Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([O:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]1[S:19][CH:20]([CH2:23][C:24]([OH:26])=O)[CH2:21][N:22]=1)=[CH:14]2.Cl.C[N:40](C)CCCN=C=NCC.[NH4+].ON1C2C=CC=CC=2N=N1.CN(C)C=O>C(OCC)(=O)C.CO>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([O:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:35])=[O:36])=[CH:30][CH:29]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]1[S:19][CH:20]([CH2:23][C:24]([NH2:40])=[O:26])[CH2:21][N:22]=1)=[CH:14]2
Reactant: Cn1ccnc1COc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: Cn1ccnc1COc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C3=NCC(CC(N)=O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 23.9 %

Procedure:
A mixture of (2-{7-[(1-methyl-1H-imidazol-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (210 mg), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (150 mg), 1-hydroxybenzotriazole ammonium salt (118 mg) and N,N-dimethylformamide was stirred at room temperature for 5 hr. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was washed with diisopropyl ether. Sodium chloride was added to the aqueous layer to give a saturated solution, and the mixture was subjected to extraction with ethyl acetate. The organic layer was dried over magnesium sulfate, filtrated, and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (methanol:ethyl acetate=0:100 to 25:75, volume ratio), and the obtained amorphous solid was crystallized from diethyl ether to give the title compound (50 mg, yield 24%) as colorless crystals. melting point 130-131° C. MS 540 (MH+).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:11][N:10]([CH2:19][CH3:20])[N:9]=2)=[C:6]([F:21])[CH:5]=[CH:4][C:3]=1[NH:22][S:23]([C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[F:33])(=[O:25])=[O:24].[C:34](Cl)(=[O:36])[CH3:35].C(OCC)C>C(Cl)Cl.O>[F:33][C:27]1[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=1[S:23]([N:22]([C:3]1[CH:4]=[CH:5][C:6]([F:21])=[C:7]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)=[CH:11][N:10]([CH2:19][CH3:20])[N:9]=2)[C:2]=1[F:1])[C:34](=[O:36])[CH3:35])(=[O:24])=[O:25]
Reactant: CC(=O)Cl
Reactant: CCn1cc(-c2ccncc2)c(-c2c(F)ccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: CCn1cc(-c2ccncc2)c(-c2c(F)ccc(N(C(C)=O)S(=O)(=O)c3cc(F)ccc3F)c2F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
N-{2,4-difluoro-3-[1-ethyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]phenyl}-2,5-difluorobenzenesulfonamide (80 mg, 0.168 mmol) was suspended in 3.5 mL of DCM and TEA (18.7 mg, 25.8 μL, 0.185 mmol) was added. Acetyl chloride (20.0 mg, 18.0 μL, 0.252 mmol) was added to the solution so obtained, and the reaction mixture was stirred at room temperature overnight, diluted with DCM, and poured in water. The organic layer was washed three times with water, once with brine, dried over Na2SO4 and concentrated to dryness. The solid so obtained was taken up with ethyl ether and filtered (79 mg, 91% yield)
Reaction SMILES: [CH2:1]([N:4]([CH2:36][CH2:37][CH3:38])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:32][C:33]([OH:35])=[O:34])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]([CH2:26][C:27]2[NH:28][CH:29]=[CH:30][N:31]=2)[CH2:19][C:20]2[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=2)=[CH:13][CH:12]=1)[CH2:2][CH3:3].[CH3:39][O:40][CH2:41][CH2:42]O>>[CH3:39][O:40][CH2:41][CH2:42][O:34][C:33](=[O:35])[CH2:32][N:9]([CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:36][CH2:37][CH3:38])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]([CH2:26][C:27]2[NH:28][CH:29]=[CH:30][N:31]=2)[CH2:19][C:20]2[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=2)=[CH:13][CH:12]=1
Reactant: CCCN(CCC)CCCCN(CC(=O)O)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Reactant: COCCO
Product: CCCN(CCC)CCCCN(CC(=O)OCCOC)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 80 °C
Reaction time: 21 h

