Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH3:13])=[C:5]1[CH:14]=O.[BH4-].[Na+].O>CO>[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH3:13])=[C:5]1[CH2:14][NH:2][CH3:1]
Reactant: Cc1c(C=O)n(C)c2ccccc12
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNCc1c(C)c2ccccc2n1C
Temperature: 0 °C
Reaction time: 5 h
Yield: 85.2 %

Procedure:
Methylamine (0.53 mL, 13.1 mmol) was added to a solution of 1,3-dimethyl-1H indole-2-carbaldehyde (760 mg, 4.3 mmol) in methanol (15 mL) and stirred for 5 h. The mixture was cooled to 0° C. and sodium borohydride (159 mg, 4.3 mmol) added slowly. The mixture was warmed to rt and stirred overnight. Water (3 mL) was added slowly at 0° C. and evaporated to a paste. Water was added and the mixture extracted with dichloromethane. The organic phase was washed with water, dried and evaporated to afford the title compound (690 mg, 85%). 1H NMR (400 MHz, DMSO-d6) δ 7.44 (d, J=7.8 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.10 (t, J=7.6 Hz, 1H), 6.98 (t, J=8.0 Hz, 1H), 3.77 (s, 2H), 3.71 (s, 3H), 2.27 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]([CH:10]1[CH2:12][CH2:11]1)[C:6]([NH:8][NH2:9])=O.Cl.Cl.[CH3:15][O:16][C:17]1[CH:18]=[C:19](/[CH:29]=[CH:30]/[C:31](=[NH:35])OCC)[CH:20]=[CH:21][C:22]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1.C(OCC)(=O)C.O>C(O)C>[CH:10]1([CH:5]2[CH2:4][CH2:3][CH2:2][N:8]3[N:9]=[C:31](/[CH:30]=[CH:29]/[C:19]4[CH:20]=[CH:21][C:22]([N:23]5[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]5)=[C:17]([O:16][CH3:15])[CH:18]=4)[N:35]=[C:6]23)[CH2:12][CH2:11]1
Reactant: NNC(=O)C(CCCCl)C1CC1
Reactant: CCOC(=N)/C=C/c1ccc(-n2cnc(C)c2)c(OC)c1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(/C=C/c2nc3n(n2)CCCC3C2CC2)ccc1-n1cnc(C)c1
Temperature: 70 °C
Reaction time: 22 h
Yield: 17.5 %

Procedure:
A solution of 5-chloro-2-cyclopropyl-valeric acid hydrazide (125 mg) in ethanol (1.5 mL) was added to a solution of ethyl (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate dihydrochloride (259 mg) and TEA (0.46 ml) in ethanol (3 ml), and the reaction solution was stirred at 70° C. for 22 hours. The reaction solution was left to cool to room temperature. Then, ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: heptane-ethyl acetate system) and again purified by silica gel column chromatography (elution solvent: ethyl acetate-methanol system) to obtain 43 mg of racemic 8-cyclopropyl-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine. Then, the racemate was separated by CHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: 20% ethanol-hexane) to obtain the title optically active compound with a retention time of 28 minutes and negative optical rotation (16.4 mg; 100% ee) and the title optically active compound with a retention time of 49 minutes and positive optical rotation (16.3 mg; 99% ee).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[O:19][CH:18]=[CH:17][C:16]=12)=[O:10].[CH3:20][C:21]1[S:22][C:23]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[C:24]([C:26](O)=[O:27])[N:25]=1>>[CH3:20][C:21]1[S:22][C:23]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[C:24]([C:26]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[O:19][CH:18]=[CH:17][C:16]=23)=[O:10])=[O:27])[N:25]=1
Reactant: O=C(NC[C@H]1NC[C@@H]2C[C@@H]21)c1cccc2occc12
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3occc23)c1

Procedure:
prepared by reaction of benzofuran-4-carboxylic acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=0.93 min; [M+H]+=472.2.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=NO)[C:10]=2[CH:11]=1.C([O-])([O-])=[O:15].[Na+].[Na+]>CC(C)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:15])[C:10]=2[CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: ON=C1CCCc2cnc(Cl)cc21
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C1CCCc2cnc(Cl)cc21
Temperature: 60 °C

