Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH2:35]([O:37][C:38](Cl)=[O:39])[CH3:36]>ClCCl>[CH2:35]([O:37][C:38](=[O:39])[NH:2][C@H:3]1[CH2:8][CH2:7][C@@H:6]([NH:9][C:10]([C:11]2[C:12]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=3)=[N:13][CH:14]=[C:15]([F:17])[CH:16]=2)=[O:27])[CH2:5][CH2:4]1)[CH3:36]
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N[C@H]1CC[C@@H](NC(=O)c2cc(F)cnc2Oc2cccc(SC)c2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 39.3 %

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (150 mg, 0.364 mmol) was suspended in dichloromethane (2 ml) under nitrogen at room temperature and triethylamine (153 μl, 1.09 mmol) was added followed by ethylchloroformate (39 μl, 0.4 mmol). The reaction was stirred at room temperature for 1.5 h and the mixture was quenched with sat. sodium bicarbonate solution (3 ml). The organic phase was separated and the aqueous phase was washed with dichloromethane (2×3 ml). The combined organic extracts were dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol (98:2, by volume) and the product was triturated with diethylether (3 ml) to give (cis-4-{[5-Fluoro-2-(3-methylsulfanyl-phenoxy)-pyridine-3-carbonyl]-amino}-cyclohexyl)-carbamic acid ethyl ester (64 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[CH:10](N)[CH2:11]C1C=CC=C(O)C=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:1]([O:8][C:9](=[O:20])[CH2:10][CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(Cc1cccc(O)c1)C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of 8.72 g (0.032 mol) of rac.-2-amino-3-(3-hydroxyphenyl)propanoic acid benzyl ester in 400 mL of ice cold dichloromethane was treated dropwise with 1.9 mL (0.020 mol) of acetic anhydride. Upon completion of the addition, a solution of 3.70 g of sodium carbonate in 30 mL of water was added simultaneously with an additional 1.9 mL of acetic anhydride. After 1 hour, the layers were separated and the organic layer was washed with water. The combined aqueous layers were extracted with dichloromethane and the combined extracts were washed with brine and dried over magnesium sulfate. Filtration and concentration afforded a residue which was chromatographed on a Waters Prep 500 liquid chromatograph fitted with two silica gel cartridges, eluting with 20% ethyl acetate-hexane to give 8.49 g (84%) of rac.-2-acetamido-3-hydroxyphenyl)propanoic acid benzyl ester as a thick oil.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:19].[O:20]=[C:21]([NH:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=1)[CH2:22][CH2:23][C:24]([OH:26])=[O:25]>>[OH:19][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)[CH:7]=2)[C:2]=1[C:31]1[CH:32]=[CH:33][C:28]([NH:27][C:21](=[O:20])[CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:29][CH:30]=1
Reactant: Oc1cccc(-c2ccc3c(Br)c(O)ccc3c2)c1
Reactant: CC1(C)OB(c2ccc(NC(=O)CCC(=O)O)cc2)OC1(C)C
Product: O=C(O)CCC(=O)Nc1ccc(-c2c(O)ccc3cc(-c4cccc(O)c4)ccc23)cc1
Reaction time: 0.17 h
Yield: 12 %

Procedure:
The compound is prepared by the reaction of 1-bromo-6-(3-hydroxyphenyl)-naphthalene-2-ol (100 mg, 0.32 mmol, 1 eq) with 4-oxo-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamino)butanoic acid (101.3 mg, 0.32 mmol, 1 eq) according to method A in 10 min. Purification by column chromatography with dichloromethane/methanol 90/10 yields the desired compound in a yield of 12%, 16 mg.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH3:24])[CH2:10][C:11]1[C:19]2[O:18][CH:17]=[CH:16][C:15]=2[CH:14]=[C:13]([C:20]([O:22]C)=[O:21])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH3:24])[CH2:10][C:11]1[C:19]2[O:18][CH:17]=[CH:16][C:15]=2[CH:14]=[C:13]([C:20]([OH:22])=[O:21])[CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(CC(C)NC(=O)OC(C)(C)C)c2occc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(Cc1cc(C(=O)O)cc2ccoc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.1 %

