Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[F:28][C:29]([F:37])([F:36])[C@H:30]([OH:35])[CH2:31][C:32](O)=[O:33]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32](=[O:33])[CH2:31][C@@H:30]([OH:35])[C:29]([F:37])([F:36])[F:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: O=C(O)C[C@@H](O)C(F)(F)F
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(C[C@@H](O)C(F)(F)F)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (72 mg, 77%), MS (ISP) m/z=471.5 [(M+H)+], mp 207° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (88 mg, 0.2 mmol) and (R)-4,4,4-trifluoro-3-hydroxybutanoic acid.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:5]1([CH3:10])[O:9][CH2:8][CH2:7][O:6]1)[CH3:4].C[O-].[Na+].[CH:14](OCC)=[O:15]>CO>[CH:14]([NH:2][CH:3]([C:5]1([CH3:10])[O:9][CH2:8][CH2:7][O:6]1)[CH3:4])=[O:15]
Reactant: CC(N)C1(C)OCCO1
Reactant: CCOC=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(NC=O)C1(C)OCCO1
Reaction time: 4 h

Procedure:
2-(1-Aminoethyl)-2-methyl-1,3-dioxolane hydrochloride (1.3 g, 0.0078 mol) was dissolved in methanol (25 ml). Sodium methoxide (25% w/w in methanol. 1.68 g, 0.0078 mol) was added and the suspension filtered through Celite. The Celite was rinsed with methanol (25 ml) and the combined filtrates had the solvent removed by rotary evaporation (25 Torr, 40° C.). The resulting clear oil was dissolved in ethyl formate (10.36 g. 0.14 mol) and heated to reflux under nitrogen. The reflux was continued for 4 hours. The excess ethyl formate and ethanol byproduct were removed by rotary evaporation (25 Torr, 40° C.) and the resulting solid was dried in vacuo (0.5 Torr, 25° C., 16 hours). The product was
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.C([O:23][C:24](=O)[C:25]([F:28])([F:27])[F:26])C>C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:24](=[O:23])[C:25]([F:28])([F:27])[F:26])[CH:15]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CCOC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(c1cc(Br)ccc1F)C(F)(F)F
Temperature: -40 °C
Reaction time: 1 h

Procedure:
Diisopropylamine (4.40 mL, 31.4 mmol) was dissolved in THF (28 mL) and cooled to −40° C. Then n-butyllithium (12.6 mL, 2.5 M in hexanes, 31.4 mmol) was added dropwise, and the reaction was stirred at −40° C. for 1 h, then cooled to −78° C. A solution of 1-bromo-4-fluorobenzene (5 g, 28.6 mmol) in THF (6.0 mL) was added, and the reaction was stirred at −78° C. for 1 h. Trifluoroacetic acid ethyl ester (3.73 mL, 31.4 mmol) in THF (6.0 mL) was then added, and the reaction was slowly warmed to 0° C. over an hour. The reaction was quenched with NH4Cl (aq. sat), and extracted with EtOAc, washed with brine, and dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column chromatography (EtOAc/heptane) provided 1-(5-bromo-2-fluorophenyl)-2,2,2-trifluoroethanone.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:25])[C:7]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:8][C:9](=[N:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][CH:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([C:5]1[CH:10]=[C:9]([CH:8]=[C:7]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=1[OH:25])[NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([OH:20])=[O:19])=[CH:16][CH:17]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1=CC(=Nc2ccc(C(=O)O)cc2)C=C(C(C)(C)C)C1=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)c1cc(Nc2ccc(C(=O)O)cc2)cc(C(C)(C)C)c1O