Procedure:
3-Chloro-7,8-dihydro-6H-isoquinolin-5-one oxime (9.10 g; 46.3 mmol) dissolved in acetone (105 ml) and HClconc (105 ml) is heated at 60° C. for 1 hour. The reaction mixture is poured on 2N Na2CO3 and extracted with ethyl acetate three times, the organic phases are combined, dried over Na2SO4 and evaporated to dryness. Chromatography (SiO2; Hexanes/acetone 85:15) yields the desired ketone as yellowish crystals. 1H-NMR (400 MHz; DMSO-d6): 8.57 (s, 1H); 7.66 (s, 1H); 2.96 (m, 2H); 2.71 (m, 2H); 2.10 (m, 2H). MS (m/z) ES+: 182 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:19][CH:20]1[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([S:30]([CH3:29])(=[O:32])=[O:31])[CH2:15][CH2:14]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:19][CH:20]1[CH2:21][CH2:22][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:24][CH2:25]1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCNCC4)[nH]c3cc2Cl)CC1
Reactant: CS(=O)(=O)Cl
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCN(S(C)(=O)=O)CC4)[nH]c3cc2Cl)CC1
Yield: 72 %

Procedure:
The title compound was synthesized in analogy to example 37, from [6-chloro-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone (example 36), and methanesulfonyl chloride, to afford the title compound as an off-white solid (72%).
Reaction SMILES: [OH-].[Na+].[NH2:3][CH:4]([CH2:8][CH2:9][P:10]([OH:13])([OH:12])=[O:11])[C:5]([OH:7])=[O:6].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C(=O)([O-])O.[Na+].C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>O.CCOCC.C(O)CCC.CC(O)=O.O>[CH2:18]([O:17][C:15]([NH:3][CH:4]([CH2:8][CH2:9][P:10]([OH:13])([OH:12])=[O:11])[C:5]([OH:7])=[O:6])=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC(CCP(=O)(O)O)C(=O)O
Agent: O=C([O-])O
Agent: O=C1c2ccccc2C(=O)C1(O)O
Agent: [Na+]
Solvent: CCCCO
Solvent: CC(=O)O
Solvent: O
Product: O=C(NC(CCP(=O)(O)O)C(=O)O)OCc1ccccc1
Temperature: 0 °C

Procedure:
After 24.0 g (600 mmol) of sodium hydroxide and 36.6 g (200 mmol) of 2-amino-4-phosphonobutanoic acid were dissolved in a two-layer system solvent mixture of 200 mL of water and 150 mL of ether, 51.2 g (300 mmol) of benzyl chloroformate and 25.2 g (300 mmol) of sodium hydrogen carbonate were added portionwise over 1 hour while being vigorously stirred at 0° C. After the mixture was vigorously stirred at room temperature for 14 hours, it was confirmed that the reaction was finished on the basis of disappearance of 2-amino-4-phosphonobutanoic acid by ninhydrin coloration of thin layer chromatography (TLC) (BuOH/AcOH/H2O=5:2:2). Thereafter, the water layer was separated and washed with 200 mL of ether three times successively, and the solution was acidified by adding 140 mL (840 mmol) of theoretical amount of 6N hydrochloric acid. The aqueous solution was concentrated in reduced pressure, 500 mL of acetone was added to the residue, and insoluble sodium chloride was removed by filtration. The filtrate was concentrated to obtain oily 2-(N-benzyloxycarbonylamino)-4-phosphonobutanoic acid as a crude product. To the crude product, was added 250 mL of an aqueous solution containing 7.2 g (180 mmol) of sodium hydroxide proper for neutralization to adjust the pH to about 3 and the aqueous solution was evaporated to dryness under reduced pressure. The obtained oily substance was mixed with acetone and kept still to obtain 2-(N-benzyloxycarbonylamino)-4-phosphonobutanoic acid monosodium salt (51.8 g, yield 76%) as white powder-like crystals.
Reaction SMILES: [CH3:1][CH2:2]O.CN1CCC(=N[N:12]([CH2:20][CH2:21][C:22]2[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=2)[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)CC1>Cl.O.C([O-])([O-])=O.[Na+].[Na+]>[CH3:20][N:12]1[CH2:2][CH2:1][C:15]2[N:12]([CH2:20][CH2:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)[C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][C:18]=3[C:14]=2[CH2:13]1
Reactant: Cc1ccc(N(CCc2ccc(C)nc2)N=C2CCN(C)CC2)cc1
Reactant: CCO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(C)C1
Temperature: 100 °C
Yield: 63 %

