Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].O1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH3:11][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH2:30]/[CH:31]=[CH:32]/[CH2:33][C:2]([CH3:7])([CH3:3])[CH3:1])[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:18]
Reactant: C1CCOC1
Reactant: CC(C(=O)OCc1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CC(C)(C)C/C=C/CC(C)(C(=O)OCc1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
A solution of 2-phenyl-propionic acid benzyl ester (3.15 g, 13.1 mmol) in tetrahydrofuran (25 mL) at −78° C. was treated dropwise with a lithium hexamethyldisilazide solution (14.4 mL, 1M in tetrahydrofuran, 14.4 mmol) and stirred for 30 minutes at −78° C. Example 35B (3.26 g, 17.0 mmol) was added to the solution and the reaction was allowed to warm to 25° C. and stirred for an additional 4 hours. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the ethyl acetate layers were combined, washed with a saturated sodium bicarbonate solution, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, then 5% ethyl acetate in hexane, and 10% ethyl acetate in hexane to give the title compound (3.32 g, 72%). 1H NMR (300 MHz, CDCl3): δ ppm 0.80 (m, 9 H) 1.53 (m, 3 H) 1.79 (m, 2H) 2.63 (m, 1 H) 2.82 (m, 1 H) 5.10 (m, 2 H) 5.18 (m, 1 H) 5.47 (m, 1 H) 7.27 (m, 10 H). MS (ESI+) m/z 368 (M+NH4)+.
Reaction SMILES: S(=O)(=O)(O)O.C1CO[C:8]([CH3:24])([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([C:21](=O)[CH3:22])[CH2:17][CH2:18][C:19]#[N:20])=[CH:12][CH:11]=2)[O:7]1.[OH2:27]>C(O)(=O)C>[CH2:9]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]=2[CH3:22])=[CH:12][CH:11]=1)[C:8]([CH3:24])=[O:7]
Reactant: O
Reactant: CC(=O)C(CCC#N)c1ccc(CC2(C)OCCO2)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)Cc1ccc(C2=C(C)NC(=O)CC2)cc1
Reaction time: 72 h

Procedure:
Concentrated sulphuric acid (5 ml) was added dropwise to a solution of 4-(4-(2,2-(ethylenedioxy)propyl)phenyl)-5-oxo-hexane nitrile (3.09 g) in glacial acetic acid (21 ml). The orange solution was allowed to stand at room temperature for 3 days then poured into water and allowed to stand for 2 hr. The solution was extracted with chloroform, the organic layer separated, washed with sodium bicarbonate solution, dried (MgSO4) and evaporated to an oil (2.44 g) which was chromatographed on silica. Elution with chloroform gave 3,4-dihydro-5-(4-acetonylphenyl)-6-methyl-2(1H)-pyridone as an oil.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=C)=[CH:10][N:9]=1>O.COCCOC.[Os](=O)(=O)(=O)=O>[CH3:7][C:8]1[N:9]=[CH:10][C:11]([CH:14]=[O:2])=[CH:12][CH:13]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1ccc(C)nc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(C=O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
80 g (0.37 mole) of sodium periodate in 200 ml of water are added dropwise with vigorous stirring to 23 g (0.19 mole) of 2-methyl-5-vinyl pyridine in 800 ml of ethylene glycol dimethyl ether. 1.0 g (0.04 mole) of osmium tetroxide is then added while cooling with a mixture of ice and common salt, after which the mixture is stirred for 8 hours at room temperature in a nitrogen atmosphere. The oil remaining after removal of the solvent by evaporation in vacuo is taken up in a little water and extracted three times with ethyl acetate. Drying of the organic phase over sodium sulfate and concentration by evaporation in vacuo leave 20 g (87%) of a light brown oil which is immediately further processed.
Reaction SMILES: [CH2:1]([C:17]1[C:22](=[O:23])[CH:21]=[C:20]([CH3:24])O[C:18]=1[CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl.[NH2:27][OH:28].C([O-])(=O)C.[Na+].O>C(O)C>[CH2:1]([C:17]1[C:22](=[O:23])[CH:21]=[C:20]([CH3:24])[N:27]([OH:28])[C:18]=1[CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCc1c(C)oc(C)cc1=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCc1c(C)n(O)c(C)cc1=O
Temperature: 25 °C

