Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:21])[CH:6]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].I[CH2:23][CH2:24][CH2:25][CH:26]([O:32][C:33](=[O:35])[CH3:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CN(C)C=O>[CH3:3][O:4][C:5]([C:6]([S:17]([CH3:20])(=[O:19])=[O:18])([CH2:23][CH2:24][CH2:25][CH:26]([O:32][C:33](=[O:35])[CH3:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:21]
Reactant: CCCCCC(CCCI)OC(C)=O
Reactant: COC(=O)CCCCCCC(C(=O)OC)S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCC(CCCC(CCCCCCC(=O)OC)(C(=O)OC)S(C)(=O)=O)OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
A suspension of 57% sodium hydride/mineral oil (3.84 g., 0.091 mole) is washed by decantation with petroleum ether to remove the mineral oil. The residual solid is suspended in dry dimethylformamide (100 ml.) and treated with a solution of dimethyl-2-methylsulfonylazelate (23.5 g., 0.08 mole) in dry dimethylformamide (60 ml.) added dropwise at ambient temperature under a nitrogen atmosphere. The resulting solution is stirred for 1 hour at room temperature, cooled to ~ 10° C., and treated with 1-iodo-4-acetoxynonane (30 g., 0.096 mole) added at such a rate as to maintain an internal temperature less than 35° C. After 19 hours at ambient temperature, the reaction mixture is filtered. Collected sodium iodide (17.1 g.) is washed with ether. The combined filtrate and washings are concentrated in vacuo at ~ 100° C. yielding a residual oil which is partitioned between ether and dilute hydrochloric acid. The organic extract is washed with water and saturated brine, dried over magnesium sulfate and evaporated in vacuo leaving the title compound as a viscous oil (37.7 g., 98%), pmr (CDCl3) δ 2.0 (s, 3H), 3.0 (s, 3H), 3.65 (s, 3H), 3.81 (s, 3H) and 4.9 (b, H).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1.O(C(C)(C)C)[Na].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(Br)cc1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: COc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 70 %

Procedure:
10 g of diphenylamine and 11 g of 4-methoxy-bromobenzene was dissolved in toluene (250 mL). NaO-t-Bu (5.3 g), Pd2(dba)3 (0.4 g), and P(t-Bu)3 (0.5 g) were added to the above solution at room temperature. The reaction mixture was stirred at 100° C. for 12 hours under N2 After cooling to room temperature, the mixture was quenched by adding aqueous ammonia (300 mL). An organic layer was separated from the reactant solution using methylene chloride and dried using magnesium sulfate. Then, methylene chloride was removed under reduced pressure and recrystallized using methylene chloride and hexane, yielding 70% of a white solid. Data of NMR spectra and elemental analysis confirmed that the product had the same structure as the compound (6) in the reaction scheme 4.
Reaction SMILES: [CH:1]1([N:6]2[CH2:14][C:11]3([CH2:13][CH2:12]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:74][CH:75]1[CH2:80][CH2:79][N:78]([CH3:81])[CH2:77][CH2:76]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:14][C:11]3([CH2:13][CH2:12]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:74][CH:75]5[CH2:80][CH2:79][N:78]([CH3:81])[CH2:77][CH2:76]5)=[O:28])=[CH:24][CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC3(CC3)C(=O)N4C)cc2)CC1
Reaction time: 0.33 h
Yield: 76.5 %

Procedure:
To a suspension of 0.0275 g (0.0000675 mole) of 4-[(9-cyclopentyl-6,7,8,9-tetrahydro-5-methyl-6-oxospiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-2-yl)amino]-benzoic acid (I-62a) in 3 mL of dimethylformamide was added 0.0157 g (0.000116 mole) of 1-hydroxybenzotriazole, 0.0396 g (0.000104 mole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate and 0.07 mL (0.000402 mole) of ethyldiisopropylamine. The mixture was stirred for 20 minutes and then 0.0125 g (0.00011 mole) of 4-amino-1-methylpiperidine was added. The mixture was stirred for an additional 2.5 hours and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with 1 M sodium hydroxide, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (98:2-80:20) to give 0.026 g of 4-[(9-cyclopentyl-6,7,8,9-tetrahydro-5-methyl-6-oxospiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-2-yl)amino]-N-(1-methyl-4-piperidinyl)benzamide (I-62).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[OH:10][CH:11]([CH3:14])[CH2:12][NH2:13].C(N(C(C)C)C(C)C)C>O>[OH:10][CH:11]([CH3:14])[CH2:12][NH:13][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: CC(O)CN
Reactant: N#Cc1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(O)CNc1ccc(C#N)cc1

