Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]3[CH3:17])=[N:7][C:6]([C:18]3[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=3)=[N:5][C:4]=2[CH2:3]1.C([O-])(O)=O.[Na+].Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:32]>C1COCC1>[CH3:1][N:2]1[CH2:10][C:9]2[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]3[CH3:17])=[N:7][C:6]([C:18]3[CH:24]=[CH:23][C:21]([NH:22][C:31](=[O:32])[O:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:20][CH:19]=3)=[N:5][C:4]=2[CH2:3]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(N)cc2)nc2c1CN(C)C2
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)nc2c1CN(C)C2
Temperature: 20 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
To a stirring solution of (S)-4-(6-methyl-4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)aniline (intermediate 9) (311 mg, 0.96 mmol) and NaHCO3 (120 mg, 1.43 mmol) in dry THF, was added phenyl chloroformate (133 μL, 1.05 mmol) dropwise. The reaction mixture was stirred at room temperature (20° C.) for 2 hours, before partitioning the crude reaction mixture between water and EtOAc. The phases were separated and the organic layer dried over magnesium sulphate, filtered and then reduced in vacuo, affording the title compound as a pink solid (425 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]C)=O)=[C:10](/[N:17]=[CH:18]/[N:19]([CH3:21])C)[CH:9]=2)=[CH:4][CH:3]=1.NC[C:24]1[CH:25]=[C:26]([CH:41]=[CH:42][CH:43]=1)[O:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[C:13](=[O:15])[N:19]([CH2:21][C:24]4[CH:25]=[C:26]([CH:41]=[CH:42][CH:43]=4)[O:27][CH:28]4[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:39])([CH3:40])[CH3:38])=[O:35])[CH2:30][CH2:29]4)[CH:18]=[N:17][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(CN)c2)CC1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1/N=C/N(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(Cn3cnc4cc(-c5ccc(Cl)cc5)sc4c3=O)c2)CC1
Temperature: 120 °C

Procedure:
Methyl 5-(4-chlorophenyl)-3-{[(1E)-(dimethylamino)methylene]amino}thiophene-2-carboxylate (522 mg, 1.62 mmol) and tert-butyl 4-[3-(aminomethyl)phenoxy]piperidine-1-carboxylate (544 mg, 1.78 mmol) were dissolved in MeOH (10 ml). The mixture was heated in a microwave for 30 minutes at 120° C. A precipitate was formed from MeOH. The precipitate was filtered off and washed with MeOH yielding the title compound as a white solid. Yield: 431 mg (48%). 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.63 (m, 2H), 7.47 (s, 1H), 7.43 (m, 2H), 7.30-7.25 (m, 1H), 6.95-6.91 (m, 2H), 6.86 (m, 1H), 5.19 (s, 2H), 4.46 (m, 1H), 3.67 (m, 2H), 3.33 (m, 2H), 1.94-1.85 (m, 2H), 1.77-1.67 (m, 2H), 1.54 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH3:30][N:31]([CH3:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:36]2[CH:37]=[CH:38][C:33]([CH2:32][N:31]([CH3:48])[CH3:30])=[CH:34][CH:35]=2)[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: CN(C)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN(C)C)cc3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Yield: 9 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)benzamide (1 equiv.) and N,N-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine (1.2 equiv.) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (3.6 equiv.) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.1 equiv.) was added and argon was purged again for 10 min. The solution was heated at 100° C. for 4 h. The reaction mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford the title compound (0.01 g, 9%). LCMS: 517.30 (M+1)+; HPLC % 98.12 (@ 254 nm) (Rt; 3.972; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% Bin 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.45 (s, 1H), 8.16 (t, 1H), 7.58 (d, 2H, J=8 Hz), 7.34-7.36 (m, 2H), 7.18 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=4 Hz), 3.84 (d, 2H, J=10.8 Hz), 3.42 (s, 2H), 3.02 (m, 2H), 2.66 (m, 1H), 2.63 (s, 3H), 2.50 (3H merged in solvent peak), 2.23 (s, 3H), 2.20 (s, 3H), 2.16 (s, 3H), 2.10 (s, 3H), 1.60 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[NH2:14][C:15]1[CH:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:19][CH:20]=1>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:16]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CSc1ncnc2cc(N)ncc12
Product: Nc1cc2ncnc(Nc3cccc(C(F)(F)F)c3)c2cn1
Temperature: 195 °C
Reaction time: 2 h
Yield: 42.2 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (234 mg, 1.22 mmol) (described in a previous experimental) and 3-aminobenzotrifluoride (2.00 mL, 16.0 mmol) is stirred under N2 at 190-200° C. for 2 h, and the resulting product is then chromatographed over silica gel (5-10% EtOH/EtOAc), and then over alumina (5-7% EtOH/CHCl3) to give 7-amino-4-(3-trifluoromethylanilino)pyrido[4,3-d]pyrimidine (157 mg, 42%) as a cream solid. 1H NMR (DMSO) δ 10.04 (1H, s), 9.37 (1H, s), 8.46 (1H, s), 8.31 (1H, s), 8.19 (1H, d, J=8.2 Hz), 7.62 (1H, t, J=8.0 Hz), 7.45 (1H, d, J=7.7 Hz), 6.69 (2H, brs), 6.47 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][NH:18]C2C=CC=CC=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[C:7]([CH3:16])[CH:6]=2.S(Cl)(Cl)=O>O1CCCC1>[Cl:1][C:2]1[C:3]2[N:4]([C:16]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:5][CH:6]=3)=[N:18][N:17]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[C:7]([CH3:16])[CH:6]=2
Reactant: COC(=O)c1cc2nc(Cl)c(NNc3ccccc3)nc2cc1C
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)c1cc2nc(Cl)c3nnc(-c4ccccc4)n3c2cc1C

