Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[OH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](O)=[O:18])=[CH:11][CH:10]=1.[NH4+].[Cl-]>C1COCC1>[OH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][OH:18])=[CH:11][CH:10]=1
Reactant: O=C(O)CCc1ccc(CO)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCc1ccc(CO)cc1
Temperature: 70 °C
Reaction time: 1.33 h
Yield: 76.7 %

Procedure:
To a suspension of LiAlH4 (155 mg, 4.0 mmol) in THF (25 mL) a solution of 3-(4-hydroxymethyl-phenyl)-propionic acid (720 mg, 4.0 mmol) in THF (20 mL) is added within 2 min. The resulting mixture is stirred at 70° C. for 80 min before it is treated with sat. aq. NH4Cl solution (10 mL). The suspension is filtered over celite, the filtrate is diluted with water (200 mL) and extracted with diethyl ether (2×75 mL) followed by EA (2×75 mL). The organic extracts are combined, dried over Na2SO4 and evaporated to leave 3-(4-hydroxymethyl-phenyl)-propan-1-ol (0.51 g) as a colourless oil; tR=0.61 min.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:31]([NH:30][C:27]4[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:33])[F:34])=[CH:29][CH:28]=4)=[O:32])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1

Procedure:
The title compound, MS: m/e=463.6 (M+H+), was prepared in accordance with the general method 4 of example 16 from (R)—N2-indan-1-yl-quinoline-2,6-diamine and 4-(trifluoromethyl)phenyl isocyanate.
Reaction SMILES: [CH2:1]([O:5][N:6]=[C:7]([C:18]#[N:19])[C:8]([N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)=[N:9][O:10][CH2:11][CH3:12])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-:21].[K+].[K+].OO.S([O-])([O-])(=S)=S.[Na+].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CO>[CH2:1]([O:5][N:6]=[C:7]([C:18](=[O:21])[NH2:19])[C:8]([N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)=[N:9][O:10][CH2:11][CH3:12])[CH2:2][CH2:3][CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CCCCON=C(C#N)C(=NOCC)n1cncn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: OO
Agent: [Br-]
Solvent: CO
Product: CCCCON=C(C(N)=O)C(=NOCC)n1cncn1
Reaction time: 10 h
Yield: 566.8 %

Procedure:
To 5 ml of a methanol solution containing 0.98 g (3.7 mmol) of the 1-(2-n-butoxyimino-2-cyano-1-ethoxyiminoethyl)-1H-1,2,4-triazole produced in Example 17 were added, at room temperature, 60 mg (0.19 mmol) of tetrabutylammonium bromide, 55 mg (0.40 mmol) of potassium carbonate and 1.7 g (15 mmol) of an aqueous 30 wt. % hydrogen peroxide solution, followed by stirring for 10 hours. To the reaction mixture was added sodium dithiosulfate, followed by stirring for 10 minutes. The reaction mixture was concentrated under reduced pressure. The resulting crystal was washed with an aqueous citric acid solution, cold water and isopropyl ether in this order, to obtain 0.64 g (yield: 61%) of a title compound.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[O:11][C:12]4[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.Cl.[CH3:22][NH:23][CH3:24].C(O)(=O)C.[BH3-]C#N.[Na+]>CO.C1COCC1>[CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[O:11][C:12]4[CH:18]=[CH:17][C:16]([CH2:19][N:23]([CH3:24])[CH3:22])=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: CNC
Reactant: O=Cc1ccc2oc(N3CCN(C4CC4)CC3)nc2c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN(C)Cc1ccc2oc(N3CCN(C4CC4)CC3)nc2c1
Yield: 60.1 %

Procedure:
To a solution of 2-(4-cyclopropylpiperazin-1-yl)benzooxazole-5-carboxaldehyde (350 mg, 1.29 mmol) and dimethylamine hydrochloride (210 mg, 2.58 mmol) in CH3OH/THF (32 mL, 1:3) was added acetic acid (124 mg, 2.06 mmol), followed by NaCNBH3 (120 mg, 2.06 mmol). The mixture was heated at reflux for 12 h. The volatiles were removed under reduced pressure and the residue was diluted with water (5 mL). The mixture was extracted with CH2Cl2 (3×10 mL) and the combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by the preparative HPLC to give 233 mg (60%) of [2-(4-cyclopropylpiperazin-1-yl)benzooxazol-5-ylmethyl]dimethylamine as a trifluoroacetate salt.
Reaction SMILES: [P:1]([O:11][CH2:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:20][O:21][Si](C(C)(C)C)(C)C)([O:7][CH2:8][CH:9]=[CH2:10])([O:3][CH2:4][CH:5]=[CH2:6])=[O:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>O1CCCC1.CCCCCC>[P:1]([O:11][CH2:12][C:13]1[C:14]([CH2:20][OH:21])=[CH:15][CH:16]=[CH:17][C:18]=1[Cl:19])([O:7][CH2:8][CH:9]=[CH2:10])([O:3][CH2:4][CH:5]=[CH2:6])=[O:2]
Reactant: C=CCOP(=O)(OCC=C)OCc1c(Cl)cccc1CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C=CCOP(=O)(OCC=C)OCc1c(Cl)cccc1CO
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 82.5 %