Procedure:
12.1 g of 4-fluoro-benzonitrile, 7.5 g of 2-hydroxypropylamine and 17.4 ml of N-ethyl-diisopropylamine were heated together to 100° C. for 2.5 hours. The mixture was poured onto 250 ml of water, extracted five times with 50 ml of ethyl acetate and the combined organic phases were evaporated down. The product remaining was purified by column chromatography (silica gel; eluant: ethyl acetate) and crystallised by triturating with a 1:1-mixture of tert.butyl-methylether and petroleum ether.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([NH:8][C:9]2[C:10]([CH3:28])=[C:11]([CH3:27])[C:12]3[O:16][C:15]([CH3:18])([CH3:17])[CH:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:13]=3[C:25]=2[CH3:26])=O)=[CH:4][CH:3]=1>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:8][C:9]2[C:10]([CH3:28])=[C:11]([CH3:27])[C:12]3[O:16][C:15]([CH3:18])([CH3:17])[CH:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:13]=3[C:25]=2[CH3:26])=[CH:29][CH:30]=1
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)c1ccc(F)cc1)C(c1ccccc1)C(C)(C)O2
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1NCc1ccc(F)cc1)C(c1ccccc1)C(C)(C)O2
Yield: 60 %

Procedure:
By using 4-fluoro-N-(2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl)benzamide, the title compound was synthesized according to Example 2b. Yield: 60%. Melting point: 93-95° C. (Methanol).
Reaction SMILES: CC1(C)C(C)(C)[O:5][B:4]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[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][CH2:12]3)[O:3]1.Cl>C1COCC1.O>[CH2:22]([O:21][C:19]([N:14]1[CH2:13][CH2:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([B:4]([OH:5])[OH:3])[CH:10]=2)[CH2:15]1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC1(C)OB(c2ccc3c(c2)CCN(C(=O)OCc2ccccc2)C3)OC1(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCc2cc(B(O)O)ccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
To a stirring solution of benzyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.991 g, 2.52 mmol, 1.00 eq) in THF (10 ml) and H2O (2.5 ml) was added NaIO4 (1.62 g, 7.56 mmol, 3.00 eq). The resulting suspension was stirred at 25° C. for 30 min and then treated with 3M HCl (1.68 ml, 5.04 mmol, 2.0 eq). The mixture was stirred for 2.5 h. The supernatant was decanted away from the solids, rinsing forward with THF. The combined organic phases were washed with brine (2×), dried (MgSO4) and concentrated in vacuo to give crude 2-(benzyloxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-ylboronic acid (0.640 g, 82% yield) as a foam which was used as is in the next reaction. 1H NMR (400 MHz, DMSO-d6) δ 7.68-7.58 (m, 2H), 7.45-7.29 (m, 6H), 7.17 (m, 1H), 5.13 (s, 2H), 4.62-4.56 (brm, 2H), 3.65 (brs, 2H), 2.86 (t, 2H, J=5.60 Hz); MS (ESI) m/z: 312.0 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][N:23]=1)[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.CC(S(N)=O)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1.[NH:70]1[C:74]([CH2:75][NH2:76])=[N:73][N:72]=[N:71]1>CN(C)C=O>[N:70]1[NH:71][N:72]=[N:73][C:74]=1[CH2:75][NH:76][C:26](=[O:28])[C:25]1[CH:29]=[CH:30][C:22]([NH:21][CH:4]([C:5]2[CH:6]=[CH:7][C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=3)=[CH:9][CH:10]=2)[CH2:3][CH:2]([CH3:1])[CH3:31])=[N:23][CH:24]=1
Reactant: NCc1nnn[nH]1
Reactant: CC(C)CC(Nc1ccc(C(=O)O)cn1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: CC(C)(C)S(N)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)CC(Nc1ccc(C(=O)NCc2nn[nH]n2)cn1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 8.4 %