Procedure:
3.38 g of methyl 3-chloro-2-hydrazine-7-methylquinoxaline-6-carboxylate was dissolved in 30.0 mL of dichloromethane, and 7.09 g of bromo(tripyrrolidin-1-yl)phosphonium hexafluorophosphate and 5.30 mL of triethylamine were added thereto under ice-cooling, followed by stirring at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by stirring at room temperature for 1 hour. The precipitated solid was collected by filtration and dried under reduced pressure to obtain methyl 3-chloro-7-methyl-2-(2-phenylhydrazino)quinoxaline-6-carboxylate. The obtained methyl 3-chloro-7-methyl-2-(2-phenylhydrazino)quinoxaline-6-carboxylate was suspended in 50.0 mL of tetrahydrofuran, and 1.85 mL of thionyl chloride was added thereto at room temperature, followed by heating and refluxing overnight. The reaction liquid was left to stand at room temperature and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 2.06 g of methyl 4-chloro-8-methyl-1-phenyl[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylate as a brown solid
Reaction SMILES: [Br:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([OH:16])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:20][O:21][CH3:22].O>CN(C=O)C>[Br:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([O:16][CH2:20][O:21][CH3:22])=[CH:4][CH:3]=1
Reactant: COCCl
Reactant: Oc1ccc(Br)c2c1Sc1ccccc1S2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(Br)c2c1Sc1ccccc1S2
Reaction time: 0.5 h

Procedure:
To a cooled (0° C.) solution of 4-Bromo-thianthren-1-ol (1.0 g, 3.21 mmol) in DMF (12 ml) was added NaH (60% dispersed in mineral oil, 0.23 g, 9.63 mmol) portionwise over 30 minutes and stirred for a further 30 minutes at this temperature. Chloromethylmethylether (0.26 g, 3.241 mmol) was then added and the reaction allowed to stir at room temperature for 2 hours. Water was added to the mixture which was then extracted using EtOAc (3×50 ml). The combined organic extracts were then dried (MgSO4), filtered and concentrated in vacuo to give a mild amber liquid. The crude residue was purified by flash chromatography (SiO2) (10:1, Hexanes/EtOAc) to give the title compound as a mild amber oil that crystallised upon standing (1.11 g, 97%). m/z (LC-MS, ESP):, RT=5.55 min, (M++1)=355.
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:7]=2[C:8]([O:10]C)=O)[CH2:3][CH2:2]1.Cl.[CH3:19][NH:20][O:21][CH3:22].[Li]CCCC>>[CH:1]1([C:4]#[C:5][C:6]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:7]=2[C:8]([N:20]([CH3:19])[O:21][CH3:22])=[O:10])[CH2:2][CH2:3]1
Reactant: CNOC
Reactant: COC(=O)c1ccc(OC)cc1C#CC1CC1
Agent: Cl
Agent: [Li]CCCC
Product: COc1ccc(C(=O)N(C)OC)c(C#CC2CC2)c1
Yield: 86 %