Procedure:
The compound (190.7 mg) obtained in Example 65-1 was dissolved in 2-methoxyethanol (4.0 ml) and the whole was stirred at 80° C. for 21 hours. After completion of the reaction, the solvent was distilled off. The resultant was added with a saturated aqueous sodium hydrogen carbonate solution and the whole was subjected to extraction with chloroform and dried with magnesium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining a hydrochloride (37.9 mg) of the subject compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:26])[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:28])[CH3:27])=[CH:4][CH:3]=1>C(OCC)(=O)C.CCCCCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:26])[CH2:21][C:22]([CH3:24])([CH3:23])[CH3:25])[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:28])[CH3:27])=[CH:6][CH:7]=1
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2(O)c1ccc(Br)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2c1ccc(Br)cc1
Yield: 88 %

Procedure:
Using N-(3-(4-bromophenyl)-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 254, the title compound was synthesized in the same manner as in Example 271. Yield: 88%. Melting point: 171-172° C. (ethyl acetate-hexane).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[N:32]1[CH:37]=[CH:36][CH:35]=[C:34](B(O)O)[CH:33]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:34]4[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: OB(O)c1cccnc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4cccnc4)cc3)oc2C)cc1

Procedure:
To a 25 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl propionic acid ethyl ester (0.410 mmoles, 200 mg) (see Ex. 2, Part B), 3-pyridyl boronic acid (0.451 mmoles), toluene (5 mL), ethanol (5 mL), and sodium carbonate (0.819 mmoles, 0.410 mL of a 2M solution). This mixture was vacuum degassed and nitrogen was added in at a positive pressure. Pd(PPh3)4 (catalytic, spatula tip) was added and the reaction was heated to reflux for 3 h. Distilled water was added to the mixture. Subsequently, this was extracted with ethyl acetate and washed with brine. The organic layer was collected, filtered over a thin pad of silica gel, and concentrated in-vacuo. The crude mixture was then purified by chromatography on silica gel affording 2-(4-{2-[2-(4-pyrid-3-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester.
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:17][CH2:18][CH2:19]Br.C(N(CC)CC)C.C1OC1C>O.CN(C)P(=O)(N(C)C)N(C)C>[CH3:13][O:12][C:11]1[C:2]([O:1][CH2:17][CH2:18][CH3:19])=[C:3]2[C:8](=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=1)[N:7]=[CH:6][CH:5]=[CH:4]2
Reactant: COc1cc([N+](=O)[O-])c2ncccc2c1O
Reactant: CCCBr
Agent: CC1CO1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCOc1c(OC)cc([N+](=O)[O-])c2ncccc12
Yield: 62.2 %

Procedure:
To a stirred mixture of 15 g (0.068 mole) of 5-hydroxy-6-methoxy-8-nitroquinoline, 16.8 g (0.14 mole) of n-propyl bromide, 1.5 g of triethylamine and 20 g of hexamethylphosphoric triamide, heated at a bath temperature of 110°, was added dropwise, during 2 hr, 20 g of propylene oxide. After an additional 48 hr at 110° the green-brown mixture was poured into 150 ml of water. The aqueous mixture was extracted with diethyl ether and the extract was dried (magnesium sulfate) and concentrated to give a dark yellow residue. Crystallization from hexane provided 11.1 grams (62%) of 6-methoxy-8-nitro-5-(n-propoxy)quinoline as yellow crystals, mp 100°-104°. Recrystallization from methanol gave an analytical sample as pale yellow crystals, mp 101°-103°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:9]=1[C:10]([O:12]C)=O)(=[O:7])=[O:6].[CH3:21][NH:22][CH3:23].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[CH3:21][N:22]([CH3:23])[C:10](=[O:12])[C:9]1[C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=[CH:17][C:8]=1[S:5]([NH:4][CH2:3][CH2:2][OH:1])(=[O:6])=[O:7]
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCO
Reactant: CNC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CN(C)C(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCO
Reaction time: 96 h
Yield: 87.7 %

