Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].C1COCC1.[CH2:17]([S:19]([C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([C:31]1[CH:36]=[C:35]([O:37][CH:38]3[CH2:43][CH2:42][N:41]([C:44](N4C=CN=C4)=[O:45])[CH2:40][CH2:39]3)[N:34]=[CH:33][N:32]=1)[CH2:26][CH2:25]2)(=[O:21])=[O:20])[CH3:18]>O>[CH2:17]([S:19]([C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([C:31]1[N:32]=[CH:33][N:34]=[C:35]([O:37][CH:38]3[CH2:39][CH2:40][N:41]([C:44]([O:5][CH:1]4[CH2:4][CH2:3][CH2:2]4)=[O:45])[CH2:42][CH2:43]3)[CH:36]=1)[CH2:26][CH2:25]2)(=[O:20])=[O:21])[CH3:18]
Reactant: OC1CCC1
Reactant: CCS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCN(C(=O)n3ccnc3)CC2)ncn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCN(C(=O)OC3CCC3)CC2)ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
Cyclobutanol (90 μL, 1.15 mmol) and potassium tert-butoxide (50 mg, 0.446 mmol) were added to a THF (2.5 mL) suspension of the 5-(ethylsulfonyl)-1-(6-{[1-(1H-imidazol-1-ylcarbonyl)piperidin-4-yl]oxy}pyrimidin-4-yl)indoline (109 mg, 0.226 mmol) produced in Reference Example 31, and the mixture was stirred at room temperature for 1 hour. To the reaction solution, water was added, followed by extraction with ethyl acetate three times. The obtained organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [(i) hexane:ethyl acetate=50:50, V/V; (ii) ethyl acetate]. The obtained crude product was washed with diisopropyl ether to obtain the title compound as white powder (34.6 mg, yield: 32%).
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.[OH:8][C@@H:9]1[CH2:13][N:12]([CH2:14][C:15]2[CH:16]=[C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)[C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[C:11](=[O:32])[CH2:10]1.O>ClCCl>[CH3:22][O:21][C:18]1[C:17]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)=[CH:16][C:15]([CH2:14][N:12]2[C:11](=[O:32])[CH2:10][C@H:9]([O:8][C:6](=[O:7])[NH2:5])[CH2:13]2)=[CH:20][CH:19]=1
Reactant: COc1ccc(CN2C[C@@H](O)CC2=O)cc1-c1cccc([N+](=O)[O-])c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CN2C[C@@H](OC(N)=O)CC2=O)cc1-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 20 mL vial with a stir bar was added chlorosulfonyl isocyanate (42 mg, 0.30 mmol), 1 mL dichloromethane, then P-248 (51.3 mg, 0.15 mmol) in 2 mL of dichloromethane. The reaction was stirred at room temperature for 18 hours after which 2 mL of water was added and the mixture was stirred at room temperature for 30 minutes. The layers were separated and the aqueous was extracted with dichloromethane. The combined organics were concentrated and then purified by preparative layer TLC using 50% acetone/dichloromethane to obtain P-253 (12.4 mg, 21%) as an off-white semi-solid. 1H NMR (400 MHz, DMSO-d6) 8.30 (s, 1H), 8.20 (dd, J=2.1, 8.6 Hz, 1H), 7.94 (d, J=7.8 Hz, 1H), 7.72 (t, J=8.0 Hz, 1H), 7.33-7.26 (m, 2H), 7.16 (d, J=9.0 Hz, 1H), 6.59 (br. s., 2H), 5.04 (t, J=5.8 Hz, 1H), 4.49-4.30 (m, 2H), 3.80 (s, 3H), 3.46-3.38 (m, 1H), 3.21 (d, J=11.4 Hz, 1H), 2.78 (dd, J=6.9, 17.5 Hz, 1H), 2.23 (d, J=18.1 Hz, 1H) ppm. LC/MS=100.0%, 386.1 (APCI+).
Reaction SMILES: O.CS[C:4]1[NH:9][C:8]2[CH:10]=[CH:11][N:12]=[CH:13][C:7]=2[S:6](=[O:15])(=[O:14])[N:5]=1.[CH2:16]([NH2:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].ClC1C=C(C)C=CC=1>>[CH2:16]([NH:24][C:4]1[NH:9][C:8]2[CH:10]=[CH:11][N:12]=[CH:13][C:7]=2[S:6](=[O:15])(=[O:14])[N:5]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CSC1=NS(=O)(=O)c2cnccc2N1
Reactant: CCCCCCCCN
Solvent: Cc1cccc(Cl)c1
Solvent: O
Product: CCCCCCCCNC1=NS(=O)(=O)c2cnccc2N1

