Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([C:17](=O)[CH3:18])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]([F:16])([F:15])[CH:12]([F:14])[F:13])[CH:5]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([NH:34][C:35]([NH2:37])=[S:36])[CH:25]=[CH:26][C:27]=1[N:28]1[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]1>C(O)C>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([NH:34][C:35]2[S:36][C:2]([CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]([F:16])([F:15])[CH:12]([F:14])[F:13])[CH:5]=3)=[C:17]([CH3:18])[N:37]=2)[CH:25]=[CH:26][C:27]=1[N:28]1[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]1
Reactant: CC(=O)C(Cl)Cc1cccc(OC(F)(F)C(F)F)c1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Solvent: CCO
Product: COc1cc(Nc2nc(C)c(Cc3cccc(OC(F)(F)C(F)F)c3)s2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 1 step e) from crude 2-chloro-1-(3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl)-butan-3-one and 53 mg (0.2 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea in ethanol (1 ml). The crude product was purified on silica gel with methylene chloride/methanol 9/1 yielding 98 mg (96%) of the title compound as a brown solid. MS ISP (m/e): 507.3 (100) (M+H)+. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.63 (s, 1H), 7.31 (t, 1H), 7.20 (s, 1H), 7.15-7.04 (m, 4H), 6.88 (d, 1H), 6.85 (s, 1H), 6.08-5.38 (tt, 1H), 3.99 (s, 2H), 3.81 (s, 3H), 2.28 (s, 6H).
Reaction SMILES: [Si]([O:8][CH2:9]/[CH:10]=[CH:11]\[Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])(C(C)(C)C)(C)C>CO>[Si:12](/[CH:11]=[CH:10]\[CH2:9][OH:8])([C:15]([CH3:17])([CH3:18])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)/C=C\CO[Si](C)(C)C(C)(C)C
Solvent: CO
Product: CC(C)(C)[Si](C)(C)/C=C\CO

Procedure:
A mixture of 1.2 g, 4.2 mmol) of (Z)-O-(t-butyldimethylsilyl)-3-(t-butyldimethylsilyl)-2-propen-1-ol and 0.04 g of diisocyanate tetrabutylstannoxane [Otera, Nozaki, Tetrahedron Lett., 27, 5743 (1986)] in 140 ml of methanol is refluxed for 9 hours. Most of solvent is removed under reduced pressure and the residue is dissolved in a ether-water mixture. Etheral phase is washed with water and brine ,dried with sodium sulfate, filtered and concentrated under reduced pressure to afford 0.7 g (quantitatif crude yield) of (Z)-3-(t-butyldimethylsilyl)-2-propen-1-ol as a colorless liquid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)=[N:15][N:14]4[CH2:23][CH2:24][CH:25]([OH:26])[C:13]=34)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)=[N:15][N:14]4[CH2:23][CH2:24][C:25](=[O:26])[C:13]=34)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: OC1CCn2nc(-c3ccccn3)c(-c3ccnc4cc(Br)ccc34)c21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C1CCn2nc(-c3ccccn3)c(-c3ccnc4cc(Br)ccc34)c21
Reaction time: 18 h

Procedure:
To a solution of 3-(7-bromo-quinolin-4-yl)-2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-4-ol (89.0 mg, 0.22 mmol) in dry dichloromethane (2 mL) is added Dess-Martin periodinane (301.0 mg, 0.71 mmol) and the resulting mixture stirred for 18 h. The reaction mixture is chromatographed on SiO2 (dichloromethane to 20% methanol in dichloromethane) to yield a yellow solid, 78 mg (88%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19][CH2:18]2.[OH:26]O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19][CH2:18]2)=[O:26]
Reactant: O=C1CCc2cc(OCCCCSc3cc(Br)ccc3Br)ccc2N1
Reactant: OO
Product: O=C1CCc2cc(OCCCCS(=O)c3cc(Br)ccc3Br)ccc2N1

Procedure:
Prepared analogous to Example 123 from 6-[4-(2,5-dibromophenyl-mercapto)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([C:10]1[NH:18][C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[CH:11]=1)([CH3:9])([CH3:8])[CH3:7].O.[OH-].[Na+].CN(C)[CH:24]=[O:25]>>[C:6]([C:10]1[NH:18][C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[C:11]=1[CH:24]=[O:25])([CH3:9])([CH3:7])[CH3:8]
Reactant: CN(C)C=O
Reactant: CC(C)(C)c1cc2cccnc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC(C)(C)c1[nH]c2ncccc2c1C=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 41 %