Procedure:
To a solution of 5.0 g (0.0147 mole) of 2,6-di(tertiary-butyl)-4-(4'-carboxyphenylimino)-2,5-cyclohexadien-1-one in 300 ml of ethanol was added 0.25 g of 5 percent palladium on charcoal. It was subjected to hydrogenation in a Paar apparatus and filtered. This solvent was removed by evaporation under vacuum and the residue was recrystallized from a 5:2 (v/v) ethanol-water mixture to provide light-orange crystals of 4-(3,5-di-tertiary-butyl-4-hydroxyanilino)benzoic acid, m.p. 241°-243° C. Analysis: Calculated for C21H27NO3 : % C, 73.9; % H, 8.0; % N, 4.1; Found: % C, 73.9; % H, 7.9; % N, 3.8.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[I:11].S(=O)(=O)(O)O.[CH3:17]O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[CH:4][C:3]=1[I:11]
Reactant: O=C(O)c1ccc(Cl)c(I)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Cl)c(I)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
4-Chloro-3-iodo-benzoic acid (5.31 g, 18.8 mmol) was dissolved in methanol (50 mL) and concentrated sulfuric acid (3 mL) was carefully added. The solution was stirred at 80° C. for 4 hours, then cooled to room temperature and the volatile organics were removed under reduced pressure. The residue was partitioned between EtOAc (50 mL) and water (50 mL) and the organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2; 0-10% EtOAc in hexanes) to yield 5.32 g (95%) of the title compound as an oil. 1H NMR (400 MHz, Chloroform-d) δ 8.54 (d, J=2.0 Hz, 1H), 7.96 (dd, J=8.4, 2.0 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 3.94 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][N:14]1[C:19]2[CH:20]=[C:21]([N+:24]([O-])=O)[CH:22]=[CH:23][C:18]=2[O:17][CH2:16][CH2:15]1)[C:6]([O:8][CH3:9])=[O:7].[H][H]>C(OCC)(=O)C.[Pd]>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]2[O:17][CH2:16][CH2:15][N:14]([CH2:13][C:12]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=3[O:2][CH3:1])[C:19]=2[CH:20]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(CN2CCOc3ccc([N+](=O)[O-])cc32)c(OC)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CN2CCOc3ccc(N)cc32)c(OC)c1
Yield: 98.9 %

Procedure:
Palladium-on-carbon (10% w/w, 0.2 g.) was added to a solution of (G) (0.69 g.) in ethyl acetate (50 ml.) in a hydrogenation bottle and the mixture hydrogenated at a pressure of 3.17 bars of hydrogen. When the uptake of hydrogen had ceased, catalyst was removed by filtration through diatomaceous earth. The filter pad was washed with ethyl acetate and the filtrate and washings were evaporated to give methyl 4-(6-amino-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl)-3-methoxybenzoate (0.625 g., 91%) as a foam; NMR 3.1(br s,2H, NH2), 3.3(t,2H, OCH2CH2N), 3.85(m,6H, OCH +CO2CH3), 4.2(t,2H, OCH2CH2N), 4.45(s, 2H, C H2 --Ar), 6.0(m,2H), 6.55(d,1H), 7.3(d,1H), 7.55(m, 2H).
Reaction SMILES: Cl[CH2:2][C@H:3]([OH:18])[CH2:4][P:5]([C:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])[CH3:11])(=[O:9])[O:6][CH2:7][CH3:8].[NH3:19]>C(O)C>[NH2:19][CH2:2][C@H:3]([OH:18])[CH2:4][P:5]([C:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])[CH3:11])(=[O:9])[O:6][CH2:7][CH3:8]
Reactant: N
Reactant: CCOC(C)(OCC)P(=O)(C[C@@H](O)CCl)OCC
Solvent: CCO
Product: CCOC(C)(OCC)P(=O)(C[C@@H](O)CN)OCC
Yield: 26 %

Procedure:
A solution of ethyl (2R)-(3-chloro-2-hydroxypropyl)(1,1-diethoxyethyl)phosphinate (5.0 g, 17 mmol) in ethanol containing 9% of ammonia was stirred in an autoclave at room temperature for 4 days and at 60° C. for one further day. The solution was evaporated and the residue was purified by chromatography on a wet-packed silica gel column eluting with methylene chloride/methanol (5–8% MeOH) containing 5% triethylamine. The appropriate fractions were combined, evaporated and diluted with methylene chloride and water. The aqueous layer was pH adjusted by the addition of a few mL of 10% aqueous Na2CO3 and repeatedly extracted with methylene chloride. The combined organic layers were dried over Na2SO4 and evaporated to give 1.2 g (26%) of ethyl (2S)-(3-amino-2-hydroxypropyl)(1,1-diethoxyethyl)phosphinate as a clear oil. Data: 1H NMR (300 MHz, CDCl3) δ 4.40–4.55 (b, 1H), 4.10–4.30 (m, 2H), 3.55–3.80 (m, 4H), 3.20–3.30 (m, 1H), 3.00–3.10 (m, 1H), 2.00–2.40 (m, 2H), 1.45–1.53 (dd, J=3.4, 11.7 Hz, 3H), 1.30–1.40 (m, 3H), 1.15–1.25 (m, 6H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[NH:40][C:39](=[O:44])[CH2:38]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[NH:40][C:39](=[O:44])[CH2:38]3)[CH:3]=1)=[O:15]
Reactant: CC1(C)OB(c2ccc3c(c2)CC(=O)N3)OC1(C)C
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc4c(c3)CC(=O)N4)nc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 74 using 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (70 mg, 0.187 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-indol-2-one (63.1 mg, 0.243 mmol), DMSO(1.5 mL), sodium carbonate (0.281 mL, 0.562 mmol), and bis(triphenylphosphine)palladium(II) chloride (10.51 mg, 0.015 mmol). The final product was collected as 30 mg (34%). LCMS E-S (M+H)=471.3 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54 (d, J=6.4 Hz, 6 H), 2.13 (s, 3 H), 2.22 (s, 3 H), 3.40 (br. s., 2 H), 4.41 (d, J=4.6 Hz, 2 H), 5.25-5.41 (m, 1 H), 5.91 (s, 1 H), 6.97 (d, J=8.1 Hz, 1 H), 8.08-8.21 (m, 3 H), 8.34 (s, 1 H), 8.96 (br. s., 1 H), 10.64 (s, 1 H), 11.58 (br. s., 1 H).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]1([C:16]2[S:17][CH2:18][CH:19]([OH:28])[CH:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:21]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClCCCl>[C:10]1([C:16]2[S:17][CH2:18][CH:19]([O:28][C:8](=[O:9])[NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:21]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: OC1CSC(c2ccccc2)=NC1c1ccccc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCCl
Product: O=C(Nc1ccccc1)OC1CSC(c2ccccc2)=NC1c1ccccc1
Yield: 60.5 %