Procedure:
A 5 mL vial equipped with a stir bar was charged with 6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butylamino)nicotinic acid (0.100 g, 0.233 mmol) as prepared in Example 1.1 using racemic 2-methylpropane-2-sulfinamide in Step B, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl uronium hexafluorophosphate (133.0 mg, 0.350 mmol), N-methylmorpholine (118.0 mg, 1.167 mmol), N,N-dimethylformamide (1.2 mL). The mixture was purged with nitrogen, heated to 50° C. and stirred for 30 minutes. Then, (1H-tetrazol-5-yl)methanamine (39.9 mg, 0.233 mmol) was added. The mixture was stirred at 50° C. overnight. The reaction mixture was purified by prep-HPLC to give (+/−)-N-((2H-tetrazol-5-yl)methyl)-6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butylamino)nicotinamide (10 mg, 4.2%) as a white solid. 1H NMR (400 MHz, CD3OD, δ): 8.50 (d, 1H), 7.86 (dd, 1H), 7.80 (d, 2H), 7.72 (d, 2H), 7.64 (d, 2H), 7.50 (d2H), 6.58 (d, 1H), 5.11 (m, 1H), 4.82 (s, 2H), 1.89-1.82 (m, 1H), 1.80-1.72 (m, 1H), 1.68-1.62 (m, 1H), 1.03 (d, 3H), 1.00 (d, 3H) ppm. MS (M+1): 510.3
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][S:5][CH2:4][CH:3]1[C:8]([O:10][CH3:11])=[O:9].CCN(C(C)C)C(C)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl.O>[CH3:21][S:22]([O:1][CH:2]1[CH2:7][CH2:6][S:5][CH2:4][CH:3]1[C:8]([O:10][CH3:11])=[O:9])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C1CSCCC1O
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CSCCC1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl 4-hydroxytetrahydro-2H-thiopyran-3-carboxylate (3.00 g, 17.0 mmol) in DCM (170 mL) was stirred at 0° C. DIPEA (5.95 mL, 34.0 mmol) was added followed by the dropwise addition of methanesulfonyl chloride (1.95 g, 17.0 mmol). The resulting mixture was stirred at 0° C. for 30 minutes then warmed to ambient temperature and stirred for an additional 30 minutes. The mixture was carefully diluted with water and extracted with DCM (2×). The combined organic extracts were washed with 1N aqueous HCl, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the title compound. The residue was carried forward without further purification.
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](=O)[CH3:4].[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([NH2:17])=[S:16]>C(O)C>[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]1[S:16][C:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[C:3]([CH3:4])[N:17]=1
Reactant: NC(=S)c1ccccc1Cl
Reactant: CC(=O)C(Br)c1ccccc1
Solvent: CCO
Product: Cc1nc(-c2ccccc2Cl)sc1-c1ccccc1
Yield: 79.1 %

Procedure:
1-Bromo-1-phenyl-2-propanone (10.6 g, 0.050 mole), o-chlorothiobenzamide (8.8 g, 0.051 mole), and ethanol (100 ml) are mixed and, after the initial exothermic reaction has subsided, heated under reflux for two hours. The ethanol is evaporated and the residue is treated with chloroform and aqueous sodium bicarbonate. The chloroform layer is separated and evaporated to leave a yellow oil which solidifies on standing. Recrystallization from acetonitrile yields 11.3 g (79%) of 2-(2-chlorophenyl)-4-methyl-5-phenylthiazole, m.p. 63°-65° C.
Reaction SMILES: [F:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][C:5]2[N:9]=[C:8]([SH:10])[NH:7][C:6]=2[CH:11]=1.Cl.[CH3:20][C:21]1[C:22]([CH2:33]Cl)=[N:23][CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]([F:32])([F:31])[F:30].[OH-].[Na+].[K+].[Br-]>C(O)C>[CH3:20][C:21]1[C:22]([CH2:33][S:10][C:8]2[NH:7][C:6]3[CH:11]=[C:2]([F:1])[C:3]([N:12]4[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]4)=[CH:4][C:5]=3[N:9]=2)=[N:23][CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]([F:32])([F:30])[F:31]
Reactant: CN1CCN(c2cc3nc(S)[nH]c3cc2F)CC1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CCl
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Product: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2cc(N3CCN(C)CC3)c(F)cc2[nH]1
Yield: 63 %