Procedure:
Phosphorous oxychloride (4.01 mL, 43 mmol) was added drop-wise to N,N-dimethylformamide (9.96 mL, 129 mmol) at 0° C. and the mixture was stirred for 20 min. A solution of 2-tert-butyl-1H-pyrrolo[2,3-b]pyridine (5.0 g, 28.7 mmol) dissolved in N,N-dimethylformamide (30 mL) was added and the resulting mixture was slowly warmed up to room temperature. The mixture was stirred at room temperature for 2 h then at 40° C. for 3 h, and cooled in an ice bath, and 0.5 mL water was added. The reaction mixture was slowly warmed to 40° C. and stirred for 20 h. The mixture was poured onto approximately 100 mL ice, neutralized with an aqueous sodium hydroxide (5%) and extracted with dichloromethane. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo, and the residue was purified via silica gel column chromatography (0-30% ethyl acetate in heptane) to obtain 2-tert-butyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (2.4 g, 11.9 mmol, 41% yield) as an off white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[C@H:7]([N:11]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([NH2:31])[CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH:33](OC)(OC)OC>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:32])[C@H:7]([N:11]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]2[N:30]=[CH:33][NH:31][C:26]=2[CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(OC)OC
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccc(N)c(N)c2)[C@@H](C(=O)OC(C)(C)C)C(C)C)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(S(=O)(=O)N(Cc2ccc3nc[nH]c3c2)[C@@H](C(=O)OC(C)(C)C)C(C)C)cc1
Temperature: 25 °C

Procedure:
To a mixture of 2(R)-{[(3,4-diamino)benzyl]-(4-methoxybenzenesulfonyl)amino}-3-methylbutyric acid tert-butyl ester (90 mg, 0.194 mmol) and trimethyl orthoformate (0.022 mL, 1.05 equiv.) in dry toluene (10 mL) was added KSF montmorillonite clay (25 mg). The reaction mixture was heated at reflux for 6.5 h and then cooled to room temperature. After reaching room temperature, the mixture was condensed in vacuo and the residue was loaded onto a preparatory thin layer chromatography plate. Elution with methanol/methylene chloride (10%) provided 2(R)-[(benzimidazol-5-ylmethyl)-(4-methoxy-benzenesulfonyl)amino]-3-methylbutyric acid tert-butyl ester (79 mg).
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH:7]=[C:8]([C:14](=O)[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)#[N:2].[CH3:19][C:20]1[NH:21][C:22]([NH2:25])=[N:23][N:24]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH:7]2[N:23]3[N:24]=[C:20]([CH3:19])[N:21]=[C:22]3[NH:25][C:14]([CH3:15])=[C:8]2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)C(=Cc1ccc(C#N)cc1)C(C)=O
Reactant: Cc1nnc(N)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)Nc2nc(C)nn2C1c1ccc(C#N)cc1
Temperature: 65 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon, ethyl 2-(4-cyanobenzylidene)-3-oxobutanoate (381 mg, 1.6 mmol) and 5-methyl-4H-1,2,4-triazole-3-amine (200 mg, 2.0 mmol, 1.3 eq.) were dissolved in DMF (4 ml), and solid sodium bicarbonate (659 mg, 7.8 mmol, 5 eq.) was added. The mixture was stirred at 65° C. for 12 h. The mixture was then filtered, and the DMF from the filtrate was distilled off under reduced pressure. The residue was purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (300 mg, 46% of theory).
Reaction SMILES: [BH4-].[Na+].[Cl-].[CH2:4]([N+:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>CCO>[CH2:4]([N:11]1[CH2:12][CH:13]=[C:14]([C:17]([F:20])([F:18])[F:19])[CH2:15][CH2:16]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1cc[n+](Cc2ccccc2)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: FC(F)(F)C1=CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
3.00 g (79.36 mmol) of sodium borohydride was added batchwise to a solution of 14.48 g (52.91 mmol) of 1-benzyl-4-trifluoromethylpyridinium chloride in 100 mL of EtOH with strong cooling at 0° C., then the cooling was stopped and the reaction mixture was stirred for 1.5 hours at 14° C. While cooling, 50 mL of water and then 50 mL of EtOH were added within 30 minutes. The reaction mixture was stirred for another 30 minutes, the resulting suspension was filtered and the filtrate was evaporated down in vacuo. Yield: 11.72 g (92% of theoretical); C13H14F3N (M=241.252); calc.: molpeak (M+H)+: 242; found: molpeak (M+H)+: 242; HPLC-MS: 3.60 minutes (method B).
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[Cl: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]([Cl: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: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: NC1CNC1
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(Cl)c32)c(F)cc1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
To 350 mg of N,N-dimethylformamide were added 100 mg of 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 80 mg of 3-aminoazetidine dihydrochloride and 150 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 1 hour. After adding 1 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 86 mg of the title compound as a colorless powder.
Reaction SMILES: C([C:3]1([CH2:17][CH3:18])[S:7][CH:6]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[CH:5]=[C:4]1[C:14]([NH2:16])=[S:15])C.Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=O>>[CH2:17]([C:3]1[S:7][C:6]([C:8]([O:10][CH:11]([CH3:12])[CH3:13])=[O:9])=[CH:5][C:4]=1[C:14]1[S:15][CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:16]=1)[CH3:18]
Reactant: CCC1(CC)SC(C(=O)OC(C)C)C=C1C(N)=S
Reactant: O=C(CBr)c1ccccc1
Product: CCc1sc(C(=O)OC(C)C)cc1-c1nc(-c2ccccc2)cs1
Yield: 48.4 %

