Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CN(C=O)C.[H-].[Na+].[Br:16][C:17]1[CH:18]=[C:19]([N+]([O-])=O)[C:20]([C:23]#[N:24])=[N:21][CH:22]=1>O>[Br:16][C:17]1[CH:18]=[C:19]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:20]([C:23]#[N:24])=[N:21][CH:22]=1
Reactant: Oc1ccc(F)cc1
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ncc(Br)cc1Oc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 113.2 %

Procedure:
A flask was charged with 4-fluorophenol (44 g, 365 mmol) and DMF (500 mL). The reaction was cooled to 0° C. Sodium hydride (16.6 g, 414 mmol) was added and stirred for 10 minutes. 5-Bromo3-nitropicolinonitrile (90 g, 395 mmol) was added and the mixture stirred at ambient temperature for 30 minutes. The reaction was poured into a flask containing water (5000 mL) and stirred for 10 minutes. The pH was adjusted to 10 to give 5-Bromo-3-(4-fluorophenoxy)picolinonitrile (121 g, 413 mmol, 105% yield) as a solid.
Reaction SMILES: C(O[C:4](=[O:17])[CH2:5][C:6]1([CH2:13][N+]([O-])=O)[CH2:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7]1)C.[CH3:18]O>[Ni]>[CH3:12][C:8]1([CH3:11])[CH2:9][CH2:10][C:6]2([CH2:5][C:4](=[O:17])[CH2:18][CH2:13]2)[CH2:7]1
Reactant: CO
Reactant: CCOC(=O)CC1(C[N+](=O)[O-])CCC(C)(C)C1
Agent: [Ni]
Product: CC1(C)CCC2(CCC(=O)C2)C1
Reaction time: 24 h
Yield: 94 %

Procedure:
The ester 3 (380 mg, 1.6 mmol) and Raney Nickel (1 g) were suspended in methanol (75 mL) and shaken under a hydrogen atmosphere for 24 hours. The catalyst was removed by filtration, the filtrate concentrated to give the lactam 4 (246 mg, 94%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH2:22][CH2:21][CH2:20][CH:19]3[CH2:23][O:24][CH3:25])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=2)[C:37]([O:39][CH3:40])=[O:38])O1.C([O-])([O-])=O.[Na+].[Na+]>O.O1CCOCC1.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>[CH3:25][O:24][CH2:23][CH:19]1[CH2:20][CH2:21][CH2:22][N:18]1[C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([C:34]3[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=3)[C:37]([O:39][CH3:40])=[O:38])[N:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COCC1CCCN1c1cccc(Nc2nc(Cl)nc3scnc23)c1
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: C1COCCO1
Solvent: O
Product: COCC1CCCN1c1cccc(Nc2nc(-c3cccc(C(=O)OC)c3)nc3scnc23)c1
Yield: 59.5 %

Procedure:
Under N2 atmosphere, 5-chloro-N-(3-(2-(methoxymethyl)pyrrolidin-1-yl)phenyl)thiazolo[5,4-d]pyrimidin-7-amine (200 mg, 0.53 mmol), methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (153 mg, 0.58 mmol), Pd(PPh3)4 (40 mg, 0.035 mmol) and Na2CO3 (112 mg, 1.06 mmol) in 5 mL of water was added in 30 mL of 1,4-dioxane. The mixture was stirred at reflux for 18 hours. The solvent was removed under reduce pressure and the residue was purified by silica gel chromatography, eluting with petroleum ether and ethyl acetate (3:1) to give methyl 3-(7-(3-(2-(methoxymethyl)pyrrolidin-1-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoate (150 mg, 59%) as a yellow sold. 1H NMR (300 MHz, CDCl3): δ 9.13 (s, 1H), 8.82 (s, 1H), 8.68 (d, 1H, J=7.8 Hz), 8.14 (d, 1H, J=7.8 Hz), 8.06 (s, 1H), 7.54 (t, 1H, J=7.8 Hz), 7.35 (s, 1H), 7.28 (t, 1H, J=7.2 Hz), 7.16 (d, 1H, J=7.8 Hz), 6.49 (d, 1H, J=7.5 Hz), 3.96 (brs, 4H), 3.57-3.50 (brs, 2H), 3.32 (s, 3H), 3.25-3.19 (m, 2H), 2.11-2.02 (m, 5H). LC-MS: 476 [M+H]+, tR=1.93 min. HPLC: 98.15% at 214 nm, 97.85% at 254 nm, tR=5.24 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH:11]=O.[CH3:13][NH:14][C:15]([C:17]1[CH:22]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][CH3:31])=[C:26]([NH2:32])[CH:25]=2)[CH:20]=[CH:19][N:18]=1)=[O:16]>>[CH3:13][NH:14][C:15]([C:17]1[CH:22]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]3[N:30]([CH3:31])[C:11]([C:5]4[C:4]5[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=5)[NH:7][N:6]=4)=[N:32][C:26]=3[CH:25]=2)[CH:20]=[CH:19][N:18]=1)=[O:16]
Reactant: CNC(=O)c1cc(Oc2ccc(NC)c(N)c2)ccn1
Reactant: O=Cc1n[nH]c2ccc(F)cc12
Product: CNC(=O)c1cc(Oc2ccc3c(c2)nc(-c2n[nH]c4ccc(F)cc24)n3C)ccn1