Procedure:
A solution of methyl 2-[N-(2-hydroxyethyl)aminosulfonyl]-6-nitrobenzoate (4.58 g, 15.1 mmol) in absolute MeoH (50 ml) was added to a solution of dimethylamine (6.8 g, 0.15 mol) and potassium tertbutoxide (0.68 ml of a 0.262 M solution in tertbutanol) in absolute MeoH (100 ml). After stirring at 20°-25° C. for 4 days, solvents were removed under reduced pressure. The residue was dissolved in EtOAc and washed with 0.5N HCl followed by a saturated aqueous NaCl solution. The EtOAc extract was dried (Na2SO4), filtered and concentrated to give 4.2 g (88%) of product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:5]([NH2:10])=[N:6][CH:7]=[CH:8][CH:9]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(O)(=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH:1][CH2:2][CH2:3][C:4]2[C:5]([NH2:10])=[N:6][CH:7]=[CH:8][CH:9]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: NCCc1cccnc1N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(NCCc2cccnc2N)CC1
Yield: 42.2 %

Procedure:
A solution of 3-(2-aminoethyl)-2-aminopyridine (0.122 g, 0.88 mmol) and 1-t-butoxycarbonyl 4-piperidone (0.177 g, 0.88 mmol) in dichloroethane (3 mL) containing 2 drops of acetic acid was treated with sodium triacetoxyborohydride (0.28 g, 1.33 mmol) at 20-75° C. until starting material was no longer consumed. The reaction was worked up with saturated sodium bicarbonate and methylene chloride, and dried over sodium sulfate. The crude product was purified by chromatography (silica gel, 0-10% {0.1% ammonium hydroxide in methanol) in methylene chloride, gradient elution) to produce the title compound (0.119 g) as a yellow oil. MS 321 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][C:28]([S:32]([N:35]([C@@H:37]([CH2:41][CH2:42][CH2:43][N+:44]([CH3:47])([CH3:46])[CH3:45])[C:38]([O-:40])=[O:39])[CH3:36])(=[O:34])=[O:33])=[CH:27][C:26]=3[F:48])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:49][CH3:50].Cl>O>[Cl-:1].[C:38]([C@@H:37]([N:35]([CH3:36])[S:32]([C:28]1[CH:27]=[C:26]([F:48])[C:25]([CH2:24][S:23][C:14]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:49][CH3:50])[CH:4]=3)([CH3:10])[CH3:9])=[CH:12][N:13]=2)=[C:30]([F:31])[CH:29]=1)(=[O:34])=[O:33])[CH2:41][CH2:42][CH2:43][N+:44]([CH3:46])([CH3:47])[CH3:45])([OH:40])=[O:39]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(S(=O)(=O)N(C)[C@@H](CCC[N+](C)(C)C)C(=O)[O-])cc3F)n2-c2ccc(F)cc2)ccc1Cl
Agent: Cl
Solvent: O
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(S(=O)(=O)N(C)[C@@H](CCC[N+](C)(C)C)C(=O)O)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Product: [Cl-]

