Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:27]([O-:29])=[O:28])=[C:6]([C:8]2[CH:9]=[C:10]([CH:24]=[CH:25][N:26]=2)[C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)=[O:12])[CH:7]=1.[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:30]([N:32]([CH2:33][CH3:34])[C:2]1[CH:3]=[CH:4][C:5]([N+:27]([O-:29])=[O:28])=[C:6]([C:8]2[CH:9]=[C:10]([CH:24]=[CH:25][N:26]=2)[C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)=[O:12])[CH:7]=1)[CH3:31]
Reactant: O=C(N[C@H]1CCCc2ccccc21)c1ccnc(-c2cc(F)ccc2[N+](=O)[O-])c1
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)c1ccc([N+](=O)[O-])c(-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-2-(5-fluoro-2-nitrophenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)isonicotinamide (12.77 mmol, 5 g), diethylamine (25.55 mmol, 1.87 g), and K2CO3 (31.93 mmol, 4.41 g) in DMF (30 mL) was stirred at 60° C. overnight. The mixture was diluted with ethyl acetate, and the resulting solution was washed with water (2×), and then with brine. The solution was dried (Na2SO4) and the solvent was removed at reduced pressure. The residue was purified by chromatography on silica gel to give a yellow solid. (4.73 g, 83%).
Reaction SMILES: O=[C:2]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[C:14](=[O:20])[CH2:13][C:12]2([CH3:22])[CH3:21])[CH:3]([CH3:8])[CH2:4][C:5](O)=[O:6].O.[NH2:24][NH2:25]>C(O)C>[CH3:8][CH:3]1[C:2]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH2:13][C:12]3([CH3:22])[CH3:21])=[N:25][NH:24][C:5](=[O:6])[CH2:4]1
Reactant: NN
Reactant: CC(CC(=O)O)C(=O)c1ccc2c(c1)C(C)(C)CC(=O)N2C
Solvent: O
Solvent: CCO
Product: CC1CC(=O)NN=C1c1ccc2c(c1)C(C)(C)CC(=O)N2C
Yield: 76.5 %

Procedure:
A mixture of 20 g of 4-oxo-4-(1,4,4-trimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-methylbutanoic acid, 10 g of hydrazine hydrate and 200 ml of ethanol was heated under reflux for one hour. After cooling, the precipitated crystals were filtered off and recrystallized from ethanol to give 15.1 g of 6-(5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-2-one, melting at 238°-241° C.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=[CH2:5].[CH:13]([Cl:16])(Cl)[Cl:14]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Cl:14][C:13]1([Cl:16])[CH2:5][C:4]1([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)[F:3]
Reactant: ClC(Cl)Cl
Reactant: C=C(F)c1ccc(C)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: Cc1ccc(C2(F)CC2(Cl)Cl)cc1
Reaction time: 16 h
Yield: 86 %

Procedure:
50% aq. sodium hydroxide solution (4.4 mL, 54 mmol) was added dropwise at 0° C. to a solution of 1-(1-fluoro-vinyl)-4-methyl-benzene (J. Med. Chem. 2004, 47, 5860; 1.84 g, 13.5 mmol) and benzyltriethylammonium chloride (123 mg, 0.54 mmol) in chloroform (20 mL), then after 30 min the ice bath was removed and stirring continued over 16 h. Ice water was added, the organic layer was subsequently washed with 0.1 M aq. hydrochloric acid solution, 5% aq. sodium hydrogencarbonate solution and brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane) afforded the title compound (2.54 g, 86%). Light yellow liquid, MS (EI) 218.0 (M+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[CH:26]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)[CH2:29][C:30]([OH:32])=[O:31].N1CCCCC1.Cl>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]([F:24])([F:25])[F:23])=[CH:19][CH:20]=2)=[CH:11][C:10]=1/[CH:26]=[CH:29]/[C:30]([OH:32])=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc(-c2ccc(OC(F)(F)F)cc2)ccc1OCc1ccccc1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)/C=C/c1cc(-c2ccc(OC(F)(F)F)cc2)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 110.1 %