Procedure:
A mixture of 3-methylsulfanyl-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide monohydrate (0.5 g), octylamine (0.5 mL) and m-chlorotoluene (3 mL) was refluxed for 2-3 h (until completion of the reaction; t.l.c.). Most of the solvents were removed by distillation and the residue was dispersed in a mixture of water (30 mL) and methanol (30 mL) and supplemented with NaOH 10% w/v in water (2 mL). The mixture was treated with charcoal, filtered, and the filtrate was adjusted to pH 6 with 1N HCl. The resulting precipitate was collected by filtration, washed with water and dried (yield: 0.29 g); m.p. 176°-179° C. (Compound 13).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([CH2:8][C:9]([C:11]1[CH:12]=[C:13]([CH2:19][CH:20]([CH2:26][CH3:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])=[O:10])=[O:7])[CH3:4].[F:28][C:29]([F:39])([F:38])[C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1.Cl>O1CCCC1>[CH2:3]([O:5][C:6]([CH:8]([CH2:34][C:33]1[CH:32]=[CH:31][C:30]([C:29]([F:28])([F:38])[F:39])=[CH:37][CH:36]=1)[C:9]([C:11]1[CH:12]=[C:13]([CH2:19][CH:20]([CH2:26][CH3:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])=[O:10])=[O:7])[CH3:4]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOC(=O)CC(=O)c1cc(CC(CC)C(=O)OCC)ccc1OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC)Cc1ccc(OC)c(C(=O)C(Cc2ccc(C(F)(F)F)cc2)C(=O)OCC)c1
Temperature: 25 °C
Yield: 98.5 %

Procedure:
Under an argon atmosphere, stirring and cooling with ice, sodium hydride (60% oil dispersion, 296 mg, 7.40 mmol) was added little by little to a solution of ethyl 3-[3-(2-ethoxycarbonylacetyl)-4-methoxyphenyl]-2-ethylpropanoate (2.59 g, 7.39 mmol) in anhydrous tetrahydrofuran (30 mL), and then the mixture was stirred for 20 minutes under cooling with ice and for 30 minutes at room temperature. Following this, a solution of 4-(trifluoromethyl)benzylbromide (1.77 g, 7.40 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise. After completion of the dropwise addition, the mixture was refluxed for 6 hours. After cooling, a mixture of 1 mol/L hydrochloric acid (15 mL) with ice water (100 mL) was added thereto, which was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (eluent n-hexane:ethyl acetate=8:1 v/v) to afford 3.70 g (98%) of the title compound as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10](=[O:12])[NH:9][C@H:8]3[CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][C@@H:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1.ClC1C2C(=O)N[C@@H]3CN(C(OC(C)(C)C)=O)C[C@H]3C=2C=CC=1.[H][H]>CO.C(O)(=O)C.[Pd]>[ClH:1].[CH2:15]1[C@H:7]2[C@@H:8]([NH:9][C:10](=[O:12])[C:11]3[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=32)[CH2:13][NH:14]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2NC(=O)c3c(Cl)cccc3[C@H]2C1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(C)(C)OC(=O)N1C[C@H]2NC(=O)c3c(Cl)cccc3[C@@H]2C1
Solvent: CC(=O)O
Solvent: CO
Product: Cl
Product: O=C1N[C@H]2CNC[C@@H]2c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (3aR,9bS)-tert-butyl 6-chloro-5-oxo-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate, the first eluting compound from Example 27, Part B (10 mg) in methanol was added 2 drops of acetic acid and 2 mg of 10% Pd/C catalyst. The mixture was shaken under 70 psi of hydrogen on a Parr shaker for 3 h. The mixture was filtered through a pad of Celite and concentrated in vacuo. The residue was taken up in 2 mL of methanol and then there was added 1 mL of 12 N HCl. The reaction was stirred at ambient temperature for 10 min and then was concentrated in vacuo at 60° C. to afford 7 mg of the title compound of Example 32 as an off-white solid. 1H NMR (CD3OD): 7.92 (d, 1H), 7.51 (app t, 1H), 7.39 (app t, 1H), 7.18 (d, 1H), 4.02-3.95 (m, 1H), 3.76-3.70 (m, 1H), 3.66-3.61 (m, 1H), 3.58-3.52 (m, 1H), 3.41-3.30 (overlapping m, 2H). LRMS (ESI): 189 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:11][CH:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[F:20])[CH2:9]2)[N:5]=[C:4]([CH3:21])[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([NH:37][CH3:38])=[O:36]>C(O)(C)C>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH:10]2[CH2:11][N:8]([C:6]3[N:5]=[C:4]([CH3:21])[N:3]=[C:2]([NH:31][C:32]4[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=4)[C:35]([NH:37][CH3:38])=[O:36])[N:7]=3)[CH2:9]2)=[C:14]([F:20])[CH:15]=1
Reactant: CNC(=O)c1cccc(N)c1
Reactant: Cc1nc(Cl)nc(N2CC(Oc3ccc(Cl)cc3F)C2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CNC(=O)c1cccc(Nc2nc(C)nc(N3CC(Oc4ccc(Cl)cc4F)C3)n2)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 4.2 %

