Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:22][C:21]2[CH:23]=[C:17]([CH:18]=[CH:19][CH:20]=2)[CH2:16][C@@H:15]([C:24]([O:26]C)=[O:25])[NH:14][C:13](=[O:28])[CH2:12][NH:11][C:10]1=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(Cl)(Cl)Cl.CO.CC(O)=O.C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>C1COCC1.CO>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:22][C:21]2[CH:23]=[C:17]([CH:18]=[CH:19][CH:20]=2)[CH2:16][C@@H:15]([C:24]([OH:26])=[O:25])[NH:14][C:13](=[O:28])[CH2:12][NH:11][C:10]1=[O:29])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1Cc2cccc(c2)C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)N1
Agent: O=C1c2ccccc2C(=O)C1(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1Cc2cccc(c2)C[C@@H](C(=O)O)NC(=O)CNC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
Cyclic peptide ester 13 (190 mg, 0.45 mmol) was dissolved in warm THF/MeOH (40 mL) and cooled to rt. NaOH (1 N, 0.5 mL) was slowly added with stirring. After 1 h, the completed reaction (TLC-disappearance of 13, 120:2:1 CHCl3 /MeOH/AcOH, ninhydrin stain) was concentrated and the residue was dissolved in water. Dropwise addition of 2 N HCl induced precipitation of the product which was collected on a filter and dried under vacuum in a dessicator to give a white solid (140 mg, 74%). mp >250° C; 1H NMR (CDCl3 /DMSO-d6): δ 8.30 (br s, 1 H), 7.98 (t, 1 H, J=6.3 Hz), 7.23 (d, 1 H, J=9.4 Hz), 7.14 (t, 1 H, J=7.0 Hz), 6.96 (d, 1 H, J=7.0 Hz), 6.66 (s, 1 H), 6.37 (d, 1 H, J=7.8 Hz), 4.39 (m, 1 H), 4.05 (m, 1 H), 3.85 (dd, 1 H, J=8.8, 14.0 Hz), 3.27 (1 H, obscured by H2O peak), 3.02-2.78 (m, 3 H), 2.67 (dd, 1 H, 8.2 Hz, J=12.9 Hz), 1.34 (s, 9 H); 13C NMR (DMSO-d6 ; CD3OD): δ 173.27, 173.05, 169.97, 156.14, 137.34, 136.43, 133.51, 129.55, 128.80, 128.18, 80.24, 56.76, 52.70, 49.45, 44.16, 37.58, 28.73. Anal. Calcd for C19H25N3O6H2O: C, 55.74; H, 6.65; N, 10.26. Found: C, 55.16; H, 6.59; N, 9.90.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:25]([F:28])([F:27])[F:26])/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([N:20]3[CH:24]=[N:23][CH:22]=[N:21]3)=[C:16]([CH:19]=2)[C:17]#[N:18])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([O-])(=O)C.[Na+].[Cl-].[OH:35][NH3+:36]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:25]([F:27])([F:26])[F:28])/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([N:20]3[CH:24]=[N:23][CH:22]=[N:21]3)=[C:16]([CH:19]=2)/[C:17](=[N:36]/[OH:35])/[NH2:18])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: N#Cc1cc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1-n1cncn1
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N/C(=N\O)c1cc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1-n1cncn1
Temperature: 25 °C

Procedure:
A solution of (E)-5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-1,2,4-triazol-1-yl)benzonitrile (0.3 g, 0.71 mmol), sodium acetate (0.087 g, 1.065 mmol) and hydroxylammonium chloride (0.072 g, 1.065 mmol) in 9:1 ethanol/water mixture (10 mL) was stirred at 70° C. for 8 h. The reaction was cooled to RT, and the ethanol was evaporated. The residue was dissolved in water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as an off white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:20][C:19]3[C:18](=[O:21])[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[NH:11][C:10]=3[CH:9]2[C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1)CCC>CN(C=O)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:39]1[CH:40]=[CH:41][C:36]([C:2]2[CH:3]=[N:4][C:5]([N:8]3[CH2:20][C:19]4[C:18](=[O:21])[C:17]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=5[NH:11][C:10]=4[CH:9]3[C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)=[N:6][CH:7]=2)=[CH:37][CH:38]=1
Reactant: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)OCO3)N(c1ncc(Br)cn1)C2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)OCO3)N(c1ncc(-c3ccncc3)cn1)C2
Temperature: 140 °C