Procedure:
A solution of (S)-2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluoro-N-methylphenylsulfonamido)-5-(trimethylammonio)-pentanoate in water was treated with 1N HCl (1.0 eq) and lyophilized to yield the title compound in quantitative yield. 1H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 7.55 (d, J=6.7 Hz, 2H), 7.29 (s, 1H), 7.26 (d, J=8.3 Hz, 1H), 7.05-6.96 (m, 2H), 6.68-6.60 (m, 1H), 6.60-6.53 (m, 2H), 6.50 (dd, J=8.3, 2.0 Hz, 1H), 4.53 (dd, J=9.5, 4.7 Hz, 1H), 4.05 (s, 2H), 3.69 (s, 3H), 3.39-3.27 (m, 2H), 3.04 (s, 9H), 2.80 (s, 3H), 1.91-1.60 (m, 4H), 1.48 (s, 3H), 1.47 (s, 3H); 19F NMR (376 MHz, DMSO) δ −111.37-111.46 (m, 2F), −112.02-112.11 (m, 1F); MS (EI) m/z 753 (M+).
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][C:2]2=[O:9].[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.[OH-].[K+]>CC(O)C.O.CCOCC>[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[C:3]2[CH:4]3[CH2:7][CH2:8][CH:1]([CH:6]=[CH:5]3)[C:2]2=[O:9])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C1CC2C=CC1CC2
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOCC
Solvent: O
Product: O=C1C(=Cc2ccc(F)cc2)C2C=CC1CC2
Temperature: 25 °C

Procedure:
A solution of bicyclo[2.2.2]oct-5-en-2-one (J. Oro. Chem. 33, 2211 (1968)) (3.34 g, 27.4 mmoles), 4-fluorobenzaldehyde (3.08 ml, 28.7 mmoles) and KOH (2 pellets) in 10 ml of 2-propanol was heated at 60° C. for 1.5 hours, cooled to room temperature and diluted with H2O and ether. The organic layer was washed with H2O, 2% aqueous HCl, saturated NaHCO3 and brine and dried (MgSO4). Removal of the volatiles in vacuo provided a residue which was recrystallized with hexanes. mp 85°-86° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]=[C:10]([C:15](=O)[CH3:16])[C:11]([O:13][CH3:14])=[O:12].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[SH:25].C(O)(=O)C>CN(C)C=O.CCOCC>[CH3:16][C:15]1[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[S:25][CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])[C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: Nc1ccccc1S
Reactant: COC(=O)C(=Cc1cccc(Cl)c1Cl)C(C)=O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)C1=C(C)Nc2ccccc2SC1c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2-[(2,3-dichlorophenyl)methylene]-3-oxobutanoic acid, methyl ester (1.0 g., 3.66 mmole) in dry dimethylformamide (7 ml.) is treated with 2-aminothiophenol (512 mg., 4.1 mmoles) and the resulting reaction mixcture is stirred at room temperature for 3 hours. Acetic acid (0.1 ml.) is added and the reaction is heated at 75° (oil bath temperature) for 48 hours. It is then cooled to room temperature and diluted with ether. The resulting solution is washed with 1N sodium hydroxide, water, and brine. After drying over anhydrous magnesium sulfate, the solvent is stripped off to provide a yellow solid. It is crystallized from isopropyl ether-dichloromethane to yield 660 mg. of light yellow crystalline product. Recrystallization from isopropyl ether-dichloromethane yields an analytically pure sample of 2,5-dihydro-4-methyl-2-(2,3-dichlorophenyl)-1,5-benzothiazepine-3-carboxylic acid, methyl ester as colorless needles; m.p. 190°-191°. TLC (silica gel; ethyl acetate:hexanes, 40:60) Rf =0.40.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]([CH3:20])[CH3:19])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:21][C:22]1[N:23]=[CH:24][N:25]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][C:28]=2[O:34][CH3:35])[CH:26]=1>C(O)(=O)C.C1COCC1>[Cl:21][C:22]1[N:23]=[CH:24][N:25]([C:27]2[CH:33]=[CH:32][C:30]([NH:31][C:2]3[N:3]=[C:4]([N:18]([CH3:20])[CH3:19])[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=5)[C:6]=4[N:7]=3)=[CH:29][C:28]=2[O:34][CH3:35])[CH:26]=1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Reactant: CN(C)c1nc(Cl)nc2c1CCC2c1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cc(Nc2nc3c(c(N(C)C)n2)CCC3c2ccc(Cl)cc2)ccc1-n1cnc(Cl)c1
Temperature: 75 °C