Procedure:
A mixture of 0.341 gm (1.02 mMol) N-tert-butoxycarbonyl 1-(5-methoxycarbonylbenzofur-7-yl)-2-aminopropane (EXAMPLE 41) and 0.204 gm (5.1 mMol) sodium hydroxide in 2 mL ethanol and 0.5 mL water was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue dissolved in water. This aqueous solution was washed with ethyl acetate and the organic phase discarded. The remaining aqueous phase was made acidic by the addition of aqueous potassium hydrogen sulfate. The aqueous phase was again extracted with ethyl acetate. This organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from a mixture of chloroform and hexane to provide 0.300 gm (92%) of the title compound as a white crystalline solid in two crops.
Reaction SMILES: [C:1]([CH:9]([CH2:15][CH2:16][CH3:17])[C:10]([O:12]CC)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[NH2:19]>C(O)C>[C:2]1([C:1]2[C:9]([CH2:15][CH2:16][CH3:17])=[C:10]([OH:12])[N:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[N:19]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ccccn1
Reactant: CCCC(C(=O)OCC)C(=O)c1ccccc1
Solvent: CCO
Product: CCCc1c(-c2ccccc2)nn(-c2ccccn2)c1O
Temperature: 100 °C
Reaction time: 20 h
Yield: 80 %

Procedure:
Ethyl 2-benzoylpentanoate (355 mg, 1.5 mmol) was dissolved in 5 mL of ethanol to which 2-hydrazinopyridine (163 mg, 1.5 mmol) was then added, followed by refluxing at 100° C. After 20 hours, ethanol was concentrated, followed by extraction with ethyl acetate. The extract was washed two or three times with water, and the organic layer was dried over anhydrous MgSO4 and then concentrated. The resulting residue was purified by column chromatography (n-hexane:EA=10:1) to afford the title compound.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.CN(CCN(C)C)C.C([Li])CCC.C([Cu])#N.[CH:31](N1CCCCC1)=[O:32]>CCOCC>[OH:8][CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[CH:31]=[O:32]
Reactant: O=CN1CCCCC1
Reactant: OCc1ccc(-c2ccccc2)cc1
Agent: N#C[Cu]
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1cc(-c2ccccc2)ccc1CO
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-biphenylmethanol (0.368 g, 2 mmol) in ether (25 mL) and TMEDA (1.21 mL, 8 mmol), at 0° C. was added n-butyllithium (2.5N hexanes; 3.2 mL, 8 mmol). The solution was then heated at reflux for 1 h, cooled to -60° C. and CuCN (0.2 g, 2.2 mmol) added. After 30 minutes, the solution was cooled to -78° C. and N-formylpiperidine (1.11 mL, 10 mmol) was then added dropwise and stirring was continued for 1 h. The mixture was then warmed to -10° C., quenched with saturated NH4Cl, extracted with ether washed with brine, dried and the solvent removed in vacuo. Chromatography of the residue (silica gel; hexane:EtOAc 4:1) afforded the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[CH:3]=1.CCCCCC.S(Cl)([Cl:34])(=O)=O>>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[C:3]=1[Cl:34]
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1c(Cl)ccc(-c2nc(C(=O)OC(C)C)cc(N)c2F)c1F
Solvent: CCCCCC
Product: COc1c(Cl)ccc(-c2nc(C(=O)OC(C)C)c(Cl)c(N)c2F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
Propan-2-yl 4-amino-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate (3.065 g, 8.59 mmol) was dissolved in sulfuryl chloride (150 mL). The solution was stirred under nitrogen at room temperature for 8 h. During this time, a white precipitate formed. Hexane (100 mL) was added, and the mixture was stored overnight at −20° C. The product was filtered, washed with hexane and then slurried in EtOAc (100 mL). The organic suspension was neutralized with satd aq NaHCO3 solution, which caused all solids to dissolve. The organic layer was separated and washed with 10% aq NaHSO3 solution and brine, dried (MgSO4), and concentrated under reduced pressure to give a white solid (1.962 g, 58%): mp 109-111° C.; 1H NMR (400 MHz, CDCl3) δ 7.25 (m, 2H), 5.32 (septet, J=6.3 Hz, 1H, CHMe2), 5.07 (br s, 2H), 3.97 (d, JF-H=1.0 Hz, 3H, OMe), 1.40 (d, J=6.3 Hz, 6H, CHMe2); 19F NMR (376 MHz, CDCl3) δ −128.16 (dd, JF-F=33.3 Hz, JF-H=2.5 Hz, phenyl F), −138.35 (d, JF-F=33.4 Hz, pyridine F5).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[NH2:11][C@H:12]1[CH2:17][C@H:16]([CH3:18])[CH2:15][N:14]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:13]1.C(N(CC)CC)C>O1CCOCC1>[CH2:22]([O:21][C:19]([N:14]1[CH2:15][C@@H:16]([CH3:18])[CH2:17][C@H:12]([NH:11][C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]([S:8][CH3:9])[N:4]=2)[CH2:13]1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CSc1ncc(Br)c(Cl)n1
Reactant: C[C@H]1C[C@H](N)CN(C(=O)OCc2ccccc2)C1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CSc1ncc(Br)c(N[C@H]2C[C@H](C)CN(C(=O)OCc3ccccc3)C2)n1