Procedure:
A stirred mixture of 1,2,3,4-tetrahydro-2-(5-bromopyrimidin-2-yl)-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one (46 mg, 0.1 mmol) (prepared as in Example 53), (PPh3)4Pd (3.5 mg, 3.0 μmol) and 4-tri-n-butylstannylpyridine (37 mg, 0.1 mmol) in dry DMF (2.0 ml) was heated at 140° C. for 12 h. More catalyst (3.5 mg) was added and the mixture was refluxed for 4 h and then cooled. The solution was diluted with ethyl acetate and filtered through filter paper. The organic phase was washed with brine and water, then dried over Na2SO4. A small amount of silica gel was added into the solution and dried in vacuo. Purification by flash column (silica gel, neat acetonitrile followed by 10% ammonium hydroxide in water:actonitrile=1:10, v/v) yielded the product as a white solid.
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:32])[C:7]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)=[CH:11][CH:10]=[CH:9][C:8]=1[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=1)C>CO>[CH2:21]1[O:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][C:12]3[CH:11]=[CH:10][CH:9]=[C:8]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=4)[C:7]=3[C:6]([OH:32])=[O:5])=[CH:15][C:16]=2[O:22]1
Reactant: CCOC(=O)c1c(Oc2cccc(OC)c2)cccc1Oc1ccc2c(c1)OCO2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cccc(Oc2cccc(Oc3ccc4c(c3)OCO4)c2C(=O)O)c1
Yield: 67.3 %

Procedure:
KOH (371 mg, 5.7 mmol) that was dissolved in methanol was added to a solution of ethyl-2-(3-methoxyphenoxy)-6-[3,4-(methylenedioxy)phenoxy]benzoate (200 mg, 0.57 mmol) in methanol (5 ml). The mixture was heated under reflux for approximately 20 hours at which time TLL had indicated the formation of a polar material. The solvent was evaporated and the remaining residue was diluted with water (7 ml, pH≈7.5) and extracted with EtOAc (2×10 ml). The aqueous fraction was then acidified to pH~2.5 using concentrated HCl and then extracted with ethyl acetate (2×10 ml). Evaporation of solvents gave an off-white solid which was recrystallized from methanol/H2O to give 146 mg (67%) of a white solid, mp 146-148° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[F:54][C:55]1[CH:60]=[CH:59][C:58]([N:61]=[C:62]=[O:63])=[CH:57][CH:56]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:62]([NH:61][C:58]2[CH:59]=[CH:60][C:55]([F:54])=[CH:56][CH:57]=2)=[O:63])[CH2:51][CH2:52]1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(F)cc1)N1CCC(CCOc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 40 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 1-fluoro-4-isocyanatobenzene as the starting materials in 40% yield. LCMS for C31H32ClFN7O2 (M+H)+: m/z=588.2.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:9]([C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[C:8]([CH3:26])[NH:7][N:6]=1)=[O:4].[OH-].[K+]>>[CH:23]([O:22][C:20]([C:9]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:5]([C:3]([OH:4])=[O:2])=[N:6][NH:7][C:8]=1[CH3:26])=[O:21])([CH3:25])[CH3:24]
Reactant: COC(=O)C1=NNC(C)=C(C(=O)OC(C)C)C1c1cccc([N+](=O)[O-])c1
Agent: [K+]
Agent: [OH-]
Product: CC1=C(C(=O)OC(C)C)C(c2cccc([N+](=O)[O-])c2)C(C(=O)O)=NN1

