Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[C-:2].C(N(CC)CC)C.[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20](Cl)=[O:21]>O1CCCC1>[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]1[O:21][CH:2]=[N:1][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C(Cl)c1cccs1
Reactant: [C-]#[N+]CC(=O)OC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ncoc1-c1cccs1
Yield: 86 %

Procedure:
29.7 g of methyl α-isocyanoacetate, 120 g of triethylamine, 450 ml of tetrahydrofuran and 48.4 g of 2-thienylcarbonyl chloride are treated in the same manner as described in Preparation 1-(1). 53.9 g of 5-(2-thienyl)-4-methoxycarbonyloxazole are thereby obtained.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:27][C:28]1[CH:32]=[CH:31][N:30]([CH2:33][C:34]([CH3:37])([OH:36])[CH3:35])[N:29]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH:13]=[N:12]2)[C:8]([NH:27][C:28]2[CH:32]=[CH:31][N:30]([CH2:33][C:34]([OH:36])([CH3:35])[CH3:37])[N:29]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: COc1ccc(Oc2cnn(C(CC3CCCC3)C(=O)O)c(=O)c2)cc1
Product: COc1ccc(Oc2cnn(C(CC3CCCC3)C(=O)Nc3ccn(CC(C)(C)O)n3)c(=O)c2)cc1
Yield: 26 %

Procedure:
Using the method described in Example 11, 3-cyclopentyl-2-[4-(4-methoxy-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 26) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-(4-methoxy-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionamide as a white solid (40.3 mg, 26%); ES+-HRMS m/e calcd for C26H33N5O5 [M+H+] 496.2555 found 496.2554. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.09 (m, 1H), 1.19-1.78 (m, 8H), 1.91 (m, 1H), 2.28 (m, 1H), 3.79 (s, 3H), 3.89 (s, 2H), 4.67 (s, 1H), 5.46 (dd, J=4.0, J=11.1 Hz, 1H), 5.67 (d, J=2.8 Hz, 1H), 6.39 (d, J=2.3 Hz, 1H), 7.05 (d, J=9.1 Hz, 2H), 7.23 (d, J=9.1 Hz, 2H), 7.52 (d, J=2.3 Hz, 1H), 8.10 (d, J=2.8 Hz, 1H), 10.79 (s, 1H).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[C:6]([C:8]1[CH:36]=[CH:35][CH:34]=[CH:33][C:9]=1[O:10][C:11]1[C:25]([O:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[CH:24][C:14]2[NH:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:17][C:13]=2[CH:12]=1)#[N:7]>>[C:6]([C:8]1[CH:36]=[CH:35][CH:34]=[CH:33][C:9]=1[O:10][C:11]1[C:25]([O:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[CH:24][C:14]2[NH:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:17][C:13]=2[CH:12]=1)(=[O:2])[NH2:7]
Reactant: N#Cc1ccccc1Oc1cc2nc(-c3ccccn3)[nH]c2cc1Oc1cccnc1
Reactant: O=S(=O)(O)O
Product: NC(=O)c1ccccc1Oc1cc2nc(-c3ccccn3)[nH]c2cc1Oc1cccnc1

Procedure:
A 80% sulfuric acid solution of 3.5 mg of 5-(2-cyano-phenoxy)-2-pyridin-2-yl-6-(pyridin-3-yloxy)-1H-benzimidazole obtained in Example 5 was stirred overnight at 50° C. The reaction mixture was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid]. The solvent of the resulting fraction was evaporated away under reduced pressure to obtain the entitled compound as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:18]O.O>C(O)(=O)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[N+:14]([O-:18])[CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OO
Reactant: c1ccc(COCCCc2cccnc2)cc1
Solvent: CC(=O)O
Solvent: O
Product: [O-][n+]1cccc(CCCOCc2ccccc2)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
3-(3-Benzyloxypropyl)pyridine (34.28 g) was dissolved in acetic acid (260 ml), followed by the addition of a 30% aqueous solution of hydrogen peroxide (52 ml), and the mixture was stirred at 50° C. overnight. After cooling as it was, water (52 ml) was added to the reaction solution, which was then evaporated. The resulting residue was dissolved in chloroform, washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give the title compound as a yellow oil (30.23 g, yield; 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][NH2:11].C(OC=[C:16]=[C:17]([C:22]#[N:23])[C:18]([O:20][CH3:21])=[O:19])C>C(O)CCC>[NH2:23][C:22]1[N:10]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=2[Cl:9])[N:11]=[CH:16][C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: CCOC=C=C(C#N)C(=O)OC
Reactant: NNc1c(Cl)cc(Cl)cc1Cl
Solvent: CCCCO
Product: COC(=O)c1cnn(-c2c(Cl)cc(Cl)cc2Cl)c1N