Procedure:
A solution of 5-bromo-4-chloro-2-(methylthio)pyrimidine (1.0 g, 4.2 mmol), (3S,5S)-benzyl 3-amino-5-methylpiperidine-1-carboxylate (2.7 g, 8.35 mmol) and triethylamine 1.3 g, 12.5 mmol) in dioxane (50 ml) were stirred for 16 hours. The reaction was concentrated and the residue dissolved in methylene chloride (50 ml) and washed with water. The organic layer was dried and concentrated and purified on a silica gel column with 10-20% ethyl acetate/dichloromethane as solvent to give (3S,5S)-3-(5-bromo-2-methylsulfanyl-pyrimidin-4-ylamino)-5-methyl-piperidine-1-carboxylic acid benzyl ester as a viscous oil. MS (ES+): 452.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[C:27]5[CH:28]=[CH:29][CH:30]=[C:21]([C:22]=45)[S:20]3(=[O:32])=[O:31])[CH2:14][CH:15]=2)=[CH:2]1.[H-].[Na+].[CH3:35]I>O1CCOCC1.O>[CH3:35][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[C:27]5[CH:28]=[CH:29][CH:30]=[C:21]([C:22]=45)[S:20]3(=[O:32])=[O:31])[CH2:12][CH:11]=2)=[CH:2]1
Reactant: CI
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CC=C(c2c[nH]c3ccccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(C2=CCN(CCCN3c4cccc5cccc(c45)S3(=O)=O)CC2)c2ccccc21
Temperature: 20 °C
Reaction time: 2 h
Yield: 29.1 %

Procedure:
A mixture of 2-{3-[4-(3-indolyl)-1,2,3,6-tetrahydro-1-pyridyl]propyl}naphtho [1,8-cd]isothiazole 1,1-dioxide (11 g) in dmethylformamide (150 cc) is added over 30 minutes to sodium hydride (1.3 g) in a 50% dispersion in vaseline oil, under a current of argon, maintaining the temperature at about 20° C. The reaction medium is stirred for 2 hours at a temperature of about 20° C. then a solution of methyl iodide (3.9 g) in dioxane (50 cc) is added over 15 minutes. Stirring is maintained for 15 hours at a temperature of about 20° C. The reaction mixture is redissolved in distilled water (250 cc) and the organic phase is extracted with dichloromethane (4×100 cc) and then washed with distilled water (400 cc), dried over anhydrous magnesium sulphate, filtered and concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue obtained is purified by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with dichloromethane as eluant, and recrystallized from boiling methyl ethyl ketone (70 cc). 2-{3-[4-(1-Methyl-3-indolyl)1,2,3,6-tetrahydro-1-pyridyl]propyl }naphtho[1,8-cd]isothiazole 1,1-dioxide (3.3 g) is obtained, m.p. 161° C.
Reaction SMILES: CC1C=CN2C=C(CS)N=C2C=1.BrC[C:15]1[CH:16]=[CH:17][C:18]2[O:22][C:21](N(CC)C=O)=[N:20][C:19]=2[CH:28]=1.CC(C)=O.C(=O)([O-])[O-].[K+].[K+]>O>[O:22]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:28][C:19]=2[N:20]=[CH:21]1
Reactant: CCN(C=O)c1nc2cc(CBr)ccc2o1
Agent: Cc1ccn2cc(CS)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: c1ccc2ocnc2c1
Reaction time: 2 h
Yield: 125.4 %