Procedure:
A mixture of 4-benzyloxy-4′-(trifluoromethoxy)biphenyl-3-carbaldehyde (4.0 g, 9.336 mmol), malonic acid (2.137 g, 20.539 mmol), pyridine (4.3 ml) and piperidine (184 μl, 1.867 mmol) was refluxed for 1 hour under argon atmosphere. The reaction mixture was cooled to room temperature, adjusted to pH 1 by addition of 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:1) to give the title compound (4.26 g, 97.0%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH:11]=O)=[C:8]([CH3:13])[C:6]=2[N:7]=1.C(O)(=O)C(O)=O.[OH:26][C@@H:27]([CH3:36])[C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29].C([O-])(=O)C.[Na+].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O.C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:33]3[CH2:32][CH2:31][N:30]([C:28](=[O:29])[C@@H:27]([OH:26])[CH3:36])[CH2:35][CH2:34]3)=[C:8]([CH3:13])[C:6]=2[N:7]=1
Reactant: C[C@H](O)C(=O)N1CCNCC1
Reactant: Cc1c(C=O)sc2c(N3CCOCC3)nc(Cl)nc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: O=C(O)C(=O)O
Solvent: CC#N
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde IV (68.9 g, 231 mmol) was charged to a suitably sized reactor, followed by acetonitrile (870 mL), (S)-2-hydroxy-1-(piperazin-1-yl)propan-1-one oxalate (V) (86.2 g, 347 mmol), sodium acetate (57.0 g, 695 mmol) and glacial acetic acid (6.90 g, 115 mmol). Molecular sieve 3 Å powder (75 g) was added to the reactor, and the slurry was heated to 80° C. and stirred for a minimum of 2 h. The mixture was cooled to 40° C. and sodium triacetoxyborohydride (59.0 g, 278 mmol) was added. After being stirred for 2 h, water (690 mL) and CELITE® (35 g) were slowly added and the mixture was heated to 50° C. and stirred for 1 h, filtered and rinsed with acetonitrile (210 mL). The filtrate was concentrated under reduced pressure to remove acetonitrile. Toluene (689 mL) was added and the pH was adjusted to 7.5-8.0 with 10% aqueous sodium carbonate solution. The organic phase was separated, extracted with a mixture of water and sulfuric acid. The aqueous phase was separated and toluene (483 mL) was added. The pH was adjusted to 7.5-8.0 with 10% aqueous sodium carbonate solution. The mixture was warmed to 20° C. and the organic phase was separated, concentrated under reduced pressure to remove acetonitrile, flushed with toluene and the resulting mixture was cooled to 0-5° C. n-Heptane (344 mL) was slowly added and the resulting slurry was filtered and rinsed a mixture of toluene and n-heptane. The cake was dried under reduced pressure to afford (S)-1-(4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one II (76.3 g, 75% yield). 1H NMR (300 MHz, DMSO-d6) δ 4.84 (d, J=6.80 Hz, 1H), 4.37-4.47 (m, 1H), 3.79-3.97 (m, 4H), 3.65-3.78 (m, 4H) 3.35-3.64 (m, 4H), 3.30 (s, 2H), 2.33-2.64 (m, 4H), 2.24 (s, 3H), 1.17 (d, J=6.80 Hz, 3H)
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:10]1[CH2:16][N:15]2[C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[N:18][N:19]=[C:14]2[C@H:13]([NH:24]C(=O)OC(C)(C)C)[CH2:12][CH2:11]1>O1CCOCC1>[NH2:24][C@@H:13]1[CH2:12][CH2:11][C@@H:10]([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([F:9])[C:3]=2[F:2])[CH2:16][N:15]2[C:17]([C:20]([OH:23])([CH3:21])[CH3:22])=[N:18][N:19]=[C:14]12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c1nnc2C(C)(C)O
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(O)c1nnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2N
Reaction time: 1 h
Yield: 130.2 %

