Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([N:18]1[CH:22]=[CH:21][CH:20]=N1)=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:23]1([CH2:29][O:30][C:31]2[CH:32]=C(CN)C=[CH:35][CH:36]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(#N)C>[C:14]([O:13][C:11](=[O:12])/[N:10]=[C:9](\[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])/[NH:18][CH2:22][C:21]1[CH:20]=[CH:35][CH:36]=[C:31]([O:30][CH2:29][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:32]=1)([CH3:15])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Reactant: NCc1cccc(OCC2CCCCC2)c1
Solvent: CC#N
Product: CC(C)(C)OC(=O)/N=C(/NCc1cccc(OCC2CCCCC2)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A solution of N,N′-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (0.71 g, 2.28 mmol) and (3-(cyclohexylmethoxy)phenyl)methanamine (0.50 g, 2.28 mmol) in acetonitrile (15 ml) was stirred at 50° C. for 18 h under argon. After cooling to room temperature, a white solid was formed, collected via filtration, and dried under vacuum to give (Z)-tert-butyl(tert-butoxycarbonylamino)(3-(cyclohexylmethoxy)benzylamino)methylenecarbamate. Yield (400 mg, 38%). 1H NMR (400 MHz, DMSO-d6) δ 11.47 (s, 1H), 8.61 (t, J=6.0 Hz, 1H), 7.20 (t, J=8.0 Hz, 1H), 6.77-6.86 (m, 3H), 4.44 (d, J=5.6 Hz, 2H), 3.72 (d, J=6.4 Hz, 2H), 1.60-1.80 (m, 6H), 1.45 (s, 9H), 1.36 (s, 9H), 0.95-1.25 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6](CC#N)[CH:7]=1.[C:12]([OH:15])(=[O:14])[CH3:13].S(=O)(=O)(O)O>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:11])=[C:4]([CH2:13][C:12]([OH:15])=[O:14])[CH:3]=1
Reactant: N#CCc1cc(Br)ccc1F
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1cc(Br)ccc1F

Procedure:
(5-Bromo-2-fluoro-phenyl)-acetonitrile (0.5 g, 2.3 mmol) was treated with acetic acid (2 mL) and sulfuric acid (2 mL) in H2O (2 mL) at 95° C. for 5 hours. Aqueous worked-up afforded the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2=[N:12][N:13]=[N:14][N:4]2[N:3]=1.[CH3:15][NH:16][CH3:17]>CO>[CH3:15][N:16]([CH3:17])[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2=[N:12][N:13]=[N:14][N:4]2[N:3]=1
Reactant: CNC
Reactant: Clc1nn2nnnc2c2c1CCCC2
Solvent: CO
Product: CN(C)c1nn2nnnc2c2c1CCCC2

Procedure:
A mixture was prepared from 6 g of 6-chloro-7,8,9,10-tetrahydrotetrazolo[5,1-a]phthalazine, 150 ml of methanol and 125 ml of 40% aqueous dimethylamine. This mixture was heated at reflux for 3 hours and then cooled. The precipitate which formed was separated by filtration and partitioned between methylene chloride and water. The organic layer was separated, dried over sodium sulfate, and concentrated to leave a residual solid. This was recrystallized from ethanol to give 6-dimethylamino-7,8,9,10-tetrahydrotetrazolo[5,1-a]phthalazine melting at about 239°-240° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].Cl.[NH2:25]O>C(O)(=O)C.O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:25])=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C#N)ccc1OCc1ccccc1
Yield: 100.3 %

Procedure:
4-benzyloxy-3-methoxybenzaldehyde (4.84 g, 20 mmol) in acetic acid (25 ml) and sodium acetate (3.3 g, 40 mmol) was reacted with hydroxylamine hydrochloride (2.8 g, 40 mmol) at reflux for 6 hours. The mixture was cooled, diluted with water, extracted with methylene chloride, dried over MgSO4, concentrated to give title compound (4.8 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[O:12]=[C:13]1[C:18]2=[CH:19][NH:20][C:21]([CH:22]=O)=[C:17]2[CH2:16][CH2:15][NH:14]1.N1CCCCC1>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:22][C:21]1[NH:20][CH:19]=[C:18]2[C:17]=1[CH2:16][CH2:15][NH:14][C:13]2=[O:12]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ccc(F)cc2C1=Cc1[nH]cc2c1CCNC2=O
Temperature: 80 °C

