Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][C:11]1[N:15](CC2C=CC=CC=2)[C:14]2[CH:23]=[CH:24][CH:25]=[CH:26][C:13]=2[N:12]=1.Cl.[H][H]>C(O)C.CCOCC.[Pd]=O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][C:11]1[NH:12][C:13]2[CH:26]=[CH:25][CH:24]=[CH:23][C:14]=2[N:15]=1
Reactant: [H][H]
Reactant: BrCCCCCOCCCc1nc2ccccc2n1Cc1ccccc1
Agent: O=[Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: BrCCCCCOCCCc1nc2ccccc2[nH]1
Yield: 69.1 %

Procedure:
A solution of 2-[3-[(5-bromopentyl)oxy]propyl]-1-(phenylmethyl)benzimidazole (1.7 g) in absolute ethanol (20 ml) containing 1:9 conc. hydrochloric acid:ethanol (3.27 ml) was hydrogenated over pre-reduced 10% palladium oxide on charcoal catalyst (300 mg) in ethanol (5 ml) until the uptake of hydrogen (101 ml) ceased. The mixture was filtered through hyflo and evaporated in vacuo to give an oil, which was dissolved in ether (150 ml) and washed with 8% sodium bicarbonate solution (100 ml), dried and evaporated in vacuo to give an oil. Purification by FCC eluting with hexane-ether (2:3→0:5) gave the title compound as a yellow oil (0.92 g).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:3]=1.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C(Cl)Cl>[F:8][C:7]1[C:2]([N:21]2[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]2)=[N:3][C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:5][CH:6]=1
Reactant: CN1CCNCC1
Reactant: Fc1ccc(Cc2ncc(F)c(Cl)n2)cc1
Solvent: ClCCl
Product: CN1CCN(c2nc(Cc3ccc(F)cc3)ncc2F)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.9 %

Procedure:
A mixture of 0.48 g (2 mmol) of 4-chloro-5-fluoro-2-(4-fluorobenzyl)-pyrimidine from Step 2 and 1.53 mL (14 mmol) of 4-methylpiperazine in 10 mL of methylene chloride was stirred at ambient temperature for 1.5 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in methylene chloride. The resultant solution was washed with 4 X 30 mL of water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 0.59 g (95% yield) of the title compound as an oil; 1H NMR (CDCl3) d 2.32 (s, 3H), 2.47 (t, 4H), 3.78 (t, 4H), 3.99 (s, 2H), 6.97 (m, 2H), 7.29 (m, 2H), 7.97 (d, 1H). The product was carried on to the next step without purification.
Reaction SMILES: C(O/[CH:4]=[C:5]1\[C:6](=O)[C:7]2[C:12]([O:13][C:14]3\1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)=[CH:11][C:10]([F:27])=[CH:9][CH:8]=2)C.[ClH:29].[NH2:30][N:31](C)[C:32](=O)OC(C)(C)C.O1CCOCC1>>[ClH:29].[ClH:29].[F:27][C:10]1[CH:9]=[CH:8][C:7]2[C:6]3[N:31]([CH3:32])[N:30]=[CH:4][C:5]=3[C:14]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[O:13][C:12]=2[CH:11]=1
Reactant: CCO/C=C1\C(=O)c2ccc(F)cc2OC12CCN(C(=O)OC(C)(C)C)CC2
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: Cn1ncc2c1-c1ccc(F)cc1OC21CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
To tert-butyl (3Z)-3-(ethoxymethylene)-7-fluoro-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (2.6 g, 5.9 mmol) was added hydrochloric acid (22.3 mL, 89.1 mmol) (4 M in dioxane). The reaction mixture was allowed to stir at 25° C. for 2 hours. Solvent was removed under vacuum, and the obtained solid was dissolved in EtOH (3×25 mL) and the solvent was evaporated to dryness. The resulting beige-white solid was fully dissolved in ethanol (21 mL) at 25° C. prior to the addition of tert-butyl N-amino-N-methyl-carbamate (1.0 g, 7.1 mmol). The solution was allowed to stir at 25° C. overnight. To the thick beige-white slurry that formed was added hydrochloric acid, 4 M in dioxane (7.4 mL, 29.7 mmol). The mixture was heated at 60° C. to yield a clear yellow solution. After 1 hour at 60° C., a thick beige-white slurry developed. The slurry was allowed to slowly cool to 25° C. over 1 hour, and solids were collected by vacuum filtration. The cake was rinsed with a 10% solution of ethanol in hexanes (2×). Residual solvent was further removed under reduced pressure providing 7-fluoro-1-methyl-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] dihydrochloride (1.4 g, 67%) as a light tan solid. ESI-MS m/z calc. 273.1, found 274.3 (M+1)+; Retention time: 1.59 minutes (3 min run). 1H NMR (400 MHz, MeOD) δ 7.80 (dd, J=8.7, 6.1 Hz, 1H), 7.45 (d, J=1.7 Hz, 1H), 7.00 (dd, J=9.8, 2.6 Hz, 1H), 6.91 (td, J=8.6, 2.6 Hz, 1H), 4.14 (s, 3H), 3.53-3.42 (m, 2H), 3.41-3.33 (m, 2H), 2.29 (d, J=13.9 Hz, 2H), 2.23-2.11 (m, 2H).
Reaction SMILES: [C:1]([NH:20][CH2:21][C:22]([OH:24])=[O:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:32][CH2:33]I.O>CN(C)C=O>[Cl:32][CH2:33][O:23][C:22](=[O:24])[CH2:21][NH:20][C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: ClCI
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CNC(c1ccccc1)(c1ccccc1)c1ccccc1)OCCl

