Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]=[C:12]([NH:14][NH2:15])[CH2:11][N:10]=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8]=2[CH:22]=1)([O-:3])=[O:2].[Cl:23][CH2:24][C:25](=O)[CH2:26][OH:27]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]=[C:12]([NH:14][N:15]=[C:25]([CH2:26][OH:27])[CH2:24][Cl:23])[CH2:11][N:10]=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8]=2[CH:22]=1)([O-:3])=[O:2]
Reactant: O=C(CO)CCl
Reactant: NNC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1)=NCC(NN=C(CO)CCl)=N2

Procedure:
In the manner given in Example 1, 7-nitro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in tetrahydrofuran can be treated with 1-chloro-3-hydroxypropanone under nitrogen to give 7-nitro-2[[2-chloro-1-(hydroxymethyl)ethylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction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
Reactant: C=CCCCCSc1nc(N)c2ncn([C@@H]3O[C@H](COP(=O)([O-])OP(=O)([O-])OP(=O)([O-])[O-])[C@@H](O)[C@H]3O)c2n1
Reactant: C=CCCCCSc1nc(N)c2ncn([C@@H]3O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]3O)c2n1
Agent: [NH4+]
Product: C=CCCCCSc1nc(N)c2ncn([C@@H]3O[C@H](COP(=O)([O-])OP(=O)([O-])[O-])[C@@H](O)[C@H]3O)c2n1

Procedure:
NMR of 2-(5-hexenylthio)adenosine 5'-triphosphate tetraammonium salt: 1H NMR (D2) d: 8.41 (S, 1H, H-8), 6.13 (d, J=5.7 Hz, 1H, H-1'), 4.64 (m, 1H, H-3'), 4.37 (m, 1H, H-4'), 4.24 (din, 2H, H-5'). High Res. FAB: calcd. for C16H25O13N5P3S: 620.0382. Found: 620.0428. Retention time: 7.7 min (91% purity) using solvent system I, 7.4 min (>98% purity) using solvent system II. 2-(5-Hexenylthio)adenosine 5'-triphosphate was also synthesized by the triphosphorylation procedure recited in Example 1.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[S:9][N:8]=[C:7]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]4[CH:19]=[C:20]5[CH2:28][C:26](=[O:27])[NH:25][C:21]5=[CH:22][C:23]=4[Cl:24])[CH2:12][CH2:11]3)[C:5]=2[CH:6]=1.[OH:29]O>C(#N)C>[CH2:14]1[N:13]([CH2:16][CH2:17][C:18]2[CH:19]=[C:20]3[CH2:28][C:26]([NH:25][C:21]3=[CH:22][C:23]=2[Cl:24])=[O:27])[CH2:12][CH2:11][N:10]([C:7]2[C:5]3[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=3)[S:9](=[O:29])[N:8]=2)[CH2:15]1
Reactant: OO
Reactant: O=C1Cc2cc(CCN3CCN(c4nsc5ccccc45)CC3)c(Cl)cc2N1
Solvent: CC#N
Product: O=C1Cc2cc(CCN3CCN(C4=NS(=O)c5ccccc54)CC3)c(Cl)cc2N1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of ziprasidone made as described in Example 1 (0.70 g, 1.7 mmol) in acetonitrile is added 30% H2O2 (1.7 mmol). After stirring for 24 hours at room temperature, the reaction mixture is cooled, filtered, and evaporated. The residue is chromatographed on silica gel, eluting the by-products with ethyl acetate (1 L) and the product with 4% methanol in ethyl acetate (1.5 L). The product fractions are evaporated, taken up in methylene chloride, and precipitated by addition of ether saturated with HCl; the solid is filtered and washed with ether, dried, and washed with acetone.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH:5]1[CH2:17][CH2:16][CH2:15][C:14]2[NH:13][C:12]3[CH:11]=[N:10][C:9]([C:18]([OH:20])=[O:19])=[C:8]([CH3:21])[C:7]=3[C:6]1=2)[CH3:2]>C(OC(N(C)C)N(C)C)(C)(C)C>[C:5]([O:19][C:18]([C:9]1[N:10]=[CH:11][C:12]2[NH:13][C:14]3[CH2:15][CH2:16][CH2:17][CH:5]([CH2:4][O:3][CH2:1][CH3:2])[C:6]=3[C:7]=2[C:8]=1[CH3:21])=[O:20])([CH3:17])([CH3:6])[CH3:4]
Reactant: CCOCC1CCCc2[nH]c3cnc(C(=O)O)c(C)c3c21
Agent: CN(C)C(OC(C)(C)C)N(C)C
Product: CCOCC1CCCc2[nH]c3cnc(C(=O)OC(C)(C)C)c(C)c3c21

