Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[S:30][C:7]3[N:8]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([C:21]5[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=5)=[CH:17][C:16]=4[F:29])[C:9](=[O:13])[NH:10][C:11](=[O:12])[C:6]=3[CH:5]=2)[CH2:3][CH2:2]1.Br[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=1[O:42][CH3:43])=[O:34].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH:1]1([C:4]2[S:30][C:7]3[N:8]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([C:21]5[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=5)=[CH:17][C:16]=4[F:29])[C:9](=[O:13])[N:10]([CH2:32][C:33]([C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=4[O:42][CH3:43])=[O:34])[C:11](=[O:12])[C:6]=3[CH:5]=2)[CH2:3][CH2:2]1
Reactant: COc1cc(F)ccc1C(=O)CBr
Reactant: N#Cc1ccccc1-c1ccc(Cn2c(=O)[nH]c(=O)c3cc(C4CC4)sc32)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1C(=O)Cn1c(=O)c2cc(C3CC3)sc2n(Cc2ccc(-c3ccccc3C#N)cc2F)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
To a mixture of 4′-[(6-cyclopropyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile (0.32 g), 2-bromo-1-(4-fluoro-2-methoxyphenyl)ethanone (0.25 g) and N,N-dimethylformamide (15 mL) was added 60% sodium hydride (0.046 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.3 g, 67%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][C:14](=[O:18])[C@@H:13]3C(C)C)=[CH:8][C:6]=2[N:7]=1.[CH2:28]1[C@H:33]2[CH2:34]NCCN2C(=O)C[O:29]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]4[C@@H:33]([CH2:28][O:29][CH2:13][C:14]4=[O:18])[CH2:34]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=C1COC[C@H]2CNCCN12
Reactant: CC(C)[C@H]1C(=O)NCCN1Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: O=C1COC[C@H]2CN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)CCN12

Procedure:
Prepared according to the method used in the preparation of (S)-4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-3-isopropyl-piperazin-2-one using (R)-hexahydro-pyrazino[2,1-c][1,4]oxazin-4-one in place of (S)-3-isopropyl-piperazin-2-one. The title compound was obtained as a tan solid (79 mg, 69%).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][O:7][CH2:8][CH:9]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:10][NH:11][C:12](=O)[O:13]C1C=CC=CC=1.[NH2:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]1.C(N(CC)CC)C>C(O)(C)C>[F:1][C:2]([F:34])([F:35])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:32])([F:31])[F:33])[CH:29]=1)[CH2:6][O:7][CH2:8][CH:9]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:10][NH:11][C:12](=[O:13])[NH:36][CH:37]1[CH2:38][CH2:39][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:41][CH2:42]1
Reactant: O=C(NCC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)NCC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)CC1
Yield: 72.1 %

Procedure:
Compound 84 produced in Example 77 (0.85 g, 1.7 mmol), tert-butyl 4-aminopiperidin-1-carboxylate (0.34 g, 1.7 mmol) and triethylamine (0.28 mL, 2.0 mmol) were dissolved in isopropyl alcohol and heated to reflux for 20 hours. After the solvent was evaporated therefrom in vacuo, the residue was purified by a column chromatography (toluene:acetone=4:1) to give Compound 85 (0.74 g, 72%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:33]/[O:34][C:35]([CH3:44])([CH3:43])[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])/[C:15](=[O:32])[NH:16][C@H:17]2[C@@H:20]([CH2:21][N:22]3[CH:26]=[C:25]([Si](C)(C)C)[N:24]=[N:23]3)[NH:19][C:18]2=[O:31])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[N:22]1([CH2:21][C@@H:20]2[C@H:17]([NH:16][C:15](=[O:32])/[C:14](=[N:33]\[O:34][C:35]([CH3:44])([CH3:43])[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])/[C:12]3[N:13]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[S:10][CH:11]=3)[C:18](=[O:31])[NH:19]2)[CH:26]=[CH:25][N:24]=[N:23]1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2cc([Si](C)(C)C)nn2)cs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2ccnn2)cs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.6 %