Procedure:
Concentrated HCl (6 cm3) was added to EtOH (4 cm3). The crude N′-(1-methyl-piperidin-4-ylidene)-N-[2-(6-methyl-pyridin-3-yl)-ethyl]-N-p-tolyl-hydrazine was dissolved in this ethanolic HCl and heated to 100° C. for 30 minutes. The reaction was then cooled, and diluted with H2O (10 cm3), saturated with Na2CO3, and extracted with CHCl3 (3×50 cm3). The combined extracts were dried (MgSO4) and solvent removed. The residual brown oil was purified by flash column chromatography over SiO2 (10×2 cm) eluting with 1:1 EtOAc/MeOH to provide the desired product as a pale brown powder (612 mg, 63% yield over 3 steps based on last pure starting material (2-methyl-5-(N-nitroso-2-p-tolylaminoethyl)pyridine)).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]=[C:11]=[O:12])[CH3:9].[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([O:25][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[CH3:14].Cl>C(OCC)(=O)C>[CH2:8]([NH:10][C:11]([N:28]1[C:29]([CH3:31])=[CH:30][C:26]([O:25][C:18]2[CH:19]=[CH:20][C:21]([N+:22]([O-:24])=[O:23])=[C:16]([O:15][CH2:13][CH3:14])[CH:17]=2)=[N:27]1)=[O:12])[CH3:9]
Reactant: CCOc1cc(Oc2cc(C)[nH]n2)ccc1[N+](=O)[O-]
Reactant: CCN=C=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCNC(=O)n1nc(Oc2ccc([N+](=O)[O-])c(OCC)c2)cc1C
Reaction time: 5 h
Yield: 64.8 %

Procedure:
Triethylamine (0.07 g, 0.7 mmol) and ethyl isocyanate (0.12 g, 0.7 mmol) were added to a solution of 3-(3-ethoxy-4-nitrophenyloxy)-5-methylpyrazole (0.16 g, 0.6 mmol) in ethyl acetate (5 ml) at 0° C., and the mixture was allowed to have room temperature gradually and stirred for 5 hours. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (10 ml) and extracted with ethyl acetate (10 ml×2). An organic layer was washed with water (10 ml×2), dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/15), to give a yellow solid of N-ethyl-3-(3-ethoxy-4-nitrophenyloxy)-5-methylpyrazole-1-carboxamide (0.13 g, yield: 61.8%). mp: 110-112° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.24 (t, J=7.3 Hz, 3H), 1.49 (t, J=7.0 Hz, 3H), 2.63 (d, J=0.5 Hz, 3H), 3.40 (dq, J=6.0 and 7.3 Hz, 2H), 4.14 (q, J=7.0 Hz, 2H), 5.80 (q, J=0.5 Hz, 1H), 6.73 (dd, J=2.4 and 9.0 Hz, 1H), 6.82 (d, J=2.4 Hz, 1H), 6.92 (br s, 1H), 7.92 (d, J=9.0 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:18][CH2:17][C:6]2([NH:10][C:9](=[O:11])[CH:8]([C:12](OC)=O)[C:7]2=[O:16])[CH2:5][CH2:4]1.[CH3:19][C:20]1(C)N[C:23](=O)[CH2:22][C:21]1=O>>[CH3:1][O:2][CH:3]1[CH2:4][CH2:5][C:6]2([NH:10][C:9](=[O:11])[CH:8]([C:12]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]2=[O:16])[CH2:17][CH2:18]1
Reactant: CC1(C)NC(=O)CC1=O
Reactant: COC(=O)C1C(=O)NC2(CCC(OC)CC2)C1=O
Product: COC1CCC2(CC1)NC(=O)C(c1ccccc1)C2=O
Yield: 90 %