Procedure:
0.1 mol of 1,4-dihydro-6-methyl-4-(3-nitrophenyl)-pyridazine-3,5-dicarboxylic acid 5-isopropyl 3-methyl ester is saponified with 0.105 mol of KOH analogously to Example 28 to give 1,4-dihydro-6-methyl-4-(3-nitrophenyl)-pyridazine-3,5-dicarboxylic acid 5-isopropyl ester. Melting point 195° C. (ethanol)
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])([O:3]C(C)(C)C)=O.[C:18]([NH:25][C@H:26](C(O)=O)[CH2:27][OH:28])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(Cl)Cl.C1(N=C=NC2CCCCC2)CCCCC1>C(O)(=O)C>[NH:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:26]([C:1]([NH:8][C@H:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])=[O:3])[CH2:27][OH:28]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Reaction time: 6 h

Procedure:
2 g of the Boc-Gln Resin obtained in Step 4 is put in 160 ml of acetic acid and allowed to stand for 6 hours at room temperature. The mixture is filtered with a glass filter. The cake is put in 160 ml of acetic acid, agitated and filtered. This operation is repeated three times. Then, the cake is agitated in 160 ml of 1N aqueous HCl/acetic acid at room temperature for half an hour to remove the Boc group from the resin. The resulting product is filtered off, washed with three portions of each of acetic acid, ethanol and dimethylformamide successively, and agitated in 160 ml of a 10% by weight solution of triethylamine in dimethylformamide to effect neutralization reaction. The resulting product is filtered off and washed with each of dimethylformamide and methylene chloride. The product is immersed in a solution made by adding 2 mmol of Boc-serine (Bzl) to 12 ml of methylene chloride, and agitated. Ten minutes later, a solution made by adding 20 mmol of dicyclohexyl carbodiimide to 60 ml of methylene chloride is added to the mixture and agitated at room temperature for 2 hours to effect coupling reaction. The resulting product is filtered off and washed with each of methylene chloride and ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=[CH:5][CH:4]=1.[CH2:24](I)[CH2:25][CH2:26][CH3:27]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:24][CH2:25][CH2:26][CH3:27])=[CH:7][CH:8]=1
Reactant: CCCCI
Reactant: COc1ccc(NCCCOc2ccc3ccccc3c2)cc1
Solvent: CC(C)=O
Product: CCCCN(CCCOc1ccc2ccccc2c1)c1ccc(OC)cc1

Procedure:
A mixture of N-(4-methoxyphenyl)-(3-(naphthalen-2-yloxy)propyl)amine (0.5 gm, 0.002 mole) and butyl iodide(1 ml, 0.003 mole) was taken in dry acetone (40 ml). It was refluxed for 12 hrs and the progress of reaction checked by TLC. Reaction mixture was filtered and the filtrate was concentrated to get oily compound which was further crystallized by benzene hexane mixture to get N-(4-methoxyphenyl)-N-butyl-(3-(naphthalen-2-yloxy) propyl) amine crystallized yellow solid, m.p. 127° C., (yield 0.78 gm, 98%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].C(N(CC)CC)C.[CH2:22]([O:29][C:30]([NH:32][C@H:33]([C:38](O)=[O:39])[CH2:34][C:35]([OH:37])=[O:36])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.COC(=O)[C@H](CC1C=CC=CC=1)N.Cl.C(N(CC)CC)C>C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[K+].[K+].[K+].C(OCC)(=O)C.OCC(CO)O>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:38](=[O:39])[C@H:33]([CH2:34][C:35](=[O:36])[OH:37])[NH:32][C:30]([O:29][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:31]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [K+]
Solvent: OCC(O)CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Papain (1 g; obtained from J. E. Siebel Son's Co.) was well suspended in 2 ml of 3.0M potassium citrate buffer (pH 5.1), the suspension was then mixed with 2 ml of glycerol. To 100 ml of ethyl acetate, 80 mmole of L-phenylalanine methyl ester hydrochloride and 80 mmole of triethylamine were added and stirred at 25° C. for 40 min then 40 mmole of N-benzyloxycarbonyl-L-aspartic acid was added and stirred for 20 min. The whole ethyl acetate mixture, containing soluble L-phenylalanine methyl ester and N-benzyloxycarbonyl-L-aspartic acid and insoluble triethylamine hydrochloride, w-as subsequently added to the papain suspension. The reaction mixture was stirred at 25° C. for 22 hr then 200 ml of ethyl acetate was added and stirred at 55° C. for 15 min and filtered. As determined by HPLC analysis the yield of the N-benzyloxycarbonyl-α-L-aspartyl-L-phenylalanine methyl ester in the filtrate was 85% calculated on the basis of the initial amount of the N-benzyloxycarbonyl-L-aspartic acid. The ethyl acetate solution was then extracted twice with 150 ml of 0.01M phosphate buffer (pH 7.0), then twice with 150 ml of 0.3N hydrochloric acid. The final organic layer was dehydrated with 10 g of anhydrous Na2SO4, then evaporated and vacuum dried to give 17.4 partially purified N-benzyloxycarbonyl-α-L-aspartyl-L-phenylalanine methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:13][N:12]3[CH:21]=2)=[CH:5][CH:4]=1.C(O)C.C(O)(=O)C>[Pd].[OH-].[NH4+]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:14][CH2:13][N:12]3[CH:21]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cn3ccc4ccccc4c3n2)cc1
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(-c2cn3c(n2)-c2ccccc2CC3)cc1
Reaction time: 3 h