Procedure:
Phenyl isocyanate (1.1 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of (4RS, 5RS)-2,4-diphenyl-5,6-dihydro-4H-1,3-thiazin-5-ol (0.86 g) in 1,2-dichloroethane (10 cc). The solution obtained is stirred under reflux for 3 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is then stirred with a mixture of ethyl acetate and cyclohexane (1:4 by volume). An insoluble precipitate is separated by filtration and the filtrate concentrated to dryness under reduced pressure (2.7 kPa). After recrystallization in diisopropyl ether, (4RS, 5RS)-2,4-diphenyl-5-phenylcarbamoyloxy-5,6-dihydro-4H-1,3-thiazine (0.75 g), m.p. 159° C., is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].[NH2:12][OH:13].Cl.C([O-])(O)=O.[Na+]>CO>[OH:13][NH:12][C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)=[NH:2]
Reactant: NO
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: N=C(NO)c1ccc2[nH]ccc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
5-Cyanoindole (1.00 g), hydroxylamine.HCl (978 mg) and NaHCO3 (2.95 g) were dissolved/suspended in MeOH (14 ml), heated to 50° C. and stirred overnight. LCMS analysis showed the reaction was incomplete after this time so a further portion of hydroxylamine.HCl (978 mg) was added and the reaction temperature raised to 80° C. The reaction was complete after 4 hours. The reaction mixture was cooled to RT and evaporated to dryness under reduced pressure. The residue was treated with 1M aqueous HCl (50 ml) and extracted with EtOAc (2×50 ml). This failed to extract the product from the aqueous solution so it was treated with 2M aqueous NaOH to adjust the pH to approximately 7 then re-extracted with EtOAc (3×50 ml). The combined organics were washed with brine (30 ml), dried over MgSO4, filtered and evaporated to dryness to give the title compound (1.36 g) as a brown oil. δH (MeOD, 400 MHz) 6.50 (1H, s), 7.27 (1H, s), 7.36-7.45 (2H, m), 7.88 (1H, s). MS (ES): C9H8N3O requires 175; found 176 (MH+).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])[CH:6]=[CH:7][CH:8]=1)=O.C([O-])(=O)C.[Na+].Cl.[NH2:25][OH:26]>C1COCC1>[OH:26][N:25]=[CH:1][C:3]1[CH:4]=[C:5]([CH:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(NC(=O)OC(C)(C)C)c1cccc(C=O)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(NC(=O)OC(C)(C)C)c1cccc(C=NO)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.3 %

Procedure:
To a solution of tert-butyl N-[1-(3-formylphenyl)ethyl]carbamate (4.0 g, 16.0 mmol) and sodium acetate (3.3 g, 40.1 mmol) in THF (69 mL) at 0° C. was added hydroxylamine hydrochloride (1.4 g, 20.9 mmol). The reaction was allowed to warm to ambient temperature and stirred for 16 hours. The reaction was concentrated in vacuo and the residue partitioned between EtOAc and water and the layers separated. The organic layer was washed with brine (×2), dried (Na2SO4), filtered and concentrated in vacuo to give the sub-title compound as a colourless gel (4.24 g, quantitative Yield). 1H NMR (400 MHz, DMSO) δ 1.30 (d, 3H), 1.33 (d, 9H), 4.61 (dd, 1H), 7.24-7.38 (m, 2H), 7.41 (q, 2H), 7.53 (s, 1H), 8.11 (s, 1H) and 11.20 (s, 1H) ppm; MS (ES+) 265.3.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]Cl.[CH:9]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14])([CH3:11])[CH3:10].C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[CH3:10][CH:9]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[N:14]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1)[CH3:11]
Reactant: CC(C)c1ccccc1N
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: CC(C)c1ccccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 30.1 %