Procedure:
A mixture of 5-fluoro-1,3-dihydro-indol-2-one (30.2 mg, 0.2 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (32.8 mg, 0.2 mmol) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 4 hours. The precipitate was collected by vacuum filtration, washed with cold ethanol and dried to give the title compound.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][CH2:8][CH2:9][C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[OH:11])[CH:2]=1.C(N(CC)CC)C.[C:26](=O)(OC(Cl)(Cl)Cl)[O:27]C(Cl)(Cl)Cl>C(Cl)Cl>[C:12]1([C@H:10]2[O:11][C:26](=[O:27])[N:7]([C:3]3[CH:2]=[C:1]([CH3:18])[CH:6]=[CH:5][CH:4]=3)[CH2:8][CH2:9]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cccc(NCC[C@H](O)c2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(N2CC[C@@H](c3ccccc3)OC2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a solution of (S)-3-(m-tolylamino)-1-phenylpropan-1-ol (40 mg, 0.17 mmol) in dry CH2Cl2 (1 mL) was added triethylamine (50 mg, 0.51 mmol) and bis(trichloromethyl) carbonate (20 mg, 0.067 mmol) at 0° C., and the reaction mixture was stirred overnight at room temperature. When the reaction was over, the mixture was concentrated to give the crude product, which was purified by preparative TLC (3:1 Petroleum ether/EtOAc) to give (S)-6-phenyl-3-m-tolyl-1,3-oxazinan-2-one (12 mg, 26%). 1H NMR: (400 MHz, CDCl3): δ=2.24-2.37 (m, 5H), 3.52-3.63 (m, 1H), 3.70-3.79 (m, 1H), 5.42 (dd, 1H), 7.01-7.10 (m, 3H), 7.18-7.23 (m, 2H), 7.32-7.39 (m, 4H).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[S:9][C:10](SC)=[C:11]([C:20]#[N:21])[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=1)=[O:7])[CH3:4]>CCO>[CH2:3]([O:5][C:6]([C:8]1[S:9][CH:10]=[C:11]([C:20]#[N:21])[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1sc(SC)c(C#N)c1-c1ccc(I)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1scc(C#N)c1-c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add NaBH4 (0.26 mmol) to a solution of 3-(4-iodophenyl)-4-cyano-5-methylsulfanyl-thiophene-2-carboxylic acid ethyl ester, prepared in example E-3, in 2 mL of EtOH at 0° C. Remove the ice-bath and stir at room temperature. After 30 min, add additional NaBH4 (0.26 mmol) and stir and additional 30 minutes. Remove the solvent in vacuo and extract the residue with 50 mL of 1/9 MeOH/CH2Cl2. Evaporate and chromatograph (hexane:ethyl acetate 3:1) over silica gel to provide the title compound: MS (ES+, m/e): 384 (M+1).
Reaction SMILES: [CH3:1][C:2]12[CH2:12][CH2:11][CH:5]([C:6](=[N:9][OH:10])[C:7]1=O)[C:4]([CH3:14])([CH3:13])[O:3]2.[NH2:15][NH2:16]>C(O)C>[CH3:1][C:2]12[CH2:12][CH2:11][CH:5]([C:6](=[N:9][OH:10])[C:7]1=[N:15][NH2:16])[C:4]([CH3:14])([CH3:13])[O:3]2
Reactant: CC12CCC(C(=NO)C1=O)C(C)(C)O2
Reactant: NN
Solvent: CCO
Product: CC12CCC(C(=NO)C1=NN)C(C)(C)O2