Procedure:
21.2 parts by weight of 2,4,6-trichlorophenylhydrazine and 15.5 parts by weight of methyl ethoxymethylene-2-cyanoacrylate in 120 parts by volume of n-butanol were refluxed for 2 hours. The mixture was cooled, and the precipitate was filtered off with suction to give 22.8 parts by weight of methyl 5-amino-1-(2,4,6-trichlorophenyl)-pyrazole-4-carboxylate of melting point 180°14 181° C.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[CH:32]1[C:44]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1.CO>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[CH:32]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=2[C:39]2[C:44]1=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN(C2c3ccccc3-c3ccccc32)[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: c1ccc(C[C@@H]2C[C@@H](NCc3ccnc4ccccc34)CCN2C2c3ccccc3-c3ccccc32)cc1

Procedure:
130 mg (0.219 mmol) (2R*,4S*)-2-benzyl-1-(9-fluorenyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 40 with 500 μl (0.500 mmol) of 1N sodium hydroxide solution in 1 ml of tetrahydrofuran and 1 ml of methanol. The title compound ##STR77## is obtained (49 mg, 45%) as white foam. TLC: toluene/ethyl acetate (1:1) Rf =0.26; FD-MS: M+ =495.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7].[CH2:18]([Li])CCC.CI>>[CH3:1][O:2][C:3]1[C:4]([CH3:18])=[C:5]([CH:15]=[CH:16][CH:17]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7]
Reactant: [Li]CCCC
Reactant: COc1cccc(C(=O)Nc2ccccc2)c1
Solvent: CI
Product: COc1cccc(C(=O)Nc2ccccc2)c1C

Procedure:
WO 95/09843 describes a multistage process for the preparation of 3-acetoxy-2-methylbenzoic acid. This process starts from 3-methoxybenzoyl chloride. The 3-methoxybenzoyl chloride is reacted with aniline to give 3-methoxy-N-phenylbenzamide. In a second step, the 3-methoxy-N-phenylbenzamide is reacted with 2 equivalents of n-butyllithium and then alkylated using methyl iodide. 3-Methoxy-2-methyl-N-phenylbenzamide is formed here, which is then reacted with aqueous hydrochloric acid and aqueous hydrogen bromide in boiling acetic acid with hydrolysis of the amide group and cleavage of the methoxy group to give 3-hydroxy-2-methylbenzoic acid. The 3-hydroxy-2-methylbenzoic acid must be acylated with acetic anhydride in order to obtain the 3-acetoxy-2-methyl-benzoic acid. The individual reaction steps are described in greater detail in WO 95/09843 under Preparation 9 A, B and C and Example 81.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.CN(C)C=O.Cl[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:16]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCCc1ccccc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCCc2ccccc2)cc1
Reaction time: 10 h
Yield: 50.4 %