Procedure:
2-Chloro-7-(4-chlorophenyl)-N,N-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (98 mg, 0.318 mmol) was added to a solution of 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (71.1 mg, 0.318 mmol) in acetic acid (1.000 mL) and THF (1 mL). The reaction mixture was heated at 75° C. overnight. Partial conversion to the desired product was observed. The reaction was further heated at 120° C. for 6 h. The crude reaction mixture was purified by preparative HPLC. The appropriate fractions were evaporated to afford N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-chlorophenyl)-N4,N4-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine, TFA salt (17.2 mg, 0.028 mmol, 8.70% yield). LC-MS (M+H)+=495.1. 1H NMR (500 MHz, CDCl3) δ ppm 11.80 (1H, s), 7.61-7.72 (1H, m), 7.34-7.42 (2H, m), 7.27-7.33 (2H, m), 7.21 (2H, d, J=8.5 Hz), 7.16 (1H, d, J=9.2 Hz), 7.06 (1H, d, J=1.5 Hz), 4.30-4.41 (1H, m), 3.82 (6H, s), 3.48 (1H, br. s.), 3.31-3.39 (2H, m), 3.18-3.27 (1H, m), 2.58-2.80 (2H, m), 2.14-2.29 (1H, m).
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1(C)C=CC=CC=1.CN(C)C=O>[C:6]1([CH3:5])[CH:11]=[CH:10][C:9]([S:12]([CH2:2][C:3]#[N:4])(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: N#CCBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)CC#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54 %

Procedure:
3.37 g (28 mmol) of bromoacetonitrile and 640 mg (2.8 mmol) of benzyltriethylammonium chloride are added to a solution of 5 g (28 mmol) of sodium 4-methyl-benzenesulfinate in 50 ml of toluene and 50 ml of dimethylformamide. The reaction mixture is stirred at room temperature for 24 h. The heterogeneous mixture is filtered. The filtrate is evaporated and then purified on silica gel (heptane then heptane/ethyl acetate, 60/40 v/v). The product is triturated in heptane then filtered and dried. 2.95 g of (toluene-4-sulfonyl)-acetonitrile is obtained in the form of a pale yellow powder. (Yield=54%).
Reaction SMILES: C1(S(O[C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=2)(=O)=O)C=CC=CC=1.[CH3:19][NH:20][CH:21]=[O:22].CCCCCC>C(OCC)(=O)C>[CH3:18][C:13]1[CH:12]=[C:11]([N:20]([CH3:19])[CH:21]=[O:22])[CH:16]=[C:15]([CH3:17])[CH:14]=1
Reactant: Cc1cc(C)cc(OS(=O)(=O)c2ccccc2)c1
Reactant: CNC=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(C)cc(N(C)C=O)c1
Yield: 93.1 %

Procedure:
Following the general procedure, 3,5-dimethylphenyl benzenesulfonate (131 mg, 0.5 mmol) was coupled with N-methylformamide (45 mg, 0.75 mmol) with the reaction time of 20 h. Chromatography on silica gel column with 4:1 hexane:ethyl acetate gave 76 mg (93%) of the title compound as a colorless oil.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7][CH2:6]1.[C:38](OC(=O)C)(=[O:40])[CH3:39].C(=O)([O-])[O-].[K+].[K+].O>C(Cl)Cl>[C:32]1([C:5]2([CH2:4][NH:3][C:38](=[O:40])[CH3:39])[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:9][CH2:10]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NCC1(c2ccccc2)CCN(CCC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)NCC1(c2ccccc2)CCN(CCC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 1 part of 4-aminomethyl-4-phenyl-1-(3,3,3-triphenylpropyl)piperidine dihydrochloride, 1 part by volume of acetic anhydride, 1 part of potassium carbonate, 10 parts by volume of water and 10 parts by volume of methylene chloride is stirred at room temperature for about 4 hours. The organic and aqueous layers are separated, the aqueous layer washed with methylene chloride and the methylene chloride fraction combined with the organic layer. The combined organic fraction is dried over potassium carbonate, the solvent evaporated and the residual colorless amorphous solid crystallized from a mixture of n-hexane and ether to afford N-([4-phenyl-1-(3,3,3-triphenylpropyl)piperidine-4-yl]methyl)acetamide melting at about 154-167° C. This compound is represented by the following structural formula ##STR14##
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].[C:16](O)(=O)[CH3:17]>>[CH3:10][O:9][C:6]1[C:7]2[N:8]=[C:16]([CH3:17])[NH:1][C:2]=2[C:3]([CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])=[CH:4][CH:5]=1
Reactant: COc1ccc(CCN(C)C)c(N)c1N
Reactant: CC(=O)O
Product: COc1ccc(CCN(C)C)c2[nH]c(C)nc12

