc(NC(=O)[C@@H](N)CCCNC(=O)OC(C)(C)C)c1N
Reactant: CC(C)(C)OC(=O)NCCC(=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cn1ncc(NC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)CCNC(=O)OC(C)(C)C)c1N
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of tert-butyl (4S)-4-amino-5-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-5-oxopentylcarbamate (4.90 g) and triethylamine (1.52 g) in chloroform (100 ml) was added N-[3-(tert-butoxycarbonylamino)propionyloxy]succinimide (4.26 g). The mixture was stirred at room temperature for 17 hours. The mixture was washed with saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a crude product of tert-butyl (4S)-5-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-4-{[3-(tert-butoxycarbonylamino)propionyl]amino}-5-oxopentylcarbamate as an oil. The crude product was used directly in the next step without further purification.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[C:20]1([C:26]2[S:30][C:29]([CH:31]=O)=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:31][C:29]2[S:30][C:26]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:27][CH:28]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1ccc(-c2ccccc2)s1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(-c2ccccc2)s1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 5-phenylthiophene-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.95 min.; [M+H]+: 408.32 g/mol.
Reaction SMILES: C([O:5][C:6]([C:8]1[S:9][C:10]([C:24]2[CH:28]=[CH:27][N:26](S(=O)(=O)N(C)C)[N:25]=2)=[CH:11][C:12]=1[NH:13][S:14]([C:17]1[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15])=[O:7])(C)(C)C.Cl>O1CCOCC1.CO.O>[NH:26]1[CH:27]=[CH:28][C:24]([C:10]2[S:9][C:8]([C:6]([OH:7])=[O:5])=[C:12]([NH:13][S:14]([C:17]3[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=3)(=[O:16])=[O:15])[CH:11]=2)=[N:25]1
Reactant: Cc1ccccc1S(=O)(=O)Nc1cc(-c2ccn(S(=O)(=O)N(C)C)n2)sc1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccccc1S(=O)(=O)Nc1cc(-c2cc[nH]n2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 26 h
Yield: 65.2 %

Procedure:
A reaction mixture of 5-(1-Dimethylsulfamoyl-1H-pyrazol-3-yl)-3-(toluene-2-sulfonylamino)-thiophene-2-carboxylic acid tert-butyl ester (10 mg, 0.019 mmol) and 4N HCl (0.3 mL) solution in dioxane in MeOH (0.3 mL) was stirred at room temperature 26 h. Reaction mixture was then diluted with water and extracted with EtOAc, concentrated and purified on preparative TLC using MeOH/CH2Cl2/AcOH (5:95:1) furnished the 5-(1H-Pyrazol-3-yl)-3-(toluene-2-sulfonylamino)-thiophene-2-carboxylic acid (4.5 mg, 65.2% yield). 1H NMR (CD3OD, 400 MHz) 7.99 (d, J=7.9 Hz, 1H), 7.81 (s, 1H), 7.43 (t, J=7.5, 1.3 Hz, 1H), 7.42-7.26 (m, 2H), 7.19 (s, 1H), 2.69 (s, 3H).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(OC(=O)C)(=O)C.[Br:18]Br.Cl.[OH-].[K+]>O.C(O)(=O)C>[Br:18][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:10]=[CH:9][C:7]=1[NH2:8]
Reactant: BrBr
Reactant: CC(C)c1ccc(N)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(C)c1ccc(N)c(Br)c1
Temperature: 50 °C

Procedure:
A mixture of 99 g (0.73 mol) of 4-isopropylaniline (Acros) and 300 ml of acetic acid was refluxed for 1 h; then, 75 g of acetic anhydride was added dropwise while vigorously stirring. The resulting solution was cooled to 50° C., and 37.4 ml of bromine was added dropwise, while vigorously stirring, over ca. 30 min. Then, 370 ml of 12 M HCl was added and this mixture was refluxed until a precipitate was formed. This precipitate was separated, washed with 2×150 ml of methyl-tert-butyl ether, and dried in vacuum. A mixture of the solid obtained and a solution of 112 g of KOH in 300 ml of water was stirred at 50-60° C. for 1 h. The organic layer was separated, and the aqueous layer was extracted with 2×150 ml of methyl-tert-butyl ether. The combined extract was dried over K2CO3 and evaporated to dryness. Fractional distillation gave the title product, b.p. 107-111° C./3 mm Hg. Yield 83.7 g (77%) of yellowish oil.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:22])[CH:11]=[C:12]([CH:19]([F:21])[F:20])[N:13]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[CH:14]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH:16]1([CH2:15][N:13]2[CH:14]=[C:9]([OH:8])[C:10](=[O:22])[CH:11]=[C:12]2[CH:19]([F:21])[F:20])[CH2:17][CH2:18]1
Reactant: O=c1cc(C(F)F)n(CC2CC2)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=c1cc(C(F)F)n(CC2CC2)cc1O
Yield: 83.3 %