Procedure:
The procedure is as in Example 1, except that 1.532 g of methyl 8-methoxy-2,4-dioxo-1-azaspiro[4.5]decane-3-carboxylate as in Example (X-2-a-1) are used instead of 5,5-dimethylpyrrolidine-2,4-dione. This gives the title compound in a yield of approximately 90% of theory.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][O:34][CH2:35][CH2:36][CH2:37][NH2:38].F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:38][CH2:37][CH2:36][CH2:35][O:34][CH3:33])=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: COCCCN
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCCCNC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)c(OC)c1
Reaction time: 18 h
Yield: 7.4 %

Procedure:
A mixture of 0.100 g (0.22 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.034 mL (0.33 mmole) of 3-methoxy-propylamine, 0.102 g (0.27 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.036 g (0.27 mmole) of 1-hydroxybenzotriazole, 0.195 mL (1.12 mmole) of diisopropylethyl amine and 2.0 mL of dimethylformamide was stirred for 18 hours. The mixture was diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase silica gel chromatography, eluting with an acetonitrile-water (gradient, 20:80-100:0) to give 0.0084 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(3-methoxy-propyl)-benzamide (I-29) as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:14][C:15]1[O:19][C:18]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[N:17][C:16]=1[CH2:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Br>O1CCCC1.CN(C)C=O>[CH3:14][C:15]1[O:19][C:18]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)=[N:17][C:16]=1[CH2:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: Cc1ccc(-c2nc(Cc3cccc(CBr)c3)c(C)o2)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cccc(Cc2nc(-c3ccc(C)cc3)oc2C)c1)C(=O)OCC
Yield: 82.2 %

Procedure:
To 15 ml of dry tetrahydrofuran and 7 ml of dry N,N-dimethylformamide, 0.88 g of 60% sodium hydride was added. To the mixture was added dropwise 4.40 g of diethyl malonate with stirring under ice-cooling. After 15-minute-stirring, a solution of 3.93 g of 3-{[5-methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzyl bromide/5 ml of dry tetrahydrofuran was added and stirred for 1 hour under ice-cooling. The reaction solution was poured into ice-cold water, extracted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane: ethyl acetate=5:1) to provide 3.95 g of the objective compound as colorless crystals.
Reaction SMILES: Cl.[O:2]1[C:7]2[CH:8]=[CH:9][C:10]([NH:12][C:13]([C@@H:15]3[CH2:24][C:23]4[C:18](=[CH:19][C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:22]=4)[CH2:17][NH:16]3)=[O:14])=[CH:11][C:6]=2[O:5][CH2:4][CH2:3]1>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[O:2]1[C:7]2[CH:8]=[CH:9][C:10]([NH:12][C:13]([C:15]3[N:16]=[CH:17][C:18]4[C:23]([CH:24]=3)=[CH:22][CH:21]=[C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=4)=[O:14])=[CH:11][C:6]=2[O:5][CH2:4][CH2:3]1
Reactant: CC(C)(C)c1ccc2c(c1)CN[C@H](C(=O)Nc1ccc3c(c1)OCCO3)C2
Agent: [Mn+4]
Agent: Cl
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc2cc(C(=O)Nc3ccc4c(c3)OCCO4)ncc2c1
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
(The title product was prepared according to the procedure of E. D. Cox; T. J. Hagen; R. M. McKernan; J. M. Cook, Med. Chem. Rest. 1995, 5, 710-718). To a solution of (3S)-7-tert-butyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (2,3-dihydro-benzo[1,4]dioxin-6-yl)-amide hydrochloride, Example 10(d), (80 mg, 0.219 mmol) in toluene (10 mL) was added manganese dioxide (110 mg, 1.1 mmol). The reaction mixture was stirred at 70° C. under N2 for 1.5 h, filtered through a pad of Celite®, and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography (8:1 hexane/EtOAc) to give the title compound as an yellow solid. Mp 154-157° C. MS (ESI, pos. ion) m/z: 363 (M+1).
Reaction SMILES: [CH3:1]/[C:2](/[C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)=[CH:3]/[CH2:4][CH3:5].[H][H]>C1(C)CCC(C(C)C)C(O)C1.[Pd]>[CH3:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=1)[CH2:3][CH2:4][CH3:5]
Reactant: [H][H]
Reactant: CC/C=C(/C)c1ccc(C(=O)OC)cc1
Agent: [Pd]
Agent: CC1CCC(C(C)C)C(O)C1
Product: CCCC(C)c1ccc(C(=O)OC)cc1
Yield: 108.2 %