Procedure:
0.35 g of 5,6,7,8-tetrahydro-5-ethoxymethyl-4-methylbeta-carboline-3-carboxylic acid is heated in tert-butoxybis(dimethylamino)methane (8 ml) in an argon atmosphere for 3 hours to 120° C. After evaporation of the volatile ingredients the residue is chromatographed on silica gel with a mixture of dichloromethane (8 parts), acetone (1 part) and ethanol (1 part). The yield is 0.2 g.
Reaction SMILES: C(=O)([O-])O.[Na+].[C:6](Cl)(=[O:8])[CH3:7].C1COCC1.O.[O:16]=[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[N:18]1[CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH:28]1[NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37]>C(OCC)(=O)C>[C:6]([N:30]1[CH2:31][CH2:32][CH:27]([N:18]2[C:17](=[O:16])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:26])[CH:28]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH2:29]1)(=[O:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)NC1CNCCC1N1C(=O)c2ccccc2C1=O
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N1CCC(N2C(=O)c3ccccc3C2=O)C(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydrogen carbonate (341 mg) and acetyl chloride (0.086 ml) were added to a THF/water (2 ml/2 ml) solution containing tert-butyl (4-(1,3-dioxoisoindolin-2-yl)piperidin-3-yl)carbamate (280 mg) obtained in the 2nd step under ice cooling, followed by stirring at room temperature for 0.5 hours. Ethyl acetate was added to the reaction solution. The organic layers were washed with saturated saline and dried over anhydrous sodium sulfate. Next, the solvent was distilled away under reduced pressure. A white solid of tert-butyl (1-acetyl-4-(1,3-dioxoisoindolin-2-yl)piperidin-3-yl)carbamate (301 mg) was thus obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:8]=O)=[N:4][CH:5]=[CH:6][N:7]=1.[CH2:10]([NH:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[NH2:19])[CH3:11].S([O-])(O)=O.[Na+]>CC(N(C)C)=O>[CH2:10]([N:12]1[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[N:19]=[C:8]1[C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[CH:5][N:4]=1)[CH3:11]
Reactant: CCNc1ccncc1N
Reactant: Nc1nccnc1C=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCn1c(-c2nccnc2N)nc2cnccc21
Temperature: 200 °C
Yield: 79.8 %

Procedure:
3-aminopyrazine-2-carbaldehyde (made in example 1(c)) (0.30 g, 2.4 mmol), N4-ethylpyridine-3,4-diamine (made in example 1(b)) (0.36 g, 2.6 mmol), and sodium hydrogensulfite (0.30 g) were combined in 3 mL of dimethylacetamide and heated to 200° C. in a SmithSynthesizer microwave for 10 minutes. The reaction mixture was partitioned between ethyl acetate and water. The reaction was extracted with ethyl acetate (×3), and the combined organic layers were washed with water and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. After filtration, the organics were concentrated in vacuo. Trituration with diethyl ether affords the title compound as tan solids (0.46 g, 80%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:19]([O:23][CH3:24])(=[O:22])[CH:20]=[CH2:21].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Cl>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O>[CH2:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH:21]=[CH:20][C:19]([O:23][CH3:24])=[O:22])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCc1ccc(-c2ccc(Br)cc2)cc1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCc1ccc(-c2ccc(C=CC(=O)OC)cc2)cc1