Procedure:
A mixture of 1.97 g. (0.01 mole) 1,3,3-trimethyl-2-oxabicyclo[2,2,2]octan-5,6-dione-5-oxime and 0.35 ml. (0.011 mole) anhydrous hydrazine (98%) in 25 ml. absolute ethanol is refluxed under nitrogen at a bath temperature of 80° C. for 1 hour. After evaporation of the solvent, the residue is recrystallized from ether to give 1,3,3-trimethyl-2-oxabicyclo [2,2,2]octan-5,6-dione-5-oxime-6-hydrazone; mp. 138° to 142° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[C:12]3[N:19]2[CH2:24][CH2:23][CH2:22][C@H:21]([NH:25]C(=O)OC(C)(C)C)[CH2:20]2)O1.FC(F)(F)S(O[C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([C:46]2[S:47][CH:48]=[CH:49][N:50]=2)[N:41]=1)(=O)=O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.COCCOC>[S:47]1[CH:48]=[CH:49][N:50]=[C:46]1[C:42]1[N:41]=[C:40]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[C:12]3[N:19]2[CH2:24][CH2:23][CH2:22][C@H:21]([NH2:25])[CH2:20]2)[CH:45]=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccnc3ccc(B4OC(C)(C)C(C)(C)O4)cc23)C1
Reactant: O=S(=O)(Oc1cccc(-c2nccs2)n1)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: COCCOC
Product: N[C@H]1CCCN(c2ccnc3ccc(-c4cccc(-c5nccs5)n4)cc23)C1
Yield: 40 %

Procedure:
A solution of (S)-tert-butyl 1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4-yl)piperidin-3-ylcarbamate (1.0 equiv.), 6-(thiazol-2-yl)pyridin-2-yl trifluoromethanesulfonate (1.5 equiv.) and Pd(dppf)Cl2—CH2Cl2 (0.15 equiv.) in 3:1 DME/2M Na2CO3 was heated in a microwave at 100° C. for 20 minutes. Upon cooling, the solution was partitioned between EtOAc and Na2CO3(sat.) washed further with NaCl(sat.), dried over MgSO4, concentrated and purified by RP HPLC. Upon lyophilization, the Boc group was deprotected by treatment with 25% TFA/CH2Cl2, concentrated, purified by RP-HPLC and lyophilized to yield (S)-1-(6-(6-(thiazol-2-yl)pyridin-2-yl)quinolin-4-yl)piperidin-3-amine (40%). LC/MS=388.1 (M+H), LC=2.02 min.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[N:2]1.[I:10]N1C(=O)CCC1=O>C(#N)C.O>[I:10][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:1][N:2]=1
Reactant: O=C1CCC(=O)N1I
Reactant: c1cnc2[nH]ncc2c1
Solvent: O
Solvent: CC#N
Product: Ic1n[nH]c2ncccc12
Temperature: 75 °C
Reaction time: 17 h

Procedure:
A solution of the intermediate from Step A above (14.3 g, 120 mmol) and N-iodosuccinimide (28.4 g, 126 mmol) in acetonitrile (210 mL) was heated at 75° C. After 17 hours, N-iodosuccinimide (5.4 g, 24 mmol) was added and the reaction solution stirred at 75° C. for an additional 1.5 hours. The reaction solution was cooled to room temperature and diluted with water. The slurry was concentrated in vacuo to remove most of the acetonitrile. The solid was collected, washed with water, and dried under a vacuum with a nitrogen sweep for 17 hours to give the title compound. 1H NMR (400 MHz, CH3CN-d3): δ 11.85 (s, 1H); 8.55 (dd, J=4.53, 1.53 Hz, 1H); 7.87 (dd, J=8.11, 1.53 Hz, 1H); 7.24 (dd, J=8.11, 4.51 Hz, 1H). m/z=246.1 (M+H).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].C(Cl)Cl.[CH3:9][N:10]1[C:14]2[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[S:17][C:13]=2[C:12]([NH2:22])=[N:11]1>N1C=CC=CC=1>[CH3:9][N:10]1[C:14]2[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[S:17][C:13]=2[C:12]([NH:22][C:1](=[O:4])[CH2:2][CH3:3])=[N:11]1
Reactant: Cn1nc(N)c2sc3ccccc3c21
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)Nc1nn(C)c2c1sc1ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.8 g. of propionyl chloride in 10 ml. of methylene chloride was added to a stirred solution of 0.01 mole of the above-referred amine in 50 ml. of methylene chloride containing 2.0 ml. of pyridine. The resulting clear solution was stirred overnight at room temperature and then washed with water, 5% aqueous hydrochloric acid, water, 10% aqueous sodium bicarbonate and finally with water. The upper organic layer was dried over magnesium sulfate and concentrated in vacuo to give a solid residue. This residue was recrystallized from ethanol to give N-(1-methyl-1H-(1)-benzothieno[3,2-c]pyrazol-3-yl)propanamide, m.p. 88°-89° C.
Reaction SMILES: [CH2:1]([C:8]1([O:12][C:13]([NH:15][C@@H:16]([CH2:21][CH2:22][CH2:23][CH3:24])[C:17]([O:19]C)=O)=[O:14])[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].[C:28]1([P:34](=[CH:47][C:48]#[N:49])([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>O1CCCC1.O.CN(C)C1C=CN=CC=1>[C:48]([C:47](=[P:34]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:17]([C@@H:16]([NH:15][C:13](=[O:14])[O:12][C:8]1([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10][CH2:11]1)[CH2:21][CH2:22][CH2:23][CH3:24])=[O:19])#[N:49]
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCC[C@H](NC(=O)OC1(Cc2ccccc2)CCC1)C(=O)OC
Agent: CN(C)c1ccncc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCC[C@H](NC(=O)OC1(Cc2ccccc2)CCC1)C(=O)C(C#N)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.7 %