Procedure:
To a solution of (Z)-methyl 4-(pent-2-en-2-yl)benzoate (600 mg, 2.15 mmol) in menthol was added Palladium 10% on Carbon (340 mg, 0.3 mmol) and the mixture was hydrogenated at hydrogen gas pressure 4 atmosphere for 8 hours. The reaction mixture was filtered. The filtrate was evaporated and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=8:1) to get methyl 4-(pentan-2-yl)benzoate (480 mg, 80%). LRMS (M+H+) m/z: calcd 206.13. found 206.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[NH2:6][CH2:7][C@H:8]([CH3:36])[O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[C:12]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[C:23]([Cl:35])[CH:22]=1)=[N:13][CH:14]=[N:15]2>>[Cl:35][C:23]1[CH:22]=[C:21]([NH:20][C:12]2[C:11]3[C:16](=[CH:17][CH:18]=[CH:19][C:10]=3[O:9][C@@H:8]([CH3:36])[CH2:7][NH:6][C:1](=[O:5])[CH2:2][OH:3])[N:15]=[CH:14][N:13]=2)[CH:26]=[CH:25][C:24]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1
Reactant: C[C@@H](CN)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: O=C(O)CO
Product: C[C@@H](CNC(=O)CO)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 47 %

Procedure:
The procedure described in Example 1 was repeated using glycolic acid and 5-[(1S)-2-amino-1-methylethoxy]-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 36, preparation of starting materials) to give the title compound in 47% yield; NMR spectrum (DMSO-d6) 1.20 (d, 3H), 3.41 (m, 1H), 3.74 (m, 1H), 3.78 (d, 2H), 4.92 (m, 1H), 5.29 (s, 2H), 5.48 (t, 1H), 7.23 (dd, 2H), 7.31 (d, 1H), 7.35 (m, 1H), 7.58 (m, 2H), 7.70 (t, 1H), 7.87 (td, 1H), 8.13 (d, 1H), 8.17 (t, 1H), 8.47 (s, 1H), 8.58 (d, 1H), 9.98 (s, 1H); Mass Spectrum MH+ 494.
Reaction SMILES: C(Cl)CCl.[NH2:5][C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)=[CH:8][CH:7]=1.[CH3:17][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH2:27][NH:28][CH3:29])=[N:19]1.C1C=CC2N(O)N=NC=2C=1.O.CCN(CC)CC>CN(C=O)C>[NH2:5][C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([N:28]([CH3:29])[CH2:27][C:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]([CH3:17])[N:19]=2)=[O:16])=[CH:8][CH:7]=1
Reactant: CNCc1nn(C)c2ccccc12
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CN(Cc1nn(C)c2ccccc12)C(=O)/C=C/c1ccc(N)nc1
Yield: 74.1 %