Procedure:
A mixture of 4-bromo-4′-pentylbiphenyl (5.0 g), methyl acrylate (2.2 ml), palladium acetate (0.11 g) and tris(o-tolyl)phosphine (0.60 g) in triethylamine (16 ml) was refluxed for 15 hours under nitrogen atmosphere. The reaction mixture was poured into a mixture of cold water and ethyl acetate, and adjusted to about pH 1.5 with 6N hydrochloric acid. The separated organic layer was washed in turn with water and brine, and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give a crude powder, which was subjected to column chromatography on silica gel (200 ml), and eluted with a mixture of (n-hexane:ethyl acetate=100:0-94:6, V/V) to give Methyl 3-[4-(4-pentylphenyl)phenyl]acrylate (4.48 g).
Reaction SMILES: [F:1][CH2:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]3[CH:17]=[C:16]([NH2:18])[N:15]=[CH:14][N:13]3[CH:19]=2)[CH:7]=[CH:8][CH:9]=1.[N:20]1([C:24]([C:26]2[CH:27]=[N:28][N:29]([CH3:34])[C:30]=2[C:31](O)=[O:32])=[O:25])[CH2:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CCOC(C)=O>[N:20]1([C:24]([C:26]2[CH:27]=[N:28][N:29]([CH3:34])[C:30]=2[C:31]([NH:18][C:16]2[CH:17]=[CH:12][N:13]3[CH:19]=[C:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:2][F:1])[CH:5]=4)[N:11]=[C:14]3[N:15]=2)=[O:32])=[O:25])[CH2:21][CH2:22][CH2:23]1
Reactant: Cn1ncc(C(=O)N2CCC2)c1C(=O)O
Reactant: Nc1cc2nc(-c3cccc(OCF)c3)cn2cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2cc(-c3cccc(OCF)c3)nc2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-(3-Fluoromethoxy-phenyl)-imidazo[1,2-c]pyrimidin-7-ylamine (100 mg, 0.387 μmol) was combined with EtOAc (2.0 ml) to give a light yellow suspension. 4-(Azetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (97 mg, 465 μmol) and DIPEA (300 mg, 406 μl, 2.32 mmol) were added. The reaction mixture was cooled down to 0° C. and n-propylphosphonic acid anhydride, cyclic trimer (616 mg, 582 μl, 968 μmol) was added drop by drop. After stirring at 0° C. for 30 min the reaction mixture was allowed to warm-up and stirred at RT overnight. The reaction mixture was then diluted with and 10% NaHCO3 aq. solution and extracted with EtOAc (3×). The combined organic layers were dried (MgSO4) and concentrated under vacuum. The crude product was purified by flash chromatography (10 g SiO2; eluent: CH2Cl2 to CH2Cl2/MeOH/NH3 140:10:1). The obtain material was dissolved in CH2Cl2 and the product was precipitated with Et2O, filtered off, washed with Et2O, and dried overnight at HV. Yellow solid (89 mg, 47%). MS (m/z)=450.2 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:13][CH:14]1[CH:19]=[C:18]([CH3:20])[CH:17]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[O:16][NH:15]1>C(#N)C.C(Cl)(Cl)Cl>[CH3:13][CH:14]1[CH:19]=[C:18]([CH3:20])[CH:17]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[O:16][N:15]1[S:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)(=[O:10])=[O:9]
Reactant: COc1ccc(C2ONC(C)C=C2C)cc1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: COc1ccc(C2ON(S(=O)(=O)c3cccc(C)c3)C(C)C=C2C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-methylbenzenesulphonyl chloride (0.075 mmol) in acetonitrile (1.5 ml) was added a solution of 3,6-dihydro-3,5-dimethyl-6-(4-methoxyphenyl)-2H-1,2-oxazine hydrochloride(0.403 mmol) in chloroform (0.5 ml) followed by poly(4-vinyl)pyridine (53 mg). The mixture was shaken at room temperature for 24 h then added polystyrene (co-divinylbenzene)amino methylated (100 mg) and the mixture shaken at room temperature for a further 24 h. The mixture was then filtered and the resin washed twice with chloroform. The filtrate was evaporated to give 3,6-dihydro-3,5-dimethyl-6-(4-methoxyphenyl)-2-(3-methylbenzenesulphonyl)-2H-1,2-oxazine as an oil. 1H NMR (CDCl3)δ 1.56(3H, d), 2.39(3H, s), 3.82(3H, s) 4.49(1H, m), 5.20(1H, s), 5.69(1H, d), 6.81(2H, d), 7.11(2H, d), 7.34(2H, m), 7.67(2H, d)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].P(Cl)(Cl)Cl.[C:17]([OH:26])(=O)[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[OH:20]>N1C=CC=CC=1>[C:17]([NH:1][C:2]1[CH:11]=[C:10]([NH:12][C:17](=[O:26])[C:18]2[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=2)[OH:20])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:26])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[OH:20]
Reactant: O=C(O)c1ccccc1O
Reactant: COC(=O)c1ccc(N)cc1N
Solvent: ClP(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)c2ccccc2O)cc1NC(=O)c1ccccc1O
Temperature: 90 °C
Reaction time: 1 h
Yield: 54.7 %