Procedure:
To a solution of diallyl 2-[(tert-butyldimethylsilyl)oxymethyl]-6-chlorobenzyl phosphate (4.41 g, 9.87 mmol) obtained from Example 27-(2) in tetrahydrofuran (50 ml) was added tetrabutylammonium fluoride (1N tetrahydrofuran solution; 10 ml, 10 mmol), and the mixture was stirred at room temperature for 40 minutes. Water was added to the mixture, then the product was extracted with ethyl acetate, and the solvent was distilled off under reduced pressure to give an oily residue. The residue was subjected to chromatography on a silica gel (50 g) column (eluent; ethyl acetate:hexane=1:1˜3:1) to afford the title compound (2.71 g, 83% yield) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:34][CH3:35])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:36].C1C=C(Cl)C=C(C(OO)=[O:45])C=1.CCOC(C)=O.CCCCCC>C(Cl)Cl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:34]([CH3:35])=[O:45])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:36]
Reactant: CSc1nc(-c2cc(C(=O)Nc3nccs3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.2 %

Procedure:
A solution of 3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide (1.65 g, 3.16 mmol) in DCM (53 mL) was mixed with mCPBA (0.736 g, 4.75 mmol). The mixture was stirred at room temperature for about 10 minutes before directly loaded onto a column. Flash chromatography (mobile phase EtOAc/Hexane) then provided the title compound as a white solid 1.38 g (81%). MS (ES) m/z 538 (M+H)+; 1H-NMR (MeOD) δ 2.35 (s, 3 H), 2.81 (s, 3 H), 6.98 (d, J=10.0 Hz, 1 H), 7.30 (d, J=3.6 Hz, 1 H), 7.46 (t, J=8.6 Hz, 2 H), 7.57 (d, J=3.6 Hz, 1 H), 7.66 (d, J=8.0 Hz, 1 H), 7.72 (m, 1 H), 7.85 (d, J=10.0 Hz, 1 H), 8.25 (d, J=8.0 Hz, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[C:15]3[NH:21]C(=O)C2C=CC=CC=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl>C(O)C>[NH2:21][C:15]1[C:14]2[C:18](=[CH:19][CH:20]=[C:12]([NH:11][S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)(=[O:10])=[O:9])[CH:13]=2)[NH:17][N:16]=1
Reactant: O=C(Nc1n[nH]c2ccc(NS(=O)(=O)c3cccc(F)c3)cc12)c1ccccc1
Agent: Cl
Solvent: CCO
Product: Nc1n[nH]c2ccc(NS(=O)(=O)c3cccc(F)c3)cc12
Yield: 44.7 %