Procedure:
A mixture of 7-methylimidazo[1,2-a]pyridin-2-ylmethanethiol (1.5 g) and 5-bromomethyl-2-(N-ethylformamido)benzoxazole (2.9 g) in a solution of acetone (40 ml) and water (30 ml) was adjusted to pH 9-10 with saturated aqueous potassium carbonate solution under ice-cooling. The mixture was stirred for 2 hours at the same temperature and the isolated precipitate was collected by filtration to give 2-(N-ethylformamido)-5-(7-methylimidazo[1,2-a]pyridin-2-yl)methylthiomethyl]benzoxazole (1.53 g).
Reaction SMILES: Br[C:2]1[C:3]([F:18])=[CH:4][C:5]([F:17])=[C:6]([C@:8]23[CH2:15][O:14][C@H:13]([CH3:16])[C@H:12]2[CH2:11][O:10][NH:9]3)[CH:7]=1.C(O)(=O)C>C1COCC1.[Zn]>[NH2:9][C@@:8]1([C:6]2[CH:7]=[CH:2][C:3]([F:18])=[CH:4][C:5]=2[F:17])[CH2:15][O:14][C@H:13]([CH3:16])[C@H:12]1[CH2:11][OH:10]
Reactant: C[C@H]1OC[C@]2(c3cc(Br)c(F)cc3F)NOC[C@H]12
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@H]1OC[C@@](N)(c2ccc(F)cc2F)[C@@H]1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
(3aR*,4R*,6aS*)-6a-(5-Bromo-2,4-difluorophenyl)-4-methylhexahydro furo[3,4-c]isoxazole (200 mg, 0.62 mmol) was dissolved in THF (10 mL). Zinc dust (0.49 g, 7.50 mmol) was added, followed by acetic acid (143 μl, 2.50 mmol) and the reaction was stirred at room temperature overnight. The reaction was filtered through Celite®, washing with MeOH and the filtrate was concentrated in vacuo. The residue was basified with saturated NaHCO3 and DCM added. The mixture was filtered and the layers separated. The aqueous layer was extracted with DCM (×2) and the combined organics were dried (MgSO4) and concentrated to leave the title compound (120 mg).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([CH3:11])[CH:5]=1.[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[OH-].[Na+]>C(O)C>[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:3][C:4]2[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([CH3:11])[CH:5]=2)=[CH:18][CH:17]=1)(=[O:14])=[O:15]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: Cc1cc(CCl)cc(C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(COc2ccc(S(C)(=O)=O)cc2)cc(C)n1
Yield: 46.6 %

Procedure:
To a solution of 1.0 g (5.21 mmol) of 4-chloromethyl-2,6-dimethylpyridine hydrochloride and 1.1 g (6.25 mmol) of 4-methylsulfonylphenol in ethanol (3.5 mL) was added 3.5 mL (14.0 mmol) of 4 N aqueous sodium hydroxide solution, followed by heating under reflux for 90 minutes. After standing to cool, ethanol was evaporated under a reduced pressure. To the obtained residue, water was added and the precipitates were collected by filtration and then dried under a reduced pressure to obtain 707 mg (yield 46.6%) of 4-(4-methanesulfonylphenoxymethyl)-2,6-dimethylpyridine (VI-4) as a colorless crystal. Its physical property is shown below.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[N:8]([CH3:16])[C:7]2=[O:17].[Cl:18][C:19]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:20]=1[CH:21]=[CH:22][C:23](O)=[O:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH2:10][CH2:11][N:12]([C:23](=[O:24])/[CH:22]=[CH:21]/[C:20]3[C:19]([Cl:18])=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:30])[CH2:13][CH2:14]1)[N:8]([CH3:16])[C:7]2=[O:17]
Reactant: CN1C(=O)c2cccc(Cl)c2C12CCNCC2
Reactant: O=C(O)C=Cc1c(Cl)cccc1Cl
Product: CN1C(=O)c2cccc(Cl)c2C12CCN(C(=O)/C=C/c1c(Cl)cccc1Cl)CC2