Procedure:
To a solution of N-tritylglycine (25.6 g) and triethylamine (14.0 ml) in dimethylformamide (DMF) (60 ml), a solution of chloroiodomethane (24.0 ml) in DMF (40 ml) was added dropwise while stirring, and the mixture was stirred for 3.5 hours at room temperature. Then the mixture was poured into water (400 ml), the organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and thereafter twice with aqueous sodium bicarbonate and again with water. The organic phase was dried and evaporated in vacuo to yield the crude ester. TLC: Rf = 0.7 (cyclohexane-ethyl acetate, 1:1), ir )CHCl3): 1765 cm-1 (ester carbonyl), nmr (CDCl3 -TMS standard): δ = 3.20 (s), 5.53 (s), 7.00-7.30 (m) ppm.
Reaction SMILES: [NH2:1][N:2]1[C:11]([OH:19])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:20])[CH:9]=2)[N:4]=[CH:3]1.[C:21]1(=[O:35])[N:25]([CH2:26][C:27](Cl)=[O:28])[C:24](=[O:30])[C:23]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:22]12>N1C=CC=CC=1>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]([C:10]1[CH:9]=[C:8]([Cl:20])[CH:7]=[CH:6][C:5]=1[N:4]([CH:3]=[N:2][NH:1][C:27](=[O:28])[CH2:26][N:25]1[C:21](=[O:35])[C:22]2[C:23](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:24]1=[O:30])[C:27](=[O:28])[CH2:26][N:25]1[C:24](=[O:30])[C:23]2[C:22](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:21]1=[O:35])=[O:19]
Reactant: NN1C=Nc2ccc(Cl)cc2C1(O)c1ccccc1Cl
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Solvent: c1ccncc1
Product: O=C(CN1C(=O)c2ccccc2C1=O)NN=CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 1, 3-amino-6-chloro-3,4-dihydro-4-hydroxy-4-(o-chlorophenyl)quinazoline with pyridine is reacted with α-phthalimidoacetyl chloride to give 1,3-dioxo-2-isoindolineacetic acid [[N-[2-(o-chlorobenzoyl)-4-chlorophenyl]-1,3-dioxo-2-isoindolineacetamido]-methylene]hydrazide.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][N:12]([CH3:15])[C:11]2=[O:16])=[CH:6][CH:5]=1)([O-])=O.[ClH:17].CCOCC>C(O)(=O)C.C(O)(C)C.C(OCC)(=O)C.[Rh]>[ClH:17].[NH2:1][C@@H:4]1[CH2:5][CH2:6][C@H:7]([N:10]2[CH2:14][CH2:13][N:12]([CH3:15])[C:11]2=[O:16])[CH2:8][CH2:9]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cc2)C1=O
Agent: [Rh]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CN1CCN([C@H]2CC[C@@H](N)CC2)C1=O
Temperature: 25 °C