Procedure:
N-(3-Amino-1H-indazol-5-yl)-3-fluorobenzenesulfonamide can be obtained in the following way: a solution of 0.3 g of N-[5-(3-fluorobenzenesulfonylamino)-1H-indazol-3-yl]benzamide, of 24 ml of ethanol and of 1.08 ml of 37% hydrochloric acid is heated at a temperature in the region of 100° C. for 30 hours. The cooled reaction medium is concentrated under reduced pressure. 20 ml of water, and aqueous sodium hydroxide, to a pH in the region of 11, are added to the residue thus obtained, which is then extracted with three times 25 ml of ethyl acetate. The pooled organic phases are filtered, dried over magnesium sulfate, filtered again and concentrated by evaporation under reduced pressure. The residue thus obtained is purified by chromatography on a silica column with a dichloromethane/methanol (99/1 by volume) mixture as eluent. The solid thus obtained is recrystallized from 5 ml of isopropanol. 0.1 g of N-(3-amino-1H-indazol-5-yl)-3-fluorobenzenesulfonamide is thus obtained, after drying under reduced pressure at 60° C., in the form of a white solid melting at 216° C. (analysis C13H11FN4O2S % calculated C, 50.97; H, 3.62; F, 6.20; N, 18.29; O, 10.45; S, 10.47. % found C, 50.80; H, 3.72; N, 18.14; S, 10.21).
Reaction SMILES: [C:1]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:14](Br)([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O.O>[C:1]([CH:9]=[CH:10][C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)Br
Reactant: O=C(O)C=CC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)C=CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3.52 g of 3-benzoylacrylic acid in 30 ml of dimethylformamide were added 8 ml of isopropylbromide, 5.5 g of potassium carbonate and a catalystic amount of sodium iodide. The mixture was stirred at room temperature for 4 hours and allowed to stand overnight. To the reaction solution was added water, the mixture was extracted with diethyl ether, and the diethyl ether layer was washed with water and dried over magnesium sulfate. The diethyl ether was removed from the solution by evaporation, and the residue was purified by silica gel column chromatography using a mixture of hexane and diethyl ether as an eluent to give 2.27 g of isopropyl 3-benzoylacrylate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:14]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[N+](C)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:20]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:21])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: Clc1ccc(-c2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Product: O=C(c1ccc(-c2ccc(Cl)cc2)cc1)C1CCCCC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a mixture of 4-chlorobiphenyl (1.0 g), cyclohexanecarbonyl chloride (0.788 mL) and nitromethane (10.6 mL) was added aluminum chloride (0.848 g) at 0° C. The reaction mixture was stirred at 0° C. for 3 hr, and water was added at 0° C. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.792 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][C:10]=1[O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH2:25])[CH:20]=1)[CH3:4].[CH3:26][NH:27][C:28](=O)[O:29]C1C=CC=CC=1.O>CN(C)C=O.C(OCC)(=O)C>[NH2:25][C:21]1[CH:20]=[C:19]([O:18][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][C:9]=2[O:8][CH2:7][CH2:6][O:5][CH2:3][CH3:4])[N:15]([C:28]([NH:27][CH3:26])=[O:29])[CH:14]=[CH:13]3)[CH:24]=[CH:23][N:22]=1
Reactant: CNC(=O)Oc1ccccc1
Reactant: CCOCCOc1cc2[nH]ccc2cc1Oc1ccnc(N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCOc1cc2c(ccn2C(=O)NC)cc1Oc1ccnc(N)c1
Reaction time: 0.17 h
Yield: 87 %

Procedure:
50-72% Oily sodium hydride (265 mg) was added to a solution of 4-((6-(2-ethoxyethoxy)-1H-indol-5-yl)oxy)pyridin-2-amine described in Production Example 24-7 (1.92 g, 6.13 mmol) in N,N-dimethylformamide (20 mL) under nitrogen atmosphere at 0° C. The reaction liquid was stirred at the same temperature for 10 minutes. Phenyl methylcarbamate described in Production Example 1-7 (1.20 g, 7.97 mmol) was added to the reaction liquid, and then the mixture was warmed to mom temperature and stirred for 1 hour. Water and ethyl acetate were added to the reaction liquid. The organic layer was washed serially with water and a saturated saline solution and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and then the filtrate was concentrated under vacuum. The residue was purified with NH silica gel column chromatography (the solution: n-heptane:ethyl acetate=9:1-0:1) to obtain the title compound (1.97 g, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][CH2:22][NH:23][C:24](=[N:27][C:28]#[N:29])SC)=[C:9]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].O.[NH2:36][NH2:37]>C(O)C>[NH2:29][C:28]1[N:27]=[C:24]([NH:23][CH2:22][CH2:21][O:20][CH2:19][C:10]2[NH:11][C:12]([CH3:18])=[C:13]([C:14]([O:16][CH3:17])=[O:15])[CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]=2[C:30]([O:32][CH2:33][CH3:34])=[O:31])[NH:37][N:36]=1
Reactant: NN
Reactant: CCOC(=O)C1=C(COCCNC(=NC#N)SC)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1=C(COCCNc2nc(N)n[nH]2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl

Procedure:
N-{2-[(4-{2-Chlorophenyl}-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl)methoxy]ethyl}-N'-cyano-S-methyl-isothiourea (0.4 g) and hydrazine hydrate (0.15 ml) were dissolved in ethanol (20 ml) and heated under reflux for 3 hours. The solvent was then evaporated and toluene (10 ml) was added to the residue, and again the solution was evaporated to dryness. The residue was chromatographed on Merck "Kieselgel 60H" (Trade Mark), eluting with 2% methanol in methylene chloride, to give a beige solid. The solid was recrystallised from ethyl acetate plus a trace of ether to give the title compound, yield 0.1 g, m.p. 137°-138°.
Reaction SMILES: FC(F)(F)S(O[CH2:7][C:8]([F:21])([F:20])[CH:9]([F:19])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)(=O)=O.[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.[K].CN1CCCC1=O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[F:20][C:8]([F:21])([CH:9]([F:19])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)[CH2:7][N:28]1[C:24](=[O:34])[C:25]2[C:26](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:27]1=[O:29]
Reactant: O=[N+]([O-])c1cccc(C(F)C(F)(F)COS(=O)(=O)C(F)(F)F)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [K]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: O=C1c2ccccc2C(=O)N1CC(F)(F)C(F)c1cccc([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 75.5 %

Procedure:
To 2,2,3-trifluoro-3-(3-nitrophenyl)propyl trifluoromethanesulfonate (C32, 709 mg) and potassium phthalimide (1.07 g), N-methylpyrrolidone (4 mL) was added at room temperature, and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was cooled to room temperature, and then ethyl acetate and saturated aqueous sodium hydrogencarbonate were added to the mixture. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 30% hexane in ethyl acetate) to obtain 2-(2,2,3-trifluoro-3-(3-nitrophenyl)propyl)isoindoline-1,3-dione (C33, 531 mg).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([NH:10][C@H:11]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:12](ON1C(=O)CCC1=O)=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].[Cl-].[NH4+]>C1COCC1.O>[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:12][OH:13])[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:9])([CH3:5])([CH3:4])[CH3:6]
Reactant: CC(C)(C)OC(=O)C[C@@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C[C@H](CO)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
Sodium borohydride (0.63 g, 16.3 mmol) was dissolved into THF (30 mL) and water (4 mL) and cooled to 0° C. (R)-4-tert-butyl 1-(2,5-dioxopyrrolidin-1-yl) 2-(tert-butoxycarbonylamino)succinate (4.6 g, 11.9 mmol) was dissolved into THF (5 mL) and added dropwise to the solution. After 1 h, saturated ammonium chloride (10 mL) was added and the mixture was extracted with ethyl acetate (4×50 mL), dried over MgSO4 and concentrated. The residue was filtered through silica gel with ethyl acetate/hexanes 1:1. The solvent was removed in vacuo to give the title compound (1.91 g, 59%) as a white foam. 1H NMR (300 MHz, DMSO-d6) δ 6.55-6.52 (m, 1H), 4.74-4.69 (m, 1H), 3.81-3.72 (m, 1H), 3.21-3.14 (m, 1H), 2.50-2.39 (m, 1H), 2.19-2.06 (m, 1H), 1.39 (s, 9H), 1.36 (s, 9H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:27]=[CH:26][C:9]2[N:10]=[C:11]([NH:14][CH:15]3[C:19]4[C:20]([O:24][CH3:25])=[CH:21][CH:22]=[CH:23][C:18]=4[O:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[CH3:25][O:24][C:20]1[C:19]2[CH:15]([NH:14][C:11]3[O:12][CH2:13][C:8]4[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)[CH:27]=[CH:26][C:9]=4[N:10]=3)[CH2:16][O:17][C:18]=2[CH:23]=[CH:22][CH:21]=1
Reactant: C1COCCN1
Reactant: COc1cccc2c1C(NC1=Nc3ccc(NC(=O)CCl)cc3CO1)CO2
Product: COc1cccc2c1C(NC1=Nc3ccc(NC(=O)CN4CCOCC4)cc3CO1)CO2
Yield: 35.4 %

Procedure:
Prepared from rac-2-chloro-N-[2-(4-methoxy-2,3-dihydro-benzofuran-3-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 8) (50 mg, 0.129 mmol) and morpholine (225 ul, 2.578 mmol) according to the procedure described for Example 3 step B (here the reaction was sonicated for 2 min, which already lead to complete conversion). Obtained the title compound as a white solid (20 mg, 35%), MS (ISP) m/e=439.3 [(M+H)+].
Reaction SMILES: [F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[N:26][NH:27][C:28]2=[O:33]>[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH:11]([NH:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=1[CH:25]=[N:26][NH:27][C:28]3=[O:33])[C:10]([OH:17])([C:13]([F:14])([F:15])[F:16])[CH2:9][C:8]2([CH3:19])[CH3:18]
Reactant: Nc1cccc2c(=O)[nH]ncc12
Reactant: COc1c(F)cccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Agent: Cl[Ti](Cl)(Cl)Cl
Product: COc1c(F)ccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2c(=O)[nH]ncc12
Yield: 12.3 %