Procedure:
The title compound (1.48 g, 64%) was prepared by the general procedure using 6-fluoro-5-(4-methylpiperazin-1-yl)-2-mercapto-1H-benzimidazole (1.33 g, 5.0 mmol) (obtained in preparation 4), 3-methyl-4-(2,2,2-trifluoroethoxy)-2-chloromethylpyridine hydrochloride (1.5 g, 5.5 mmol), sodium hydroxide (0.4 g, 10.0 mmol) and ethanol (25 mL). mp 109-110° C.; IR (KBr) 3397, 1584, 1258 cm-1 ; 1H NMR (DMSO-d6) δ 2.38 (s, 3H, CH3), 2.80 (s, 3H, CH3), 3.12 (m, 4H, N(CH2)2), 3.40 (m, 4H, N(CH2)2), 4.48 (q, J=7.9 Hz, 2H, OCH2CF3), 4.60 (s, 2H, SCH2), 6.80 (d, J=5.8 Hz, 1H), 7.14 (d, J=7.1 Hz, 1H), 7.24 (d, J=11.7 Hz, 1H), 8.40 (d, J=5.5 Hz, 1H); Mass (m/z) 469 (M+).
Reaction SMILES: C([O:3][C:4](=[O:55])[C:5]1[CH:10]=[C:9]([CH2:11][CH2:12][C:13]2[S:22][C:21]3[N:20]4[C:23]([CH3:26])=[N:24][N:25]=[C:19]4[CH2:18][N:17]=[C:16]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:33])[C:15]=3[CH:14]=2)[CH:8]=[CH:7][C:6]=1[CH2:34][C:35]([NH:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40](/[CH:44]=[CH:45]/[C:46]2[S:47][CH:48]=[C:49]([CH:51]3[CH2:54][CH2:53][CH2:52]3)[N:50]=2)[CH:39]=1)=[O:36])C.[OH-].[Na+].O.C(O)C>C(O)(=O)C>[OH2:3].[Cl:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:16]1[C:15]2[CH:14]=[C:13]([CH2:12][CH2:11][C:9]3[CH:8]=[CH:7][C:6]([CH2:34][C:35]([NH:37][C:38]4[CH:43]=[CH:42][CH:41]=[C:40](/[CH:44]=[CH:45]/[C:46]5[S:47][CH:48]=[C:49]([CH:51]6[CH2:54][CH2:53][CH2:52]6)[N:50]=5)[CH:39]=4)=[O:36])=[C:5]([CH:10]=3)[C:4]([OH:55])=[O:3])[S:22][C:21]=2[N:20]2[C:23]([CH3:26])=[N:24][N:25]=[C:19]2[CH2:18][N:17]=1
Reactant: CCOC(=O)c1cc(CCc2cc3c(s2)-n2c(C)nnc2CN=C3c2ccccc2Cl)ccc1CC(=O)Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1nnc2n1-c1sc(CCc3ccc(CC(=O)Nc4cccc(/C=C/c5nc(C6CCC6)cs5)c4)c(C(=O)O)c3)cc1C(c1ccccc1Cl)=NC2
Yield: 123.5 %

Procedure:
A solution of 0.2 g (0.25 mmol) of (E)-5-[2-[4-(2-chlorophenyl)-9-methyl-6H-thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]ethyl]-2-[2-[3-[2-(4-cyclobutyl-2-thiazolyl)ethenyl]phenylamino]-2-oxoethyl]-benzoic acid ethyl ester, 4 mL of 1N NaOH, 11 mL of H2O, and 15 mL of ethanol was stirred for 40 hours and acidified with acetic acid. The product was extracted with CH2Cl2, which was dried and concentrated. The residue was chromatographed on silica gel using ethyl acetate/ethanol (10:1) followed by the same mixture (4:1) as the eluent. The fractions containing the product were concentrated and the residue triturated with ether/pet. ether and filtered to give 0.12 g (61%) of (E)-5-[2-[4-(2-chlorophenyl)-9-methyl-6H-thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]ethyl]-2-[2-[3-[2-(4-cyclobutyl-2-thiazolyl)ethenyl]phenylamino]-2-oxoethyl]-benzoic acid monohydrate as an off-white powder: mp 143°-148° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH2:36]([C:43]1([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:46]3[CH2:45][CH2:44][C:43]([CH2:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: NC(=O)C1(Cc2ccccc2)CCNCC1
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Cc4ccccc4)(C(N)=O)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5 mmol) and 4-benzyl-piperidine-4-carboxylic acid amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:6].CS[C:15]1[NH:20][C:19](=[O:21])[C:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:17][N:16]=1>N1C=CC=CC=1>[CH3:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:15]1[NH:20][C:19](=[O:21])[C:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:17][N:16]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: CN(CCCN)c1ccccn1
Reactant: CSc1ncc(Cc2ccc(F)cc2)c(=O)[nH]1
Solvent: c1ccncc1
Product: CN(CCCNc1ncc(Cc2ccc(F)cc2)c(=O)[nH]1)c1ccccn1