Procedure:
The title compound was synthesized from 5-fluoro-1H-indazole-3-carbaldehyde and 4-(3-amino-4-methylamino-phenoxy)-pyridine-2-carboxylic acid methylamide as described above in Example 4. LC/MS (m/z) 417.4 (MH+), Rt 3.62 minutes.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>C1C=CC=CC=1>[CH3:1][CH:2]1[CH2:7][CH2:6][C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][CH2:3]1
Reactant: C1COCCN1
Reactant: CC1CCC(=O)CC1
Solvent: c1ccccc1
Product: CC1CC=C(N2CCOCC2)CC1
Yield: 70.8 %

Procedure:
In a flask equipped with a dean stark, a solution of 4-methylcyclohexanone (20.1 g, 179.3 mmol, 22 mL) and morpholine (31.3 g, 359.0 mmol, 31.4 mL) were refluxed in benzene (55 mL) for 26 hours. The benzene was removed under vacuum and the crude product was purified by distillation under reduced pressure to afford 23 g (70%) of 4-(4-methyl-cyclohex-1-enyl)-morpholine (44) as an oil (b.p. 120° C. at 10 mmHg). The structure was confirmed by 1H NMR (300 MHz, CDCl3): δH 0.94 (3H, d, J=6.0 Hz, CH3), 1.15-1.35 (1H, m, CH2CH═CN), 1.50-1.80 (3H, m, CH2CH2CHCH3), 2.00-2.25 (4H, m, CH2CH═CN and CH2CH2CHCH3), 2.65-2.95 (4H, m, OCH2NCH2), 3.73 (4H, t, J=6.0 Hz, OCH2NCH2), and 4.60-4.65 (1H, m, CH2CH═CN).
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15].[CH2:17]([CH:22]1[CH2:28][CH:27]2[NH:29][CH:24]([CH2:25][CH2:26]2)[CH2:23]1)[CH2:18][CH2:19][CH2:20][CH3:21]>CCN(CC)CC>[CH3:16][C@H:3]([CH2:2][N:29]1[CH:24]2[CH2:25][CH2:26][CH:27]1[CH2:28][CH:22]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:23]2)[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15]
Reactant: C[C@H](CI)CN1C(=O)COc2ccccc21
Reactant: CCCCCC1CC2CCC(C1)N2
Solvent: CCN(CC)CC
Product: CCCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)COc2ccccc21
Yield: 63.4 %

Procedure:
The compound (S)-4-(3-Iodo-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (108LM27-24) (0.083 g, 0.25 mmol) and 3-pentyl-8-aza-bicyclo[3.2.1]octane (104KS32-2) (0.051 g, 0.28 mmol) in Et3N (½ mL) were reacted according to GP15 to give the title compound (108LM39-36) (0.061 g, 63%). 1H NMR (CDCl3) δ 7.33-7.29 (m, 1H), 7.03-6.96 (m, 3H), 4.60 (ABq, J=14.8 Hz, J=37.1 Hz, CH2), 4.14-4.00 (m, 2H), 3.13 (bs, 1H), 3.05 (bs, 1H), 2.63-2.50 (m, 1H), 2.17-2.03 (m, 3H), 2.00-1.80 (m, 3H), 1.72-1.53 (m, 3H), 1.42-1.15 (m, 10H), 0.93-0.85 (m, 6H); 13C NMR (CDCl3) δ 165.0, 145.7, 128.9, 123.7, 122.6, 117.1, 116.1, 67.9, 60.9, 58.9, 58.2, 45.3, 38.4, 37.0, 36.8, 32.2, 31.7, 28.5, 28.3, 27.2, 22.9, 17.1, 14.3; HPLC-MS (ammonium acetate) [M+H]+=385.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[Cl:8].N1C(C)=CC=CC=1C.Br[CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>C1(C)C=CC=CC=1>[C:24]([O:23][C:21](=[O:22])[CH2:20][CH2:19][NH:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)CCBr
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CCNc1ccc(Cl)c(Cl)c1
Reaction time: 30 h
Yield: 52.2 %