Procedure:
A solution of 450 mg (1.75 mmol) of isopropyl 5-ethyl-4-(aminothioxomethyl)-5-ethylthiophene-2-carboxylate was reacted with 348 mg (1.75 mmol) of 2-bromoacetophenone (Aldrich, Milaukee, Wis., USA) in a manner similar to Example 8, step (a) to give isopropyl 5-ethyl-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxylate (303 mg, 49%) as an off-white solid. 1H-NMR (DMSO-d6; 300 MHz) δ8.22 (s, 1H), 8.07 (s, 1H), 8.03 (m, 2H), 7.49 (m, 2H), 7.38 (m, 1H), 5.13 (septet, 1H, J=6.2 Hz), 3.34 (q, 2H, J=7.4 Hz), 1.39 (t, 3H, J=7.4 Hz), 1.33 (d, 6H, J=6.2 Hz). Mass spectrum (ESI, m/z): Calcd. for C19H19NO2S2 358.1 (M+H), found 358.1.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[N:14][C:15]([N:18]3[C:26]4[C:21](=[CH:22][C:23]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:24][CH:25]=4)[CH:20]=[CH:19]3)=[CH:16][CH:17]=2)[CH2:7][CH2:6]1)=[O:4].[I-].[K+].[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:30][S:27]([C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[N:18]([C:15]1[N:14]=[CH:13][C:12]([O:11][CH:8]3[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)[CH2:6][CH2:7]3)=[CH:17][CH:16]=1)[CH:19]=[CH:20]2)(=[O:28])=[O:29]
Reactant: C1CCNC1
Reactant: CS(=O)(=O)c1ccc2c(ccn2-c2ccc(OC3CCN(C(=O)CCl)CC3)cn2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc2c(ccn2-c2ccc(OC3CCN(C(=O)CN4CCCC4)CC3)cn2)c1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 52.1 %

Procedure:
To a solution of 2-chloro-1-(4-((6-(5-(methylsulfonyl)-1H-indol-1-yl)pyridin-3-yl)oxy)piperidin-1-yl)ethanone (0.080 g, 0.179 mmol) in DMF (2 mL), potassium iodide (0.009 g, 0.054 mmol), pyrrolidine (0.044 mL, 0.536 mmol), potassium carbonate (0.025 g, 0.179 mmol) were added and stirred at 80° C. for 45 minutes. The reaction was quenched by adding water (20 mL), the mixture was extracted with ethyl acetate, organic layer was concentrated under reduced pressure. The resulting crude was purified by flash column chromatography to give 1-(4-((6-(5-(methylsulfonyl)-1H-indol-1-yl)pyridin-3-yl)oxy)piperidin-1-yl)-2-(pyrrolidin-1-yl)ethanon (0.045 g, 52.32%).
Reaction SMILES: [NH2:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:12]([N:20]=[C:21]=[O:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH3:11])[C:2]=1[NH:1][C:21]([NH:20][C:12](=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:22])#[N:5]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: COc1cccc(C#N)c1N
Product: COc1cccc(C#N)c1NC(=O)NC(=O)c1ccccc1