Procedure:
Treatment of methyl 2-(cyclopropylethynyl)-4-(methyloxy)benzoate (149) (0.49 g, 2.13 mmol) with a mixture of N,O-dimethylhydroxylamine hydrochloride and nBuLi gave 0.47 g (86%) of the title compound (150) as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 0.70-0.90 (m, 4H), 1.40-1.50 (m, 1H), 3.28 (br s, 3H), 3.63 (br s, 3H), 3.80 (s, 3H), 6.83 (dd, J1=8.5 Hz, J2=2.6 Hz, 1H), 6.91 (d, J=2.4 Hz, 1H), 7.24 (d, J=8.6 Hz, 1H). LCMS (ESI): m/z 260 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:24][C:21]4([CH2:23][CH2:22]4)[N:20]([S:25](=[O:28])(=[O:27])[NH2:26])[CH2:19][CH2:18]3)[C:11]=2[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:36][CH2:37][CH2:38][C:39]#[N:40].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:24][C:21]4([CH2:23][CH2:22]4)[N:20]([S:25](=[O:27])(=[O:28])[N:26]([CH2:12][CH2:11][CH2:10][C:9]#[N:8])[CH2:36][CH2:37][CH2:38][C:39]#[N:40])[CH2:19][CH2:18]3)[C:11]=2[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc2c(N3CCN(S(N)(=O)=O)C4(CC4)C3)ncnc21
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)n1ccc2c(N3CCN(S(=O)(=O)N(CCCC#N)CCCC#N)C4(CC4)C3)ncnc21
Temperature: 0 °C
Reaction time: 16 h

Procedure:
4-(4-Sulfamoyl-4,7-diaza-spiro[2.5]oct-7-yl)-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (intermediate 2) (112 mg, 0.27 mmol) was dissolved in dry DMF (2 ml), added K2CO3 (38 mg, 0.27 mmol) and cooled to 0° C. A solution of 4-bromobutyronitrile (40 mg, 0.27 mmol) in dry DMF (0.5 mL) was added and the reaction mixture was stirred at rt for 16 h. The crude mixture was treated with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic phases were washed with H2O (2×10 mL), brine (2×10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The products were purified by flash chromatography on silica using EtOAc in heptane as eluent.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:7]1[CH2:8][N:9]([OH:13])[CH2:10][CH2:11][CH:12]=1)[C:5]#[N:6].C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22]>O1CCCC1>[CH3:1][O:2][N:3]=[C:4]([C:7]1[CH2:8][N:9]([O:13][C:21](=[O:23])[CH3:22])[CH2:10][CH2:11][CH:12]=1)[C:5]#[N:6]
Reactant: CC(=O)Cl
Reactant: CON=C(C#N)C1=CCCN(O)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CON=C(C#N)C1=CCCN(OC(C)=O)C1
Temperature: 25 °C
Yield: 37.4 %

Procedure:
α-(Methoxyimino)-α-(1-hydroxy-1,2,5,6-tetrahydropyridin-3-yl)acetonitrile (E2) (0.5 g, 0.0028 moles) was dissolved in dry tetrahydrofuran (20 ml) and treated with triethylamine (0.43 ml, 0.0031 moles) with stirring at room temperature. This mixture was then treated with acetyl chloride (0.22 ml, 0.0031 moles) and stirred at ambient temperature for 2 h. The mixture was filtered and the filtrate evaporated to dryness. The residue was chromatographed on silica gel eluting with chloroform. The crystalline residue was recrystallised from 60-80 petrol to give the title compound (E10) as an off-white crystalline solid (0.234 g, 38%) m.p. 87°-8° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([CH2:14][NH2:15])[OH:13]>>[OH:13][CH2:12][CH2:14][NH:15][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: NCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)NCCO)cc1