Procedure:
Prepared according to the method described in WO2013/028590. To a solution of tert-butyl 2-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxo-2-(((3S,4R)-2-oxo-4-((4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)methyl)azetidin-3-yl)amino)ethylidene)amino)oxy)-2-methylpropanoate (140 mg, 0.261 mmol) in THF (4 mL) was added TBAF (1 M in THF, 860 μL, 0.86 mmol). After stirring at rt for 16 h, additional TBAF (1M in THF, 1.0 mL, 1.0 mmol) was added. After stirring for an another 48 h, the solution was concentrated in vacuo. The crude residue was purified via silica gel chromatography (MeOH-DCM, 7%) affording the title compound (84 mg, 68%) as an off white solid. LCMS: m/z=579.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[CH:27]([N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1)([CH3:29])[CH3:28].C(=O)(O)[O-].[Na+].O1CCOCC1>CO.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.O>[CH:27]([N:30]1[CH:34]=[C:33]([C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]4[CH:17]=[C:16]([N:18]5[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]5)[N:15]=[C:14]([NH2:25])[N:13]=4)[CH2:9]3)=[CH:4][CH:3]=2)[CH:32]=[N:31]1)([CH3:29])[CH3:28]
Reactant: CC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
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: CO
Solvent: O
Solvent: C1COCCO1
Product: CC1Cc2ccc(-c3cnn(C(C)C)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.2 mg, 0.026 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol), and sodium bicarbonate (6.0 mg, 0.072 mmol) in a solution of 1,4-dioxane (0.2 mL) and water (0.1 mL) in a reaction vial was stirred at 90° C. overnight. It was diluted with methanol. After filtration the filtrate was purified with RP-HPLC (pH=10) to afford the desired product (4.4 mg). LCMS (M+H)+: m/z=447.4.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]([O:23]CC)=[O:22])[NH:6]2.CO.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]([OH:23])=[O:22])[NH:6]2
Reactant: CCOC(=O)c1cc2c(C)c(C)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(NS(=O)(=O)c2cccs2)c2[nH]c(C(=O)O)cc2c1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.9 %

Procedure:
To a mixed solution of ethyl 4,5-dimethyl-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (1.69 g) in tetrahydrofuran (30 mL)-methanol (20 mL) was added aqueous solution (10 mL) of 85% potassium hydroxide (0.90 g), and the mixture was stirred at room temperature for 15 hr. Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (1.47 g, yield 94%) as colorless crystals. melting point>285° C. (decomposition).
Reaction SMILES: O1CCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:16]([N:18]([CH2:28][CH2:29][CH2:30][C:31](=[O:33])[CH3:32])[CH2:19]/[CH:20]=[CH:21]/[C:22]#[C:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:17].[S:34]1[CH:38]=[CH:37][C:36]([C:39]2[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=2)[CH:42]=[O:43])=[CH:35]1>O.C(OCC)(=O)C.C(O)(=O)C>[CH2:16]([N:18](/[CH:28]=[CH:29]/[CH2:30][C:31](=[O:33])[CH2:32][CH:42]([OH:43])[C:41]1[CH:44]=[CH:45][CH:46]=[C:39]([C:36]2[CH:37]=[CH:38][S:34][CH:35]=2)[CH:40]=1)[CH2:19][CH:20]=[CH:21][C:22]#[C:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH3:17]
Reactant: CCN(C/C=C/C#CC(C)(C)C)CCCC(C)=O
Reactant: O=Cc1cccc(-c2ccsc2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN(/C=C/CC(=O)CC(O)c1cccc(-c2ccsc2)c1)CC=CC#CC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
A 1M tetrahydrofuran solution (0.6 ml) of lithium bis-(trimethylsilyl)amide was added to 1 ml of tetrahydrofuran under an argon atmosphere, and the mixture was cooled to -78° C. To this solution were added, dropwise with stirring, a tetrahydrofuran solution (2 ml) of 125 mg of (E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-4-oxo-pentylamine, followed by a tetrahydrofuran solution (2 ml) of 94 mg of 3-(3-thienyl)-benzaldehyde. The mixture was stirred at -78° C. for 1 hour, and then at 0° C. for 1 hour. The reaction mixture was neutralized with acetic acid, and ethyl acetate and water were added to extract it. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The desiccant was separated by filtration, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [ethyl acetate→ethyl acetate/methanol=20/1] to give 78 mg (yield 40%) of (E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-6-hydroxy-4-oxo-6-[3-(3-thienyl)phenyl] hexenylamine.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:17]([C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:29]=3[N:28]=[CH:27][CH:26]=[CH:25]4)(=[O:19])=[O:18])[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=1.Cl.C(=O)([O-])[O-].[NH4+:45].[NH4+]>CO>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:17]([C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:29]=3[N:28]=[CH:27][CH:26]=[CH:25]4)(=[O:19])=[O:18])[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([C:38](=[NH:45])[NH2:39])=[CH:36][CH:37]=1
Reactant: COC(=O)CN(c1ccc2c(c1)nc(COc1ccc(C#N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Product: COC(=O)CN(c1ccc2c(c1)nc(COc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12