Procedure:
12.2 g of 4-hydroxybenzaldehyde is mixed with 35 ml of dimethylformamide, 16.9 g of (2-chloroethyl)benzene and 16.6 g of potassium carbonate. The resulting mixture is stirred in a stream of nitrogen at 80°-90° C. for 10 hours and then cooled. The cooled mixture is added to 500 ml of water and then extracted with 500 ml of chloroform. The extract is washed with water until it becomes neutral. The washed extract is dried with anhydrous sodium sulfate and then chloroform is distilled away. The resulting residue is distilled under reduced pressure to obtain 11.4 g of 4-phenethyloxybenzaldehyde. Thus obtained 4-phenethyloxybenzaldehyde has a boiling point of 173°-181° C./2-3 mmHg.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]2[C:10]([C:11](=[O:15])[C:12]([OH:14])=O)=[CH:9][NH:8][C:7]=12.[C:18]1([N:24]2[C:28]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:27][N:26]=[N:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]2[C:10]([C:11](=[O:15])[C:12]([N:32]3[CH2:33][CH2:34][N:29]([C:28]4[N:24]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[N:25]=[N:26][N:27]=4)[CH2:30][CH2:31]3)=[O:14])=[CH:9][NH:8][C:7]=12
Reactant: c1ccc(-n2nnnc2N2CCNCC2)cc1
Reactant: COc1cnc(Cl)c2[nH]cc(C(=O)C(=O)O)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cnc(Cl)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
To a solution of 2-(7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (5.3 g, 20.8 mmol) (prepared as described on US20050090522A1) in DMF (100 mL) was added 1-(1-phenyl-1H-tetrazol-5-yl)piperazine (4.8 g, 20.8 mmol), TBTU (7.4 g, 23.0 mmol), and N,N-diisopropylethylamine (12.0 mL, 68.9 mmol). The mixture was stirred at rt for 16 hr. The solvent was removed under reduced pressure, and the remaining residue was dissolved in hot MeOH. Upon cooling, precipitate formed. The precipitate was collected by filtration, and was washed with H2O (3×75 mL). The mother liquor was concentrated under reduced pressure, then subjected to a second crystallization using the same method. The combined precipitates gave 1-(7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione as a light brown solid (7.3 g, 15.6 mmol). 1H NMR (500 MHz, CDCl3) δ 9.64 (s, 1H), 8.11 (s, 1H), 7.76 (s, 1H), 7.62-7.50 (m, 5H), 4.00 (s, 3H), 3.83-3.81 (m, 2H), 3.57-3.56 (m, 2H), 3.43-3.41 (m, 2H), 3.33-3.32 (m, 2H). LCMS: m/e 467.3 (M+H)+, ret time 1.99 min (method 2).
Reaction SMILES: CS(O[C@@H:6]([C:8]#[CH:9])[CH3:7])(=O)=O.[C:10]([O:14][C:15](=[O:21])[NH:16][CH2:17][CH2:18][CH2:19][NH2:20])([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:7][C@H:6]([NH:20][CH2:19][CH2:18][CH2:17][NH:16][C:15](=[O:21])[O:14][C:10]([CH3:12])([CH3:11])[CH3:13])[C:8]#[CH:9]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: C#C[C@@H](C)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#C[C@H](C)NCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.1 %

Procedure:
A solution of (R)-but-3-yn-2-yl methanesulfonate (2189 mg, 14.77 mmol) in ACN (10 ml) was added dropwise to a suspension of tert-butyl(3-aminopropyl)carbamate (2831 mg, 16.25 mmol) and potassium carbonate (2446 mg, 17.72 mmol) in ACN (50 ml). The reaction mixture was stirred at room temperature for 24 h, whereupon the slurry was filtered and the filtrate was concentrated in vacuo. The crude residue was purified via silica gel chromatography (MeOH-DCM, 0-8%) to afford the title compound (570 mg, 17%) as a light orange oil. LCMS: R=0.43 min, m/z=227.0 (M+1) Method 2m_acidic.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9](Cl)[N:8]=[N:7][C:6]=1[Cl:12])([CH3:4])([CH3:3])[CH3:2].O.[NH2:14][NH2:15]>C(O)C>[C:1]([C:5]1[CH:10]=[C:9]([NH:14][NH2:15])[N:8]=[N:7][C:6]=1[Cl:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)c1cc(Cl)nnc1Cl
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(NN)nnc1Cl
Yield: 60.7 %