Procedure:
A mixture of 2 (200 mg, 0.57 mmol), hydroxylamine hydrochloride (399 mg, 5.7 mmol), sodium acetate (471 mg, 5.7 mmol), water (1 mL), and ethanol (2 mL) was heated at reflux for 3 days. After the reaction mixture was cooled to room temperature, the crude product was concentrated under diminished pressure to a yellow oil. The residue was purified by chromatography on a silica gel column. Elution with 5:1 chloroform/methanol gave 3-hexadecyl-1-hydroxy-2,6-dimethylpyridin-4(1H)-one (CPD-8) as a white solid: yield 0.088 g (42%); silica gel TLC Rf 0.5 (3:1 ethyl acetate/methanol); 1H NMR (CDCl3, 400 MHz) δ 0.83-0.85 (m, 3H), 1.22-1.27 (m, 28H), 2.32 (s, 3H), 2.46 (s, 3H), 2.55 (t, 2H, J=8 Hz) and 6.7 (s, 1H).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[C:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:11]=2[NH:10][N:9]=1)=[O:7])C>CO>[NH:10]1[C:11]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[C:8]([C:6]([OH:7])=[O:5])=[N:9]1
Reactant: CCOC(=O)c1n[nH]c2c1CCCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1n[nH]c2c1CCCCC2

Procedure:
Freshly prepared aq. NaOH (10 M in H2O, 9.66 mmol) was added to a stirring, room temperature solution of 14 (0.4029 g, 1.93 mmol) in MeOH (4.8 mL, 0.4 M) under N2. The reaction was then heated to reflux until the reaction was judged complete by TLC (0.5 h): The reaction was concentrated and then dissolved in 3.8 mL H2O. 10% aq. HCl was added dropwise until the pH=2. The white solid that precipitated from the reaction was filtered off and washed with cold H2O. The solid was dried under vacuum overnight to obtain 15. Note: An undesired impurity that does not crash out of solution upon HCl addition has a retention time of 8.708 min by HPLC. 1H (CD3OD, 400 MHz): δ 2.98-2.90 (2H, m), 2.80-2.72 (2H, m), 1.92-1.82 (2H, m), 1.70-1.58 (4H, m) ppm. 13C (CD3OD, 100 MHz): δ 164.81, 151.31, 136.87, 125.13, 33.36, 29.73, 28.78, 28.49, 25.17 ppm. DEPT (CD3OD, 100 MHz): CH2 carbons: 33.36, 29.73, 28.78, 28.49, 25.17 ppm. HPLC: 7.545 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[C:22]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CCOCC.O.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>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:3]([C:8]3[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:22]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:21]=1
Reactant: OB(O)c1ccc(Cl)cc1OCc1ccccc1
Reactant: CCOC(=O)c1ccccc1-c1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1ccccc1-c1ccccc1-c1ccc(Cl)cc1OCc1ccccc1
Temperature: 90 °C
Yield: 47 %

Procedure:
A mixture of ethyl 2′-bromo-2-biphenylcarboxylate (153 mg, 0.5 mmol), {4-chloro-2-[(phenylmethyl)oxy]phenyl}boronic acid (144 mg, 0.55 mmol), potassium carbonate (552 mg, 4 mmol) and tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol) was stirred and heated at 90° C. under nitrogen for 18 hours. After cooling the mixture was diluted with ether/water and the organic phase dried (magnesium sulphate), evaporated and chromatographed on silica eluting with ethyl acetate/iso-hexane (1:19) to give 104 mg of colourless gum.
Reaction SMILES: C([O:5][C:6](=[O:51])[C:7]([O:10]/[N:11]=[C:12](/[C:38]1[N:39]=[C:40]([NH:43]C(OC(C)(C)C)=O)[S:41][CH:42]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][N:26]1[CH:30]=[C:29]([C:31]([O:33]C(C)(C)C)=[O:32])[N:28]=[N:27]1)=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:43][C:40]1[S:41][CH:42]=[C:38](/[C:12](=[N:11]/[O:10][C:7]([C:6]([OH:51])=[O:5])([CH3:9])[CH3:8])/[C:13]([NH:15][C@@H:16]2[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:22])=[O:23])[C@@H:17]2[CH2:25][N:26]2[CH:30]=[C:29]([C:31]([OH:33])=[O:32])[N:28]=[N:27]2)=[O:14])[N:39]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2cc(C(=O)OC(C)(C)C)nn2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1cc(C(=O)O)nn1)c1csc(N)n1)C(=O)O
Yield: 27 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)methyl)-4-oxoazetidine-1-sulfonic acid (180 mg, 0.237 mmol), DCM (8 mL) and TFA (2 mL, 26 mmol). The crude residue was purified by reverse phase prep HPLC (T3, 30×150 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 1 mL/min), affording the title compound (35 mg, 27%) as a white solid. LCMS: m/z=544.9 (M−1); 1H NMR (400 MHz, D2O): δ 8.43 (s, 1H), 6.99 (s, 1H), 5.38 (d, J=5.2 Hz, 1H), 4.92-4.71 (m, 3H; partially obscured by solvent residual peak), 1.33 (s, 6H).
Reaction SMILES: [Na].CC(C)=O.Cl.[C:7]([NH2:16])(=[NH:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>C1C=CC=CC=1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:15][C:7](=[NH:16])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:26])=[CH:20][CH:19]=1
Reactant: CCCCCCCC(=N)N
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: CCCCCCCC(=N)NC(=O)Nc1ccc(Cl)cc1