Procedure:
To 2.44 g (7.32 mmol) of methyl(2S)-2-({[(1-benzylcyclobutyl)oxy]carbonyl}amino)hexanoate in 24 mL of tetrahydrofuran:water (1:1) was added 429.9 mg (10.24 mmol) of lithium hydroxide monohydrate and the mixture was stirred at room temperature for 4 h. The solution was concentrated and extracted with diethyl ether. The aqueous layer was acidified with 1 N hydrochloric acid and extracted with diethyl ether. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was dissolver in 36 mL of dichloromethane, then 44.7 mg (365.9 μmol) of 4-dimethylaminopyridine was added. To this solution was added 2.31 g (7.68 mmol) of (triphenylphosphoranylidene)acetonitrile, followed by 1.55 g (8.05 mmol) of 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide, and the mixture was stirred at room temperature for 17 h. Water was added to the solution and it was extracted with ethyl acetate. The organic layer was washed with 10% citric acid, followed by saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with an ethyl acetate:hexanes solution (1:1) to give 3.25 g (74%) of 1-benzylcyclobutyl(1S)-1-[cyano(triphenylphosphoranylidene)acetyl]pentylcarbamate. Rf=0.25 (1:1 ethyl acetate:hexanes); 1H NMR (300 MHz, DMSO-d6) δ 7.75-7.66 (m, 3H), 7.64-7.54 (m, 12H), 7.20-7.14 (m, 5H), 7.03 (d, J=8 Hz, 1H), 4.55-4.50 (m, 1H), 3.21 (m, 2H), 2.24-2.16 (m, 2H), 2.14-2.06 (m, 2H), 1.80-1.70 (m, 2H), 1.70-1.60 (m, 1H), 1.60-1.46 (m, 1H), 1.42-1.24 (m, 4H), 0.89 (t, J=7 Hz, 3H); ES-LCMS m/z 603 (M+H).
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:20]([F:23])([F:22])[F:21])[CH:9]=[C:10]([C:11]3[CH:16]=[C:15]([F:17])[C:14]([F:18])=[C:13]([F:19])[CH:12]=3)[C:4]=2[N:3]=1.[Br:24][C:25]1[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[N:27][CH:28]=[CH:29][CH:30]=1>>[Br:24][C:25]1[C:26]([N:31]2[CH2:32][CH2:33][N:34]([C:2]3[NH:3][C:4]4[C:10]([C:11]5[CH:16]=[C:15]([F:17])[C:14]([F:18])=[C:13]([F:19])[CH:12]=5)=[CH:9][C:8]([C:20]([F:23])([F:22])[F:21])=[CH:7][C:5]=4[N:6]=3)[CH2:35][CH2:36]2)=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: Brc1cccnc1N1CCNCC1
Reactant: Fc1cc(-c2cc(C(F)(F)F)cc3[nH]c(Cl)nc23)cc(F)c1F
Product: Fc1cc(-c2cc(C(F)(F)F)cc3nc(N4CCN(c5ncccc5Br)CC4)[nH]c23)cc(F)c1F