Procedure:
4-t-Butyl-3,6-dichloropyridazine (Samaritoni, J. G.; Org. Prep. & Proc. Intl., 1988, 20(2), 117-121) (16 g, 78 mmol) and hydrazine monohydrate (24.7 mL, 780 mmol) in ethanol (250 mL) were heated at reflux for 16 hours. The solvent was removed and hydrochloric acid (5M) was added and the resulting mixture was washed with dichloromethane. The aqueous layer was poured onto ice and ammonium hydroxide was added until the mixture was basic. The mixture was extracted with dichoromethane, dried (MgSO4) filtered and evaporated to give a yellow solid (9.5 g, 61%) 1HNMR (360 MHz, CDCl3) δ 1.46 (9H, s, t Bu), 378 (2H, br s, NH2), 6.84 (1H, br s, NH), 7.10 (1H, s, ArH); MS (ES+) m/e 201 [MH+].
Reaction SMILES: C(O[C:4](=[O:11])[CH2:5][NH:6][CH2:7][CH:8]([CH3:10])[CH3:9])C.[CH3:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]=[C:23]=[S:24]>>[CH3:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]=[C:23]1[N:6]([CH2:7][CH:8]([CH3:9])[CH3:10])[CH2:5][C:4](=[O:11])[S:24]1
Reactant: CCOC(=O)CNCC(C)C
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SC(=O)CN1CC(C)C

Procedure:
N-Isobutylglycine ethyl ester was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C11a to afford 2-(2-methyl-4-nitrophenylimino)-3-isobutyl-1,3-thiazolidin-5-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](=[CH:17]/[C:18]2[C:26]3[C:21](=[CH:22][C:23]([Cl:28])=[CH:24][C:25]=3[Cl:27])[N:20]([S:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[C:19]=2[C:39]([O:41][CH2:42][CH3:43])=[O:40])/[C:10]([O:12]C(C)(C)C)=[O:11])=[CH:5][CH:4]=1>C(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6](/[C:9](=[CH:17]/[C:18]2[C:26]3[C:21](=[CH:22][C:23]([Cl:28])=[CH:24][C:25]=3[Cl:27])[N:20]([S:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)(=[O:30])=[O:31])[C:19]=2[C:39]([O:41][CH2:42][CH3:43])=[O:40])/[C:10]([OH:12])=[O:11])=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1c(/C=C(\C(=O)OC(C)(C)C)c2ccc(OC)cc2)c2c(Cl)cc(Cl)cc2n1S(=O)(=O)c1ccc(C)cc1
Solvent: O=CO
Product: CCOC(=O)c1c(/C=C(\C(=O)O)c2ccc(OC)cc2)c2c(Cl)cc(Cl)cc2n1S(=O)(=O)c1ccc(C)cc1
Reaction time: 24 h

Procedure:
Combine (E) and (Z)-2-(4-methoxyphenyl)-3-(1-p-toluensulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoic acid, t-butyl ester (427 mg) and 96% formic acid (6 mL). After 24 hours, evaporate in vacuo to obtain a residue and recrystallize that residue, if desired, from cyclohexane/ethyl acetate to obtain the intermediate (E) and (Z)-2-(4-methoxyphenyl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoic acid: mp 175°-178° C.; IR (KBr) νmax 1728, 1692, 1371, 1271, 1250, 1179 cm-1 ; 1H NMR (CDCl3) δ8.01 (s, 1H), 7.92 (d, 1H, J=1.7 Hz), 7.63 (d, 2H, J=8.5 Hz), 7.26 (d, 1H, J=1.7 Hz), 7.22 (d, 2H, J=8.5 Hz), 7.01 (d, 2H, J=8.8 Hz), 6.67 (d, 2H, J=8.9 Hz), 4.16 (q, 2H, J= 7.2 Hz), 3.76 (s, 3H), 2.38 (s, 3H), 1.24 (t, 3H, J=7.2 Hz).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:18]([C:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=3)[O:22][N:21]=2)=[O:19])[CH:15]2[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+].C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH:15]1([N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:18]([C:20]2[CH:24]=[C:23]([C:25]3[CH:26]=[CH:27][C:28]([C:31]#[N:32])=[CH:29][CH:30]=3)[O:22][N:21]=2)=[O:19])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2cc(-c3ccc(C#N)cc3)on2)C2CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(-c2cc(C(=O)N(C3CCNCC3)C3CC3)no2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-{[5-(4-cyano-phenyl)-isoxazole-3-carbonyl]-cyclopropyl-amino}-piperidine-1-carboxylic acid tert-butyl ester (90 mg) and trifluoroacetic acid (0.20 mL) in dichloromethane (3 mL) is stirred for 3 h at room temperature. The reaction mixture is diluted with dichloromethane prior to the addition of 2 N aqueous NaOH solution (1.5 mL) and aqueous Na2CO3 solution. The resulting mixture is stirred vigorously for 10 min. The organic phase is separated and the aqueous phase is extracted with dichloromethane. The combined extracts are dried over MgSO4 and concentrated in vacuo to give the desired product. LC (method 4): tR=1.02 min; Mass spectrum (ESI+): m/z=337 [M+H]+.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:4]1.C1(=O)[NH:23]C(=O)C2=CC=CC=C12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[NH2:23][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:4]1
Reactant: COC(=O)COc1cccc2c1CCC(CO)C2
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)COc1cccc2c1CCC(CN)C2
Reaction time: 2 h
Yield: 61.1 %