Procedure:
A solution of 9.61 g (59.33 mmol) of 3,4-dichloro-phenylamine and 10.21 ml (59.33 mmol) of 2,6-lutidine in 55 ml of toluene was treated slowly with 6.50 ml (59.33 mmol) of tert-butyl 3-bromopropionate and stirred 30 h at reflux temperature. The reaction was then partitioned between 10% aq. KHSO4 solution and EtOAc (3×). The organic phases were washed with 10% aq. NaCl solution, dried over Na2SO4 evaporated and purified by flash silica gel column (n-heptane:EtOAc 9:1) to yield 8.98 g (52%) of the title compound as off-white solid. MS: 290.0 (MH+, 2Cl).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[C:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH2:15]2)=[CH:9][CH:8]=1)(=O)=O.C([O-])([O-])=O.[Na+].[Na+].[O:39]1[CH:43]=[CH:42][CH:41]=[C:40]1B(O)O>C1COCC1>[F:30][C:27]1[CH:26]=[CH:25][C:24]([C:13](=[C:14]2[CH2:15][C:16]([CH3:22])([CH3:23])[CH2:17][C:18]([CH3:20])([CH3:21])[CH2:19]2)[C:10]2[CH:9]=[CH:8][C:7]([C:40]3[O:39][CH:43]=[CH:42][CH:41]=3)=[CH:12][CH:11]=2)=[CH:29][CH:28]=1
Reactant: CC1(C)CC(=C(c2ccc(F)cc2)c2ccc(OS(=O)(=O)C(F)(F)F)cc2)CC(C)(C)C1
Reactant: OB(O)c1ccco1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(F)cc2)c2ccc(-c3ccco3)cc2)CC(C)(C)C1
Temperature: 120 °C
Yield: 80.7 %

Procedure:
The Suzuki procedure described for 28 was utilized using triflate 25 (150 mg, 0.319 mmol), PdCl2 (Ph3P)2 (23 mg, 0.032 mmol), 2 N aqueous Na2CO3 (1.6 mL, 3.2 mmol), 2-furanylboronic acid (179 mg, 1.6 mmol), and THF (2 mL). The mixture was heated at 120° C. for 15 min using microwave conditions. Standard work-up followed by purification gave 100 mg (81%) of the title product 30 as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 7.58 (d, J=8.4 Hz, 2H), 7.44 (s, 1H), 7.18-7.12 (m, 4H), 6.96 (t, J=8.8 (Hz, 2H), 6.60 (d, J=3.2 Hz, 1H), 7.45 (br s, 1H), 2.0 (s, 2H), 1.96 (s, 2H), 1.30 (s, 2H), 0.93 (s, 12H). LCMS (APCI): m/z 389 (M+H)+.
Reaction SMILES: C(OP([CH2:9][C:10]1[C:11]([NH:16][C:17](=O)[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:12][CH:13]=[CH:14][CH:15]=1)(=O)OCC)C.C(O[K])(C)(C)C>C1(C)C=CC=CC=1.O1CCCC1>[C:20]1([CH2:19][CH2:18][C:17]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOP(=O)(Cc1cccnc1NC(=O)CCc1ccccc1)OCC
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: c1ccc(CCc2cc3cccnc3[nH]2)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 25.2 %

Procedure:
To a solution of diethyl[[2-[(3-phenylpropionyl)amino]-3-pyridyl]methyl]phosphonate (13.56 g, 36.03 mmol) in toluene (150 mL) was added a suspension of tert-butoxy potassium (11.41 g, 86.47 mmol) in tetrahydrofuran (86.47 mL), and the resulting mixture was stirred at 90° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-0/1) and recrystallized from hexane/ethyl acetate to give the title compound (2.02 g, yield 25%) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.S(Cl)([Cl:16])=O>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:16])=[O:8])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Product: O=C(Cl)c1ccc(C(F)(F)F)cc1

