Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:15]=[N:14][C:9]3[O:10][CH2:11][CH2:12][NH:13][C:8]=3[CH:7]=2)=[CH:2]1.[Br:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([Br:28])[C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21].C(N(CC)CC)C.O>ClCCl>[Br:16][C:17]1[CH:18]=[C:19]([C:20]([N:13]2[CH2:12][CH2:11][O:10][C:9]3[N:14]=[CH:15][C:6]([C:3]4[CH:4]=[CH:5][O:1][CH:2]=4)=[CH:7][C:8]2=3)=[O:21])[CH:23]=[C:24]([Br:28])[C:25]=1[O:26][CH3:27]
Reactant: c1cc(-c2cnc3c(c2)NCCO3)co1
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4ccoc4)cc32)cc1Br
Temperature: 0 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
In a 5 ml flask, 7-furan-3-yl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (18 mg, 0.089 mmol) and 3,5-dibromo-4-methoxy-benzoyl chloride (32.1 mg, 0.098 mmol) were dissolved in dichloromethane (1 ml). Triethylamine (0.037 ml, 0.267 mmol) was added thereto and then stirred at 0° C. for 3 hours. After completion of the reaction by adding water dropwise, the mixture was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by preparative TLC eluting a solvent of dichloromethane:methanol=20:1. Silica gels containing the product were eluted with dichloromethane and the solvent was evaporated to obtain (3,5-dibromo-4-methoxy-phenyl)-(7-furan-3-yl-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl)-methanone as white solid (40 mg, 91%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:9][C@H:8]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:7][C@H:6]1[CH2:20]OS(C)(=O)=O)(=[O:4])=[O:3].[Na+].[I-].[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([NH:35][CH2:20][C@@H:6]1[CH2:7][C@@H:8]([S:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[CH2:9][N:5]1[S:2]([CH3:1])(=[O:3])=[O:4])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(CS[C@@H]2C[C@@H](COS(C)(=O)=O)N(S(C)(=O)=O)C2)cc1
Agent: [I-]
Agent: [Na+]
Product: COc1ccc(CS[C@@H]2C[C@@H](CNCc3ccccc3)N(S(C)(=O)=O)C2)cc1
Yield: 65 %