Procedure:
A solution of 1-(p-nitrophenyl)-3-methyl-2-imidazolidinone (12.45 g) in 150 ml glacial acetic acid, to which is added 6 g of 5% rhodium on alumina, is hydrogenated at 50° and 45 lbs. pressure. The catalyst is filtered off and the filtrate concentrated under reduced pressure. Water (25 ml) is added to the residue which is basified by addition of 50% aqueous sodium hydroxide while the mixture is cooled in an ice bath. Extraction with methylene chloride (5×70 ml), drying over anhydrous sodium sulfate, filtering and concentrating under reduced pressure gives crude 1-(4-aminocyclohexyl)-3-methyl-2-imidazolidinone. The oil is converted to the hydrochloride salt by dissolving in 100 ml isopropanol and adding a saturated solution of hydrogen chloride gas in ethyl acetate. Ether (50 ml) is added and the salt crystallizes on cooling to room temperature. Mixture is cooled further in the refrigerator. The solid is filtered off and dried to give cis 1-(4-aminocyclohexyl)-3-methyl-2-imidazolidinone hydrochloride, m.p. 287°-298°.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:19]=[C:18]([CH3:20])[O:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:21][C:22]1[C:27]([N+:28]([O-:30])=[O:29])=C(Cl)[C:25]([Br:32])=[CH:24][N:23]=1.C(N(C(C)C)CC)(C)C>ClCCl.C(O)(C(F)(F)F)=O.C(O)(C)C>[Br:32][C:25]1[C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:15]3[CH:19]=[C:18]([CH3:20])[O:17][N:16]=3)[CH2:12][CH2:13]2)=[C:27]([N+:28]([O-:30])=[O:29])[C:22]([NH2:21])=[N:23][CH:24]=1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Reactant: Cc1cc(CN2CCN(C(=O)OC(C)(C)C)CC2)no1
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)no1
Temperature: 45 °C
Reaction time: 20 h

Procedure:
A solution of 4-(5-methyl-isoxazol-3-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (0.200 g, 0.71 mmol) in dichloromethane (6 ml) and TFA (8 ml) was stirred at room temperature for 2 h then concentrated in vacuo, and the resulting residue was dried in vacuo. This material (supposedly 0.70 mmol) was dissolved in isopropanol (13 ml) and to this solution 2-amino-5-bromo-4-chloro-3-nitropyridine (0.157 g, 0.63 mmol) was added followed by diisopropylethylamine (0.65 ml, 3.70 mmol). The reaction mixture was stirred at 45° C. for 20 h, then allowed to cool to room temperature and diluted with isopropanol (5 ml). The resulting orange solid was collected by filtration, washed with isopropanol (2×5 ml), diethyl ether (3×5 ml), and dried (0.170 g, 60%); 1H-NMR (500 MHz, DMSO-d6) 2.38 (s, 3H, isoxazole 5-CH3), 2.53 (br s, 4H, piperazine N(CH2)2), 3.05 (br s, 4H, piperazine N(CH2)2), 3.55 (s, 2H, NCH2 isoxazole), 6.21 (s, 1H, isoxazole 4-H), 6.97 (s, 2H, NH2), 8.16 (s, 1H, pyridine 6-H);
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2].S([O-])(O[CH3:22])(=O)=O>[OH-].[Na+]>[CH3:22][N:13]([CH2:12][CH2:11][NH:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[S:14]([CH3:17])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)NCCNc1ccc([N+](=O)[O-])cc1
Reactant: COS(=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: CN(CCNc1ccc([N+](=O)[O-])cc1)S(C)(=O)=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
25.9 g (0.1 mol) of N-[2-(4-nitrophenylamino)ethyl]methanesulfonamide (22) were dissolved in 200 mL of 1N sodium hydroxide at 50° C. The insoluble matter was filtered off, the filtrate was cooled to 30° C. and 11.4 mL (0.12 mol) of methyl sulfate were added dropwise. The mixture was stirred for 1 hour at room temperature and then heated to 40° C. and the yellow precipitate was filtered off. The product was reslurried in 0.5N sodium hydroxide and in water. The wet crude product was recrystallized from 50 mL of 96% ethanol with carbon black. 13.3 g of product with a melting point of 109° C. were isolated.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]([C:11]([O:13]C)=O)[CH2:5]2>C(N)CCC>[CH2:6]([NH:7][C:11]([CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([CH3:1])[CH:3]=2)[NH:7]1)=[O:13])[CH2:5][CH2:4][CH3:3]
Reactant: COC(=O)C1Cc2cc(C)ccc2N1
Solvent: CCCCN
Product: CCCCNC(=O)C1Cc2cc(C)ccc2N1