Procedure:
The preparation is carried out as in Example 1(a) but this time 381.3 g of p-toluenesulphonyl chloride (2 mol) and 128.3 g of ethanolamine (2.1 mol) are used for the reaction.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:5]([CH3:15])=[C:6]([N+:12]([O-])=O)[C:7]([CH3:11])=[CH:8][C:9]=1[CH3:10])#[N:2].[Cl-].[NH4+]>CO.[Zn]>[C:1]([CH2:3][C:4]1[C:5]([CH3:15])=[C:6]([C:7]([CH3:11])=[CH:8][C:9]=1[CH3:10])[NH2:12])#[N:2]
Reactant: Cc1cc(C)c([N+](=O)[O-])c(C)c1CC#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Cc1cc(C)c(CC#N)c(C)c1N
Yield: 69 %

Procedure:
To a solution of 3-cyanomethyl-1-nitro-2,4,6-trimethylbenzene (5.8 g in methanol (150 mL) were sequentially added ammonium chloride (6 g in 50 mL of water), zinc powder (6 g). The exothermic reaction was vigorously stirred until it was back to RT (2 h). To work up the crude mixture was filtered off and the cake was washed with methanol. The methanolic solutions were concentrated and the residue partitioned between ethyl acetate and 1N NaOH. The organic layer was dried over MgSO4 and concentrated to give 3-cyanomethyl-2,4,6-trimethylaniline as a light brown solid (3.4 g, 69%).
Reaction SMILES: [H-].[Na+].Cl.[CH3:4][N:5]([CH2:7][CH2:8]Cl)[CH3:6].[CH3:10][N:11]1[C:17]2=[CH:18][S:19][CH:20]=[C:16]2[C:15](=[O:21])[NH:14][C:13]2[CH:22]=[CH:23][CH:24]=[N:25][C:12]1=2>CN(C)C=O>[CH3:4][N:5]([CH3:6])[CH2:7][CH2:8][N:14]1[C:15](=[O:21])[C:16]2=[CH:20][S:19][CH:18]=[C:17]2[N:11]([CH3:10])[C:12]2[N:25]=[CH:24][CH:23]=[CH:22][C:13]1=2
Reactant: CN(C)CCCl
Reactant: CN1c2cscc2C(=O)Nc2cccnc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCN1C(=O)c2cscc2N(C)c2ncccc21
Reaction time: 18 h

Procedure:
A mixture of 0.20 g. of 55% sodium hydride-mineral oil dispersion and 0.3 g. of dimethylaminoethylchloride hydrochloride in 12 ml. of dry dimethylformamide is stirred at room temperature for 0.5 hours. To the mixture is added 0.23 g. of 5,10-dihydro-10-methyl-6H-pyrido[3,2-b]thieno[3,4-e][1,4]diazepin-6-one and stirring is continued for 18 hours. The reaction mixture is cooled, quenched with water and extracted with chloroform. The dried chloroform extracts are concentrated to give an amber oil, which is crystallized from hexane to give an off-white solid, m.p. 129°-130° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][S:8][C:5]2=[CH:6][N:7]=1.[O-:11][CH2:12][CH3:13].[Na+]>CCO>[CH2:12]([O:11][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][S:8][C:5]2=[CH:6][N:7]=1)[CH3:13]
Reactant: Clc1cc2ccsc2cn1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc2ccsc2cn1
Temperature: 175 °C
Yield: 68.8 %

Procedure:
A sealable vial was charged with 5-chlorothieno[2,3-c]pyridine (240 mg, 1.41 mmol), sodium ethoxide (557 mg, 7.78 mmol) and EtOH (6.5 mL). The reaction was heated in a microwave reactor at 175° C. for 2 h, then purified by ISCO chromatography (0 to 25% EtOAc:hexane) to afford 174 mg (69%) of the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.69-8.70 (m, 1 H), 7.63 (d, J=5.6 Hz, 1 H), 7.20 (dd, J=5.6, 0.8 Hz, 1 H), 7.08 (d, J=0.8 Hz, 1 H), 4.39 (quartet, J=7.2 Hz, 2 H), 1.43 (t, J=7.2 Hz, 3 H); MS (ESI): 180.04 [M+H]+; HPLC tR=1.39 min (TOF: polar—3 min).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][OH:8])=[CH:2]1.[CH3:9][S:10](Cl)(=[O:12])=[O:11].C(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:9][S:10]([O:8][CH2:7][CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)(=[O:12])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccsc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)OCCc1ccsc1
Temperature: 25 °C
Reaction time: 0.29 h
Yield: 65 %