Procedure:
To a solution of 2-chloro-4-(3-(4-chloro-2-fluorophenoxy)azetidin-1-yl)-6-methyl-1,3,5-triazine (1.0 g, 3.04 mmol) in Isopropanol (10 mL) was added DIPEA (0.8 mL) and 3-amino-N-methylbenzamide (0.460 g, 3.04 mmol) and the reaction mixture was stirred at 80° C. for 24 h. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2×40 mL) and water (2×40 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided 3-((4-(3-(4-chloro-2-fluorophenoxy) azetidin-1-yl)-6-methyl-1,3,5-triazin-2-yl)amino)-N-methylbenzamide (0.057 g, 6%) as a solid. Observed mass (M+1): 443.1.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].C(Cl)(Cl)Cl.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>C(OCC)(=O)C>[Br:1][CH2:2][C:3]([N:20]1[CH2:19][CH2:18][N:17]([C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[CH2:22][CH2:21]1)=[O:4]
Reactant: O=C(Br)CBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CBr)CC1
Reaction time: 0.5 h

Procedure:
With cooling with ice, bromoacetyl bromide (680 μL) was added to a chloroform (10 ml) solution of 1-tert-butyloxycarbonylpiperazine (1 g) and triethylamine (2.2 mL). At that temperature, this was stirred for 0.5 hours, and then at room temperature for further 0.5 hours. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=7/3) to obtain 340 mg of the entitled compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][CH2:5][CH2:6][N+:7]([O-:9])=O.[C:11]([O:15][CH3:16])(=[O:14])[CH:12]=[CH2:13].C(N(CC)CC)C.C1(N=C=O)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:16][O:15][C:11](=[O:14])[CH2:12][CH2:13][C:6]1[CH2:5][CH:4]([C:3]([O:2][CH3:1])=[O:10])[O:9][N:7]=1
Reactant: C=CC(=O)OC
Reactant: COC(=O)CCC[N+](=O)[O-]
Solvent: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)CCC1=NOC(C(=O)OC)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 23.8 g of 4-nitrobutyric acid methyl ester (made in accordance with Bruson, U.S. Pat. No. 2,342,119) 39.6 g of methyl acrylate, 0.2 g triethyl amine in 200 ml of toluene is stirred and treated dropwise with 23.8 g of phenyl isocyanate. The mixture is stirred for 72 hours at room temperature and heated at 90° C. for two hours. The mixture is cooled, filtered to remove the diphyl urea, and concentrated under reduced pressure. The resulting oil is chromatographed on SiO2 (elution with hexane:ethyl-acetate; 75:25) to yield 4,5-dihydro-5-(methoxycarbonyl)-3-isoxazolepropanoic acid methyl ester as a colorless oil. NMR (CDCl3) and 4.93 (t, J=9 Hz, 1H), 3.72 (s, 3H), 3.63 (s, 3H), 3.20 (d, J-9 Hz, 2H), 2.61 (s, 4H). IR (KBr) 2956, 2851, 1739, 1632, 1439, 1367, 1340, 1215. IR (cm-1).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[CH:25]=[N:24][C:23]([CH2:26][NH:27][CH3:28])=[CH:22][N:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[CH3:30][O:31][C:32](Cl)=[O:33].C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[N:21]=[CH:22][C:23]([CH2:26][N:27]([CH3:28])[C:32](=[O:33])[O:31][CH3:30])=[N:24][CH:25]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CNCc1cnc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)cn1