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 1 using 7-chloro-2-methylspiro[isoindoline-1,4′-piperidin]-3-one and 2,6-dichlorocinnamic acid. 1H NMR (CDCl3) 1.82 (m, 2H), 2.99 (m, 2H), 3.35 (s, 3H), 3.68 (m, 1H), 3.88 (m, 1H), 4.18 (m, 1H), 4.49 (m, 1H), 7.06 (d, 1H), 7.1-7.6 (5H), 7.76 (2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[NH:8][CH:9]=[C:10]([C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[C:11](=O)[C:6]=2[S:5][CH:4]=1.[OH-].[Na+].P(Cl)(Cl)([Cl:22])=O>>[C:13]([C:10]1[C:11]([Cl:22])=[C:6]2[S:5][CH:4]=[C:3]([O:2][CH3:1])[C:7]2=[N:8][CH:9]=1)(=[O:17])[CH2:14][CH2:15][CH3:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCC(=O)c1c[nH]c2c(OC)csc2c1=O
Agent: [Na+]
Agent: [OH-]
Product: CCCC(=O)c1cnc2c(OC)csc2c1Cl
Reaction time: 0.5 h

Procedure:
3-Methoxy-6-butyrylthieno[3,2-b]pyridin-7(4H)-one (3 g) and phosphorus oxychloride (10 ml) were heated under reflux for one hour. The reaction mixture was poured onto ice water (100 g) stirred for 30 minutes and then basified with 40% sodium hydroxide solution cooling with ice, then extracted with chloroform (3×100 ml). The chloroform extracts were combined dried over magnesium sulphate, filtered and evaporated under reduced pressure to give a brown solid, 3.1 g, m.p. 76°-78°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[CH:10][N:9]=1.[H-].[Na+].Cl.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26]Cl.O>CN(C)C=O>[CH3:23][N:24]([CH2:25][CH2:26][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:11]=[CH:10][N:9]=1)[CH3:28]
Reactant: CN(C)CCCl
Reactant: Oc1ccccc1-c1cc(-c2ccccc2)ncn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccccc1-c1cc(-c2ccccc2)ncn1
Temperature: 100 °C
Reaction time: 6 h
Yield: 77.8 %

Procedure:
A solution of 4-(2-hydroxyphenyl)-6-phenyl-pyrimidine (0.5 g, example 1) and sodium hydride (0.12 g, 80% in oil) in anhydrous dimethylformamide (5 ml) was stirred 20 minutes at room temperature. Then 2-dimethylaminoethyl chloride hydrochloride (0.29 g) was added and the solution was heated at 100° C. under stirring for 6 hours. The reaction mixture was cooled, then poured into water, and the separated oil was extracted with ethyl acetate. The organic layer was dried, then evaporated to dryness to give 500 mg of the title compound as a crude residue, which was purified through its hydrochloride salt. This was obtained by dissolving the free base in acetone, adding a hydrochloric acid ethereal solution and filtering off the crystallized salt.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:15])([CH3:14])[CH2:7][N:8]2[C:11](=[O:13])[CH3:12])=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][O:19][CH2:20][CH2:21]Br.C([O-])([O-])=O.[Na+].[Na+]>CO.O>[CH3:14][C:6]1([CH3:15])[C:5]2[C:9](=[CH:10][C:2]([N:1]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:3][CH:4]=2)[N:8]([C:11](=[O:13])[CH3:12])[CH2:7]1
Reactant: BrCCOCCBr
Reactant: CC(=O)N1CC(C)(C)c2ccc(N)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)N1CC(C)(C)c2ccc(N3CCOCC3)cc21
Temperature: 150 °C
Reaction time: 2.5 h