Procedure:
A mixture of bis(2-chloroethyl)amine hydrochloride (19.78 g, 0.111 mole) and 200 mL of n-butanol was treated dropwise with 2-isopropylaniline (15.0 g, 0.111 mole) and the resulting mixture was stirred for 48 hr at reflux under an argon atmosphere. After cooling to room temperature, anhydrous sodium carbonate (5.86 g, 0.555 mole) was added and the reaction mixture was stirred for another 24 hr at reflux. The reaction was cooled in ice and a white precipitate was filtered off. This material was mixed thoroughly in methylene chloride and 3N sodium hydroxide until the aqueous layer was basic. The methylene chloride layer was separated, dried over anhydrous potassium carbonate, filtered and evaporated affording 6.82 g of 1-[2-(methylethyl)phenyl]piperazine as an oil. The fumarate acid salt was prepared from isopropanol/methanol and recrystallized from methanol to give a white crystalline solid, mp 188-189° C. (Ho).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[N:3]=1.[CH:16]1([C:19]2[NH:23][N:22]=[C:21]([NH2:24])[CH:20]=2)[CH2:18][CH2:17]1>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:24][C:21]2[CH:20]=[C:19]([CH:16]3[CH2:18][CH2:17]3)[NH:23][N:22]=2)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[N:3]=1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: Clc1cc(-c2ccccc2Cl)nc(Cl)n1
Solvent: CCO
Product: Clc1nc(Nc2cc(C3CC3)[nH]n2)cc(-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 96 h
Yield: 38.7 %

Procedure:
2,4-Dichloro-6-(2-chloro-phenyl)-pyrimidine (180 mg, 0.694 mmol) and 5-cyclopropyl-1H-pyrazol-3-ylamine (128 mg, 1.04 mmol) was taken into 3 ml of ethanol. The reaction was stirred at room temperature for 4 days. The reaction was evaporated in vacuo and the crude product purified by flash chromatography (SiO2) eluting with ethyl acetate/hexane (1:1) to afford 93 mg of the desired product. HPLC (C18 column) Rt 6.23 mins.; MS m/z 346.1 (M+H) 344.1 (M-H)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1>COC(C)(C)C>[Br:15][C:11]1[CH:10]=[C:9]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:14]=[CH:13][CH:12]=1
Reactant: CN1CCNCC1
Reactant: Brc1cccc(Br)c1
Solvent: COC(C)(C)C
Product: CN1CCN(c2cccc(Br)c2)CC1

Procedure:
1-Methyl-piperazine (1 ml, 8.99 mmol) and 1,3-dibromo-benzene (3 ml, 24.82 mmol) are heated to 200° C. in a sealed tube under microwave irradiation for 300 min (150 W, 9 bar). The residue is diluted with tert-butyl methyl ether (50 ml) and extracted with 1M HCl. The aqueous layer is neutralized with sodium bicarbonate, and extracted with ethyl acetate (150 ml). The organic layer is separated and dried over MgSO4. The drying agent is filtered and the solvent is removed in vacuum; yield: 700 mg 1-(3-bromo-phenyl)-4-methyl-piperazine; HPLC/MS: 1.24 min, [M+H]=255.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)([CH3:24])[C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]([NH2:23])[CH:17]=3)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[O:33]1[C:37]2[CH:38]=[CH:39][C:40]([C:42]3([C:45](O)=[O:46])[CH2:44][CH2:43]3)=[CH:41][C:36]=2[O:35][CH2:34]1.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)([CH3:24])[C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]([NH:23][C:45]([C:42]4([C:40]5[CH:39]=[CH:38][C:37]6[O:33][CH2:34][O:35][C:36]=6[CH:41]=5)[CH2:44][CH2:43]4)=[O:46])[CH:17]=3)=[CH:14][CH:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(S(C)(c2ccc(OC)cc2)c2ccc(-c3cc(N)ccc3C)cc2)cc1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COc1ccc(S(C)(c2ccc(OC)cc2)c2ccc(-c3cc(NC(=O)C4(c5ccc6c(c5)OCO6)CC4)ccc3C)cc2)cc1
Temperature: 65 °C

