Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:17])([CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=2[S:21](=[O:35])(=[O:34])[N:20]=1.[ClH:36]>O1CCOCC1>[Cl:36][C:14]([CH3:15])([CH3:16])[CH2:13][CH2:12][C:5]1([CH3:17])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([OH:1])=[C:3]([C:19]2[NH:24][C:23]3[CH:25]=[CH:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=3[S:21](=[O:35])(=[O:34])[N:20]=2)[C:4]1=[O:18]
Reactant: Cl
Reactant: CC(C)=CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Solvent: C1COCCO1
Product: CC(C)(Cl)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21

Procedure:
To a solution of Example 139 (40 mg, 0.078 mmol) in dioxane (3 mL) was added a solution of 6N aqueous hydrochloric acid (3 mL). The mixture was heated at 65 C for 3 hours, and the solvent removed in vacuo. The resultant residue was purified by reverse phase preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile/0.1% trifluoroacetic acid in water over 8 minutes (10 minutes run time) at a flow rate of 40 mL/min to provide the title (4 mg, 9%). MS (ESI) m/z=550 (M−H)+. 1H NMR (300 MHz, DMSO-d6): δ 0.96 (m, 1H), 1.24 (m, 1H), 1.40 (s, 3H), 1.42 (s, 3H), 1.60 (s, 3H), 2.29 (m, 1H), 2.42 (m, 1H), 3.08 (s, 3H), 7.56 (m, 3H), 7.73 (m, 3H), 8.16 (d, J=7.4 Hz, 1H), 10.24 (s, 1H), 13.81 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[CH:18][C:11]=12)[NH2:5].Cl[C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:23]=[C:22]([NH2:30])[N:21]=1.[OH-].[Na+].CO>O.Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:27])[F:28])[N:23]=[C:22]([NH2:30])[N:21]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[CH:18][C:11]=12
Reactant: Nc1ccc(Cc2ccnc3[nH]ccc23)c(F)c1
Reactant: Nc1nc(Cl)cc(C(F)(F)F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1nc(Nc2ccc(Cc3ccnc4[nH]ccc34)c(F)c2)cc(C(F)(F)F)n1

Procedure:
32 mg (0.11 mmol) of 3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)aniline and 26 mg (0.12 mmol) of 4-chloro-6-(trifluoromethyl)pyrimidine-2-amine are suspended in 5 ml of water and 0.07 ml of 2N hydrochloric acid. The reaction mixture is heated at reflux for 20 hours. After cooling, the mixture is made alkaline using dilute aqueous sodium hydroxide solution, a little methanol is added and the mixture is extracted with ethyl acetate. The extract is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2.[CH3:15][C:16]1[O:20][N:19]=[C:18]([C:21]2[CH:26]=[C:25]([CH3:27])[C:24](O)=[C:23]([CH3:29])[CH:22]=2)[N:17]=1.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:15][C:16]1[O:20][N:19]=[C:18]([C:21]2[CH:22]=[C:23]([CH3:29])[C:24]([O:1][CH2:2][CH2:3][CH2:4][C:5]3[CH:6]=[N:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)=[C:25]([CH3:27])[CH:26]=2)[N:17]=1
Reactant: Cc1nc(-c2cc(C)c(O)c(C)c2)no1
Reactant: OCCCc1cnc2ccccc2c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(-c2cc(C)c(OCCCc3cnc4ccccc4c3)c(C)c2)no1
Reaction time: 8 h
Yield: 72.7 %