Procedure:
2-[N-(3-aminopropyl)-N-methylamino]pyridine (1.0 g) and 2-methylthio-5-(4-fluorobenzyl)pyrimid-4-one (1.25 g) were heated together under reflux in pyridine (3 ml) for 24 hr. The mixture was stripped and the residue recrystallised twice from ethanol/water to give 2-[3-(N-methyl-N-pyrid-2-ylamino) propylamino]-5-(4-fluorobenzyl)-pyrimid-4-one 0.5H2O, 1.2 g (64%) mp ca. 70° C. (softens).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)([O-:17])=[O:16].C(N(CC)CC)C.C(OC(=O)C)(=O)C>O>[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:4]=2)[C:10]([OH:12])=[O:11])=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=C(O)C(=Cc1ccc([N+](=O)[O-])cc1)c1cccc(C(F)(F)F)c1
Yield: 80 %

Procedure:
A solution of (3-trifluoromethyl-phenyl)-acetic acid (7.5 g, 36.7 mmol), 4-nitro-benzaldehyde (5.55 g, 36.7 mmol), triethylamine (4.8 g, 47.8 mmol), and acetic anhydride (14.3 g, 140 mmol) was refluxed for 6 hours. The reaction mixture was poured in acidified water (sulfuric acid, pH 1) and extracted with ethyl acetetate. The organic layer was evaporated and the residue was stirred with sodium bicarbonate solution. The precipitate was sucked off and the filtrate extracted with ethyl acetate. The water was acidified with hydrochloric acid and the resulting oil extracted with ethyl acetate to give 9.9 g of the desired product (80% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([O-])=O>C(OCC)(=O)C.[C].[Pd]>[CH2:11]([NH:10][C:5]1[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCCCNc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCCNc1ccccc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.1 %

Procedure:
10% of palladium-carbon (1.52 g) was added to a solution containing N-(2-nitrophenyl)-1-octadecanamine (7.600 g) in ethyl acetate (76 ml) and the mixture was stirred for 18 hours under a hydrogen gas atmosphere at room temperature. After the catalyst was removed out by filtration, the filtrate was concentrated, thereby yielding the entitled compound (6.95 g) as pink solid.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:12])[CH2:9][CH2:10][CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>CN(C=O)C>[CH3:15][N:16]([CH3:18])[CH:17]=[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8](=[O:12])[CH2:9][CH2:10][CH3:11]
Reactant: CCCC(=O)Cc1ccccc1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CCCC(=O)C(=CN(C)C)c1ccccc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 52.4 %

Procedure:
To a solution of 1-phenylpentan-2-one (5.00 g, 30.8 mmol) in dry DMF (80.0 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (6.16 mL, 46.2 mmol). The resulting mixture was heated at 90° C. After 16 h, the reaction mixture was quenched with water, extracted with EtOAc (3×) and washed with brine. The combined organics were dried over MgSO4, filtered, and concentrated to give a yellow oil. This yellow oil was purified by silica gel flash chromatography to give the title compound as a yellow oil (3.51 g). 1H NMR (400 MHz, CDCl3) δ ppm 0.76-0.83 (m, 3H), 0.83-0.89 (m, 2H), 2.11-2.19 (m, 2H), 2.62-2.71 (m, 6H), 7.15-7.42 (m, 5H), 7.61 (s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][CH2:27][CH2:28][CH3:29])=[O:25])=[C:19]([Cl:30])[CH:18]=3)=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:31][CH3:32].C(=O)([O-])[O-].[K+].[K+].[CH3:39][NH:40][CH2:41][CH2:42][OH:43].O>CN(C)C=O>[Cl:30][C:19]1[CH:18]=[C:17]([O:16][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:40]([CH2:41][CH2:42][OH:43])[CH3:39])=[C:7]([O:31][CH3:32])[CH:8]=3)[N:13]=[CH:12][CH:11]=2)[CH:22]=[CH:21][C:20]=1[NH:23][C:24]([NH:26][CH2:27][CH2:28][CH3:29])=[O:25]
Reactant: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCCCBr)c(OC)cc23)cc1Cl
Reactant: CNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCCCN(C)CCO)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A starting compound (N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinolyl]oxy}-2-chlorophenyl)-N′-propylurea, 52 mg), potassium carbonate (138 mg), and 2-(methylamino)ethanol (0.040 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 51 mg (yield 98%) of the title compound.