Procedure:
Prepared as in Example 53a from 2-amino-3-methoxybenzonitrile and benzoyl isocyanate as a light orange solid (280 mg, 95%). 1H NMR (400 MHz, DMSO-d6) δ 3.89 (s, 3H), 7.42 (t, J=3.2 Hz, 2H), 7.46 (d, J=3.6 Hz, 1H), 7.54 (t, J=8 Hz, 2H), 7.66 (t, J=7.6 Hz, 1H), 8.05 (d, J=8.6 Hz, 2H), 10.55 (s, 1H), 11.32 (s, 1H). MS 295 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:12]([OH:14])=O)[CH2:11][CH2:10]1.S(Cl)([Cl:17])=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:12]([Cl:17])=[O:14])[CH2:11][CH2:10]1
Reactant: COc1ccccc1C1(C(=O)O)CC1
Reactant: O=S(Cl)Cl
Product: COc1ccccc1C1(C(=O)Cl)CC1

Procedure:
1-(2-methoxyphenyl)cyclopropane carboxylic acid (19 g) and thionyl chloride (30 ml) were heated under gentle reflux for 2 hours. The solvent was evaporated to yield 1-(2-methoxyphenyl)cyclopropane carbonyl chloride.
Reaction SMILES: CC([CH:5]1[CH2:11][N:10](C([O-])=O)[CH2:9][C:8]2[CH:15]=[C:16]([C:19]3[CH:20]=[N:21][C:22]([NH2:28])=[C:23]([N+:25]([O-:27])=[O:26])[CH:24]=3)[CH:17]=[CH:18][C:7]=2[O:6]1)(C)C.[ClH:29]>CO.O1CCOCC1>[ClH:29].[ClH:29].[N+:25]([C:23]1[C:22]([NH2:28])=[N:21][CH:20]=[C:19]([C:16]2[CH:17]=[CH:18][C:7]3[O:6][CH2:5][CH2:11][NH:10][CH2:9][C:8]=3[CH:15]=2)[CH:24]=1)([O-:27])=[O:26]
Reactant: CC(C)(C)C1CN(C(=O)[O-])Cc2cc(-c3cnc(N)c([N+](=O)[O-])c3)ccc2O1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1ncc(-c2ccc3c(c2)CNCCO3)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
A mixture of 1,1-dimethylethyl 7-(6-amino-5-nitropyridin-3-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (3.5 g, 9.1 mmol, example 26, step 1) in methanol (75 mL) and 4N hydrogen chloride in dioxane (11 mL) was stirred at 50° C. for 1.5 h and then concentrated. The resulting residue was triturated with a 10% methanol in diethyl ether solution (50 mL) to provide 3-nitro-5-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)pyridin-2-amine dihydrochloride (3.1 g, 95%) as a red solid. 1H NMR (400 MHz, d6-DMSO) δ 9.76 (bs, 2H), 8.80 (d, 1H), 8.60 (s, 1H), 7.90 (s, 1H), 7.73 (dd, 1H), 7.16 (d, 1H), 4.39 (bs, 2H), 4.25 (bs, 2H), 3.48 (bs, 2H); MS (EI) for C14H14N4O3: 287 (MH+).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]([NH:12][CH2:13][CH2:14][OH:15])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[OH:15][CH2:14][CH2:13][N:12]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:10][CH3:11]
Reactant: O=Cc1ccc(F)cc1
Reactant: CCNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCN(CCO)c1ccc(C=O)cc1
Temperature: 95 °C