Procedure:
A mixture of 3-(3-hydroxypropyl)-quinoline (250 mg, 1.34 mmol), 4-(5-methyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenol (273 mg, 1.34 mmol), and DEAD (256 mg, 1.47 mmol) was dissolved in 12 ml of THF. To the above solution was added triphenylphosphine (385 mg, 1.47 mmol) at 20° C. and the mixture was stirred overnight. The solvent was removed in vacuo, and the residue was partitioned between an aqueous sodium bicarbonate solution and methylene chloride. The aqueous layer was extracted with methylene chloride (3×) and the organic layer dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography (20 cm column, ethyl acetate/hexane, from 1/5 to 1/3) to afford 364 mg (73%) of 3-[3-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]-propyl]-quinoline, m.p. 105°-107° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:6]([S:8]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([O:16][CH3:17])=[O:15])(=[O:10])=[O:9])[CH:7]=1)=O.CO.[CH3:29][NH2:30].[BH4-].[Na+]>>[CH3:29][NH:30][CH2:1][C:3]1[CH:4]=[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:6]([S:8]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([O:16][CH3:17])=[O:15])(=[O:10])=[O:9])[CH:7]=1
Reactant: CN
Reactant: COC(=O)c1cccc(S(=O)(=O)n2cc(C=O)cc2-c2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(C(=O)OC)c2)c1
Yield: 48.6 %

Procedure:
Using methyl 3-[(4-formyl-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzoate (1.32 g), 40% methylamine methanol solution (416 mg) and sodium borohydride (100 mg), a procedure as in Reference Example 145 was performed to give the title compound as a pale-yellow oil (yield 668 mg, 49%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12]1([P:18]([O:21]C)[O:19][CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCOC(C)=O>[CH3:20][O:19][P:18]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:21]
Reactant: COP(OC)c1ccccc1
Reactant: COC(=O)c1ccc(Br)cc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(P(=O)(OC)c2ccccc2)cc1
Temperature: 160 °C

Procedure:
From a related procedure (Helv. Chim. Acta, 2004, 87, 825) a mixture of methyl 4-bromobenzoate (676 mg, 3.14 mmol), anhydrous NiBr2 (34.3 mg, 0.157 mmol), and PhP(OMe)2 (0.500 mL, 3.14 mmol) was added to a pressure vessel and heated to 160° C. (oil bath temperature) for 2 h. The reaction was cooled, diluted with EtOAc and washed with water (3×), brine, dried (MgSO4) and concentrated to afford ˜800 mg of a clear, colorless oil that solidified upon standing. The product was purified by MPLC (15-50% EtOAc in CH2Cl2) to afford the requisite product: MS: cal'd 291 (MH+), exp 291 (MH+).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:44])[CH2:30][CH2:31][CH2:32][N:33]([C:41](=[O:43])[CH3:42])[C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=1>>[CH3:44][N:29]([CH3:28])[CH2:30][CH2:31][CH2:32][N:33]([C:34]1[CH:39]=[CH:38][C:37]([NH:40]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:36][CH:35]=1)[C:41](=[O:43])[CH3:42]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CC(=O)N(CCCN(C)C)c1ccc(N)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(CCCN(C)C)C(C)=O)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-(3-dimethylamino-propyl)-N-acetyl-p-phenylenediamine Rf value: 0.5 (aluminium oxide, methylene chloride/methanol=20:1) C30H32N4O4
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C([Li])CCC.[Cl:24][C:25]1[CH:36]=[CH:35][C:28]([C:29](N(OC)C)=[O:30])=[CH:27][C:26]=1[S:37](=[O:40])(=[O:39])[NH2:38]>O1CCCC1>[C:13]([Si:10]([CH3:12])([CH3:11])[O:9][CH2:8][CH2:7][O:6][C:5]1[CH:17]=[CH:18][C:2]([C:29]([C:28]2[CH:35]=[CH:36][C:25]([Cl:24])=[C:26]([S:37]([NH2:38])(=[O:39])=[O:40])[CH:27]=2)=[O:30])=[CH:3][CH:4]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CON(C)C(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1
Temperature: -78 °C
Reaction time: 18 h
Yield: 53.1 %