Procedure:
Methyl 5-methylindoline-2(R/S)-carboxylate (0.3 g, 4.18 mmol) was dissolved in butylamine (20 ml) and the mixture was refluxed for 4 h under nitrogen. The excess amine was removed under vacuum to give a solid, which was recrystallized from ether in order to allow the product to be collected.
Reaction SMILES: [CH:1]1([CH:7]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[CH:8]2[C:13](=O)[O:12]C(C)(C)OC2=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:27]1C=CC=C[CH:28]=1.CN>O>[CH:1]1([CH:7]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[CH2:8][C:13]([NH:27][CH3:28])=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC1(C)OC(=O)C(C(c2c[nH]c3ncccc23)C2CCCCC2)C(=O)O1
Reactant: c1ccncc1
Agent: CN
Solvent: O
Product: CNC(=O)CC(c1c[nH]c2ncccc12)C1CCCCC1
Temperature: 120 °C

Procedure:
A mixture of 5-[cyclohexyl-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-2,2-dimethyl-[1,3]dioxane-4,6-dione (560 mg, 1.57 mmol), pyridine (8 mL) and MeNH2 (2 M in THF, 16 mL) heated to 120° C. in sealed vial for 3 h. The reaction was cooled to RT and poured into water. The pH was adjusted to 7. And the resulting solution was extracted 5 times with EtOAc (100 mL) and 3 times with DCM (200 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated, affording crude 3-Cyclohexyl-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propionamide (270 mg), which was used in the next step without purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:11]([O:14][CH3:15])[O:12][CH3:13])[CH:3]=1.[C:16]1([OH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].C(OC(C)C)(C)C>CC(N(C)C)=O.C(Cl)Cl.O>[CH3:13][O:12][CH:11]([O:14][CH3:15])[C:4]1[CH:3]=[C:2]([O:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: Oc1ccccc1
Reactant: COC(OC)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)OC(C)C
Solvent: O
Solvent: ClCCl
Product: COC(OC)c1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 6 h

Procedure:
A mixture of 4-chloro-2-dimethoxymethyl-1-nitrobenzene (11.55 g, 0.0500 mol), phenol (4.70 g, 0.0500 mol), and potassium carbonate (8.16 g, 0.0600 mol) in DMA (100 mL) was stirred at 150° C. for 6 h. After cooling, the reaction mixture was poured into water and treated with diisopropyl ether. The organic layer was separated, washed with 10% aqueous KOH solution, dried (MgSO4), filtered, and concentrated. The resulting residue was purified by column chromatography on silica gel using as eluent CH2Cl2:petroleum ether (40:60, 60:40, 100:0 gradient). The product containing fractions were combined and evaporated to yield a residue which was dissolved in CH2Cl2 and washed with 10% aqueous KOH solution to remove the remaining phenol. Drying and evaporation yielded a residue.
Reaction SMILES: [CH2:1]([C:6]1[CH2:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]([CH3:5])([CH3:4])[CH3:3].C([Li])CCC.[Cl-].[CH3:21][C:22]([NH:25][SiH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23]>C1COCC1>[CH2:1]([C:6]1[CH:14]([Si:26]([CH3:28])([CH3:27])[NH:25][C:22]([CH3:24])([CH3:23])[CH3:21])[C:13]2[C:8]([CH:7]=1)=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)CC1=Cc2ccccc2C1
Reactant: C[SiH](C)NC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)CC1=Cc2ccccc2C1[Si](C)(C)NC(C)(C)C
Reaction time: 1 h
Yield: 103.2 %