Procedure:
To a one liter autoclave are charged 7.1 g. of 2-(4-methoxyphenyl)imidazo[2,1-a]isoquinoline, 210 ml. of ethanol, 150 ml. of acetic acid and 0.55 g. of 10% palladium on charcoal. After flushing and filling the autoclave with hydrogen, the mixture is hydrogenated at 90° C. and 10 atmospheres for 3 hours. After absorption of 1.5 atmospheres of hydrogen gas, the autoclave is cooled and vented and 200 ml. of CHCl3 is added to the reaction mixture. The catalyst is filtered off, and the solution is evaporated to dryness, giving a solid residue which is suspended in 10% ammonium hydroxide, then extracted with dichloromethane. After drying over Na2SO4, the organic solvent is evaporated off and the residue is crystallized from ethanol giving 4.55 g. of the title product, which melts at 179°-81° C.
Reaction SMILES: C(OCCOC)(=O)CC(C)=O.[CH3:12][C:13]1([CH3:21])[O:18][C:17](=[O:19])[CH:16]=[C:15]([CH3:20])O1.[NH3:22].C(OC(C)C)(=O)CC(C)=O>CC(O)C.COCCO>[NH2:22]/[C:15](/[CH3:20])=[CH:16]\[C:17]([O:18][CH:13]([CH3:21])[CH3:12])=[O:19]
Reactant: N
Reactant: CC1=CC(=O)OC(C)(C)O1
Agent: CC(=O)CC(=O)OC(C)C
Agent: COCCOC(=O)CC(C)=O
Solvent: COCCO
Solvent: CC(C)O
Product: C/C(N)=C/C(=O)OC(C)C

Procedure:
The ester, 2-methoxyethyl acetoacetate (51), was prepared by the reaction of 2-methoxyethanol with 2,2,6-trimethyl-4H-1,3-dioxin-4-one (53) (eq. 28). (Hyatt, J. A. J. Org. Chem. 1984, 49, 5102. Hyatt, J. A.; Feldman, P. L.; Clemens, R. J. Ibid. 1984, 49, 5105. Kato, T.; Sato, M.; Kanuma, N. Chem. Pharm. Bull. 1982, 30, 1315). The enamine, 1-methylethyl 3-aminocrotonate (52) was prepared by the reaction of ammonia with 1-methylethyl acetoacetate (54) (eq. 29) (Iwanami, J. et al. Chem. Pharm. Bull. 27, 1426 (1979)) which was obtained by the reaction of 2-propanol with 53 (eq. 30) as shown in Schemes IIa, IIb and IIc. ##STR13##
Reaction SMILES: [O:1]1[C:5]([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[N:16])[CH:13]=3)[NH:8][N:7]=2)=[CH:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.C([Sn]([N:34]=[N+:35]=[N-:36])(CCCC)CCCC)CCC.O1CCOCC1.Cl>C1(C)C=CC=CC=1>[N:16]1[NH:34][N:35]=[N:36][C:15]=1[C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:5]1[O:1][C:2]2[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=2[CH:4]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#Cc1ccc2[nH]nc(-c3cc4ccccc4o3)c2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: c1ccc2oc(-c3n[nH]c4ccc(-c5nn[nH]n5)cc34)cc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 12 %