Procedure:
To a solution of methyl (2-hydroxymethyl-l,2,3,4-tetrahydronaphthalen-5-yl)oxyacetate (1.15 g), phthalimide (1.22 g) and triphenylphosphine (2.17 g) in tetrahydrofuran (50 ml) was added diethyl azodicarboxylate (1.6 ml) at -20° C. After stirred for 2 h, the mixture was quenched by addition of water. The mixture was extracted with ether. The extract was washed with a saturated aquous solution of sodium chloride, dried over anhydrous magnesium sulfate and evaporated. To a solution of the obtained residue in ethanol (30 ml) was added hydrazine monohydrate (0.7 ml) at room temperature. The mixture was stirred overnight. The mixture was quenched by addition of water (20 ml) and evaporated. The residue was crystallized from 2N hydrochloric acid (20 ml) to give the title compound (700 mg) having the following physical data.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=O)[CH:5]=[CH:6][O:7]2>[Pd].CCO.C1COCC1>[O:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:2]([OH:1])[C:3]=2[CH2:4][CH2:5][CH2:6]1
Reactant: O=c1ccoc2cccc(O)c12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Oc1cccc2c1CCCO2
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.8 %

Procedure:
To a solution of 5-hydroxy-chromen-4-one (J. Het. Chem, 13, 1976, 211) (2.5 g, 15.4 mmol) and 1 mL HCl(c) in 75 mL de-gassed EtOH/THF (3:1) was added 0.5 g 10% Pd/C. The reaction mixture was stirred at room temperature for 20 h under an atmosphere of 1 atm H2(g). The Pd/C was then filtered off, the filtrate collected and concentrated in vacuo to give 2.1 g (91%) of the title compound pure enough for subsequent use. 400 MHz 1H NMR (DMSO-d6) δ 9.27 (s, 1H), 6.76 (t, 1H, J=8.1 Hz), 6.26 (d, 1H, J=8.1 Hz), 6.12 (d, 1H, J=8.1 Hz), 3.98 (t, 2H, J=5.0 Hz), 2.46 (m, 2H), 1.80 (m, 2H).
Reaction SMILES: [C:1]1([S:7]([NH:10][C@@H:11]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH:31]3[CH2:36][CH2:35][N:34](C(OCC4C=CC=CC=4)=O)[CH2:33][CH2:32]3)=[CH:26][CH:25]=2)[CH2:12][O:13][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=2I)[C:17]#[N:18])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:47]([C:51](=[CH2:56])[C:52]([O:54][CH3:55])=[O:53])[C:48]([CH3:50])=[O:49].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CCCC)CCCC)CCC>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:48]([NH:47][C:51](=[CH:56][C:21]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=1[O:13][CH2:12][C@@H:11]([NH:10][S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:9])=[O:8])[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH:31]2[CH2:32][CH2:33][NH:34][CH2:35][CH2:36]2)=[CH:28][CH:29]=1)[C:52]([O:54][CH3:55])=[O:53])(=[O:49])[CH3:50]
Reactant: N#Cc1ccc(I)c(OC[C@H](Cc2ccc(OC3CCN(C(=O)OCc4ccccc4)CC3)cc2)NS(=O)(=O)c2ccccc2)c1
Reactant: C=C(NC(C)=O)C(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCCCN(CCCC)CCCC
Product: COC(=O)C(=Cc1ccc(C#N)cc1OC[C@H](Cc1ccc(OC2CCNCC2)cc1)NS(=O)(=O)c1ccccc1)NC(C)=O