Procedure:
A slurry of 300 mg (0.73 mmol) (2S,4R)-methanesulfonic acid 1-methanesulfonyl-4-(4-methoxy-benzylsulfanyl)-pyrrolidin-2-ylmethyl ester and 109 mg (0.73 mmol) of NaI in 5 ml benzylamine was heated in the oil bath to 100° C., evaporated in the kugelrohr at 50–70° C./1 Torr and extracted with aqueous saturated NaHCO3 solution/Et2O (3×). The organic phase was dried over Na2SO4, evaporated and the residue was crystallized from Et2O/pentane at −20° C. to give 200 mg (65%) of (2S,4R)-benzyl-[1-methanesulfonyl-4-(4-methoxy-benzylsulfanyl)-pyrrolidin-2-ylmethyl]-amine, mp 63–64° C., MS: 421 (MH+).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[CH2:15][CH2:14][CH2:13][CH2:12][C:8]=2[S:9][C:10]=1[NH2:11])=[O:5])C.[CH3:16][O:17][CH2:18][C:19]#[N:20]>O1CCOCC1.Cl>[CH3:16][O:17][CH2:18][C:19]1[N:20]=[C:4]([OH:5])[C:6]2[C:7]3[CH2:15][CH2:14][CH2:13][CH2:12][C:8]=3[S:9][C:10]=2[N:11]=1
Reactant: COCC#N
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Agent: Cl
Solvent: C1COCCO1
Product: COCc1nc(O)c2c3c(sc2n1)CCCC3
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred mixture of 2-Amino-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester (2.0 g, 0.0088 mol) and methoxyacetonitrile (1.3 ml, 0.0177 mol) in 1,4-dioxane (200 nml), dry HCl gas was purged for 30-45 minutes at 0-5° C. The reaction mixture was then warmed to room temperature and stirred for about 20 h under inert atmosphere. After completion of the reaction, the mixture was quenched with the addition of crushed ice (˜200 g). The aqueous layer was then extracted well with ethyl acetate (2×250 ml). Combined organic layers was washed with brine solution (100 ml) dried over anhydrous Na2SO4 and concentrated under vacuum to get crude 2-Methoxymethyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-ol as brown colored solid which was forwarded as such for the next step. Yield: (2 g, 90%); 1H NMR (400 MHz, DMSO) δ ppm=12.27 (s, 1H), 4.28 (s, 2H), 3.31 (s, 3H), 2.87-2.84 (m, 2H), 2.74-2.71 (m, 2H), 1.81-1.73 (m, 4H); LCMS: [M+H]=251.1.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])OC4C=CC=CC=4)=[CH:16][C:15]=3[F:30])[CH:10]=[CH:9][N:8]=2)=[O:5])[CH2:3][CH2:2]1.[NH2:31][C:32]1[CH:33]=[C:34]([CH:42]([N:44]2[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]2)[CH3:43])[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1.CCN(C(C)C)C(C)C>C1COCC1>[CH:1]1([C:4]([NH:6][C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:31][C:32]4[CH:33]=[C:34]([CH:42]([N:44]5[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:54])([CH3:56])[CH3:55])=[O:51])[CH2:46][CH2:45]5)[CH3:43])[CH:35]=[C:36]([C:38]([F:40])([F:41])[F:39])[CH:37]=4)=[O:29])=[CH:16][C:15]=3[F:30])[CH:10]=[CH:9][N:8]=2)=[O:5])[CH2:2][CH2:3]1
Reactant: O=C(Nc1ccc(Oc2ccnc(NC(=O)C3CC3)c2)c(F)c1)Oc1ccccc1
Reactant: CC(c1cc(N)cc(C(F)(F)F)c1)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(c1cc(NC(=O)Nc2ccc(Oc3ccnc(NC(=O)C4CC4)c3)c(F)c2)cc(C(F)(F)F)c1)N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 75.8 %

Procedure:
Add phenyl N-[4-[[2-(cyclopropanecarbonylamino)-4-pyridyl]oxy]-3-fluoro-phenyl]carbamate (220 mg, 0.53 mmol), tert-butyl 4-[1-[3-amino-5-(trifluoromethyl)phenyl]-ethyl]piperazine-1carboxylate (165 mg, 0.442 mmol) and DIEA (120 mg, 0.88 mmol) in THF (10 mL), stir the reaction under N2 at 80° C. for 12 hrs. Concentrate under reduced pressure to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=1:1) affords the title compound (230 mg, 75.6%).
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Br:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[NH2:34][CH:35]1[CH2:38][NH:37][CH2:36]1.CN1CCCC1>C(O)C>[NH2:34][CH:35]1[CH2:38][N:37]([C:20]2[C:21]([Br:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([F:30])=[CH:9][C:8]([F:31])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:36]1
Reactant: NC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Br)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Br)c32)c(F)cc1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To 300 mg of N,N-dimethylformamide were added 105 mg of 1-(6-amino-3,5-difluoropyridine-2-yl)-8-bromo-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 70 mg of 3-aminoazetidine dihydrochloride, and 150 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 1 hour. After adding 0.3 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively.to obtain 79 mg of the title compound as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6]2.ClS([N:20]=[C:21]=O)(=O)=O.CN(C)C=O.O>C(#N)C>[C:21]([C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:8][C:7]=1[C:12]([F:15])([F:13])[F:14])#[N:20]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COc1ccc2[nH]c(C(F)(F)F)cc2c1
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: COc1ccc2[nH]c(C(F)(F)F)c(C#N)c2c1
Reaction time: 2.5 h
Yield: 25 %