Procedure:
2-Chloro-6-(trifluoromethyl)-4-(3,4,5-trifluorophenyl)-1H-benzoimidazole (140 mg, 0.4 mmol, Example 51b) reacted with 1-(3-bromo-pyridin-2-yl)-piperazine (120 mg, 0.5 mmol, Example 41a) under the conditions of Example 3c to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 556 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][CH3:12])[C:5]([OH:7])=[O:6].[N:13](OC(C)(C)C)=O.C([O-])(=O)C.[K+].C1OCCOCCOCCOCCOCCOC1>O1CCCC1.C(Cl)(Cl)Cl>[C:5]([C:4]1[CH:3]=[C:2]2[C:10]([C:11]([CH3:12])=[N:13][NH:1]2)=[CH:9][CH:8]=1)([OH:7])=[O:6]
Reactant: CC(C)(C)ON=O
Reactant: CCc1ccc(C(=O)O)cc1N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Cc1n[nH]c2cc(C(=O)O)ccc12
Temperature: -12 °C
Reaction time: 0.33 h
Yield: 17.3 %

Procedure:
To chloroform (75 ml), which had been passed through an alumina column, was added boron trifluoride diethyl ether complex (3.75 g, 26.4 mmol) and the mixture was cooled at −12° C. A solution of 3-amino-4-ethylbenzoic acid (2.5 g, 15.1 mmol) in tetrahydrofuran (25 ml) was dropwise added thereto for 20 min. After the completion of the addition, t-butyl nitrite (1.87 g, 18.1 mmol) was added and the mixture was heated to 5° C. The mixture was stirred at 5° C. for 1.5 hr. Then potassium acetate (7.4 g, 75.4 mmol) and 18-crown-6-ether (400 mg, 1.51 mmol) were added and the mixture was stirred at room temperature for 40 hr. The brown reaction mixture was concentrated under reduced pressure. Ethyl acetate/acetone (7/3, 100 ml) and 1N hydrochloric acid (25 ml) was added to the residue and the mixture was stirred at room temperature for 1 hr. Saturated brine (25 ml) was added thereto. The insoluble matter was filtered off and the filtrate was partitioned. The water layers were extracted with ethyl acetate/acetone (7/3, 40 ml) and the combined organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The obtained brown oil (4.3 g) was dissolved in ethyl acetate, and then hydrogen chloride-diethyl ether (6 of hydrogen chloride in 40 ml of ether) and diethyl ether (100 ml) were added. The precipitated solid was collected by filtration. The obtained solid was extracted with ethyl acetate/acetone (7/3, 100 ml) and saturated brine (25 ml), and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The obtained solid was washed with diethyl ether to give the objective compound (0.46 g, 17%) as brown crystals.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][O:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:16](OS(C(F)(F)F)(=O)=O)[N:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F-:32].C([N+](CCCC)(CCCC)CCCC)CCC>O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][O:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:16]([F:32])[N:15]=2)=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)c1ccc(CCOc2nc(OS(=O)(=O)C(F)(F)F)nc3ccccc23)cc1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Product: CC(C)(C)c1ccc(CCOc2nc(F)nc3ccccc23)cc1