Procedure:
In 200 ml of pyridine was dissolved 8.3 g of methyl 2,4-diaminobenzoate, and to the solution was added a solution of 4.4 ml of phosphorus trichloride in 30 ml of pyridine under cooling with ice, followed by stirring at 50° to 70°C for one hour. To the mixture was added 21 g of salicylic acid was added, followed by heating at 90°C for three hours. After the cooling of the mixture by allowing it to stand, undissolved substances were filtered off and the filtrate was subjected to concentrate under reduced pressure. The concentrate was added to cold diluted hydrochloric acid to precipitate crystals. The crystals were recovered by filtration, washed with water and recrystallized from an acetone-dioxane-water mixture to obtain 11.1 g of methyl 2,4-bis(salicylamido)-benzoate having a melting point between 259° - 260°C. It was confirmed that the product was identical to that obtained in Example 7.
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([CH2:7][NH:8][C:9](=[O:27])[CH:10]([C:14]2[C:19]([F:20])=[CH:18][C:17]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][C:15]=2[F:26])[O:11][CH2:12][CH3:13])=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:31][OH:32]>>[F:20][C:19]1[CH:18]=[C:17]([C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)[CH:16]=[C:15]([F:26])[C:14]=1[CH:10]([O:11][CH2:12][CH3:13])[C:9]([NH:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:1](=[NH:2])[NH:31][OH:32])=[CH:29][CH:28]=1)=[O:27]
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(-c2ccco2)cc1F
Reactant: NO
Agent: Cl
Product: CCOC(C(=O)NCc1ccc(C(=N)NO)cc1)c1c(F)cc(-c2ccco2)cc1F

Procedure:
In analogy to example 15.5, (RS)-N-(4-cyano-benzyl)-2-(2,6-difluoro-4-furan-2-yl-phenyl)-2-ethoxy-acetamide was reacted with hydroxylamine hydrochloride to give (RS)-2-(2,6-difluoro-4-furan-2-yl-phenyl)-2-ethoxy-N-[4-(N-hydroxycarbamimidoyl)-benzyl]-acetamide. Colorless solid. MS 430.0 ([M+H]+)
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)(=O)/C=C/C(O)=O.[CH2:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][CH2:38][CH:37]1[CH2:46][CH:47]1[CH2:51][NH:50][CH:49]=[N:48]1>C1C=CC=CC=1>[CH2:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][CH2:38][CH:37]1[CH2:46][CH:47]1[CH2:51][N:50]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:49]=[N:48]1
Reactant: C1=NC(CC2CCc3ccccc3C2)CN1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)/C=C/C(=O)O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C1=NC(CC2CCc3ccccc3C2)CN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
1.25 ml (9 mmol) of triethylamine and 2.36 g (8.50 mmol) of trityl chloride are added, in succession, at 20° C., to a solution of the compound obtained in Example 16 (Step 4) in the form of the free amine (1.80 g, 8.40 mmol) in 50 ml of benzene, under nitrogen. After stirring for 15 hours at 20° C., the mixture is washed with H2O, and the organic phase is dried and concentrated in vacuo to yield an oily residue. Chromatography on a chiral column, eluting with a solution of triethylamine in toluene (0.5%), allows the 4 isomers to be separated in the form of white solids.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.FC(F)(F)C(O[C:28]1[C:33]([F:34])=[C:32]([F:35])[C:31]([F:36])=[C:30]([F:37])[C:29]=1[F:38])=O>C1COCC1.CC(=O)OCC>[CH3:3][C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][C:28]2[C:29]([F:38])=[C:30]([F:37])[C:31]([F:36])=[C:32]([F:35])[C:33]=2[F:34])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:2]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)CC1
Reaction time: 3 h