Procedure:
A solution of 5-methoxy-2-(trifluoromethyl)indole (3.0 g, 13.0 mmole) in acetonitrile is treated dropwise with chlorosulfonyl isocyanate (2.02 g, 14.3 mmole) at 0° C., stirred at ambient temperatures for 2.5 hours, treated with dimethylformamide (DMF) (2.1 g, 28.6 mmole), stirred at ambient temperatures for 0.75 hour and poured into water. The resultant mixture is extracted with diethyl ether. The combined extracts are washed sequentially with water and brine, dried over MgSO4 and concentrate in vacuo to give a brown oil residue. The oil is crystallized in ether/hexanes to give the title product as brown crystals, 0.78 g (25% yield), mp 189°-190° C., identified by IR, 1HNMR, 13CNMR and 19FNMR.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[C:4]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:3]=1.C[N:23]([CH:25]=O)C.Br[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])=[CH:33][CH:32]=1)=O>O.CCOC(C)=O>[CH2:15]([C:25]1[N:11]([C:10]2[CH:12]=[CH:13][C:7]([O:6][C:5]3[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][C:4]=3[CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:8][CH:9]=2)[CH:28]=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])=[CH:33][CH:32]=2)[N:23]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccc(Oc2ccc(Cl)cc2C2CCCCC2)cc1
Reactant: CN(C)C=O
Reactant: CCN(CC)CCCOc1ccc(C(=O)CBr)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCc1nc(-c2ccc(OCCCN(CC)CC)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2C2CCCCC2)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-(4-chloro-2-cyclohexylphenoxy) aniline (1.2 eq., 2.5 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (2.4 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold H2O and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product obtained from 2–4% MeOH/DCM (yield ˜50–60%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[Cl:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)/[CH:19]=[CH:20]/[C:21](Cl)=O.Cl>CO>[ClH:15].[Cl:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)/[CH:19]=[CH:20]/[C:21]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=1
Reactant: Nc1ccccc1Nc1ccccn1
Reactant: O=C(Cl)/C=C/c1cccc(Cl)c1
Agent: Cl
Solvent: CO
Product: Clc1cccc(/C=C/c2nc3ccccc3n2-c2ccccn2)c1

Procedure:
Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine and (E)-3-Chlorocinnamoyl chloride (Amino, Y.; Kawada, K.; Toi, K.; Kumashiro, I.; Fukushima, K. Chem. Pharm. Bull, 1988, 36, 4426) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-H-benzimidazole (Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate/ethanol yielded the titled compound. MW: 368.27; mp:>230° C.; 1H-NMR (DMSO) δ: 8.85-8.81 (1H, m), 8.31-8.22 (1H, m), 8.20 (1H, d, J=16.1 Hz), 7.90-7.81 (3H, m), 7.78-7.72 (1H, m), 7.68-7.43 (6H, m), 7.33 (1H, d, J=16.1 Hz).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[C:8]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][N:22]=2)(=[O:20])=[O:19])[N:7]([CH3:30])[N:6]=1.[H-].[Na+].Cl[C:34]1[N:39]=[CH:38][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:36][N:35]=1>C1COCC1.CC(N(C)C)=O>[CH:27]([C:24]1[CH:25]=[CH:26][C:21]([S:18]([NH:17][C:8]2[N:7]([CH3:30])[N:6]=[C:5]([O:4][CH2:3][CH2:2][O:1][C:34]3[N:39]=[CH:38][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:36][N:35]=3)[C:9]=2[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:19])=[O:20])=[N:22][CH:23]=1)([CH3:28])[CH3:29]
Reactant: CS(=O)(=O)c1cnc(Cl)nc1
Reactant: Cc1ccc(-c2c(OCCO)nn(C)c2NS(=O)(=O)c2ccc(C(C)C)cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cc1ccc(-c2c(OCCOc3ncc(S(C)(=O)=O)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)C)cn2)cc1
Reaction time: 0.08 h
Yield: 20.4 %