Procedure:
Hydrochloric acid (4.0 M in dioxane; 5 mL, 20.0 mmol) was added to a solution of tert-butyl [(6S,9R)-6-(2,3-difluorophenyl)-3-(1-hydroxy-1-methylethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-yl]carbamate (176 mg, 0.417 mmol) in 1,4-dioxane (5 mL). After 1 h, the reaction mixture was concentrated to give the bis hydrochloride salt of the title compound (175 mg). MS 323.1 (M+1).
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:19]=[CH:18][C:9]([CH2:10][C:11]2[CH:12]=[C:13]([CH:16]=O)[S:14][CH:15]=2)=[CH:8][CH:7]=1.[S:20]1[CH2:26][C:24](=[O:25])[NH:23][C:21]1=[S:22].C([O-])(=O)C.[Na+]>O>[Cl:5][C:6]1[CH:19]=[CH:18][C:9]([CH2:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:26]3[S:20][C:21](=[S:22])[NH:23][C:24]3=[O:25])[S:14][CH:15]=2)=[CH:8][CH:7]=1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1cc(Cc2ccc(Cl)cc2)cs1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1cc(Cc2ccc(Cl)cc2)cs1
Temperature: 80 °C
Yield: 81 %

Procedure:
To a 20-mL scintillation vial fitted with a magnetic stir bar was added 3 mL of glacial acetic acid (AcOH). The vial was capped tightly and heated to 80° C. To the hot AcOH was added 4-(4-chlorobenzyl)thiophene-2-carbaldehyde (example 1.1.a); 0.37 g, 1.56 mmol, 1 equiv) and rhodanine (0.23 g, 1.7 mmol, 1.1 equiv) with stirring until a solution was formed. To the mixture was then added anhydrous sodium acetate (0.45 g, 5.5 mmol, 3.5 equiv), and the vial was capped tightly and heated to 110° C. for approx. 1 h. The reaction vial was cooled to rt and the contents were poured into water. The resulting precipitate was filtered, washed with water and a cold mixture of 1:1 water/ethanol. The solid was dried thoroughly in vacuo at 40° C. to give 5-((4-(4-chlorobenzyl)thiophen-2-yl)methylene)-2-thioxothiazolidin-4-one (451 mg, 81%). 1H NMR (400 MHz, (CD3)2SO) δ (ppm): 7.70 (s, 1H), 7.67 (s, 1H), 7.46 (s, 1H), 7.34-7.38 (m, 2H), 7.25-7.29 (m, 2H), 3.96 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].Cl>ClCCl>[CH3:17][S:18]([O:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([NH:1][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:3][CH:4]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(CCO)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(CCOS(C)(=O)=O)cc1
Reaction time: 2 h
Yield: 29.4 %

Procedure:
4-Aminophenethyl alcohol (2.74 g) was dissolved in dichloromethane (10 ml) and pyridine (5 ml) and then methanesulphonyl chloride (2×2.52 g) was added in 2 portions one hour apart, with stirring at 0°. After a further 2 hours, the mixture was acidified (to pH about 2) with 2N aqueous hydrochloric acid. The title compound (4.85 g) was filtered from the two-phase mixture. The organic layer plus a further dichloromethane extract of the aqueous layer yielded a further 0.95 g product after drying (sodium sulphate) and evaporation. The combined solids were washed with ether and recrystallized from ethyl acetate, yield of the title compound 4.13 g, m.p. 135°-7°.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][N:28]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[C:17]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=2[N:13]=1)=[O:7].[CH3:29][O:30][CH2:31][CH2:32][NH:33][CH3:34]>>[CH3:29][O:30][CH2:31][CH2:32][N:33]([CH2:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][N:28]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[C:17]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=2[N:13]=1)=[O:7])[CH3:34]
Reactant: CNCCOC
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(CCl)c3)nc12
Product: COCCN(C)Cc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1
Temperature: 60 °C