Procedure:
To a mixture of 2-neopentylindene (0.81 g, 4.3 mmol) in 30 mL of hexanes were added 2.9 mL of butyl lithium (1.6 M hexane; 4.7 mmol). The mixture was stirred for one hour, diluted with 20 mL of THF and to this added N-(1,1-dimethylethyl)dimethylsilanamine chloride (1.84 g, 11.2 mmol) in 10 mL of THF. After stirring overnight, the volatiles were removed in vacuo, the residue extracted with hexane, filtered and the volatiles removed in vacuo to give 1.4 g (102 percent) of a yellow oil.
Reaction SMILES: [Li]C(CC)C.C1CCCCC1.C(=O)=O.CC(C)=O.CN(CCN(C)C)C.[CH2:27]([N:29]([CH3:44])[C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]([CH3:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[CH3:28].[Cl:45]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.O>[Cl:45][C:36]1[CH:35]=[CH:34][CH:33]=[C:32]([N:37]([C:38]([CH3:39])([CH3:40])[CH3:41])[CH3:42])[C:31]=1[C:30]([N:29]([CH2:27][CH3:28])[CH3:44])=[O:43]
Reactant: CCN(C)C(=O)c1ccccc1N(C)C(C)(C)C
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CN(C)CCN(C)C
Agent: O=C=O
Agent: [Li]C(C)CC
Solvent: O
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCN(C)C(=O)c1c(Cl)cccc1N(C)C(C)(C)C
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 46.7 %

Procedure:
A solution of 1.3M s-BuLi in cyclohexane (3.7 mL, 4.8 mmol) was added dropwise to a dry-ice/acetone cooled solution of TMEDA (0.7 mL, 4.8 mmol) in THF (10 mL), followed by the dropwise addition of a solution of N-ethyl-N-methyl 2-(N-methyl-N-tert-butylamino)benzamide (1.0 g, 4.0 mmol) in THF (5 mL). The reaction mixture was briefly warmed to −30° C., then cooled to −78° C. and stirred for 15 min. A solution of hexachloroethane (2.8 g, 12.1 mmol) in THF (5 mL) was added. This mixture was stirred for 1 h at −78° C., then was warmed to −30° C., diluted with water, and extracted with EtOAc (2×). The combined organic extracts were dried (MgSO4), concentrated, and purified by HPLC with 1:4 EtOAc/cyclohexane to give 528 mg of the title compound as a yellow oil, a 46% yield.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=3[Cl:30])=[C:19]([CH2:31]Cl)[N:18]=[C:17]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:39]1([O-:45])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[Na+].C1(O)C=CC=CC=1.[OH-].[Na+]>CC(C)=O.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=3[Cl:30])=[C:19]([CH2:31][O:45][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:18]=[C:17]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)[N:16]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: [O-]c1ccccc1
Reactant: COc1ccc(Cl)c(Oc2c(CCl)nc(N3CCOCC3)nc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: Oc1ccccc1
Solvent: O
Product: COc1ccc(Cl)c(Oc2c(COc3ccccc3)nc(N3CCOCC3)nc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
0.145 g of 4-tert.-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-chloromethyl-2-(morpholin-4-yl)-pyrimidin-4-yl]benzenesulphonamide (Example 4) in 3 ml of acetone was added to a sodium phenolate solution from 0,024 g of phenol and 0.06 g of NaOH in 2 ml of acetone and 1 ml of water. The reaction mixture was stirred at 80° C. under argon for 48 hours. Thereafter, the acetone was distilled off and the residue was partitioned between chloroform and water. The chloroform phase was washed with water, dried over sodium sulphate and the solvent was distilled off. The residue was chromatographed over silica gel with chloroform. 0.07 g of 4-tert.-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-2-morpholin-4-yl-6-phenoxymethyl-pyrimidin-4-yl]benzenesulphonamide, MS: M=639, was obtained.
Reaction SMILES: C(SCC(CC1C=CC=CC=1)C(NC1C=C(C=CC=1)C(O)=O)=O)(=O)C1C=CC=CC=1.C([S:34][CH2:35][CH:36]([CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:37]([NH:39][C:40]1[CH:48]=[CH:47][C:43]([C:44]([OH:46])=[O:45])=[CH:42][CH:41]=1)=[O:38])(=O)C>>[SH:34][CH2:35][CH:36]([CH2:49][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[C:37]([NH:39][C:40]1[CH:48]=[CH:47][C:43]([C:44]([OH:46])=[O:45])=[CH:42][CH:41]=1)=[O:38]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)Nc1ccc(C(=O)O)cc1
Agent: O=C(O)c1cccc(NC(=O)C(CSC(=O)c2ccccc2)Cc2ccccc2)c1
Product: O=C(O)c1ccc(NC(=O)C(CS)Cc2ccccc2)cc1