Procedure:
Prepared analogously to Example 1e from 1-methyl-2-[(4-cyanophenyl)-oxymethyl]-5-[N-(methoxycarbonylmethyl)-quinoline-8-sulphonylamino)-benzimidazole and methanolic hydrochloric acid, methanol and ammonium carbonate.
Reaction SMILES: N12CCN(CC1)CC2.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:27])/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)=[CH:12][C:11]=1[C:28]([F:31])([F:30])[F:29].Cl[C:33]1[N:41]=[CH:40][N:39]=[C:38]2[C:34]=1[N:35]=[CH:36][NH:37]2>ClCCCl.[Cl-].[Na+].O>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:27])/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:33]3[N:41]=[CH:40][N:39]=[C:38]4[C:34]=3[N:35]=[CH:36][NH:37]4)[CH:21]=2)=[CH:12][C:11]=1[C:28]([F:29])([F:30])[F:31]
Reactant: O=C(/C=C/c1cccc(O)c1)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Clc1ncnc2[nH]cnc12
Agent: C1CN2CCN1CC2
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: O=C(/C=C/c1cccc(Oc2ncnc3[nH]cnc23)c1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 60 °C
Yield: 11.2 %

Procedure:
To a mixture of 1,4-diazabicyclo[2.2.2]octane (0.098 g, 0.87 mmol) in DCE (25 mL) was added (2E)-N-[4-chloro-3-(trifluoromethyl)phenyl]-3-(3-hydroxyphenyl)-acrylamide (300 mg, 0.87 mmol) and 6-chloro-9H-purine (1.95 mmol). TEA (366 μL, 2.61 mmol) was added, and the resulting solution was stirred at 60° C. The solution was diluted with brine and extracted with EtOAc. The combined organic solutions were dried over Na2SO4, filtered and concentrated. Purification by column chromatography (SiO2, 10-80% EtOAc in hexanes) provided the title compound as a white solid (45 mg). 1H NMR (400 MHz, d6-DMSO): 813.68 (br s, 1H), 10.67 (s, 1H), 8.55 (bs, 1H), 8.45 (s, 1H), 8.30 (s, 1H), 7.92 (dd, 1H), 7.70 (d, 1H), 7.65 (s, 1H), 7.60 (m, 2H), 7.38 (d, 1H) and 6.80 (d, 1H). LCMS, AA: Rt=1.71 min, [MH+ 460.0].
Reaction SMILES: [ClH:1].Cl.[N+:3]([C:6]1[CH:18]=[CH:17][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4].[Cl:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:25][CH:24]=1)=[O:22].C([O-])([O-])=O.[K+].[K+]>>[ClH:19].[ClH:1].[N+:3]([C:6]1[CH:18]=[CH:17][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH2:20][C:21]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:25][CH:24]=3)=[O:22])[CH2:13][CH2:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: CC(=O)Nc1ccc(C(=O)CCl)cc1
Reactant: O=[N+]([O-])c1ccc(CN2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)Nc1ccc(C(=O)CN2CCN(Cc3ccc([N+](=O)[O-])cc3)CC2)cc1
Yield: 74 %

Procedure:
A mixture of N-(4-nitrobenzyl)piperazine dihydrochloride (2.94 g, 10 mmol), N-[4-(2-chloroacetyl)phenyl]acetamide (2.37 g, 12 mmol) and anhydrous K2CO3 (4.83 g, 35 mmol) was treated according to general preparation 2 to give compound (IV-18), yield 74%, mp 228-230° C. M+ 396.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[OH:6][C:7]1([C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[OH:5][CH2:4][CH2:3][CH2:2][NH:1][C:8]1[C:7]([C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)([OH:6])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: NCCCO
Reactant: Cc1cccc(C2(O)C(=O)Nc3ccccc32)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Cc1cccc(C2(O)C(NCCCO)=Nc3ccccc32)c1