Procedure:
Following a procedure similar to that described in Example 1 but using 2.2 g. sodium in 200 ml. dry acetone, 17.8 g. octanamidine hydrochloride, and 15.3 g. 4-chlorophenyl isocyanate in 100 ml. benzene, there was obtained after recrystallization from acetonitrile 19.7 g. of the hydrochloride of 1-(4-chlorophenyl)-3-(octanimidoyl)urea; m.p. 156°-165°C.
Reaction SMILES: [NH3:1].[S:2]([C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9])(O)(=[O:4])=[O:3]>>[S:2]1(=[O:4])(=[O:3])[C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8](=[O:9])[NH:1]1
Reactant: O=C(O)c1ccccc1S(=O)(=O)O
Reactant: N
Product: O=C1NS(=O)(=O)c2ccccc21

Procedure:
In the third step the reaction of ammonia is reacted with the reaction product produced in the second step. It is possible to react the components by injecting ammonia into the reaction mixture after the second step. Thus, it is preferable to react ammonia and the second step product by mixing an aqueous solution of ammonia with the reaction mixture after the second step. The amount of ammonia employed is preferably in a range of 3.5 - 4.5 mole per mole of the o-sulfobenzoic acid (I) or the alkali metal salt or alkaline earth metal salt thereof. Preferably, a 4 - 28 % of an aqueous solution of ammonia is used. The reaction temperature is usually in the range of 5° - 35° C, and if desired, the reaction is conducted while cooled. After the reaction with ammonia, the ammonium salt of 1.2-benzoisothiazole-3-on-1.1-dioxide (III) is obtained. The desired compound, i.e. 1.2-benzoisothiazole-3-on-1.1-dioxide (III) can be separated by precipitation by treating the solution with a mineral acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or the like. In accordance with the process of the invention, the desired 1.2-benzoisothiazole-3-on-1.1-dioxide compound (III) having high purity can be easily produced in substantial industrial efficiency in yields greater than 80 % based on the o-sulfobenzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([C:8](=[O:16])[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)[C:5](=O)[CH3:6].Cl.[NH2:19]O>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[C:5]([CH3:6])=[N:19][O:16][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)=[O:17]
Reactant: NO
Reactant: COC(=O)C(C(C)=O)C(=O)c1ccc(Br)cc1
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)c1c(C)noc1-c1ccc(Br)cc1
Temperature: 115 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-(4-bromo-benzoyl)-3-oxo-butyric acid methyl ester (11 g, 39 mmol) in acetic acid (50 mL) was added hydroxylamine hydrochloride (2.66 g, 39 mmol) and the reaction was stirred at 115° C. for 1 hour. After cooling, aqueous workup provided the title compound, which was used directly in the hydrolysis step.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:41])[N:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]([C:29](=[O:31])[CH3:30])[C@@H:24]([CH3:32])[CH2:23][C@H:22]4[NH:33]C(OC(C)(C)C)=O)=[CH:15][CH:14]=2)[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C>CO>[C:29]([N:25]1[C:26]2[C:21](=[CH:20][C:19]([C:16]3[CH:17]=[CH:18][C:13]([CH2:12][N:10]([CH3:11])[C:9](=[O:41])[O:8][CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:14][CH:15]=3)=[CH:28][CH:27]=2)[C@H:22]([NH2:33])[CH2:23][C@@H:24]1[CH3:32])(=[O:31])[CH3:30]
Reactant: CC(=O)N1c2ccc(-c3ccc(CN(C)C(=O)OCc4ccccc4)cc3)cc2[C@H](NC(=O)OC(C)(C)C)C[C@@H]1C
Solvent: CO
Solvent: CC(=O)Cl
Product: CC(=O)N1c2ccc(-c3ccc(CN(C)C(=O)OCc4ccccc4)cc3)cc2[C@H](N)C[C@@H]1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
To a solution of phenylmethyl({4-[(2S,4R)-1-acetyl-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]phenyl}methyl)methylcarbamate (for a preparation see intermediate 81) (1 g, 1.793 mmol) in methanol (50 mL) was added acetyl chloride (2 mL, 28.1 mmol). The resulting mixture was stirred at room temperature for 3 h then concentrated in vacuovacuo. The residue was loaded on a 50 g SCX column, then eluted with MeOH (3 column volume (CV)) followed by 2N NH3 in methanol (4 CV). The ammonia fractions were combined and evaporated in vacuovacuo. Purification of the residue obtained by flash chromatography on silica gel (40 g column, gradient:0 to 5% (2N NH3 in MeOH) in DCM) gave phenylmethyl ({4-[(2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]phenyl}methyl)methylcarbamate (581 mg, 1.27 mmol, 71%) as a colourless oil which solidified on standing.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH3:22])=[O:10].Br[CH2:24][C:25]1[S:29][CH:28]=[C:27]([C:30]#[N:31])[CH:26]=1>>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH3:22])=[O:10])[O:8][CH2:24][C:25]1[S:29][CH:28]=[C:27]([C:30]#[N:31])[CH:26]=1
Reactant: N#Cc1csc(CBr)c1
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(O)cc1F
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(OCc2cc(C#N)cs2)cc1F