Procedure:
100 g (436 mmol) of piperidine-1,4-dicarboxylic acid 1-tert butyl ester were dissolved in 1.3 l of anhydrous THF, 39 ml of anhydrous pyridine were added and 86 ml (500 mmol) of pentafluorophenyl trifluoroacetate were added dropwise with stirring and with ice-cooling in the course of 30 minutes, and the mixture was allowed to stand at room temperature for 3 h. The solvent was then stripped off in vacuo and the residue was taken up in about 2 l of EA, extracted twice each with 0.5 N HCl, saturated NaHCO3 solution and saturated NaCl solution, and the organic phase was dried over Na2SO4. After evaporating off the solvent in vacuo, an oil remained which crystallized after addition of heptane. Yield 151.5 g (88%), colorless crystals. M.p. 87–88° C. (heptane).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:19]([F:29])[CH:18]=1)[N:9]=[C:8]2[NH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36](C([O-])=O)[N:35]=[CH:34]2.[CH3:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.O>CS(C)=O>[F:29][C:19]1[CH:18]=[C:17]([C:10]2[N:9]=[C:8]([NH:30][C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[NH:36][N:35]=[CH:34]4)[C:7]3[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([O:4][CH2:3][CH2:2][N:47]4[CH2:48][CH2:49][N:44]([CH3:43])[CH2:45][CH2:46]4)[CH:6]=3)[N:11]=2)[CH:22]=[CH:21][C:20]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1cc2nc(-c3ccc(-c4ccccc4)c(F)c3)nc(Nc3ccc4c(cnn4C(=O)[O-])c3)c2cc1OCCCl
Reactant: CN1CCNCC1
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2nc(-c3ccc(-c4ccccc4)c(F)c3)nc(Nc3ccc4[nH]ncc4c3)c2cc1OCCN1CCN(C)CC1
Temperature: 85 °C

Procedure:
A mixture of 5-(6-(2-chloroethoxy)-2-(3-fluoro-4-(phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.35 g, 0.55 mmol) and 4-methyl piperazine in DMSO (1.5 mL) was heated at 85° C. for 3 h. The mixture was allowed to cool to RT, upon which it was poured into water (100 mL). The solid that formed was collected via filtration and purified by preparative TLC (SiO2, CH2Cl2:MeOH 9:1) to give the desired compound. The lower running spot was isolated and then taken up in CH2Cl2 (6 mL) and TFA (5 mL). The mixture was stirred for 2.5 h at RT. The volatiles were removed in vacuo to give a solid which was triturated with Et2O, filtered and dried under vacuum to give the desired product 2-(3-fluoro-4-(phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-(4-methylpiperazin-1-yl)ethoxy)quinazolin-4-amine (0.111 g, 0.184 mmol, 33%). MS 604.5 (M+1). HPLC retention time 5.10 mins.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.[NH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.[BH4-].[Na+].[OH-].[Na+]>C1C=CC=CC=1.CCOCC.O.C(O)(=O)C.C(O)C>[N:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][NH:22][CH:18]1[CH2:19][CH2:20][N:15]([C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)[CH2:16][CH2:17]1
Reactant: NCc1ccccn1
Reactant: COc1cc2ncnc(N3CCC(=O)CC3)c2cc1OC
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: O
Product: COc1cc2ncnc(N3CCC(NCc4ccccn4)CC3)c2cc1OC
Reaction time: 2 h
Yield: 52.2 %