Procedure:
[2-(4-Bromo-phenoxy)-ethoxy]tert-butyl-dimethyl-silane (7.3 g, 22.12 mmol) is dissolved in tetrahydrofuran (120 mL) and cooled to −78° C. The solution is treated with a solution of n-butyllithium (1.6 M in hexanes, 13.8 mL, 22.12 mmol) and stirred 30 minutes after which a solution of 4-chloro-N-methoxy-N-methyl-3-sulfamoyl-benzamide (2.05 g, 7.37 mmol) in tetrahydrofuran (20 mL) is added. The reaction is allowed to stir for 18 hours while warming to ambient temperature. The reaction is quenched with a saturated solution of ammonium chloride and extracted twice with ether. The organic phase is separated and concentrated in vacuo. The residue is purified by column chromatography (gradient of ethyl acetate in hexanes 10-50%) affording 1.84 g (53% yield) of the title compound. MS (m/z): 470.2 (M+1).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([C:41]([F:44])([F:43])[F:42])[CH:34]=1>CN(C=O)C>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([C:41]([F:42])([F:43])[F:44])[CH:34]=3)[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: COc1ccc(CBr)cc1C(F)(F)F
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(CN2CCC(N(C3CC3)S(=O)(=O)c3cccc(C(F)(F)F)c3)CC2)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 12 h
Yield: 79.8 %

Procedure:
N-Cyclopropyl-N-piperidin-4-yl-3-trifluoromethylbenzenesulfonamide (200 mg, 0.57 mmol) was dissolved in DMF (4 mL) and triethylamine (200 μL, 1.43 mmol) added, followed by 4-bromomethyl-1-methoxy-2-trifluoromethyl-benzene (154 mg, 0.57 mmol). The reaction mixture was stirred for 12 hours at 80° C. and then the solvent was evaporated. The residue was purified by flash chromatography to give 244 mg of the title compound 18 as a yellow solid. 1H NMR (CDCl3): δ 8.14-8.11 (m, 1H), 8.07-8.03 (m, 1H), 7.86-7.80 (m, 1H), 7.70-7.64 (m, 1H), 7.50-7.47 (m, 1H), 7.42-7.37 (m, 1H), 6.96-6.91 (m, 1H), 3.93-3.79 (m, 4H), 3.42 (s, 2H), 2.91-2.80 (m, 2H), 2.03-1.85 (m, m, 5H), 1.53-1.44 (m, 2H), 1.02-0.96 (m, 2H), 0.83-0.76 (m, 2H). LC: 100%. MS (EI): m/z 537 (M+H+).
Reaction SMILES: C([O:8][C:9](=[O:24])[C@H:10]([O:15][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1)[CH2:11][CH:12]([CH3:14])[CH3:13])C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[C:16]([O:15][C@H:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:9]([OH:24])=[O:8])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1
Reactant: [H][H]
Reactant: CC(C)C[C@@H](OC(=O)c1cccnc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)C[C@@H](OC(=O)c1cccnc1)C(=O)O