Reactant: COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)N(C)Cc1cnc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)cn1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
To a cold (5° C.) solution of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-({5-[(methylamino)methyl]pyrazin-2-yl}methyl)pyridin-2(1H)-one (0.20 g, 0.4 mmol) in DMF (2.0 ml), was added methylchloroformate (0.049 g, 0.52 mmol), followed by the addition of triethylamine (0.072 g, 0.71 mmol). The mixture was stirred at 5° C. for 30 min and at room temperature for an additional 30 min and concentrated in vacuo. The residue was partitioned between water (5.0 mL) and EtOAc (10.0 mL). The organic extract was washed with water, dried (Na2SO4), and concentrated to dryness. The resulting material was purified by reverse-phase HPLC using 10-90% CH3CN/Water gradient (60 min) at a flow rate of 70 mL/min. The appropriate fractions (m/z=523 M+H) were combined and freeze dried to give a white powder. This was partitioned between 5% NaHCO3 (10 mL) and EtOAc (15 mL). The organic layer was washed with water, dried (Na2SO4), and concentrated to dryness to afford the title compound (0.12 g, 53%) as a white powder: 1H NMR (CD3OD/400 MHz) δ 8.59 (s, 1H), 8.41 (m, 1H), 7.60 (m, 1H), 7.05 (m, 2H), 6.52 (s, 1H), 5.45 (s, 2H), 5.29 (s, 2H), 4.58 (s, 2H), 3.69 and 3.64 (s, 3H), 2.97 (s, 3H), 2.85 (s, 3H), and 2.55 (s, 3H); 19F NMR(CD3OD/400 MHz) −111.69 (m) and −116.09 (m); ES-HRMS m/z 523.0775(M+H calcd for C22H22BrF2N4O4 requires 523.0787).
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]([CH2:44][CH2:45][O:46][CH3:47])[CH3:43])=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][N:42]([CH2:44][CH2:45][O:46][CH3:47])[CH3:43])=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: COCCN(C)C(=O)CCl
Product: CCN(Cc1ccc(OCCN(C)CCOC)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 33.4 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-N-(2-methoxyethyl)-N-methylacetamide (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (6.9 mg) was obtained.
Reaction SMILES: ClC1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[NH:9][CH3:10].Cl[C:12]([Cl:22])(OC(=O)OC(Cl)(Cl)Cl)Cl.C1C[O:26][CH2:25]C1>>[Cl:22][C:12]1[N:7]=[CH:6][N:5]=[C:4]2[C:3]=1[N:9]([CH3:10])[C:25](=[O:26])[NH:8]2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CNc1c(N)ncnc1Cl
Reactant: C1CCOC1
Product: Cn1c(=O)[nH]c2ncnc(Cl)c21
Temperature: 0 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
Add 6-chloro-N5-methyl-pyrimidine-4,5-diamine (0.41 g, 0.0025 mol) to THF (12.3 mL). Cool to 0° C., add TEA (0.51 g; 0.005 mol), triphosgene (0.92 g; 0.0031 mol) and stir at RT for 1 h. Quench with water and extract with EA. Evaporate the organic layer to give the title compound (0.2 g; 42%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:6][C:5]2=[O:18].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br.[CH3:28][NH:29][CH3:30]>>[CH3:28][N:29]([CH3:30])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:6][C:5](=[O:18])[C:4]=2[CH:3]=1
Reactant: BrCCCCCCCBr
Reactant: CNC
Reactant: O=c1cc(-c2ccccc2)oc2ccc(O)cc12
Product: CN(C)CCCCCCCOc1ccc2oc(-c3ccccc3)cc(=O)c2c1