Procedure:
To a solution of N-[3-(2-hydroxyethoxy)-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]-5-isopropyl-2-pyridinesulfonamide (Example 40) (112 mg) in anhydrous THF (5 ml) at 0° C. and under an atmosphere of nitrogen was added sodium hydride (60% dispersion in oil, 21.8 mg) and the mixture was stirred for 5 minutes. To the mixture was added 2-chloro-5-(methylsulfonyl)pyrimidine (50 mg) in dimethylacetamide (1 ml). After stirring for 150 min, the reaction mixture was partitioned between ethyl acetate (50 ml) and saturated ammonium chloride solution (50 ml). The ethyl acetate layer was washed with brine (50 ml), dried (MgSO4), filtered and evaporated to dryness. Purification of the residue on a Phenomenex Magellen™ column using a 0.1M NH4OAc:MeCN gradient (95;5 to 60:40) over 5 min. and then an isocratic flow (60:40) for 15 minutes gave the title compound as a white solid (31 mg).
Reaction SMILES: [CH2:1]=[N:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:10].ClC([O:14][C:15](Cl)(Cl)Cl)=O.[CH3:19][NH:20][C:21]([NH:23][CH3:24])=[S:22].[OH-].[Na+]>>[CH3:19][N:20]=[C:21]1[N:23]([CH3:24])[C:15](=[O:14])[N:2]([C:3]2[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:10])[CH2:1][S:22]1
Reactant: CNC(=S)NC
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: C=Nc1c(C)cccc1C
Agent: [Na+]
Agent: [OH-]
Product: CN=C1SCN(c2c(C)cccc2C)C(=O)N1C
Yield: 22.5 %

Procedure:
Similarly, 2.7 g (0.02 mole) of N-methylene-2,6-dimethylaniline, 2.0 g of trichloromethyl chloroformate, 2.0 g (0.02 mole) of 1,3-dimethylthiourea, and 18 g of a 10% aqueous sodium hydroxide solution were used to obtain 0.6 g (12% yield) of 2-methylimino-3-methyl-5-(2,6-dimethylphenyl)-tetrahydro-1,3,5-thiadiazin-4-one (compound No. 389) of the formula, ##STR179## as a colorless oily substance (nD20 1.5967).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[C:8]2[CH:15]=[N:14][N:13]([CH2:16][CH3:17])[C:9]2=[N:10][C:11]=1[CH3:12])=[O:5])[CH3:2].[OH:19][CH:20]([CH3:24])[CH2:21][CH2:22][NH2:23]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:23][CH2:22][CH2:21][CH:20]([OH:19])[CH3:24])=[C:8]2[CH:15]=[N:14][N:13]([CH2:16][CH3:17])[C:9]2=[N:10][C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CC(O)CCN
Reactant: CCOC(=O)c1c(C)nc2c(cnn2CC)c1Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)nc2c(cnn2CC)c1NCCC(C)O
Temperature: 45 °C

Procedure:
2.75 each of 4-chloro-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester and 3-hydroxy-n-butylamine are combined with 15.6 ml of dry toluene under N2 and heated at 45° C. for 48 hours. The mixture was cooled to room temperature and the toluene layer was decanted from the oil that separated out. The toluene layer was washed with water and then dried and concentrated in vacuo to yield 3.7 g of product which crystallized on trituration with hexane. This was recrytallized from hexane to yield 1.91 g of white product mp 94.5°-96.5° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:31])/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[CH:19]=2)=[CH:10][CH:9]=1.ClC1C=CC=C(C(OO)=[O:40])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[O-:40][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:31])/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[CH:19]=2)=[CH:12][CH:13]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(Cc4ccccn4)cc3)c2)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(Cc4cccc[n+]4[O-])cc3)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.3 %

Procedure:
To a solution of (E)-N-[4-(2-pyridylmethyl)phenyl]-3-(4-methylphenyl)cinnamamide (302 mg) in tetrahydrofuran (10 ml) was added 3-chloroperbenzoic acid (70%, 0.27 g) at 0° C., and the mixture was stirred at room temperature for 18 hours. To the reaction mixture was added sodium thiosulfate solution, and the mixture was stirred for a few minutes. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was recrystallized from ethanol to give (E)-N-[4-(1-oxidopyridin-2-ylmethyl)-phenyl]-3-(4-methylphenyl)cinnamamide (Compound 191) (180 mg) as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]([Cl:9])=[O:8])=[CH:5][N:6]=1.[NH2:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[C:13]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[N:12]=1>>[ClH:9].[NH2:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[C:13]([N:25]2[CH2:30][CH2:29][N:28]([C:7]([C:4]3[S:3][C:2]([CH3:1])=[N:6][CH:5]=3)=[O:8])[CH2:27][CH2:26]2)[N:12]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: Cc1ncc(C(=O)Cl)s1
Product: COc1cc2nc(N3CCN(C(=O)c4cnc(C)s4)CC3)nc(N)c2cc1OC
Product: Cl