Procedure:
2-Chloromethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide (240 mg, 0.55 mmol) is dissolved in N-(2-methoxyethyl)-methylamine (1.0 g, 12 mmol) and the mixture heated to 60° C. for 1 h. The volatile components are removed in vacuo and the residue chromatographed over SiO2 eluting with dichloromethane/methanol 19/1. The title compound was obtained as yellow crystals (170 mg, 71% yield). MS: m/e=472(M+H+). Following the general method of example 46 the compounds of examples 47-62 were prepared.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Cl[CH2:27][CH2:28][S:29](Cl)(=[O:31])=[O:30].O>C(Cl)Cl>[CH:28]([S:29]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2][CH2:3]1)(=[O:31])=[O:30])=[CH2:27]
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: O=S(=O)(Cl)CCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C=CS(=O)(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: -15 °C
Yield: 42.8 %

Procedure:
A mixture of 11 g (50 mmol) of benzyl 1-piperazinecarboxylate and 16.1 g (125 mmol) of DIPEA in 200 mL CH2Cl2 was cooled to −15° C. and 6.3 mL (9.8 g, 60 mmol) of 2-chloroethanesulfonyl chloride was added slowly over 15 min. The mixture was allowed to warm to 0° C. over 30 min and water was then added. The organic layer was separated and washed successively with dil. HCl and aq. NaHCO3. After drying, the solvent was removed and the residue was chromatographed on silica, eluting with CH2Cl2/EtOAc 95:5, to give an oil, which was recrystallized from CH2Cl2/hexanes to give 6.64 g (43% yield) of benzyl 4-(vinylsulfonyl)-1-piperazinecarboxylate: mp (CH2Cl2/hexanes) 85-87° C.; 1H NMR (CDCl3) δ 7.39-7.30 (m, 5H), 6.40 (dd, J=16.6, 9.8 Hz, 1H), 6.25 (d, J=16.6 Hz, 1H), 6.06 (d, J=9.8 Hz, 1H), 5.14 (s, 2H), 3.61 (m, 4H), 3.14 (m, 4H); Anal. Calcd. for C14H18N2O4S: C, 54.2; H, 5.85; N, 9.0. Found: C, 54.1; H, 5.7; N, 9.1%.
Reaction SMILES: C(C1C=CC=CC=1N[C@@H](CC1C=CC(C2C=CC=C(N(C)C(NCCCCCCC)=O)C=2)=CC=1)C(O)=O)(=O)C1C=CC=CC=1.[C:45]([CH2:53][NH:54][CH2:55][C:56]1[CH:57]=[C:58]([C:62]2[CH:67]=[CH:66][C:65]([CH2:68][C@H:69]([NH:75][C:76]3[CH:81]=[CH:80][CH:79]=[CH:78][C:77]=3[C:82](=[O:89])[C:83]3[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=3)[C:70]([O:72]CC)=[O:71])=[CH:64][CH:63]=2)[CH:59]=[CH:60][CH:61]=1)(=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[OH-].[Li+]>>[C:45]([CH2:53][NH:54][CH2:55][C:56]1[CH:57]=[C:58]([C:62]2[CH:67]=[CH:66][C:65]([CH2:68][C@H:69]([NH:75][C:76]3[CH:81]=[CH:80][CH:79]=[CH:78][C:77]=3[C:82](=[O:89])[C:83]3[CH:84]=[CH:85][CH:86]=[CH:87][CH:88]=3)[C:70]([OH:72])=[O:71])=[CH:64][CH:63]=2)[CH:59]=[CH:60][CH:61]=1)(=[O:52])[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(-c2cccc(CNCC(=O)c3ccccc3)c2)cc1)Nc1ccccc1C(=O)c1ccccc1
Agent: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C[C@H](Nc3ccccc3C(=O)c3ccccc3)C(=O)O)cc2)c1
Agent: [Li+]
Agent: [OH-]
Product: O=C(CNCc1cccc(-c2ccc(C[C@H](Nc3ccccc3C(=O)c3ccccc3)C(=O)O)cc2)c1)c1ccccc1
Yield: 74.7 %