Procedure:
1-(6,7-Dimethoxyquinazolin-4-yl)piperid-4-one (2.9g) (which may be prepared as in part A of Example 91, hereinafter), and 2-aminomethylpyridine (1.19g) were refluxed together for two hours in benzene (50 ml.) in a flask fitted with a Dean and Stark trap. Ethanol (50 ml.) was added to the cooled solution followed by the slow addition of sodium borohydride (0.76g) with stirring. On completion of the addition stirring as continued for two hours followed by the addition of excess acetic acid. The mixture was poured into water, basified with 5N sodium hydroxide and was extracted with chloroform. Evaporation of the chloroform layer gave a yellow oil which solidified on trituration with ether. Recrystallization from ethyl acetate gave 4-[4-(2-pyridylmethyl-amino)piperidino]-6,7-dimethoxyquinazoline (2 g) m.p. 151°-155° C.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][NH:6][C:7](=[O:33])[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:15][C:16](=[O:30])[C:17]3[C:22]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[N:21][N:20]([CH3:29])[C:18]=3[N:19]=2)=[C:10]([O:31][CH3:32])[CH:9]=1)C.[OH-].[Na+]>CO>[CH:23]1([C:22]2[C:17]3[C:16](=[O:30])[NH:15][C:14]([C:11]4[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][C:4]([OH:34])=[O:3])=[O:33])=[CH:9][C:10]=4[O:31][CH3:32])=[N:19][C:18]=3[N:20]([CH3:29])[N:21]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CCOC(=O)CNC(=O)c1ccc(-c2nc3c(c(C4CCCCC4)nn3C)c(=O)[nH]2)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)NCC(=O)O)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a 1 ml methanol/3 ml 1,4-dioxane mixed solution of 60 mg (0.13 mmol) of the compound obtained in Example 71, 1 ml of a 1M aqueous solution of sodium hydroxide was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. Then, the solvent was distilled off under reduced pressure, and the residue was diluted with water, followed by washing the dilution with ether. The aqueous layer was acidified with a 2M aqueous solution of hydrochloric acid, and then extracted with chloroform. The organic layer was washed with water and a saturated aqueous solution of sodium chloride. After the washed layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 53 mg (93%) of the captioned compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH:24]([CH:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)O)[CH:8]=2)[N:3]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:15]1[CH2:16][CH2:17][N:12]([C:11]2[C:2]([NH2:1])=[N:3][C:4]3[C:9]([CH:10]=2)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[CH:6][CH:5]=3)[CH2:13][CH2:14]1
Reactant: Nc1nc2ccc(-c3ccccc3C(O)C3CCOCC3)cc2cc1N1CCOCC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc2ccc(-c3ccccc3CC3CCOCC3)cc2cc1N1CCOCC1
Temperature: 70 °C

Procedure:
(2-(2-Amino-3-morpholinoquinolin-6-yl)phenyl)(tetrahydro-2H-pyran-4-yl)methanol (0.085 g, 0.203 mmol, see Example 12) was dissolved in DCM (20 mL) and treated with triethylsilane (1.0 mL, 6.26 mmol) and TFA (2.0 mL, 26.9 mmol). The mixture was heated to 70° C. for 30 min after which analysis showed the reduction was complete. The solution was evaporated to dryness under reduced pressure. The crude was partitioned between water (10 mL), saturated sodium bicarbonate (10 mL) and DCM (20 mL). The organic layer was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (0-10% methanol in DCM gradient) gave the desired 3-morpholino-6-(2-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)quinolin-2-amine. MS (ESI, pos. ion) m/z: 404 (M+1).