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 200 mg of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal and 105 mg of 5-amino-phthalazin-1-one. As in Example 3, 50 mg of imine is reacted by reaction with 0.22 ml of titanium tetrachloride, and 36 mg of the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH2:19](O)[CH3:20].C(N(CC)CC)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([O:6][CH2:19][CH3:20])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: CCO
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
First, 50 g (0.29 mol) of 2-chloro-4-fluorobenzoic acid was dissolved in 150 ml of hydrochloric acid at room temperature, to which a mixed acid of 28 ml (0.31 mol) of fuming nitric acid and 56 ml of concentrated sulfuric acid was added dropwise at 35° to 45° C. Then, the solution was stirred at 40° C. for 1 hour and poured into 250 ml of ice-water. The precipitated crystals were collected by filtration and recrystallized from a mixed solution of hexane and ethyl acetate, which afforded 55 g (0.25 mol) of 2-chloro-4-fluoro-5-nitrobenzoic acid. Then, 55 g (0.25 mol) of 2-chloro-4-fluoro-5-nitrobenzoic acid was dissolved in 50 ml of ethyl acetate, to which 33 g (0.28 mol) of thionyl chloride was added, and the mixture was heated under reflux for 3 hours and then allowed to stand for cooling to room temperature. Then, 20 ml of ethanol and 30 g of triethylamine were added under ice cooling, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled out, and the residue was purified by silica gel chromatography, which afforded 57 g (0.23 mol) of ethyl 2-chloro-4-fluoro-5-nitrobenzoate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])=[C:6]([CH:11]=1)[C:7](OC)=[O:8].ClC1C=CC=CC=1COC1C=CC(F)=CC=1CO>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:21])([F:22])[F:23])=[C:6]([CH2:7][OH:8])[CH:11]=1
Reactant: COC(=O)c1cc(F)ccc1OCc1ccccc1C(F)(F)F
Agent: OCc1cc(F)ccc1OCc1ccccc1Cl
Product: OCc1cc(F)ccc1OCc1ccccc1C(F)(F)F
Yield: 72 %

Procedure:
The title compound is prepared in 72% yield from methyl 5-fluoro-2-{[2-(trifluoromethyl)benzyl]-oxy}benzoate (Example 47A) in analogy to [2-(2-chlorobenzyloxy)-5-fluorophenyl]methanol (Example 45A).
Reaction SMILES: [CH3:1][N:2]([CH3:48])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:46][CH3:47])=[C:12]([NH:15][C:16]3[N:29]4[C:20](=[N:21][C:22]5[C:27]([C:28]4=[O:30])=[C:26]([F:31])[C:25]([F:32])=[CH:24][CH:23]=5)[C:19]4[CH:33]=[CH:34][N:35]([S:36]([C:39]5[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=5)(=[O:38])=[O:37])[C:18]=4[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[OH-].[NH4+:50]>C1COCC1.C(OCC)(=O)C>[CH3:1][N:2]([CH3:48])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:46][CH3:47])=[C:12]([NH:15][C:16]3[N:29]=[C:20]([NH:21][C:22]4[C:27]([C:28]([NH2:50])=[O:30])=[C:26]([F:31])[C:25]([F:32])=[CH:24][CH:23]=4)[C:19]4[CH:33]=[CH:34][N:35]([S:36]([C:39]5[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=5)(=[O:38])=[O:37])[C:18]=4[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: [NH4+]
Reactant: COc1cc2c(cc1Nc1nc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c3nc4ccc(F)c(F)c4c(=O)n13)N(C(=O)CN(C)C)CC2
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc2c(cc1Nc1nc(Nc3ccc(F)c(F)c3C(N)=O)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(C(=O)CN(C)C)CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-8,9-difluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (300 mg, 0.445 mmol) in THF (5 mL) was added ammonium hydroxide (27% aqueous) (100 mL, large excess). The resulting mixture was let stir at rt for 16 h at which time it was diluted with ethyl acetate and washed with water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure. The residue was purified via chromatography on SiO2 and afforded 6-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-2,3-difluorobenzamide (133 mg, 0.193 mmol) as an off white solid. (ESIMS (M+H)+=691)