Procedure:
A total of 17.8 g of nicotinoyl chloride hydrochloride was dissolved in 150 ml of pyridine and 50 ml of dimethylfromamide and the solution treated slowly with stirring at a temperature not over 15° with 22.2 g of benzyl-(R)-α-hydroxy-isovalerate (prepared from (R)-2-hydroxy-isovaleric acid and benzyl chloride in a manner analogous to that described, for the preparation of the corresponding compound in Example 1). After stirring for 2 hours at room temperature, the mixture was evaporated under reduced pressure. The residue was taken up in ether, washed three times with water and extracted six times with ice-cold 3-N hydrochloric acid. The hydrochloride phases were immediately allowed to run into saturated sodium bicarbonate solution and the base which was thus released was extracted three times with ether. After washing and drying, it was evaporated under reduced pressure and there were obtained 27 g of a resin which contained benzyl-(R)-2-(nicotinoyloxy)-isocaproate. The resin was then hydrogenated in 200 ml. of ethanol with 2 g. of 5 percent palladium-on-charcoal unit 2 equivalents of hydrogen had been taken up. After filtration and evaporation, the residue was taken up in 10 percent potassium bicarbonate, washed twice with ether and adjusted to pH 3 with citric acid. After extraction with ether, washing, drying and evaporation of the extract, there was obtained a crystallizing oil. Recrystallization from ethyl acetate/petroleum ether yielded 14 g of (R)-2-(nicotinoyloxy)-isocaproic acid; mp 101°-103°; [α]D25 = + 18.8° (c = 1.0 in methanol).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[C:6](=[O:15])[CH:5]=[CH:4][C:3]=1[C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.[CH:25]1([O:30][C:31](=[O:41])[C@H:32]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[NH2:33])[CH2:29][CH2:28][CH2:27][CH2:26]1.N#N.[BH3-]C#N.[Na+]>CO.CC(O)=O>[NH2:1][C:2]1[N:7]([CH:8]2[CH2:13][CH2:12][CH:11]([NH:33][C@@H:32]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:31]([O:30][CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29]3)=[O:41])[CH2:10][CH2:9]2)[C:6](=[O:15])[CH:5]=[CH:4][C:3]=1[C:16](=[O:24])[C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OC1CCCC1
Reactant: Nc1c(C(=O)c2ccc(F)cc2)ccc(=O)n1C1CCC(=O)CC1
Agent: N#N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1c(C(=O)c2ccc(F)cc2)ccc(=O)n1C1CCC(N[C@@H](Cc2ccccc2)C(=O)OC2CCCC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Intermediate 6 (50 mg, 0.15 mmol) was added to a colourless solution of L-phenylalanine cyclopentyl ester (89 mg, 0.38 mmol) in MeOH (10 ml) at RT/N2 and stirred at RT for 1 h. AcOH glacial was added dropwise to adjust the pH to 6 followed by the NaCNBH3 (38 mg, 0.61 mmol). The resultant colourless solution was stirred at RT overnight and then carefully quenched with sat. NaHCO3 (20 ml) and extracted into CH2Cl2 (3×15 ml). The combined organic phases were washed with 2M HCl (2×20 ml), brine (20 ml), dried (Na2SO4), filtered and concentrated in vacuo giving a cream coloured solid. Purification by flash column chromatography (silica, gradient elution 40-100% EtOAc/heptane) gave the desired material, separable as two isomers, isomer 1 (Example 34) as a white solid (Yield=39 mg, 47%) LCMS purity 100%, m/z 546 [M+H]+, 1H NMR (400 MHz, CD3OD), δ: 1.40-2.05 (16H, m), 2.85-3.10 (3H, m), 3.60-3.70 (1H, m), 4.55-4.65 (1H, m), 5.10-5.20 (1H, m), 5.70 (1H, d), 7.15-7.40 (7H, m), 7.45-7.50 (1H, m), 7.50-7.60 (2H, m) and isomer 2 (Example 35) LCMS purity 97%, m/z 546 [M+H]+, 1H NMR (400 MHz, CD3OD), δ: 1.25-1.85 (12H, m), 1.95-2.20 (2H, m), 2.45-2.95 (4H, m), 3.00-3.10 (1H, m), 3.65-3.75 (1H, m), 4.55-4.65 (1H, m), 5.05-5.15 (1H, m), 5.65 (1H, d), 7.20-7.35 (7H, m), 7.40-7.50 (1H, m), 7.50-7.60 (2H, m) as a colourless film (Yield=15 mg, 18%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[C:18]([CH:20]=O)[CH:17]=[CH:16][C:5]=1[O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[O:12])=[CH:9][N:8]=1)[CH3:2].[CH2:22]([NH2:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4]1[CH:19]=[C:18]([CH2:20][NH:30][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:17]=[CH:16][C:5]=1[O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[O:12])=[CH:9][N:8]=1)[CH3:2]
Reactant: CCOc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Reactant: NCCc1ccccc1
Product: CCOc1cc(CNCCc2ccccc2)ccc1Oc1ccc(C(N)=O)cn1
Yield: 99 %