Procedure:
To a solution of 3-benzo[b]furan-2-yl-1H-indazole-5-carbonitrile (185 mg, 0.713 mmol) in toluene (10 mL) was added tributyl tin azide (0.780 mL). The solution was brought to 110° C. for 18 hours. The solution was cooled and toluene condensed to give an oil. Dioxane (3 mL) and 6 N HCl (3 mL) was added and the solution stirred for 3 hours at ambient temperature. The resulting precipitate was basified using 6 N HCl. The basic aqueous layer was washed with hexanes and ethyl acetate. The aqueous hydroxide solution was filtered through celite and acidified with 6 N HCl to pH 4. The resulting precipitate was filtered and dried to afford the title compound (25 mg, 12% yield). 1H NMR (DMSO-d6) δ 13.88 (s, 1H), 8.90 (s, 1H), 8.10 (d, 1H), 7.83 (d, 1H), 7.73 (d, 2H), 7.54 (s, 1H), 7.34 (m, 2H); ES-MS (m/z) 303 [M+1]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH:15]([N-]C(C)C)(C)C.[Li+].IC>O1CCCC1>[CH3:15][CH:7]1[C:2](=[O:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 638.7 %

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (10.0 g, 50.2 mmol) in tetrahydrofuran (50 mL) was added lithium diisopropylamide (2.0 M in THF, 1.5 mL, 3.01 mmol) at −78° C. After 1 h, iodomethane (0.19 mL, 3.01 mmol) was added and the reaction mixture was allowed to warm to ambient temperature over 48 h before being quenched with 1M ammonium chloride and extracted with ethyl acetate. The organic layer was concentrated in vacuo and the residue purified by flash column chromatography (SiO2, 9:1 hexanes/ethyl acetate) to give tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate (4.1 g, 38%) as a yellow solid: 1H NMR (CDCl3, 300 MHz) δ 4.24-4.12 (m, 2H), 3.32-3.20 (m, 1H), 2.94-2.75 (m, 1H), 2.61-2.38 (m, 3H), 1.50 (s, 9H), 1.05 (d, J=6.9 Hz, 3H).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([C:13]2[CH:14]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:23]([O:27][CH2:28][CH3:29])(=[O:26])[CH:24]=[CH2:25]>C(O)(=O)C>[CH2:28]([O:27][C:23](=[O:26])[CH2:24][CH2:25][N:16]1[CH:17]=[C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:14]=[C:15]1[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:29]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)c1cc(-c2ccccc2)c[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CCOC(=O)CCn1cc(-c2ccccc2)cc1C(=O)OCC
Yield: 69 %