Procedure:
A 15 ml round bottom flask is charged with 4-(2-(4-tert-butylphenyl)-ethoxy)-2-(trifluoromethanesulfonyloxy)-quinazoline (0.3 g, 0.66 mmol). Tetrabutylammonium fluoride solution (1M in THF, 3.3 ml, 3.3 mmol) is then added to it and the solution refluxed for 60 minutes. The mixture is then cooled and water is added to it. It is then extracted with dichloromethane, washed with water and dried. The crude obtained after concentration is purified by silica gel flash chromatography (ethyl acetate/hexanes) to obtain the desired compound.
Reaction SMILES: CN1CCOCC1.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]1[CH2:28][CH2:29][OH:30])=[O:14])([CH3:11])([CH3:10])[CH3:9]>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]1[CH2:28][CH:29]=[O:30])=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(CCO)C1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(CC=O)C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
In methylene chloride (150 ml) was dissolved 1,4-bis(tert-butoxycarbonyl)-2-(2-hydroxyethyl)piperazine. Under ice cooling, N-methylmorpholine (2.14 g) and tetra-n-propylammonium perruthenate (0.97 g) were added to the reaction mixture, followed by stirring at room temperature for 17 hours. The reaction mixture was then distilled off under reduced pressure. The residue was subjected to chromatography on a silica gel column (hexane:ethyl acetate=9:1 to 2:1), whereby the title compound (3.11 g) was obtained as colorless powder.
Reaction SMILES: [C:1]([C:5]1([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[CH2:7][O:6]1)([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1>C(#N)C.C(OCC)(=O)C>[C:1]([C:5]([OH:6])([CH2:7][N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)[CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)C1(COC2CCCCO2)CO1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)C(O)(COC1CCCCO1)Cn1ccnc1
Yield: 71.2 %

Procedure:
A solution of 59 g (0.28 mol of 2-tert.-butyl-2-(tetrahydro-2H-pyran-2-yloxy-methyl)-oxirane in 100 ml of acetonitrile is added dropwise to a mixture of 119 g 1.75 mol of imidazole, 1 g 9 mols) of potassium tert.-butylate and 500 ml of acetonitrile under a nitrogen atmosphere, the reaction mixture being boiled under reflux. When the addition has ended, the mixture is boiled under reflux for a further 10 hours, the solvent is then stripped off under reduced pressure and the residue which remains is taken up in ethyl acetate. The organic phase is washed with water, dried over sodium sulphate and concentrated under reduced pressure. The product thus obtained is purified chromatographically over silica gel with chloroform as the mobile phase. 56.3 g (72% of theory) of 2-tert.-butyl-3-(imidazol-1-yl)-1-(tetrahydro-2H-pyran-2-yloxy)-propan-2-ol are obtained in this manner in the form of a solid substance of melting point 107° C.
Reaction SMILES: [C:1]1([N:7]([CH2:14][C:15]([O:17][CH2:18][C:19]2C=CC=CC=2)=[O:16])[CH2:8][C:9]([O:11]CC)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Pd]>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][N:7]([CH2:8][C:9]([OH:11])=[O:10])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:19]
Reactant: CCOC(=O)CN(CC(=O)OCc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CN(CC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
Benzyl ethyl 2,2′-(phenylimino)diacetate (1.0 g) was dissolved in methanol (15 mL) and 10% palladium on carbon (100 mg) was added to the mixture. The mixture was stirred at ambient temperature for 3 hours under hydrogen atmosphere (3 atms) and filtered through bed of celite. The filtrate was concentrated in vacuo to afford [(2-ethoxy-2-oxoethyl)(phenyl)amino]acetic acid (0.698 g) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5]P(=O)(OCC)OCC.C[Si](C)(C)N[Si](C)(C)C.[Li].[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH2:36][C@@H:35]1[CH:39]=O)=[O:33])([CH3:30])([CH3:29])[CH3:28]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:39]/[C@H:35]2[CH2:36][CH2:37][CH2:38][N:34]2[C:32]([O:31][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:33])[CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Reactant: CCOP(=O)(Cc1cccc(Cl)c1)OCC
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1/C=C/c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
775 mg of commercially available diethyl 3-chlorobenzylphosphonate are dissolved in 20 ml of THF, and 3 ml of lithium hexamethyldisilazane are added dropwise at −78° C. under protective gas. After 1 h, a solution of 500 mg of tert-butyl-(R)-2-formylpyrrolidine-1-carboxylate in 5 ml of THF is added dropwise at the temperature indicated. The batch is stirred at RT for 3 h and subsequently subjected to aqueous work-up, giving 1 g of tert-butyl (R)-2-[(E)-2-(3-chlorophenyl)vinyl]pyrrolidine-1-carboxylate as colourless oil, which is immediately reacted further.