Procedure:
Reaction of 4-trifluoromethylbenzoic acid with thionyl chloride affords 4-trifluoromethylbenzoyl chloride, which, on reaction with diethylamine, affords 4-trifluoro-methyl-N,N-diethylbenzamide. Following a procedure similar to that described in Preparation 5, reaction of the latter with s-butyl lithium and reaction of the resulting lithium salt with sulfur dioxide followed by sodium hydroxylamine-O-sulfonate affords 4-trifluoromethyl-2-aminosulfonyl-N,N-diethylbenzamide, which on heating in glacial acetic acid, affords 6-trifluoro-methylsaccharin.
Reaction SMILES: [NH2:1][C:2]1[O:3][C@@H:4]([C@@H:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH3:9])[C:5](=[O:7])[N:6]=1.[CH3:19]N>>[CH3:9][C@H:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)[C@@H:4]1[O:3][C:2]([NH:1][CH3:19])=[N:6][C:5]1=[O:7]
Reactant: C[C@H](c1c[nH]c2ccccc12)[C@@H]1OC(N)=NC1=O
Reactant: CN
Product: CNC1=NC(=O)[C@H]([C@H](C)c2c[nH]c3ccccc23)O1
Reaction time: 3 h
Yield: 60 %

Procedure:
(5S)-2-Amino-5-[(1R)-1-(indol-3-yl)ethyl]-4-oxazolone (1.22 g) was dissolved in 40% aqueous solution of methylamine (9 ml). The vessel was stoppered and kept standing for 3 hours at 5° C. The reaction mixture was concentrated under reduced pressure to make the volume to about half. The precipitated solid substance was collected by filtration and washed with water (20 ml). The solid substance was recrystallized from methanol-water to give indolmycin (0.777 g) as white crystals (yield: 60%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][O:6][C@H:5]([C@@H:8]([OH:22])[CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[N:18]=3)[N:13]=[CH:12][CH:11]=2)[CH2:4][CH2:3]1.[N:23]1[C:28]2[O:29][CH2:30][CH2:31][O:32][C:27]=2[CH:26]=[C:25]([CH:33]=O)[N:24]=1>>[N:23]1[C:28]2[O:29][CH2:30][CH2:31][O:32][C:27]=2[CH:26]=[C:25]([CH2:33][NH:1][C@H:2]2[CH2:7][O:6][C@H:5]([C@@H:8]([OH:22])[CH2:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[N:18]=4)[N:13]=[CH:12][CH:11]=3)[CH2:4][CH2:3]2)[N:24]=1
Reactant: O=Cc1cc2c(nn1)OCCO2
Reactant: COc1ccc2nccc(C[C@H](O)[C@@H]3CC[C@@H](N)CO3)c2n1
Product: COc1ccc2nccc(C[C@H](O)[C@@H]3CC[C@@H](NCc4cc5c(nn4)OCCO5)CO3)c2n1

Procedure:
Starting from (1S)-1-((2S,5R)-5-amino-tetrahydro-pyran-2-yl)-2-(6-methoxy-[1,5]naphthyridin-4-yl)-ethanol (0.1 g, 0.33 mmol, prepared according to WO 2006/032466) and 6,7-dihydro-[1,4]dioxino[2,3-c]pyridazine-3-carbaldehyde (0.06 g, 1 eq.; prepared according to WO 2007/071936), and using the procedure of Example 1, the title compound was obtained as a colourless oil (0.008 g, 8% yield). The compound was purified by CC (DCM-MeOH 93-7 containing 0.7% aq. NH4OH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](OC)=[O:12])=[CH:5][N:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][OH:12])=[CH:5][N:4]=1
Reactant: COC(=O)CCc1ccc(OC)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1ccc(CCCO)cn1