Procedure:
197 mg (0.26 mmol)) of 3-[(2S)-2-(benzenesulfonylamino)-3-[4-(1-benzyloxycarbonyl-4-piperidyloxy)phenyl]propoxy]-4-iodobenzonitrile and 74.4 mg (0.52 mmol) of methyl 2-acetaminoacrylate were dissolved in 6 ml of acetonitrile. 7.3 mg (0.03 mmol) of palladium (II) acetate, 55 mg (0.18 mmol) of tri-o-tolylphosphine and 96 mg (0.52 mmol) of tributylamine were added to the solution, and they were heated under reflux overnight. The solvent was distilled off and the residue was treated with ethyl acetate as the extractant in an ordinary manner to obtain the crude product, which was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [CH3:1]/[C:2](=[CH:6]\[CH3:7])/[C:3](=[O:5])[CH3:4].CCN(CC)CC.[Si:15](OS(C(F)(F)F)(=O)=O)([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:16]([Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[O:5][C:3](/[C:2](/[CH3:1])=[CH:6]/[CH3:7])=[CH2:4])[CH3:17]
Reactant: C/C=C(\C)C(C)=O
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(O[Si](CC)(CC)CC)/C(C)=C/C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (E)-3-methylpent-3-en-2-one (2.69 mL, 24.1 mmol) in DCM (200 mL) cooled to 0° C. was added Et3N (10.5 mL, 79.5 mmol) followed by TESOTf (6.0 mL, 26.5 mmol). The mixture was warmed to room temperature and stirred for 18 hr. Saturated aqueous NaHCO3 solution (100 mL) and DCM (200 mL) were added. The aqueous layer was extracted with DCM (3×200 mL) and the combined organic layers were washed with brine (100 mL), separated, dried over MgSO4 and concentrated under reduced pressure to give (E)-triethyl((3-methylpenta-1,3-dien-2-yl)oxy)silane. To a solution of 2-methyl-4-nitro-pyrazole-3-carbaldehyde (1.0 g, 8 mmol, intermediate 3) in CDCl3 (28 mL) was added (E)-triethyl((3-methylpenta-1,3-dien-2-yl)oxy)silane (1.6 g, 7.55 mmol) followed by EuFOD (220 mg, 0.50 mmol). The reaction mixture was heated at 65° C. behind a blast shield for 18 hr in a pressure tube. The mixture was cooled to room temperature and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 5-(5,6-dimethyl-4-((triethylsilyl)oxy)-3,6-dihydro-2H-pyran-2-yl)-1-methyl-4-nitro-1H-pyrazole as a colourless oil (2.92 g, quantitative). 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 5.64 (dd, J=10.9, 3.6 Hz, 1H), 4.33-4.28 (m, 1H), 4.25-3.94 (m, 3H), 2.50-2.41 (m, 1H), 2.31 (m, 1H), 1.61 (s, 3H), 1.31 (d, J=6.4 Hz, 3H), 1.05-0.97 (m, 6H), 0.73-0.61 (m, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([O:19]C)=[O:18])=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[CH:4][CH:3]=1.O[Li].O>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(-c3ccc(F)cc3)c[nH]c2c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2c(-c3ccc(F)cc3)c[nH]c2c1
Yield: 123.5 %

Procedure:
A solution of compound 53d (303 mg, 0.79 mmol), and LiOH.H2O (132.7 mg, 3.16 mmol) in THF/H2O (10 mL/10 mL) was stirred at 45° C. for 5 h. The resulting mixture was concentrated and diluted with water. The water layer was acidified with 1N aqueous HCl to pH˜4 and extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated to give 53e (249 mg), which was used in the next reaction without further purification. MS m/z (M+H+) 256.0.