Procedure:
The compound was prepared by a method similar to Example 2 from 6-hydroxyflavone, 1,7-dibromoheptane and dimethylamine: mp 90°-91° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:22][CH:23]=[C:24](C)[CH3:25])[CH:9]2[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([OH:21])[CH:14]=2)=[CH:4][C:3]=1[O:27][CH3:28].F[C:30](F)(F)C(O)=O>O=[V].Cl.Cl.Cl.C(Cl)Cl>[OH:1][C:2]1[C:11]2=[C:10]3[CH:9]([CH2:12][C:13]4[CH:14]=[C:15]([OH:21])[C:16]([O:19][CH3:20])=[CH:17][C:18]=42)[N:8]([CH2:22][C:23]([CH3:30])=[CH:24][CH3:25])[CH2:7][CH2:6][C:5]3=[CH:4][C:3]=1[O:27][CH3:28]
Reactant: COc1ccc(CC2c3cc(O)c(OC)cc3CCN2CC=C(C)C)cc1O
Reactant: O=C(O)C(F)(F)F
Agent: O=[V]
Agent: Cl
Solvent: ClCCl
Product: CC=C(C)CN1CCc2cc(OC)c(O)c3c2C1Cc1cc(O)c(OC)cc1-3

Procedure:
6.49 g. (16.9 mmol) (-)-7-Hydroxy-1-(3-hydroxy-4-methoxybenzyl)-6-methoxy-2-(3-methylbut-2-enyl)-1,2,3,4-tetrahydroisoquinoline are then reacted in 55 ml. trifluoroacetic acid and 55 ml. anhydrous methylene chloride with 2.3 ml. (4.23 g., 24.4 mmol) vanadium oxytrichloride at -10° C. in a manner analogous to that described in Example 1. The (+)-5,6,6a,7-tetrahydro-1,9-dihydroxy-2,10-dimethoxy-6-(2-methylbut-2-enyl)-4H-dibenzo(de,g)quinoline obtained upon working up can, without further purification, be used in the subsequent methylation.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Cl:7][C:8]1[CH:9]=[C:10](B(O)O)[CH:11]=[CH:12][CH:13]=1>>[Cl:7][C:8]1[CH:13]=[C:12]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Brc1cccs1
Product: Clc1cccc(-c2cccs2)c1

Procedure:
2-Bromothiophene and 3-chlorophenylboronic acid were treated in a manner similar to Reference Example 26-(2) to give 2-(3-chlorophenyl)thiophene as colorless oil.
Reaction SMILES: [OH:1][CH:2]([CH2:5][O:6][CH3:7])[C:3]#[N:4].ClCCl.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>O>[C:3]([CH:2]([O:1][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:5][O:6][CH3:7])#[N:4]
Reactant: COCC(O)C#N
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COCC(C#N)OS(C)(=O)=O

Procedure:
27.3 gr (0.27 Mol) of 2-hydroxy-3-methoxy-propionitrile was dissolved dichloromethane (250 ml) and treated first with 56.4 ml (0.40 Mol) triethylamine keeping the temperature below −8° C., followed by dropwise addition of 23.1 ml (0.297 mol) methansulfonyl chloride keeping the temperature below +7° C. under cooling. After the exothermic reaction ceased the mixture was left to reach room-temperature. Water was stirred in, and the mixture was extracted with tert.-butylmethylether, washed with brine, dried and evaporated. To remove some polar side-products the crude liquid obtained was filtered through silica gel (eluent: cyclohexane/ethylacetate 1:1). Methanesulfonic acid 1-cyano-2-methoxy-ethyl ester of 89% purity (GC-MS) was obtained; 1H-NMR (CDCl3): 5.33, t, 1H, 3.81, d, 2H, 3.48, s, 3H, 3.21, s, 3H.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10](OC)[CH:11]=2)[NH:6][CH:5]=1.[CH3:15][O:16]C1C=C2C(C=CN2)=CC=1>>[Br:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([O:16][CH3:15])=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: COc1ccc2cc[nH]c2c1
Reactant: COc1ccc2[nH]cc(CCBr)c2c1
Product: COc1ccc2c(CCBr)c[nH]c2c1