Procedure:
To a solution of 5.0 g (7.8×10-3 mol) of 2-(3-thienyl)-ethanol (Aldrich Chemical) in 10 ml of dry, freshly distilled pyridine was added 3.62 ml (1.2 equiv.) of methanesulfonyl chloride in 20 ml of pyridine at 5°-10° C. The addition was carried out gradually, over a period of about 15-20 min. The reaction mixture was stirred overnight at room temperature and was quenched by pouring into a separatory funnel containing water and ether. The layers were separated and the aqueous layer was extracted three times with ether. The combined organic extracts were extracted once with 10% hydrochloric acid, followed by water and drying over Na2SO4. Evaporation of the solvent afforded 5.3 g of a light brown oil (65% yield), and tlc (CHCl3) showed a single spot. Chromatographic purification on silica gel afforded a light yellow oil. Nmr (CDCl3, δ rel TMS) 2.9s, 3H; 3.1t, 2H; 4.4t, 2H; 7.0-7.4m, 3H. Ir (neat, ν cm-1) 3100w, 2930w, 2920w 1415w, 1355s, 1335s, 1245w, 1173s, 1080w, 1055w, 970s, 955s, 903m, 850m, 825w, 795s, 775s, 740w. MS, 206.0.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([OH:12])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[C:13]([O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1)([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:13]([O:17][C:18](=[O:27])[C:19]1[CH:20]=[CH:21][C:22]([CH2:25][N:8]2[C:7](=[O:12])[CH:6]=[C:5]3[C:10]([CH:11]=[C:2]([Br:1])[CH:3]=[CH:4]3)=[CH:9]2)=[CH:23][CH:24]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: Oc1cc2ccc(Br)cc2cn1
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(Cn2cc3cc(Br)ccc3cc2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 7-bromo-3-hydroxy-isoquinoline (7.02 g, 28.2 mmol) in dimethylformamide (75 mL) is treated with 4-bromomethylbenzoic acid tert-butyl ester (12.5 g, 36.7 mmol) and cesium carbonate (11.94 g, 36.7 mmol), then stirred overnight at room temperature. The dimethylformamide is evaporated in vacuo, the residue is diluted with ethyl acetate, washed with 1N HCl, the organic portion washed with brine, dried over MgSO4 and evaporated to dryness. The residue is triturated with hot hexanes/ethyl acetate, cooled to room temperature, and the solid is collected by filtration and dried to give the desired product.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([NH2:19])[C:13]1[N:20]=[C:21]3[CH2:26][O:25][CH2:24][C@H:23]([CH:27]([CH3:29])[CH3:28])[N:22]3[C:12]2=1)C1C=CC=CC=1.C(Cl)(Cl)Cl>C(O)C.[Pd]>[NH2:19][C:14]1[C:13]2[N:20]=[C:21]3[CH2:26][O:25][CH2:24][C@H:23]([CH:27]([CH3:28])[CH3:29])[N:22]3[C:12]=2[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=2)[N:15]=1
Reactant: CC(C)[C@H]1COCc2nc3c(N)nc4ccc(OCc5ccccc5)cc4c3n21
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC(C)[C@H]1COCc2nc3c(N)nc4ccc(O)cc4c3n21
Reaction time: 20 h
Yield: 59.2 %