Procedure:
The compound of example 224 step 1 was reductively aminated with phenethylamine using procedures similarly to those previously described to afford the title compound in 99% yield.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][C@H:18]1[CH2:20][O:19]1)[N:12]=[CH:11][CH:10]=[C:9]2[O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[O:30])=[C:24]([F:39])[CH:23]=1)#[N:5]>O1CCCC1>[C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][C@H:18]([OH:19])[CH2:20][N:2]([CH3:3])[CH3:1])[N:12]=[CH:11][CH:10]=[C:9]2[O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)=[O:30])=[C:24]([F:39])[CH:23]=1)#[N:5]
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)ccnc2cc1OC[C@H]1CO1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)C[C@@H](O)COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)c2cc1C#N

Procedure:
After adding tetrahydrofuran (0.5 ml) and a dimethylamine-2N tetrahydrofuran solution (Aldrich, 0.2 ml) to N-(4-{6-cyano-7-[(2R)-oxiran-2-yl]methoxyquinolin-4-yloxy}-2-fluorophenyl)-N′-(4-fluorophenyl)urea (40 mg), the mixture was stirred overnight at room temperature. The reaction solution was purified by NH silica gel column chromatography (ethyl acetate-methanol system) to obtain the title compound (45 mg) as light yellow crystals.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([O:12][C:13]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1)[CH2:9][CH2:10][CH3:11]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([O:12][C:13]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][NH:15][CH2:14]1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOC1(c2ccccc2)CN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCOC1(c2ccccc2)CNC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
1 ml of trifluoroacetic acid is added to a solution containing 500 mg (1.64 mmol) of 3-butoxy-3-phenyl-1-(tert-butoxycarbonyl)azetidine dissolved in 5 ml of dichloromethane. The reaction medium is stirred at ambient temperature for 3 hours and then concentrated. The crude product obtained is purified by silica gel chromatography (eluent 90/10 dichloromethane/methanol). 400 mg in the form of a pale yellow powder are obtained with a yield of 76%.
Reaction SMILES: [O:1]=[C:2]1[NH:15][CH:14]=[C:5]2[S:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[NH:9][C:4]2=[C:3]1[C:16]#[N:17].C(O)(=O)C.[Br:22]Br>C(Cl)(Cl)(Cl)Cl>[Br:22][C:12]1[CH:11]=[CH:10][C:8]2[NH:9][C:4]3[C:5](=[CH:14][NH:15][C:2](=[O:1])[C:3]=3[C:16]#[N:17])[S:6][C:7]=2[CH:13]=1
Reactant: BrBr
Reactant: N#Cc1c2c(c[nH]c1=O)Sc1ccccc1N2
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: N#Cc1c2c(c[nH]c1=O)Sc1cc(Br)ccc1N2

Procedure:
To a solution of 20 parts of 2,3-dihydro-3-oxo-5H-pyrido[3,4-b][1,4]benzothiazine-4-carbonitrile in 1575 parts of glacial acetic acid is added a solution of 34 parts of bromine in 320 parts of carbon tetrachloride. The resultant mixture is heated at the boiling point under reflux for 23/4 hours, then chilled. The precipitate which forms is filtered off and recrystallized from N,N-dimethylformamide to give 8-bromo-2,3-dihydro-3-oxo-5H-pyrido[3,4-b][1,4]benzothiazine-4-carbonitrile melting above 305°.
Reaction SMILES: C(O)(C)C.[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14](=O)[C:15](OC)=[O:16])=[CH:6]1.[BH4-].[Na+]>O>[OH:16][CH2:15][CH2:14][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:5][CH:6]=1
Reactant: COC(=O)C(=O)c1c[nH]c2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: OCCc1c[nH]c2ccccc12