Procedure:
Using the procedure of Example 3, replace the product of Example 1 with the product of Example 6 to obtain the title compound as a white solid, m.p.=166°-168° C. TLC: Rf=0.6 (silica gel; dichloromethane:methanol:acetic acid, 95:4.5:0.5).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:14]1[N:18]=[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[C:30]([CH3:32])[N:29]=[N:28][CH:27]=3)=[C:22]([O:33][CH3:34])[CH:21]=2)[NH:16][N:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[F:13][C:10]1[CH:11]=[CH:12][C:7]([CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][N:15]3[N:16]=[C:17]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]5[CH:31]=[C:30]([CH3:32])[N:29]=[N:28][CH:27]=5)=[C:22]([O:33][CH3:34])[CH:21]=4)[N:18]=[C:14]23)=[CH:8][CH:9]=1
Reactant: COc1cc(Nc2nc(C(CCCCCl)c3ccc(F)cc3)n[nH]2)ccc1-c1cnnc(C)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Nc2nc3n(n2)CCCCC3c2ccc(F)cc2)ccc1-c1cnnc(C)c1
Temperature: 55 °C
Yield: 38.2 %

Procedure:
A mixture of 3-(5-chloro-1-(4-fluorophenyl)pentyl)-N-(3-methoxy-4-(6-methylpyridazin-4-yl)phenyl)-1H-1,2,4-triazol-5-amine (102 mg, 0.212 mmol), potassium carbonate (117 mg, 0.848 mmol), and potassium iodide (70.4 mg, 0.424 mmol) in DMF (5 mL) was heated at 55° C. for 5 hrs. The solvent was removed in vacuo. The crude product was purified using silica gel column chromatography (0-10% MeOH/CH2Cl2, linear gradient) to afford 36 mg (36% yield) of the titled compound as a solid. LC-MS (M+H)+ 455.3. 1H NMR (500 MHz, methanol-d4) δ ppm 9.19 (s, 1 H) 7.68 (s, 1 H) 7.45 (s, 1 H) 7.33 (d, J=8.55 Hz, 1 H) 7.20 (dd, J=8.09, 5.65 Hz, 2 H) 7.00-7.10 (m, 3 H) 4.34 (d, J=8.24 Hz, 1 H) 4.14-4.30 (m, 2 H) 3.77 (s, 3 H) 2.64 (s, 3 H) 2.11-2.26 (m, 1 H) 1.71-2.08 (m, 5 H).
Reaction SMILES: [OH:1][C@@:2]1([C:18]([F:21])([F:20])[F:19])[CH2:6][CH2:5][N:4](C(OCC2C=CC=CC=2)=O)[C@H:3]1[CH3:17]>[Pd].O>[CH3:17][C@H:3]1[C@@:2]([C:18]([F:20])([F:19])[F:21])([OH:1])[CH2:6][CH2:5][NH:4]1
Reactant: C[C@@H]1N(C(=O)OCc2ccccc2)CC[C@@]1(O)C(F)(F)F
Agent: [Pd]
Solvent: O
Product: C[C@@H]1NCC[C@@]1(O)C(F)(F)F