Procedure:
To a three neck flask fitted with a mechanical stirrer, a thermometer, and a condenser, is added 124 g (1 mo1e) of 4-fluorobenzaldehyde, 89.1 g (1 mole) of 2-(N-ethylamino)ethanol, 138.2 g (1 mole) of anhydrous potassium carbonate, and dimethylsulfoxide. The mixture is heated at 95° C. for 3 hours. After cooling to room temperature, the solution is poured into a four-fold excess of ice water, and the solid product is collected by filtration and recrystallized from water.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][C:10]2[C:11]3[NH:34][CH:33]=[CH:32][C:12]=3[N:13]=[C:14]([N:16]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[N:15]=2)=[C:4]([CH3:35])[CH:3]=1.[Li+].[CH3:37][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:35])[C:5]([S:9][C:10]2[C:11]3[N:34]([CH3:37])[CH:33]=[CH:32][C:12]=3[N:13]=[C:14]([N:16]([C:24]3[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=3)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[N:15]=2)=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Br)cc(C)c1Sc1nc(N(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)nc2cc[nH]c12
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(C)c1Sc1nc(N(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)nc2ccn(C)c12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cold mixture of tert-butyl 4-(4-bromo-2,6-dimethylphenylthio)-5H-pyrrolo[3,2-d]pyrimidin-2-yl(4-cyanophenyl)carbamate (1.5 mmol) in THF (5 ml) at −78° C. is added a solution of LiHMDS (2 mmol). The mixture is warmed to 0° C. over 2 hours and then cooled to −78° C. Iodomethane (6 mmol) is added and the mixture warmed to room temperature over 2 hours and then stirred at room temperature for an additional 2 hours. The mixture is washed with brine and extracted with ethyl acetate (×3). The combined organic layers are dried over MgSO4 and concentrated to dryness. The crude material is purified by chromatography on silica.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([OH:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][C@H:37]2[C@:35]([N:39]([CH3:41])[CH3:40])([CH2:36]2)[CH2:34]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([O:20][CH2:30][CH2:31][CH2:32][N:33]4[CH2:38][C@H:37]5[C@:35]([N:39]([CH3:41])[CH3:40])([CH2:36]5)[CH2:34]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(C)[C@]12C[C@H]1CN(CCCCl)C2
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1C[C@@H]2C[C@]2(N(C)C)C1
Temperature: 80 °C
Yield: 67.6 %

Procedure:
To a mixture of 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (136 mg, 0.42 mmol, 1.0 eq) and anhydrous K2CO3 (290 mg, 2.10 mmol, 5.0 eq) in DMF (3 mL) was added a solution of (1R,5S)-3-(3-chloropropyl)-N,N-dimethyl-3-azabicyclo[3.1.0]hexan-1-amine (103 mg, 0.52 mmol, 1.2 eq) in DMF (2 mL) at room temperature. The reaction mixture was heated at 80° C. for 11 h and cooled to room temperature. Then the reaction mixture was quenched with water (5 mL) and diluted with EtOAc (10 mL). The organic phase was separated from the mixture, and the water phase was extracted with EtOAc (5 mL×3). The combined organic phases were, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by a silica gel column chromatography (10:1 (v/v)CH2Cl2/CH3OH) to give the crude product, which was then recrystallized from CH2Cl2/PE to afford title compound as a yellow solid (138 mg, 67.7%), HPLC: 96.5%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 486.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 0.81 (1H, m), 1.11 (1H, m), 1.26 (1H, br s), 1.52 (1H, m), 2.38 (6H, s), 2.65-2.81 (3H, m), 3.11 (2H, m), 3.42 (1H, br s), 3.98 (3H, s), 4.18 (2H, t, J=6.8 Hz), 7.14 (1H, t, J=8.8 Hz), 7.25 (1H, d, J=14.4 Hz), 7.41 (1H, s), 7.66 (1H, m), 7.98 (1H, dd, J=5.2, 6.8 Hz), 8.64 (1H, s) ppm.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13](=[O:28])[C:14]2[CH:19]=[CH:18][C:17]([O:20]CC3C=CC=CC=3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C1CCCCC=1>[OH-].[OH-].[Pd+2].C(O)C>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13](=[O:28])[C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(OC(=O)c2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CCCCCc1ccc(OC(=O)c2ccc(O)cc2)cc1
Yield: 93.2 %