Procedure:
Potassium tert-butoxide (100 mg, 0.90 mmol), ethyl 4-phenyl-1H-pyrrole-2-carboxylate (1.0 g, 4.65 mmol) and ethyl acrylate (50 mL) were heated at reflux for 90 min. The reaction mixture was allowed to cool to room temperature and neutralized with acetic acid (1 mL). Excess ethyl acrylate was evaporated in vacuo, the residue diluted with water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude compound. Purification by column chromatography over neutral alumina using 5% ethyl acetate in petroleum ether as eluent gave ethyl 1-(3-ethoxy-3-oxo-propyl)-4-phenyl-pyrrole-2-carboxylate (1.0 g, 69%) as an oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:24][CH2:23][C:22]2[C:21]([O:25][C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31]([C:35](=[O:48])[NH:36][C:37]3[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][C:38]=3[F:47])[CH:30]=[CH:29]4)=[N:20][CH:19]=[N:18][C:17]=2[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[F:47][C:38]1[CH:39]=[CH:40][C:41]([C:43]([F:44])([F:45])[F:46])=[CH:42][C:37]=1[NH:36][C:35]([N:31]1[C:32]2[C:28](=[CH:27][C:26]([O:25][C:21]3[C:22]4[CH2:23][CH2:24][NH:15][CH2:16][C:17]=4[N:18]=[CH:19][N:20]=3)=[CH:34][CH:33]=2)[CH:29]=[CH:30]1)=[O:48]
Reactant: CC(C)(C)OC(=O)N1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(C(F)(F)F)ccc3F)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(C(F)(F)F)ccc1F)n1ccc2cc(Oc3ncnc4c3CCNC4)ccc21

Procedure:
TFA (1 mL, 13.0 mmol) is added to a solution of 4-[1-(2-fluoro-5-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester (0.125 g, 0.219 mmol) and DCM (2.5 mL). After 1 h the solution is concentrated in vacuo. The residue is taken up in MeOH and neutralized to pH 7 by the addition of NH4OH and the solution is separated via semi-prep HPLC (C18; 10-100% I/H2O with 0.1% NH4OH) to give 5-(5,6,7,8-Tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (2-fluoro-5-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 472.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.40 (s, 1 H), 8.25 (d, J=8.8 Hz, 1 H), 8.07 (d, J=3.8 Hz, 1 H), 8.03-8.07 (m, 1 H), 7.67-7.75 (m, 1 H), 7.56-7.64 (m, 1 H), 7.45 (d, J=2.5 Hz, 1 H), 7.11 (dd, J=9.0, 2.4 Hz, 1 H), 6.79 (d, J=3.5 Hz, 1 H), 3.83 (s, 2 H), 3.04 (t, J=5.8 Hz, 2 H), 2.73 (t, J=5.6 Hz, 2 H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][N:14]=2)[S:7][CH:6]=1)=[O:4].[OH-].[Na+]>CO>[O:11]1[CH:12]=[CH:13][N:14]=[C:10]1[C:8]1[S:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:9]=1
Reactant: COC(=O)c1csc(-c2ncco2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1csc(-c2ncco2)c1
Reaction time: 2 h
Yield: 73.8 %

Procedure:
5-Oxazol-2-yl-thiophene-3-carboxylic acid methyl ester (0.105 g, 0.50 mmol) was suspended in methanol (1 mL) then sodium hydroxide (1 M, 0.603 mL) was added and the mixture stirred for 2 hours. A further portion of sodium hydroxide (1 M, 0.60 mL) was added and the mixture stirred overnight. The solution was evaporated, the residue was taken up in HCl (1 N, 1.5 mL) and the resultant precipitate was collected by filtration, washed with water and dried to afford 5-oxazol-2-yl-thiophene-3-carboxylic acid as a tan solid (0.072 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][N:11]1[N:15]=[N:14][CH:13]=[N:12]1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([O:16][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=1)=[CH:10][N:11]1[N:15]=[N:14][CH:13]=[N:12]1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C(Cn1ncnn1)c1ccc(Cl)cc1Cl
Product: COc1ccc(COC(=Cn2ncnn2)c2ccc(Cl)cc2Cl)cc1

Procedure:
Analogously to Example 7a,b, after reacting 1-(2,4-dichlorophenyl)-2-tetrazol-2-yl-ethanone with 4-methoxybenzyl chloride there was obtained 2-[2-(2,4-dichloro-phenyl)-2-(4-methoxy-benzyloxy)-vinyl]-2H-tetrazole as a colourless oil. [M+H]+=376.