Procedure:
By an operation in the same manner as in Reference Example 4 and using benzyl (2S,3S)-3-hydroxy-2-methyl-3-(trifluoromethyl)pyrrolidine-1-carboxylate (1.05 g) and 50% water containing-10% Pd/C (0.05 g), the title compound was obtained as a colorless solid (yield: 0.65 g, yield: 88%).
Reaction SMILES: FC1C=CC(OC)=C(C2C=CC(CNS(C3C=CC(OC)=CC=3)(=O)=O)=CC=2OC)C=1.[Cl:31][C:32]1[CH:33]=[C:34]([C:41]2[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:42]=2[O:48][CH3:49])[CH:35]=[CH:36][C:37]=1[CH:38]([NH2:40])[CH3:39].[Cl:50][C:51]1[CH:56]=[C:55]([C:57]#[N:58])[CH:54]=[CH:53][C:52]=1[S:59](Cl)(=[O:61])=[O:60]>>[Cl:50][C:51]1[CH:56]=[C:55]([C:57]#[N:58])[CH:54]=[CH:53][C:52]=1[S:59]([NH:40][CH:38]([C:37]1[CH:36]=[CH:35][C:34]([C:41]2[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:42]=2[O:48][CH3:49])=[CH:33][C:32]=1[Cl:31])[CH3:39])(=[O:60])=[O:61]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)c(Cl)c1
Reactant: COc1ccc(F)cc1-c1ccc(C(C)N)c(Cl)c1
Agent: COc1ccc(S(=O)(=O)NCc2ccc(-c3cc(F)ccc3OC)c(OC)c2)cc1
Product: COc1ccc(F)cc1-c1ccc(C(C)NS(=O)(=O)c2ccc(C#N)cc2Cl)c(Cl)c1

Procedure:
To a stirred solution of 4-bromo-2-chloro-acetophenone (4.66 g, 20 mmol) in methanol (50 ml) under nitrogen atmosphere was added ammonium acetate (29 g, 0.4 mol) and sodium cyanoborohydride (1.21 g, 20 mmol). The reaction mixture was stirred at ambient temperature for 10 days. The solvent was evaporated and the residue partitioned between dichloromethane and aqueous sodium carbonate solution. The organic phase was dried over anhydrous sodium sulfate and the solvent evaporated. The residue was dissolved in diethyl ether and treated with 2M Hydrogen chloride in diethyl ether The resulting precipitate was filtered and dried to give 1-(4-bromo-2-chloro-phenyl)-ethylamine hydrochloride (3.2 g). A mixture of 1-(4-bromo-2-chloro-phenyl)-ethylamine hydrochloride (0.25 g, 1.07 mmol), 5-fluoro-2-methoxyphenyl boronic acid (0.364 g, 2.14 mmol), palladium acetate (0.005 g, 0.021 mmol) in water (4 ml) was heated in a microwave oven at 190° C. for 4 min. The mixture was added to a SCX column (eluted with 1:1 dichloromethane/methanol then 10% 7M ammonia/methanol) and solvent evaporated to give 1-(3-chloro-5′-fluro-2′-methoxy-biphenyl-4-yl)-ethylamine (0.266 g). The title compound was prepared in a similar manner to N-(5′-fluoro-2,2′-dimethoxy-biphenyl-4-ylmethyl)-4-methoxy-benzenesulfonamide (Example 6) using 1-(3-chloro-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine and 2-chloro-4-cyanobenzene sulfonyl chloride instead of 4-methoxybenzene sulfonyl chloride: 1H NMR (400 MHz, DMSO-d6): δ 9.1 (d 1H), 8.1 (s, 1H), 7.9 (d, 1H), 7.8 (d, 1H), 7.5 (d, 1H), 7.3 (d, 2H), 7.2 (m, 1H), 7-7.18 (m, 2H), 4.9 (m, 1H), 3.8 (s, 3H), 1.4 (d, 3H) ppm. MS (ESI) m/z: value [M+H]+.