Procedure:
To 100 mL of dehydrated ethanol, 15.6 g (41.5 mmol) of 4-benzyloxy-benzoic acid 4-pentyl-phenyl ester, 25 mL of cyclohexene, and 0.78 g of palladium hydroxide/carbon were added. Then, the mixture was refluxed for 10 hours under argon. The resulting reaction mixture was filtered, and the filtered liquid was concentrated. The residue was recrystallized from toluene. As a result, 11.0 g of a white solid was obtained.
Reaction SMILES: O[C:2]1[C:7]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([O:17][CH3:18])=[C:12]([CH3:19])[CH:11]=2)=[C:6](O)[N:5]=[C:4]([S:22][CH3:23])[N:3]=1.S(=O)(=O)(O)[O-].[Na+].P(Cl)(Cl)([Cl:32])=O>>[Cl:32][C:2]1[C:7]2[N:8]=[C:9]([C:10]3[CH:15]=[C:14]([CH3:16])[C:13]([O:17][CH3:18])=[C:12]([CH3:19])[CH:11]=3)[O:20][C:6]=2[N:5]=[C:4]([S:22][CH3:23])[N:3]=1
Reactant: COc1c(C)cc(C(=O)Nc2c(O)nc(SC)nc2O)cc1C
Reactant: O=P(Cl)(Cl)Cl
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: COc1c(C)cc(-c2nc3c(Cl)nc(SC)nc3o2)cc1C
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
At room temperature, 45.95 g of N-(4,6-dihydroxy-2-methylsulfanylpyrimidin-5-yl)-4-methoxy-3,5-dimethylbenzamide were suspended with stirring in 125 ml of phosphorus oxychloride, and the mixture was heated at 70° C. for 36 hours. After cooling, the reaction mixture was sucked through a glass frit, giving a yellow solid which was introduced with stirring into a saturated aqueous sodium bisulfate solution and stirred for 10 min. The solid was then filtered off with suction, washed until neutral and dried. This gave 10.47 g (22%) of the title compound, which was reacted further without any further purification.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[NH:27][C:26](=[O:28])[O:25][CH2:24][C:23]=4[CH:29]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:30]O>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([S:13]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[NH:27][C:26](=[O:28])[O:25][CH2:24][C:23]=4[CH:29]=3)=[O:30])=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1Nc2ccc(OCCCCSc3ccc(C4CCCCC4)cc3)cc2CO1
Reactant: OO
Product: O=C1Nc2ccc(OCCCCS(=O)c3ccc(C4CCCCC4)cc3)cc2CO1

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-cyclohexyl-phenylmercapto)-butoxy]-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: COC1C=C(N[C:21]2[C:22]3[N:23]([CH:32]=[CH:33][N:34]=3)[C:24]([C:27]3[CH:28]=[N:29][NH:30][CH:31]=3)=[CH:25][N:26]=2)C=CC=1C(NCC1C=NC(C)=CC=1)=O.[CH:35]([N:38]1[CH2:43][CH2:42][N:41]([C:44]2[N:49]=[CH:48][C:47]([NH2:50])=[CH:46][CH:45]=2)[CH2:40][CH2:39]1)([CH3:37])[CH3:36]>>[CH:35]([N:38]1[CH2:39][CH2:40][N:41]([C:44]2[N:49]=[CH:48][C:47]([NH:50][C:21]3[C:22]4[N:23]([CH:32]=[CH:33][N:34]=4)[C:24]([C:27]4[CH:28]=[N:29][NH:30][CH:31]=4)=[CH:25][N:26]=3)=[CH:46][CH:45]=2)[CH2:42][CH2:43]1)([CH3:37])[CH3:36]
Reactant: COc1cc(Nc2ncc(-c3cn[nH]c3)n3ccnc23)ccc1C(=O)NCc1ccc(C)nc1
Reactant: CC(C)N1CCN(c2ccc(N)cn2)CC1
Product: CC(C)N1CCN(c2ccc(Nc3ncc(-c4cn[nH]c4)n4ccnc34)cn2)CC1

Procedure:
This compound may be prepared using the same methods as described for Compound 184, using 6(4-isopropylpiperazin-1-yl)pyridin-3-ylamine in Step 3. LCMS: Rt=0.72 min (95%), m/z (ESI) 404 (M+H)+.