Procedure:
A vigorously-stirred mixture of isopropanol (3 1), methyl 3- indolylglyoxylate (305 g) and sodium borohydride (125 g) was warmed to 40° - 50° and held at that temperature until the initial exothermic reaction was complete. The mixture was then heated to reflux for 4 hours, cooled and diluted with water (5 l). After acidification with hydrochloric acid the product was extracted into dichloromethane. The separated extract was washed with sodium carbonate solution to remove 3-indolylacetic acid and then with water. Evaporation of the solvent gave the crude product as a brown oil. This was distilled at 0.5 - 1 mm pressure (vapour temperature 160° - 190° ) and crystallised from toluene (1 l) to give the title compound as white to pale brown crystals m.p. 57° - 59°. Yield 170 g. (70% of theory).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:21][CH2:20][C:11]2[C:12]3[C:17](Cl)=[N:16][CH:15]=[N:14][C:13]=3[S:19][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([O:30][CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH:24]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:21][CH2:20][C:11]2[C:12]3[C:17]([NH:27][C:26]4[CH:28]=[CH:29][C:23]([F:22])=[CH:24][C:25]=4[O:30][CH:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[N:16][CH:15]=[N:14][C:13]=3[S:19][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Reactant: Nc1ccc(F)cc1OC1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Nc4ccc(F)cc4OC4CCOCC4)c23)C1
Temperature: 120 °C
Yield: 19.5 %

Procedure:
A solution of 4-chloro-5,8-dihydro-6H-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (prepared according to WO2007/109279, 0.141 g, 0.43 mmol), 4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)aniline (0.092 g, 0.44 mmol) and para-toluene sulfonic acid (0.08 g, 0.04 mmol) in 1,4-dioxane (2 mL) was purged with nitrogen and then heated at 120° C. for 5 hours. The reaction mixture was diluted with EtOAc, washed with 10% aqueous K2CO3 and brine. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (100% iso-hexane→66% iso-hexane/EtOAc→100% EtOAc) followed by trituration with MeOH afforded the title compound as white solid (0.042 g, 20%).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([C:16]2[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=2[C:18](O)=[O:19])=[O:15])=[C:6]1[CH3:25])[CH2:2][CH2:3][CH3:4].[CH3:26][N:27]([CH3:37])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]([CH3:36])[CH3:35])[CH:29]=1.C(OC(=O)C)(=O)C.[OH-].[Na+]>O>[CH3:35][N:34]([CH3:36])[C:30]1[CH:29]=[C:28]([N:27]([CH3:37])[CH3:26])[CH:33]=[CH:32][C:31]=1[C:14]1([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]=2[CH3:25])[C:16]2[C:17](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:18](=[O:19])[O:15]1
Reactant: CCCCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Reactant: CN(C)c1cccc(N(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCCCn1c(C)c(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3ccccc32)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3.35 g (0.01 mole) of 2-[(1-n-butyl-2-methyl-3-indolyl)carbonyl]benzoic acid, prepared as described in part A above, 1.80 g (0.011 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine and five ml of acetic anhydride was stirred at ambient temperature for a period of approximately 18 hours. The reaction mixture was then poured into a mixture of 40 ml of water, 40 ml of ligroin and 20 ml of 10 percent aqueous sodium hydroxide. The ligroin layer was separated and the white crystals which separated from the solution on standing, were collected by filtration and dried to obtain 3-[2,4-bis(dimethylamino)phenyl]-3-(1-n-butyl-2-methyl-3-indolyl)phthalide (Formula III: R0 =R1 =R2 =R3 =Y1 =H; R=R5 =CH3 ; R4 =N(CH3)2 ; R6 =(CH2)3CH3) which melted at 165°-167° C. A characteristic infrared maximum appeared at 1752 cm-1 (C=O; s). A toluene solution of the product spotted on silica gel developed an intense purple-colored image.