Procedure:
The title compound was synthesized according to above mentioned procedure for 3-(2-bromoethyl)-5-methoxy-1H-indole, starting with 6-methoxyindole yielding a brown oil which was stored in the freezer. LC-MS conditions B: tR=0.81 min, [M+H]+=254.13.
Reaction SMILES: ClCCl.[C:4]1([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(N(CC)CC)C>[CH3:22][S:23]([O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:25])=[O:24]
Reactant: OCCCCCCCCCCCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCCCCCCCCc1ccccc1

Procedure:
To a mixture of 750 ml. of dichloromethane, 37.2 g. of 11-phenyl-1-undecanol (prepared as described in Example 6) and 32 ml. of triethylamine cooled in an ice-salt bath to -10° C. is added dropwise, over 15 minutes, 13.2 ml. of methanesulfonyl chloride. The mixture is cooled at -10° C. to -15° C. for 30 minutes and then washed with 300 ml. of cold water, 300 ml. of cold 10% hydrochloric acid, 300 ml. of cold 5% sodium carbonate and with 200 ml. of cold, saturated, sodium chloride solution. The organic layer is dried over magnesium sulfate and concentrated in vacuo to give a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].S(=O)(=O)(O)O.[CH3:18]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:18])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: O=C(O)Cc1ccc(O)c(O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(O)c(O)c1

Procedure:
3,4-Dihydroxyphenylacetic acid is refluxed in methanol in the presence of sulfuric acid, to give methyl 2-(3,4-dihydroxyphenyl)acetate.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([O:23][CH3:24])[C:11](=[O:22])[N:12]([CH3:21])[C:13]=3[C:17]([O:19]C)=[O:18])[C:8]2=[O:25])=[CH:4][CH:3]=1.[Li+].[OH-]>CO.O>[F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([O:23][CH3:24])[C:11](=[O:22])[N:12]([CH3:21])[C:13]=3[C:17]([OH:19])=[O:18])[C:8]2=[O:25])=[CH:4][CH:3]=1
Reactant: COC(=O)c1c2c(c(OC)c(=O)n1C)C(=O)N(Cc1ccc(F)cc1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1c2c(c(C(=O)O)n(C)c1=O)CCN(Cc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 6-(4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate (0.575 g, 1.536 mmol) in methanol was added LiOH (0.11 g, 4.61 mmol) in water. The reaction mixture was heated to reflux. After 0.5 hours, the product mixture cooled to room temperature and concentrated under vacuum. The residual material was partitioned between EtOAc and 1 N HCl. The organic extract was washed with brine, dried with Na2SO4, filtered, and concentrated under vacuum to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:20][C:21]4[NH:26][CH2:25][CH2:24][O:23][C:22]=4[N:27]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:20][C:21]4[N:26]([S:43]([CH3:42])(=[O:45])=[O:44])[CH2:25][CH2:24][O:23][C:22]=4[N:27]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NCCO4)cc2)CCC1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(S(C)(=O)=O)CCO4)cc2)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a solution of tert-butyl(1-(4-(7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (50 mg, 0.11 mmol) in dry DCM (1 ml) was added triethyl amine (46 μl, 0.33 mmol) and methanesulfonyl chloride (26 μl, 0.33 mmol) under nitrogen. The resulting mixture was stirred for 1 hour at room temperature. A saturated solution of NaHCO3 was added and the mixture was extracted with dichloromethane (3×10 ml) using a phase separator (Isolute® SPE). The combined organic phases were concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 50% EtOAc in cyclohexane) to give the title compound (45 mg, 77%). 1H NMR (500 MHz, CDCl3): 8.00 (1H, s), 7.25 (2H, d), 7.19-7.17 (5H, m), 7.11-7.10 (2H, m), 4.95 (1H, s), 4.43 (2H, t), 3.90 (2H, t), 2.55-2.25 (7H, m), 2.06-1.98 (1H, m), 1.82-1.73 (1H, m), 1.44-1.15 (9H, br).