Procedure:
0.6 g of N-[2-(2,3-diamino-4-methoxyphenyl)ethyl]-N,N-dimethylamine is heated under reflux with 10 ml of acetic acid for 3 hours. The reaction mixture is concentrated, taken up in ethyl acetate, and extracted by shaking with sodium bicarbonate solution. The organic phase is separated, dried with sodium sulfate, and concentrated, thus obtaining 286 mg of 7-methoxy-4-[2-(N,N-dimethylamino)ethyl]-2-methylbenzimidazole as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:27][NH:28][C:29]([C:31]1[C:39]2[C:34](=[CH:35][C:36]([OH:40])=[CH:37][CH:38]=2)[N:33]([CH3:41])[C:32]=1[CH3:42])=[O:30].C([O-])([O-])=O.[Cs+].[Cs+]>>[C:21]([O:20][C:19](=[O:25])[N:18]([C@@H:15]1[CH2:16][CH2:17][N:13]([C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[O:40][C:36]3[CH:35]=[C:34]4[C:39]([C:31]([C:29]([NH:28][CH3:27])=[O:30])=[C:32]([CH3:42])[N:33]4[CH3:41])=[CH:38][CH:37]=3)[CH:8]=2)=[O:12])[CH2:14]1)[CH3:26])([CH3:24])([CH3:23])[CH3:22]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Reactant: CNC(=O)c1c(C)n(C)c2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(C)n(C)c2cc(Oc3ccnc4cc(C(=O)N5CC[C@@H](N(C)C(=O)OC(C)(C)C)C5)sc34)ccc12
Yield: 39.5 %

Procedure:
This material was prepared by the reaction of tert-butyl (3R)-1-[(7-chlorothieno[3,2-b]pyridin-2-yl)carbonyl]pyrrolidin-3-yl(methyl)carbamate 34c (0.181 g, 0.46 mmole) with 6-hydroxy-N,1,2-trimethyl-1H-indole-3-carboxamide 16e (0.10 g, 0.46 mmole) and Cs2CO3 (0.149 g, 0.46 mmole) in a manner as previously described for example 1 to give a yellow solid (0.105 g, 40%). 1H NMR (300 MHz, CDCl3) δ8.48 (1H, d, J=5.4 Hz), 7.82 (1H, s), 7.75 (1H, d, J=8.7 Hz), 7.15 (1H, d, J=2.1 Hz), 7.02 (1H, dd, J=2.1, 8.7 Hz), 6.56 (1H, d, J=5.4 Hz), 5.91 (1H, d, J=4.7 Hz), 4.82 (1H, m), 4.07 (2H, m), 3.87 (1H, m), 3.68 (1H, m), 3.65 (3H, s), 3.05 (3H, d, J=4.7 Hz), 2.84 (3H, s), 2.73 (3H, s), 2.17 (2H, m), 1.45 (9H, s); HRMS (MH+): Calcd: 578.2450; Found: 578.2437.