Procedure:
The title compound was prepared from 2-methylthiazole-5-carbonyl chloride (0.42 g.) and 4-amino-6,7-dimethyoxy-2-(1-piperazinyl)-quinazoline (0.75 g.) following previously described procedures. The product had a m.p. of 294°-297° C. with decomposition.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH3:12][O:13][C:14](=[O:33])[CH:15]([NH:22]C(OCC1C=CC=CC=1)=O)P(OC)(OC)=O.[CH3:34][C:35]1[CH:36]=[C:37]([CH:43]=O)[C:38](=[CH:41][CH:42]=1)[CH:39]=O.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:34][C:35]1[CH:36]=[C:37]2[C:38](=[CH:41][CH:42]=1)[CH:39]=[N:22][C:15]([C:14]([O:13][CH3:12])=[O:33])=[CH:43]2
Reactant: Cc1ccc(C=O)c(C=O)c1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)c1cc2cc(C)ccc2cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 14.6 %

Procedure:
DBU (4.71 mL, 31.5 mmol) and methyl{[(benzyloxy)carbonyl]amino}(dimethoxyphosphoryl)acetate (10.43 g, 31.5 mmol) are dissolved in CH2Cl2 (175 mL). The resulting solution is added drop-wise a solution of 4-methylphthalaldehyde (4.24 g, 28.6 mmol) in CH2Cl2 (200 mL) at 0° C. The reaction is stirred cold for 1 hour at 0° C. and then for an additional 18 hours at rt. The volatiles are evaporated to an orange oil, which is dissolved in CHCl3 (200 mL). DBU (4.79 mL, 32.0 mmol) and TFAA (4.52 mL, 32.0 mmol) are added. The reaction is stirred under N2 for 3 hours. Upon completion, the reaction is quenched with 250 mL of saturated NaHCO3 solution. The organic layer is separated and the aqueous layer is extracted with 2×250 mL of CHCl3. The organic layers are combined, dried (MgSO4), filtered, and concentrated. The crude reaction mixture is purified by column chromatography using a step gradient of 20% EtOAc to 26% EtOAc in hexanes in 2% intervals. The resulting product-containing fractions are concentrated and purified via preparative achiral HPLC to yield 0.84 g of methyl 6-methyl-isoquinoline-3-carboxylate as a yellow solid. HRMS (FAB) calculated for C12H11N O2+H+: 202.0868, found 202.0863.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:17]([O:19]CC)=O.[NH2:22][NH2:23]>>[CH3:1][C:2]1[NH:6][C:5]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:17]([NH:22][NH2:23])=[O:19]
Reactant: NN
Reactant: CCOC(=O)c1nc(-c2cccc3ccccc23)[nH]c1C
Product: Cc1[nH]c(-c2cccc3ccccc23)nc1C(=O)NN