Procedure:
In substantially the same manner as in Reference Example 82, methyl 3-(2-methoxy-5-pyridyl)propionate was reduced by lithium aluminum hydride to give 3-(2-methoxy-5-pyridyl)propanol. The yield was quantative. Oily substance.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]([NH:27][NH2:28])=[O:26])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[N:42]#[C:43]Br>O1CCOCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]4[O:26][C:43]([NH2:42])=[N:28][N:27]=4)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:35])([F:36])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CBr
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C(=O)NN)cc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(-c4nnc(N)o4)cc32)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine-8-carbohydrazide (intermediate 57, 0.040 g, 0.0771 mmol) and NaHCO3 (7 mg in 0.187 mL of water) in dioxane (0.75 mL) was added cyanogen bromide (9 mg in 0.084 mL of dioxane) was in four equal portions over 5 min. After stirring at rt for 2 h, the reaction was quenched with saturated aqueous NaHCO3 and the product was extracted with EtOAc and DCM. The combined extracts were washed with brine, dried (MgSO4) and concentrated. The residue was purified by SiO2 column chromatography to provide the title compound. LC/MS: m/e 545.1 (M+H)+. 1H NMR (500 MHz, CD3OD): δ 7.78 (1H, s), 7,76 (1H, d, J=8.5 Hz), 7.67 (1H, d, J=3.6 Hz), 7.63 (1H, d, J=7.3 Hz), 7.07-7.13 (3H, m), 6.91 (1H, d, J=8.5 Hz), 4.6-4.9 (2H, br), 3.53 (3H, s), 1.22 (9H, s).
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[N:16]([CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:15]=2[CH2:37][CH2:38][NH2:39])[CH3:11])=[CH:6][CH:5]=1.[CH3:41][O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[S:49](Cl)(=[O:51])=[O:50]>>[CH:24]([N:16]1[C:17]2[C:22](=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:14]([CH2:13][CH2:12][N:10]([CH3:11])[C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:2])=[O:40])=[CH:9][CH:8]=2)=[C:15]1[CH2:37][CH2:38][NH:39][S:49]([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=1[O:42][CH3:41])(=[O:51])=[O:50])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COc1ccccc1S(=O)(=O)Cl
Reactant: COC(=O)c1ccc(N(C)CCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Product: COc1ccccc1S(=O)(=O)NCCc1c(CCN(C)c2ccc(C(=O)O)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Yield: 95 %

Procedure:
The intermediate from example 146 step 7 was treated with 2-methoxy-benzenesulfonyl chloride according to the procedure in Example 87 step 2 to generate the desired product in 95% yield.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C@H:6]2[C@H:10]([NH:11][C:12]3[C:13](=[O:24])[N:14]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:15]=[CH:16][N:17]=3)[CH2:9][O:8][CH2:7]2)[CH2:3][CH2:2]1.[Cl:25]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[CH:1]1([CH2:4][O:5][C@H:6]2[C@H:10]([NH:11][C:12]3[C:13](=[O:24])[N:14]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:15]([Cl:25])=[CH:16][N:17]=3)[CH2:9][O:8][CH2:7]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)Cn1ccnc(N[C@@H]2COC[C@H]2OCC2CC2)c1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cn1c(Cl)cnc(N[C@@H]2COC[C@H]2OCC2CC2)c1=O
Reaction time: 6 h

Procedure:
A stirred solution of 3-(trans-3-cyclopropylmethoxytetrahydrofuran-4-ylamino)-1-ethoxycarbonylmethylpyrazinone from step 5 above (1.4 g, 4.15 mmol) and N-chlorosuccinimide (0.61 g, 4.57 mmol) in CHCl3 was heated to reflux for 6 h. More N-chlorosuccinimide (0.11 g, 0.83 mmol) was added and refluxing was continued for an additional 6 h. The reaction was diluted with CHCl3 and washed with aqueous NaHCO3. The organic phase was separated, dried over Mg SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using a gradient elution of 25-50% EtOAc:hexanes to give the title compound as an amorphous solid (1.1 g, TLC Rf=0.5, 1:1 EtOAc:hexanes; HPLC RT=7.97 min, method A).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:26]=[CH:25][C:16]4[C:17]([C:21]([NH:23][CH3:24])=[O:22])=[C:18]([CH3:20])[O:19][C:15]=4[CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.Br[CH2:28][CH:29]1[CH2:31][O:30]1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH3:24][NH:23][C:21]([C:17]1[C:16]2[CH:25]=[CH:26][C:13]([O:12][C:6]3[C:5]4[C:10](=[CH:11][C:2]([O:1][CH2:28][CH:29]5[CH2:31][O:30]5)=[CH:3][CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:14][C:15]=2[O:19][C:18]=1[CH3:20])=[O:22]
Reactant: BrCC1CO1
Reactant: CNC(=O)c1c(C)oc2cc(Oc3ccnc4cc(O)ccc34)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CNC(=O)c1c(C)oc2cc(Oc3ccnc4cc(OCC5CO5)ccc34)ccc12
Yield: 93.8 %