Procedure:
In a manner similar to the preparation of the (S)-2-(2-benzoylphenylamino)-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propionic acid (Example 2), using 0.63 g (1.06 mmol) of ethyl (S)-3-{3′-[(benzoylmethylamino)methyl]biphenyl-4-yl}-2-(2-benzoylphenylamino)-propionate (Example 28g) and 55 mg (1.04 mmol) of lithium hydroxide, 0.45 g of (S)-3-{3′-[(benzoylmethylamino)methyl]biphenyl-4-yl}-2-(2-benzoylphenylamino)propionic acid is obtained with a 75% yield.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:30](=[O:32])[CH3:31])[CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:9]2[CH:33]=[CH:34][C:35](Br)=[CH:36][C:8]1=2)=[O:6])([CH3:3])[CH3:2].[CH3:38]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.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]>[C:30]([N:14]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1)[CH:10]1[CH2:11][CH2:12][CH2:13][N:7]([C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])[C:8]2[CH:36]=[C:35]([CH3:38])[CH:34]=[CH:33][C:9]1=2)(=[O:32])[CH3:31]
Reactant: CB1OB(C)OB(C)O1
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Br)ccc21
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(C)ccc21
Yield: 41.1 %

Procedure:
Purge with nitrogen, a suspension of isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (0.153 g, 0.257 mmol), trimethylboroxine (36 μl, 0.257 mmol), and potassium carbonate (0.106 g, 0.771 mmol) in N,N-dimethylformamide (2 mL) in a 10 mL microwave vessel. Add tetrakis(triphenylphosphine)palladium (0) (0.030 g, 0.026 mmol) and irradiate the mixture at 150° C. for 20 min (50 W). Dilute the mixture with ethyl acetate (20 mL), wash with water and brine (10 mL each), then dry the organic layer over sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue first using chromatography on silica gel, eluting with hexanes/ethyl acetate (60:40), to provide the title compound as a white solid (0.056 g, 41%): 531 (M+H).
Reaction SMILES: [CH2:1]([C:5]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:8][O:9][CH3:10])[CH2:6][OH:7])[CH2:2][CH2:3][CH3:4].[CH3:15][Si:16](Cl)([CH3:18])[CH3:17]>>[CH2:1]([C:5]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:6][O:7][Si:16]([CH3:18])([CH3:17])[CH3:15])[CH2:8][O:9][CH3:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(CO)(CCCC)COC
Reactant: C[Si](C)(C)Cl
Product: CCCCC(CCCC)(COC)CO[Si](C)(C)C

Procedure:
According to the procedure as described in Example 1,2,2-di-n-butyl-1-methoxy-3-[(trimethylsilyl)oxy]propane was prepared from intermediate 2,2-di-n-butyl-3-methoxy-1-propanol and reagent trimethylsilyl chloride.
Reaction SMILES: [CH2:1]=[C:2]([CH2:8][CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[CH2:10]([NH:17][CH2:1][CH:2]([CH2:8][CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=C(CC)C(=O)OCC
Reactant: NCc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(CC)CNCc1ccccc1
Temperature: 70 °C
Reaction time: 17 h

Procedure:
The compound obtained in Step 1 was dissolved in ethanol (7 mL). To the solution, benzylamine (2.7 mL) was added at room temperature, and the mixture was stirred at 70° C. for 17 hours. The solvent in the reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: hexane-hexane/ethyl acetate=7/3) to obtain the title compound (2.34 g).
Reaction SMILES: [N:1]1[N:2]([CH2:6][CH2:7][CH2:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)[N:3]=[CH:4][CH:5]=1.O.NN.CO>CO.O1CCCC1>[N:1]1[N:2]([CH2:6][CH2:7][CH2:8][NH2:9])[N:3]=[CH:4][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCn1nccn1
Agent: NN
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: NCCCn1nccn1
Temperature: 25 °C
Reaction time: 120 h
Yield: 19.6 %