Procedure:
(11S)-2-(Benzyloxy)-11-isopropyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (530 mg, 1.36 mmol) was dissolved in ethanol (50 mL) and the solution was placed in a pressure bottle. Palladium on carbon (10%, 220 mg) was added and the reaction mixture was shaken under H2 at 48 PSI (3.3×105 Pa) for 20 hours. The reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with 1:1 CH2Cl2/ethanol (200 mL) and the combined filtrates were concentrated under reduced pressure to give a white solid. Chromatography (SiO2, 30-50% CMA/CHCl3) gave (11S)-6-amino-11-isopropyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-2-ol (240 mg) as a white powder, mp 208-210° C.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([OH:24])[C:9]2[C:17]3[C:12](=NC=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[NH:11][CH:10]=2)=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[OH:26].O.[CH3:28][N:29](C)C=O>O1CCCC1>[F:1][C:2]1[C:3]([OH:26])=[CH:4][CH:5]=[C:6]([F:25])[C:7]=1[C:8]([C:9]1[C:28]2[N:29]=[C:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:16]=[CH:17][C:12]=2[NH:11][CH:10]=1)=[O:24]
Reactant: Oc1ccc(F)c(C(O)c2c[nH]c3ncc(-c4cccnc4)cc23)c1F
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1c(F)ccc(O)c1F)c1c[nH]c2ccc(-c3cccnc3)nc12
Temperature: 25 °C
Reaction time: 50 h

Procedure:
To 2,4-difluoro-3-[hydroxy-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenol (P-0009, 45.0 mg, 1.27 mmol) in tetrahydrofuran (15 mL) and N,N-dimethylformamide (5 mL) was added dichlorodicyanoquinone (87 mg, 3.8 mmol). The reaction was stirred at room temperature for 50 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The desired compound was isolated by silica eel column chromatography eluting with 5% methanol in methylene chloride to give a white solid (P-0066, 7 mg, 15.6%). MS(ESI) [M+H+]+=352.1.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]([CH2:17][C:16]3[CH:19]=[CH:20][C:13]([Cl:12])=[CH:14][CH:15]=3)[C:2](=[NH:1])[N:3]([CH2:17][C:16]3[CH:19]=[CH:20][C:13]([Cl:12])=[CH:14][CH:15]=3)[C:4]=2[CH:10]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: Nc1nc2ccc(Cl)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N=c1n(Cc2ccc(Cl)cc2)c2ccc(Cl)cc2n1Cc1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
A mixture of 2-amino-5-chloro-benzimidazole (9.4 g, 56.1 mmol), 4-chlorobenzylchloride (9.93 g, 61.7 mmol), potassium carbonate (15.5 g, 112 mmol) and dimethyl formamide (150 ml) was stirred at 50° C. for 20 h. Water (150 ml) was added and the product was filtered off. The crude product was purified by chromatography using silica gel and a mixture of ethanol (5%) and dichloromethane as eluent. The product was isolated as the free base. Yield 0.37 g, 2%. M.p. 175-177° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].CN(C=O)C.Br[CH2:18][CH:19]1[CH2:21][CH2:20]1>>[CH:19]1([CH2:18][N:8]2[C:9]3[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[CH:7]2)[CH2:21][CH2:20]1
Reactant: BrCC1CC1
Reactant: N#Cc1ccc2[nH]ccc2c1
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(ccn2CC2CC2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
To a solution of 5-cyano-indole (0.15 mg, 1.05 mmol) in dry DMF (3.5 mL) sodium hydride (55% in oil) (69 mg, 1.58 mmol) was added in one portion at 0° C. The mixture was stirred at 0° C. for 30 min and (bromomethyl)-cyclopropane (0.133 mL, 1.37 mmol) was added. The resulting mixture was allowed to warm to room temperature, and stirred for 30 min. After completion monitored by TLC, reaction mixture was quenched with ice and extracted with EtOAc. The organic layer was washed with water, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (EtOAc:hexane, 1:9) to give the product as a colorless solid (180 mg, 87%). 1H NMR (CDCl3, 400 MHz,): 0.40 (m, 1H), 0.68 (m, 1H), 0.89 (m, 1H), 4.02 (d, J=6.7 Hz, 2H), 6.60 (d, J=3.2 Hz, 7.98 (s, 1H), 7.36 (d, J=3.2 Hz, 2H), 1H), 7.42 (d, J=3.4 Hz, 2H). 13C NMR (CDCl3, 100 MHz,): 4.14, 11.1, 50.9, 102.2, 110.2, 120.9, 124.3, 126.5, 128.2, 129.8, 137.6.