Procedure:
A mixture of 5-benzyloxy-1-cyclopropylmethyl-2-difluoromethyl-1H-pyridin-4-one (3.0 g, 9.82 mmol) and 10% Pd/C (300 mg) in methanol (90 mL) was subjected to hydrogenation in a Parr apparatus under a 15 psi hydrogen pressure for 27 min. Work-up as described above for the cyclopropyl derivative, afforded the title product (1.76 g, 83% yield) after vacuum oven drying. HPLC purity (peak area percent) of the title compound is 99.5% at λ=288 nm using HPLC Method 1 as described above.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[C:6]([C:17]([F:20])([F:19])[F:18])[CH:5]=1)([O-:3])=[O:2].[O:21]1[CH2:24][C:23](=O)[CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(Cl)Cl>[N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH:23]3[CH2:24][O:21][CH2:22]3)[CH2:11][CH2:10]2)=[C:6]([C:17]([F:20])([F:18])[F:19])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(OC2CCNCC2)c(C(F)(F)F)c1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(OC2CCN(C3COC3)CC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A solution of 4-(4-nitro-2-(trifluoromethyl)phenoxy)piperidine (1.0 g, 1.0 eq, 3.5 mmol) and oxetan-3-one (0.35 g, 1.4 eq, 4.8 mmol) in 1,2-dichloroethane (50 mL) was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (1.3 g, 1.8 eq, 6.2 mmol) was added in portions to the above solution and the heterogeneous mixture was stirred at room temperature overnight. The reaction mixture was diluted with CH2Cl2 (50 mL) and pardoned with aqueous saturated NaHCO3 solution (100 mL). The layers were separated and the organic layer was washed with brine solution (2×50 mL). The combined organic layers were dried over Na2SO4. Removal of the solvents and purification of the crude mixture by column chromatography on silica gel (ISCO System) using 20% MeOH in CH2Cl2/CH2Cl2 (gradient system from 0:1 to 1:9) as eluent gave the product in 77% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=[O:7].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([Mg]Cl)[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1>C1COCC1>[CH3:12][O:11][C:9]1[CH:8]=[C:5]([CH:6]([C:17]2[CH:16]=[C:15]([O:14][CH3:13])[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=2)[OH:7])[CH:4]=[C:3]([O:2][CH3:1])[CH:10]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: COc1cc(OC)cc([Mg]Cl)c1
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(O)c2cc(OC)cc(OC)c2)c1
Temperature: 40 °C

Procedure:
3,5-Dimethoxybenzaldehyde (5.0 g, 30 mmol) was dissolved in 150 mL THF in a 500 mL round bottom flask. 3,5-Dimethoxyphenyl magnesium chloride (1 M in THF, 45 mL) was added slowly. The reaction was heated at 40° C. for 4 hours then quenched with saturated ammonium chloride. The mixture was extracted with 3 portions of ether and the combined organic layers washed with brine, dried over anhydrous MgSO4, then concentrated to a crude pale yellow solid which was carried forward to the next step: 1H NMR (250 MHz, C6D6): δ 3.29 (d, J=5.0 Hz, 12H), 6.46 (m, 2H), 6.56 (m, 1H), 6.76 (m, 2H), 7.04 (t, J=8.2 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:20])([CH3:19])[CH:13]=[C:12]2[CH2:21]SCC(NC)=O.BrCC1[C:39]2[C:34](=[CH:35][CH:36]=[C:37](C3C=CC=CC=3OC)[CH:38]=2)[NH:33]C(C)(C)C=1.CSNC(=O)C.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:19])([CH3:20])[CH:13]=[C:12]2[CH2:21][NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Reactant: CNC(=O)CSCC1=CC(C)(C)Nc2ccc(-c3ccccc3OC)cc21
Agent: CSNC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
2-[6-(2-Methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethylsulfanyl]-N-methylacetamide 50 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 15 mg of N-methylmercaptoacetoamide, and 58 mg of potassium carbonate reacted to give 22 mg of the title compound as a foam.
Reaction SMILES: C1(N2CC[O:9]CC2)CCCC=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=O.Cl.[CH:25]1[CH:30]=[CH:29][CH:28]=[CH:27]C=1>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=[C:27]1[CH2:28][CH2:29][CH2:30][C:25]1=[O:9]
Reactant: COc1ccc(C=O)cc1OC
Reactant: c1ccccc1
Reactant: C1=C(N2CCOCC2)CCC1
Agent: Cl
Product: COc1ccc(C=C2CCCC2=O)cc1OC
Temperature: 30 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
With reflux device installed, 36.8 g (0.24 mol) of N-cyclopentenyl morpholine, 0.20 mol of 3,4-dimethoxybenzaldehyde and 200 mL benzene were added to a round bottom flask and heated under reflux for 20 h. The resulting solution was cooled to 30° C. and slowly stirred while 62 mL of hydrochloric acid (6 mol/L) was added. After stirring for 2 h at room temperature, the benzene layer was separated and washed with water to neutral, and dried over anhydrous sodium sulfate overnight. Then the mixture was filtered to remove anhydrous sodium sulfate and benzene was recovered by evaporation under reduced pressure. The residue was cooled and solidified, then recrystallized in cyclohexane/ethanol to yield a light yellow flaky crystal product with a yield of 80.3%.
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]([OH:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([CH3:4])([CH3:3])[CH3:2].[CH3:26]I>>[CH3:2][CH2:1][O:5][CH2:6][CH3:7].[C:1]([O:5][CH2:6][CH:7]([O:25][CH3:26])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(O)COC(C)(C)C
Reactant: CI
Product: CCCCC/C=C\C/C=C\CCCCCCCC(COC(C)(C)C)OC
Product: CCOCC

Procedure:
(Z,Z)-(±)-1-t-butoxy-10,13-nonadecadiene-2-ol, from Example 1, was reacted with methyl iodide under Williamson conditions as in Example 1 to yield the mixed ether (Z,Z)-(±)-1-t-butoxy-2-methoxy-10,13-nonadecadiene; and the ether on the C-1 hydroxyl was cleaved by ferric chloride in acetic anhydride to yield (Z,Z)-(±)-2-methoxy-10,13-nonadecadien-1-ol having the following characteristics.