Procedure:
A mixture of 5.0 g of the above ester and 25 ml of hydrazine was refluxed overnight and then cooled. The solid was collected, stirred with water and cooled. The solid was collected, giving 4.5 g of 5-methyl-2-(1-naphthalenyl)-1H-imidazole-4-carboxylic acid, hydrazide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][CH:42]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([CH:37]=[CH:38][CH:39]=4)[CH2:23][CH:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1>CO.CCOCC.Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][CH:42]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:39]=[CH:38][CH:37]=[C:22]([CH2:23][CH:24]5[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]5)[CH:21]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)c2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Fc1cccc(Cn2cc(-c3c[nH]c4ncc(-c5cccc(CC6CCNCC6)c5)cc34)cn2)c1
Yield: 97.6 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(3-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzyl)piperidine-1-carboxylate (50 mg, 0.088 mmol) was deprotected in methanol/ether HCl (5/1 ml). This afforded 40 mg (90.9% yield) of the titled compound. 1H NMR (DMSO-d6, 300 MHz): δ 11.9 (s, 1H), 8.75-8.65 (bs, 1H), 8.53-8.52 (d, 1H), 8.42-8.38 (m, 2H), 7.98 (s, 1H), 7.78-7.77 (d, 2H), 7.62-7.57 (m, 2H), 7.43-7.35 (m, 2H), 7.19-7.05 (m, 4H), 5.40 (s, 2H), 3.23-3.18 (d, 2H), 2.80-2.54 (m, 5H), 2.25-2.15 (bs, 1H), 1.76-1.71 (d, 2H), 1.45-1.30 (m, 2H). MS: m/z=466.2 (M+1), HPLC: 97.04% in method A.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[C:17]([NH2:18])=[CH:16][C:15]([C:19]([CH3:22])([CH3:21])[CH3:20])=[N:14]2)[CH:8]=1)[CH3:2].[C:24]1([C:34](F)=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[C:17]([NH:18][C:34]([C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)=[O:35])=[CH:16][C:15]([C:19]([CH3:22])([CH3:21])[CH3:20])=[N:14]2)[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cccc(-n2nc(C(C)(C)C)cc2N)c1
Reactant: O=C(F)c1cccc2ccccc12
Solvent: ClCCl
Product: CCOC(=O)CCc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)c2cccc3ccccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 372.7 %

Procedure:
A solution of Example Z (315 mg, 1.0 mmol) and Barton's base (0.5 mL) in anhydrous CH2Cl2 (5 mL) under N2 was stirred at RT for 30 min, and then added to a solution of naphthalene-1-carbonyl fluoride (348 mg, 0.2 mmol) in anhydrous CH2Cl2 (5 mL). The resulting mixture was stirred at RT overnight. After quenching with water (100 mL), the reaction mixture was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine, dried (NaSO4), filtered and concentrated under reduced pressure to yield a residue which was purified by flash chromatography to afford 3-(3-{3-t-butyl-5-[(naphthalene-1-carbonyl)-amino]-pyrazol-1-yl}-phenyl)-propionic acid ethyl ester, (350 mg, 74%). 1H-NMR (CDCL3): 8.29 (d, J=8.0 Hz, 1H), 7.98 (d, J=7.2 Hz, 2H), 7.89 (d, J=7.2 Hz, 1H), 7.62-7.57 (m, 3H), 7.49-7.28 (m, 4H), 7.03 (s, 1H), 3.94 (q, J=7.2 Hz, 2H), 2.96 (t, J=7.2 Hz, 2H), 2.58 (t, J=7.2 Hz, 2H), 1.45 (s, 9H), 1.13 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 470 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:3]=1[NH2:4].[C:11]([O:14][C:15]1[CH2:16][C:17](=[O:22])O[C:19](=[O:21])[CH:20]=1)(=[O:13])[CH3:12].[C:23](O)(=O)C>>[C:11]([O:14][C:15](=[CH:20][C:19](=[O:21])[CH3:23])[CH2:16][C:17]([NH:4][C:3]1[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:2]=1[Br:1])=[O:22])(=[O:13])[CH3:12]
Reactant: COc1ccc(Br)c(N)c1
Reactant: CC(=O)O
Reactant: CC(=O)OC1=CC(=O)OC(=O)C1
Product: COc1ccc(Br)c(NC(=O)CC(=CC(C)=O)OC(C)=O)c1
Temperature: 35 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
2-bromo-5-methoxyaniline (6 g; 29.7 mmol) was dissolved in acetic acid (33.7 ml) and 2,6-dioxo-3,6-dihydro-2H-pyran-4-yl acetate (4.59 g; 27.0 mmol) was added. The reaction was stirred at 35° C. in a sand bath for 2 h. The reaction was quenched by adding ice-water (250 ml), the precipitate formed was filtered, washed with water and dried over phosphorus pentoxide under reduced pressure to afford 8.98 g (71%) of 1-(2-bromo-5-methoxyphenylamino)-1,5-dioxohex-3-en-3-yl acetate as a grey solid.