Procedure:
A mixture of 1-(6-amino-3,3-dimethylindolin-1-yl)ethanone (5 g, 24.5 mmol), 1-bromo-2-(2-bromoethoxy)ethane (6.25 g, 26.9 mmol), and Na2CO3 (5.19 g, 49 mmol) in MeOH (25 mL) was heated to 150° C. in a sealed tube. After 2.5 h, the mixture was cooled to rt. The reaction mixture was diluted with water (100 mL). The resulting solid was filtered, washed with water (300 mL), and dried in the air to give 1-(3,3-dimethyl-6-morpholinoindolin-1-yl)ethanone as a grey solid: 1H NMR (500 MHz, DMSO-d6) δ ppm 7.74 (1H, s), 7.06 (1H, d, J=8.1 Hz), 6.61 (1H, dd, J=8.2, 2.1 Hz), 3.82 (2H, s), 3.67-3.76 (4H, m), 2.95-3.06 (4H, m), 2.13 (3H, s), 1.26 (6H, s). Mass Spectrum (ESI) m/e=275.2 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.C(O[CH:14](OCC)[CH2:15][S:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)C.Cl>C(O)(C)C>[ClH:2].[Cl:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][CH:14]=[C:15]2[S:16][CH:17]1[CH2:18][CH2:19][N:20]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:21][CH2:22]1
Reactant: NNc1ccc(Cl)cc1
Reactant: CCOC(CSC1CCN(Cc2ccccc2)CC1)OCC
Agent: Cl
Solvent: CC(C)O
Product: Clc1ccc2[nH]cc(SC3CCN(Cc4ccccc4)CC3)c2c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 127.4 %

Procedure:
4-Chlorophenylhydrazine hydrochloride (1 g) and 4-[(2,2-diethoxyethyl)thio]-1-(phenylmethyl)piperidine (1.8 g, prepared in Example 13) in isopropanol (20 ml) are stirred at room temperature under nitrogen until a solution is formed. After cooling to 0° C., the solution is saturated with gaseous hydrogen chloride. After 4 hours, the precipitate is filtered off, taken up in sodium hydroxide and extracted with ether and then with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated. The residual oil is taken up in a solution of hydrogen chloride in ether to give 5-chloro-3-[[1-(phenylmethyl)piperidin-4-yl]thio]-1H-indole hydrochloride (1.4 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Cl.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[N:8]1
Reactant: Fc1cccc(CCl)c1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(cnn2Cc2cccc(F)c2)c1
Temperature: 70 °C
Yield: 33 %

Procedure:
A mixture of 5-nitro-1H-indazole (8.15 gm, 50 mmole), m-fluoro-benzyl chloride (7.95 gm, 1.1 equiv), K2CO3 (7.59 gm, 1.1 equiv), and KI (8.47 gm, 1.02 equiv) in dry DMF (75 mL) was heated at 70° C. overnight. After cooling to RT, water (75 mL) was slowly added to give a precipitate that consisted of about a one to one mixture of isomers [HPLC Ret Time: 1.92 (1-substitued isomer vs. 2.03 (2-substituted isomer) YMC C18 S5 4.6×50 mm, 3 min gradient, 4 mL/min]. This was collected by filtration and washed with water. The solid was crystallized twice from acetone/water to afford the desired 1-(3-fluoro-benzyl)-5-nitro-1H-indazole (4.47 gm, 33%). A suspension of this material (3.00 gm, 11.1) and 10% Pd/C (3.00 gm) in EtOH (21 mL) was kept under an H2 atmosphere (balloon) for 24 hr. The catalyst was removed by filtration and the solvent was evaporated to leave the product as a solid (2.4 gm, 90%). 1H NMR (CDCl3): δ 3.61 (br s, 2H), 5.52 (s, 2H), 6.81-7.85 (m, 7H), 7.85 (s, 1H); MS: 242 (M+H)+; HPLC Ret Time: 1.03 min (YMC Xterra ODS S7, 3.0×50 mm column, 2 min gradient, 5 mL/min).