Procedure:
Reaction of 3-aminopropanol with 3-hydroxy-3-(m-tolyl)-3H-indol-2-one in presence of toluene-p-sulphonic acid by a procedure analogous to that of Example 1 gives 2-(3-hydroxypropylamino)-3-(m-tolyl)-3H-indol-3-ol.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]([C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][CH2:23]Br)[CH2:17][CH2:16]1)[CH2:11][CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[CH2:10]([C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][CH2:23][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:17][CH2:16]1)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCC[C@H]1CC[C@H](CCCBr)CC1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCCCC[C@H]1CC[C@H](CCCOc2ccc(C=O)cc2)CC1
Yield: 121.9 %

Procedure:
A mixture of 1.9 g of 4-hydroxybenzaldehyde, 5.0 g of 3-(trans-4-pentylcyclohexyl)-1-propyl bromide, 8.3 g of potassium carbonate and 50 ml of butanone was heated under reflux overnight. Subsequently, the cooled reaction mixture was poured into water and extracted three times with 50 ml of diethyl ether each time. The combined organic phases were washed with 500 ml of water, dried over magnesium sulphate, filtered and concentrated. Chromatography of the residue on silica gel with toluene and recrystallization from ethanol gave 6.0 g of pure 4-[3-(trans-4-pentylcyclohexyl)-1-propyloxy]benzaldehyde.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([NH:8]C(=O)C)[CH:7]=1.ClC1C=CC([N+]([O-])=O)=C(C=1)N.[CH3:26][O:27][CH:28]1[CH:32]([CH2:33]OC)[CH2:31][CH:30](OC)O1>CC(O)=O>[CH3:26][O:27][CH2:28][C:32]1[CH:31]=[CH:30][N:1]([C:2]2[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([NH2:8])[CH:7]=2)[CH:33]=1
Reactant: CC(=O)Nc1cc(N)ccc1[N+](=O)[O-]
Reactant: COCC1CC(OC)OC1OC
Agent: Nc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: COCc1ccn(-c2ccc([N+](=O)[O-])c(N)c2)c1

Procedure:
The title compound was prepared from N-(5-amino-2-nitro-phenyl)-acetamide [prepared from commercially available 5-chloro-2-nitroaniline as described in Example F6] and 2,5-dimethoxy-3-methoxymethyl-tetrahydro-furan [prepared from (2,5-dimethoxy-tetrahydro-furan-3-yl)-methanol [CAS-no. 207119-66-2] by methylation with 2.1 eq. NaH (95%) and 5.5 eq. Mel in Et2O at 0° C. for 2 h] in HOAc at 60° C. for 18 h according to the general procedure F. Obtained as a light yellow solid (86 mg). Deacetylation of this material was perfomed by stirring with 2 eq. 2 N NaOH-sol. in 1,4-dioxane at 60° C. for 2 h. Obtained as a yellow solid (69 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH:16]([F:18])[F:17])[O:11][C:10]=1[CH:19](O)[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl.CCOC(C)=O.Cl>CC#N.[Zn]>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH:16]([F:18])[F:17])[O:11][C:10]=1[CH2:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)c1oc(C(F)F)cc(=O)c1OCc1ccccc1
Agent: Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: CCc1oc(C(F)F)cc(=O)c1OCc1ccccc1
Reaction time: 9 h
Yield: 50.5 %

Procedure:
To a solution of 3-benzyloxy-6-difluoromethyl-2-(1-hydroxy-ethyl)-pyran-4-one (1.30 g, 4.38 mmol), described in step 2 of Example 10, in CH3CN (14 mL) cooled in an ice-salt bath was added a solution of SOCl2 (0.45 mL, 5.44 mmol) in CH3CN (0.5 mL). The reaction mixture was stirred at ice-cold temperature for 9 hrs. The progress of the reaction was monitored by TLC using a mixture of hexanes and EtOAc (1/1, v/v) as eluant. Volatile materials were removed in vacuo, and ice-cold i-PrOH (15 mL) was added, and the mixture was cooled in an ice-salt bath. Then Zn dust (600 mg, 9 mmol) was added followed by concentrated HCl (1.1 mL). After 20 min, the reaction mixture was filtered through a CELITE™ bed, and the filtrate was evaporated to dryness. The residue was taken up in CH2Cl2 (100 mL), and the organic layer was washed with brine (2×30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residual oil was purified by column chromatography on silica gel using a mixture of hexanes and EtOAc (10/3, v/v) as eluant. Fractions rich in product were combined together, and concentrated to give 3-benzyloxy-6-difluoromethyl-2-ethyl-pyran-4-one (0.62 g) as a yellow oil. HPLC purity (peak area percent) of this material is 99.0% at λ=280 nm using HPLC Method 1 as described above. 1H NMR (400 MHz, DMSO-D6) δ(ppm): 7.30-7.40 (m, 5H), 7.06 (t, J=52.7 Hz, 1H, CF2H), 6.76 (s, 1H), 5.07 (s, 2H), 2.56 (q, J=7.4 Hz, 1H, CH2CH3), 0.97 (t, J=7.5 Hz, 3H, CH2CH3).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([Br:15])=[C:11]([NH2:14])[CH:12]=2)[N:7]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:6][C@@H:5]1[CH3:22])(=[O:3])[CH3:2].[C:23](NC1C=C2C(=CC=1C1C=NN(C3CC3)C=1)N(C(OC(C)C)=O)C[C@H](C)N2C(=O)C)(=[O:25])[CH3:24]>>[C:23]([NH:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[Br:15])[N:7]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:6][C@H:5]([CH3:22])[N:4]2[C:1](=[O:3])[CH3:2])(=[O:25])[CH3:24]
Reactant: CC(=O)Nc1cc2c(cc1-c1cnn(C3CC3)c1)N(C(=O)OC(C)C)C[C@H](C)N2C(C)=O
Reactant: CC(=O)N1c2cc(N)c(Br)cc2N(C(=O)OC(C)C)C[C@@H]1C
Product: CC(=O)Nc1cc2c(cc1Br)N(C(=O)OC(C)C)C[C@H](C)N2C(C)=O