Procedure:
EDC (230 mg, 1.2 mmole) was added to a solution (E)3-(6-aminopyridin-3-yl)acrylic acid (164 mg, 1.0 mmole), 1-methyl-3-(methylaminomethyl)-1H-indazole (210 mg, 1.2 mmole), HOBt.H2O (162 mg, 1.2 mmole), and Et3N (0.28 mL, 2.0 mmole) in dry DMF (5 mL) at RT. After 18 hr the mixture was concentrated. Flash chromatography on silica gel (5% EtOH/EtOAc) gave the title compound (238 mg, 74%) as a white foam: 1H NMR (400 MHz, CDCl3) δ 8.24 (m, 1 H), 7.90 (m, 1 H), 7.65 (m, 2 H), 7.35 (m, 2 H), 7.09 (m, 1 H), 6.73 (m, 1 H), 6.50 (m, 1 H), 5.04 (s, 2 H), 4.83 (bs, 2 H), 4.04 (s, 3 H), 3.10 (s, 3 H); MS (ES) m/e 322 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:15]=[CH:16][C:17]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:31]=[C:32]([NH:46][C:47](OC2C=CC=CC=2)=[O:48])[C:33](=[CH:44][CH:45]=1)[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]>>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([S:25]([NH:28][C:47]([NH:46][C:32]2[CH:31]=[C:30]([Cl:29])[CH:45]=[CH:44][C:33]=2[C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])=[O:48])(=[O:27])=[O:26])[CH:15]=[CH:16][C:17]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1cc(Cl)ccc1C(=O)OCc1ccccc1)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(S(N)(=O)=O)cc1NC(=O)OCc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(S(=O)(=O)NC(=O)Nc2cc(Cl)ccc2C(=O)OCc2ccccc2)cc1NC(=O)OCc1ccccc1
Yield: 77.1 %

Procedure:
g (6.99 mmol) of 3-benzyloxycarbonylamino-4-t-butoxycarbonylbenzenesulfonamide and 2.67 g (6.99 mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way as in Preparation Example 8 to obtain 3.74 g (yield 77%) of benzyl 2-{[(3-benzyloxycarbonylamino-4-t-butoxycarbonylbenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate. Properties: colorless amorphous, PMR (δ ppm, DMSO-d6): 1.54 (9H, s), 5.19 (2H, s), 5.34 (2H, s), 7.05 (1H, m), 7.34-7.58 (10H, m), 7.60 (1H, d), 7.90 (1H, d), 7.98 (1H, d), 8.50. (1H, br), 8.62 (1H, s), 10.00 (1H, br), 10.41 (1H, s).
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[C:4](=[O:35])/[CH:5]=[C:6](/[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])=[C:10]([O:24][CH2:25][CH2:26][CH2:27][O:28]C2CCCCO2)[CH:9]=1)\[CH3:7])[CH3:2]>CO.Cl>[CH2:36]([N:3]([CH2:1][CH3:2])[C:4](=[O:35])/[CH:5]=[C:6](/[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:17]([F:23])=[CH:18][CH:19]=[CH:20][C:21]=2[F:22])=[C:10]([O:24][CH2:25][CH2:26][CH2:27][OH:28])[CH:9]=1)\[CH3:7])[CH3:37]
Reactant: CCN(CC)C(=O)/C=C(\C)c1ccc(OCc2c(F)cccc2F)c(OCCCOC2CCCCO2)c1
Agent: Cl
Solvent: CO
Product: CCN(CC)C(=O)/C=C(\C)c1ccc(OCc2c(F)cccc2F)c(OCCCO)c1
Reaction time: 1 h

Procedure:
To a solution of N,N-diethyl (E)-3-{4-(2,6-difluorobenzyloxy)-3-[3-(tetrahydropyran-2-yloxy)-propoxy]-phenyl}-2-butenamide (3.53 g, 6.83 mmol) in methanol (72 mL) is added IN HCl (39.0 mL), and the resulting mixture is stirred for 1 hour. After this time, the solution is concentrated to 40 mL in vacuo, and the residue is extracted with EtOAc (2×75 mL). The combined organic phase is washed with water (1×100 mL) and brine (1×100 mL), dried over MgSO4, and concentrated in vacuo to yield N,N-diethyl (E)-3-[4-(2,6-difluorobenzyloxy)-3-(3-hydroxypropoxy)-phenyl]-2-butenamide.