Procedure:
A solution of 6-[(7-hydroxyquinolin-4-yl)oxy]-N,2-dimethyl-1-benzofuran-3-carboxamide 123-A (1 g, 2.9 mmol), 2-(bromomethyl)oxirane (467 mg, 3.4 mmol) and Cs2CO3 (1.4 g, 4.2 mmol) in CH3CN (25 ml) was heated to 65° C. for 3 hours. The solution was extracted with EtOAc. N,2-dimethyl-6-{[7-(oxiran-2-ylmethoxy)quinolin-4-yl]oxy}-1-benzofuran-3-carboxamide 123-B (1.1 g) was isolated by a silica gel column using 1-5% MeOH in CH2Cl2. To a solution of 123-B (150 mg, 0.35 mmol) in THF (5 ml) was added a solution of methylamine in MeOH (1N, 1 ml). The solution was heated to 65° C. for 2 hours. The crude product was purified by HPLC (10-40% CH3CN/H2O over 30 min.) to give 6-({7-[2-hydroxy-3-(methylamino)propoxy]quinolin-4-yl}oxy)-N,2-dimethyl-1-benzofuran-3-carboxamide 123.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])/[CH:2]=[CH:3]/[CH2:4][CH3:5].[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>>[N:9]1([CH:3]([CH2:4][CH3:5])[CH2:2][C:1]([O:7][CH3:8])=[O:6])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: C1CNCCN1
Reactant: CC/C=C/C(=O)OC
Product: CCC(CC(=O)OC)N1CCNCC1
Temperature: 60 °C
Reaction time: 44 h
Yield: 51.8 %

Procedure:
A mixture of 213 g of methyl 2-trans-pentenoate and 64 g of piperazine was stirred for 44 hours at 60° C. Fractional distillation gave 77.1 g of methyl 3-piperazinovalerate of boiling point 105° C./0.4 mbar, nD20 =1.4740, the yield being 51%, based on piperazine used. delta =0.70-1.80 (m, 5 H), 1.72 (s, 1 H), 2.0-3.2 (m, 11 H), 3.70 ppm (s, 3 H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH2:12]([NH:19][CH2:20][CH2:21][NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C(OCC)(=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([NH:22][CH2:21][CH2:20][NH:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:3][CH:4]=1
Reactant: NCCNCc1ccccc1
Reactant: COC(=O)c1ccc(Cl)nc1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(NCCNCc2ccccc2)nc1

Procedure:
4.6 g of methyl 6-chloronicotinate and 40.5 ml of N-benzylethylenediamine are heated at 135° C. for 6 hours in a round-bottomed flask. The resulting product is poured into water and extraction is carried out with ethyl acetate. The resulting product is dried and evaporated under vacuum; the crude product thus obtained is purified by flash chromatography.
Reaction SMILES: N1C=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC([N:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][C:16]3[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=3[C:18]=2[NH2:22])[CH2:13]1)=O)C.S(OC)(OC)(=O)=O>O>[N:22]1([C:18]2[C:17]3[CH:23]=[CH:24][CH:25]=[CH:26][C:16]=3[CH:15]=[C:14]3[C:19]=2[CH2:20][CH2:21][NH:12][CH2:13]3)[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: CCOC(=O)N1CCc2c(cc3ccccc3c2N)C1
Reactant: c1ccncc1
Solvent: COS(=O)(=O)OC
Solvent: O
Product: c1ccc2c(-n3cccc3)c3c(cc2c1)CNCC3
Reaction time: 8 h

Procedure:
3 ml of pyridine are added to a mixture of 27.0 g of 5-amino-1,2,3,4-tetrahydrobenzo[g]isoquinolin-2-ylcarboxylic acid ethyl ester in 50 ml of water. 50.4 g of dimethyl sulphate are added dropwise to this mixture within 10 minutes and the mixture is stirred for 8 hours at 55° - 60°. The resulting clear solution is diluted with 100 ml of water, and is extracted several times with chloroform. The extracts are washed neutral with water, are dried over sodium sulphate and concentrated by evaporation. The oily residue is taken up in ether, is made acid with ethereal hydrochloric acid solution and the precipitated product is filtered off and recrystallized from ethanol/ether. M.Pt. of 5-methylamino-1,2,3,4-tetrahydrobenzo[g]isoquinolin-2-ylcarboxylic acid ethyl ester hydrochloride 214° - 215°.