Procedure:
4′-[Bis-(4-methoxyphenyl)-methylsulfanyl]-6-methylbiphenyl-3-ylamine (˜10 mmol) and 1-benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (2.28 g, 11 mmol) were dissolved in chloroform (25 mL) followed by addition of TCPH (4.1 g, 12 mmol) and DIEA (5.0 mL, 30 mmol). The reaction mixture was heated at 65° C. for 48 h. The volatiles were removed under reduced pressure. The residue was distributed between water (200 mL) and ethyl acetate (150 mL). The organic layer was washed with 5% NaHCO3 (2×150 mL), water (1×150 mL), brine (1×150 mL) and dried over MgSO4. Evaporation of the solvent yielded crude 1-benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid 4′-[bis-(4-methoxyphenyl)-methylsulfanyl]-6-methylbiphenyl-3-ylamide as a pale oil, which was used without further purification. ESI-MS m/z calc. 629.0, found 630.0 (M+1) (HPLC purity ˜85-90%, UV254 nm).
Reaction SMILES: P([O-])(O)(O)=O.[Na+].Cl([O-])=O.[Na+].[OH:11]O.[CH3:13][O:14][C:15]1[C:16]([CH3:40])=[C:17]([C:31]([O:38][CH3:39])=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:27][CH:28]([CH3:30])[CH3:29])=[C:23]([CH:26]=1)[CH:24]=[O:25]>O.C(#N)C>[CH3:13][O:14][C:15]1[C:16]([CH3:40])=[C:17]([C:31]([O:38][CH3:39])=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:27][CH:28]([CH3:30])[CH3:29])=[C:23]([CH:26]=1)[C:24]([OH:11])=[O:25]
Reactant: OO
Reactant: COc1c(C)c(Cc2ccc(OC(C)C)c(C=O)c2)c(OC)c(OC)c1OC
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC#N
Solvent: O
Product: COc1c(C)c(Cc2ccc(OC(C)C)c(C(=O)O)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 86 %

Procedure:
An aqueous solution (5 ml) of sodium dihydrogenphosphate (1.28 g, 10.65 mmol), an aqueous solution (7 ml) of sodium chlorite (0.533 g, 6.15 mmol) and aqueous hydrogen peroxide (0.18 ml, 30%) were added to an acetonitrile solution (5 ml) of 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-isopropoxybenzaldehyde (0.530 g, 1.37 mol) and the resulting solution was stirred at room temperature for 5 hours. The reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with an aqueous saturated sodium hydrosulfite (Na2S2O4) solution and saturated brine, then dried and concentrated to obtain the titled compound (0.475 g, 1.18 mmol, 86%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[C:10]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([C:24]2[CH:25]=[CH:26][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:28][CH:29]=2)[C:10]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COc1ccc2c(c1)C(C(=O)N(Cc1ccc(N)cc1)c1ccc(C(C)C)cc1)CCC2
Reactant: BrCc1ccccc1
Product: COc1ccc2c(c1)C(C(=O)N(Cc1ccc(NCc3ccccc3)cc1)c1ccc(C(C)C)cc1)CCC2

Procedure:
By the reaction and treatment in the same manner as in Example 162 using N-[(4-aminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.33 g) and benzyl bromide (0.1 mL) as starting materials, N-[(4-benzylaminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.13 g) was obtained.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O)([O:21][CH3:22])=[O:20]>C(OCC)(=O)C.CCCCCC>[CH3:22][O:21][C:19](=[O:20])[C:23]1[CH:30]=[CH:29][CH:28]=[C:25]([CH2:26][NH:1][C@@H:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][CH2:4][C@H:3]2[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:24]=1
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: NC1c2ccccc2CCC1Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(CN[C@@H]2c3ccccc3CC[C@H]2Cc2ccccc2)c1
Yield: 28 %

Procedure:
In a procedure similar to preparation C, the title compound was prepared from 1-amino-2-benzyltetralin and 3-carbomethoxybenzaldehyde. The trans isomer was isolated as an oil in 28% yield following chromatography on silica gel with ethyl acetate/hexane.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[S:25]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26]1>O1CCCC1>[C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:31]([NH:30][C:27]4[CH:28]=[CH:29][S:25][CH:26]=4)=[O:32])[CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C=Nc1ccsc1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccsc1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.6 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 3-thienyl isocyanate (0.152 ml, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was purified by high performance liquid chromatography (YMC HPLC Column eluted with 10% to 100% Liquid A; Liquid A: a 0.1% solution of trifluoroacetic acid in acetonitrile; Liquid B: an aqueous 0.1% trifluoroacetic acid solution) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 50.0 mg (16.6%) of the desired product.