Procedure:
Isopropyl (S)-6-acetamido-4-acetyl-7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate was prepared from isopropyl (S)-4-acetyl-6-amino-7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate according to the procedure described above for isopropyl (S)-6-acetamido-4-acetyl-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (Example 235). MS (ESI, pos. ion) m/z 412, 414 [M+H]+.
Reaction SMILES: ClCCl.[NH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:17]2[C:12](=[C:13]([F:22])[CH:14]=[CH:15][C:16]=2[O:18][CH2:19][CH2:20][CH3:21])[C:11](=[O:23])[C:10]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[CH:9]1.C(N(CC)CC)C.[Cl:39][CH2:40][C:41](Cl)=[O:42]>O>[Cl:39][CH2:40][C:41]([NH:4][CH2:5][CH2:6][CH2:7][N:8]1[C:17]2[C:12](=[C:13]([F:22])[CH:14]=[CH:15][C:16]=2[O:18][CH2:19][CH2:20][CH3:21])[C:11](=[O:23])[C:10]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[CH:9]1)=[O:42]
Reactant: O=C(Cl)CCl
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CCCN)c12
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CCCNC(=O)CCl)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.3 %

Procedure:
A dichloromethane solution (6 ml) of 1-(3-aminopropyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one (645 mg, 1.67 mmol) was ice-cooled. Triethylamine (253 mg, 2.5 mmol) and chloroacetyl chloride (207 mg, 1.83 mmol) were added to the solution and stirred at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction using dichloromethane. The thus-obtained organic layer was condensed, and the residue was then purified using silica gel column chromatography (dichloromethane:ethyl acetate=4:1→2:1). The purified product was concentrated to dryness under reduced pressure, giving a white powder of 2-chloro-N-{3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]propyl}acetamide (372 mg, yield: 48%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].N1C=CC=CC=1.[NH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[S:19][CH2:20][C:21]#[N:22]>C1COCC1>[C:21]([CH2:20][S:19][C:13]1[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=1[NH:11][C:1](=[O:3])[CH3:2])#[N:22]
Reactant: N#CCSc1ccc(F)cc1N
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(F)ccc1SCC#N
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 86 %

Procedure:
Acetyl chloride (1.5 ml) in THF (10 ml) and subsequently pyridine (1.7 ml) in THF (10 ml) was added to a stirred solution of (2-amino-4-fluoro-phenylsulfanyl)acetonitrile (3.5 g) in THF (30 ml) at 0° C. The mixture was stirred at 0° C. for 50 min. Then the solvent was removed in vacuo and the residue was triturated with water (80 ml). The precipitate was filtered off and dried yielding 3.7 g (86%) of the title compound as yellow crystals; mp 113-115° C.; 1H-NMR (DMSO-d6), δ (ppm): 9.59 (s, 1H, NH), 7.73-7.57 (m, 2H, Ar—H), 7.19-7.05 (m, 1H, Ar—H), 4.05 (s, 2H, CH2), 2.12 (s, 3H, CH3). The title compound was used for the next step without further purification.