Procedure:
To a mixture solution of 2-(3-[1,2,3]triazol-2-yl-propyl)-isoindol-1,3-dione (1782 mg, 6.95 mmol) in methanol-tetrahydrofuran (5:4, 27 mL) was added hydrazine monohydrate (371 μl, 7.65 mmol), and the solution was stirred for 5 days at room temperature. Methanol (8 mL) was added thereto, followed by further stirring for 3.25 hours under reflux. The reaction mixture was filtered, and the filtrate was concentrated. The resulting residue was dissolved in tetrahydrofuran, adsorbed onto NH silica gel, purified by NH silica gel chromatography (ethyl acetate-methanol), and the title compound (491 mg, 1.36 mmol, 19.6%) was obtained.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:13]=[CH:12][C:8]([NH:9][CH2:10][CH3:11])=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)#[N:4].[Cl:17][C:18]1[S:22][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:20][CH:19]=1.O>O1CCCC1>[Cl:17][C:18]1[S:22][C:21]([S:23]([N:9]([C:8]2[CH:12]=[CH:13][C:5]([C:3]#[N:4])=[CH:6][C:7]=2[N+:14]([O-:16])=[O:15])[CH2:10][CH3:11])(=[O:25])=[O:24])=[CH:20][CH:19]=1
Reactant: CCNc1ccc(C#N)cc1[N+](=O)[O-]
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCN(c1ccc(C#N)cc1[N+](=O)[O-])S(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Yield: 29.7 %

Procedure:
To a suspension of sodium hydride (60%, 0.10 g (2.50 mmol)) in tetrahydrofuran (THF) (3.0 ml), 4-cyano-N-ethyl-2-nitroaniline (0.38 g (1.99 mmol)) was added with stirring at room temperature. To the mixture, upon stirring for 15 minutes at room temperature and after the solution had turned deep purple, 5-chloro-2-thiophenesulfonyl chloride (0.55 g (2.53 mmol)) was added and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into water and the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:3) as eluent, to give 0.22 g (30%) of the title compound as yellow crystals.
Reaction SMILES: C([O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[NH:17][CH:16]([N:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:21](=[O:23])[CH3:22])[NH:15][C:14]2=[O:28])=[CH:9][CH:8]=1)=[O:6])(=O)C.O>COCCOC>[C:5]([C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:14](=[O:28])[NH:15][CH:16]([N:20]([CH2:24][CH:25]([CH3:26])[CH3:27])[C:21](=[O:23])[CH3:22])[NH:17][C:18]2=[O:19])=[CH:11][CH:12]=1)([OH:6])=[O:4]
Reactant: CC(=O)OC(=O)c1ccc(N2C(=O)NC(N(CC(C)C)C(C)=O)NC2=O)cc1
Solvent: COCCOC
Solvent: O
Product: CC(=O)N(CC(C)C)C1NC(=O)N(c2ccc(C(=O)O)cc2)C(=O)N1
Reaction time: 20 h
Yield: 38.8 %

Procedure:
A solution of 3-[4-(acetoxycarbonyl)phenyl]-6-[(N-acetyl)isobutylamino]tetrahydro-1,3,5-triazine-2,4-dione (2.6 g.) in 1,2-dimethoxyethane (20 ml.) containing water (2 ml.) was left for 20 hours and then evaporated. The residue was pressure-chromatographed on silica using a mixture of 44 parts by volume of ethyl acetate and 1 part by volume of acetic acid to yield 3-(4-carboxyphenyl)-6-[(N-acetyl)isobutylamino]tetrahydro-1,3,5-triazine-2,4-dione (0.9 g., 39%), m.p. 191°-193° C.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH2:6][CH2:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH2:9]1)[CH3:4].Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1>CN(C=O)C>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][N:19]=[C:18]2[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]([CH2:7][CH2:6][CH2:5][N:3]([CH3:4])[CH3:2])[CH2:9]1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: CN(C)CCCC1CNc2ccccc21
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(N3CC(CCCN(C)C)c4ccccc43)c2cc1OC
Yield: 52 %

Procedure:
Utilizing a procedure analogous to that described in Example 24 (with conversion to its HCl salt using a procedure analogous to that as described in Example 2), this product was prepared in 52% yield from 3-(N,N-dimethylamino-propyl)indoline (1.1 eq.), and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in DMF. (M.P. 230°-232° C.; LC-MS: 393 (MH+); anal. RP18-HPLC RT: 3.23 min.).