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure C from (2-Fluoro-4-hydroxy-phenyl)-[2-(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-methanone and 5-(bromomethyl) 3-thiophenecarbonitrile [CAS 186552-10-3]. MS (ES+) m/e 428.3
Reaction SMILES: [O:1]=[C:2]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C:3](OCC)=[O:4].[NH3:15]>CO>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][C:2](=[O:1])[C:3]([NH2:15])=[O:4])[CH:10]=1
Reactant: N
Reactant: CCOC(=O)C(=O)Nc1cccnc1
Solvent: CO
Product: NC(=O)C(=O)Nc1cccnc1

Procedure:
A solution of the product from Example 35A and ammonia in methanol was processed as described in Example 1B to provide the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.C([O:14][C:15]([CH2:17][NH:18][CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27])[CH3:20])=O)C>O>[OH:14][CH2:15][CH2:17][NH:18][CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27])[CH3:20]
Reactant: CCOC(=O)CNC(C)c1ccccc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1C(C)NCCO
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
To a mixture of 3.8 g of lithium aluminium hydride (0.1M) and 150 ml of tetrahydrofuran, 23.3 g of the compound (0.105M) prepared in Step 2 above was dropwise added at room temperature and stirred for 30 minutes. The resultant was added with water and solids produced were filtered. The filtrate was dried over anhydrous sodium sulfate and concentrated under a reduced pressure, to give 13.8 g of the title compound.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:3].[NH2:9][C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][CH:23]=1)[NH:13][C:14](=[O:20])/[CH:15]=[C:16](\[O:18][CH3:19])/[CH3:17].O1CCCC1>C(N(CC)CC)C>[CH2:5]([O:4][C:2]([NH:9][C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][CH:23]=1)[NH:13][C:14](=[O:20])/[CH:15]=[C:16](\[O:18][CH3:19])/[CH3:17])=[O:3])[CH2:6][CH2:7][CH3:8]
Reactant: CCCCOC(=O)Cl
Reactant: CO/C(C)=C\C(=O)Nc1cccc(N)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCOC(=O)Nc1cccc(NC(=O)/C=C(/C)OC)c1
Temperature: 5 °C
Reaction time: 16 h
Yield: 89.8 %

Procedure:
12 g of n-butyl chloroformate were slowly added to a mixture of 16.5 g of m-amino-3-methoxy-crotonanilide, 320 ml of tetrahydrofuran and 8.9 g of triethylamine cooled to 5° C. and the mixture was stirred for 16 hours and then vacuum filtered. The residue was chromatographed over silica gel and was eluted with an 8- 2 methylene chloride-acetone mixture to obtain 22 g of m-(n-butoxycarbonylamino)-3-methoxy-crotonanilide melting at 100° C.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([OH:12])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][N:24]=1)[C:19]([NH2:21])=[O:20].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO>CN(C1C=CN=CC=1)C.CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([NH:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][N:24]=2)[C:19]([NH2:21])=[O:20])=[O:12])=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: O=C(O)COc1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)c1ccnc(N)c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CO
Solvent: CN(C)C=O
Product: NC(=O)c1ccnc(NC(=O)COc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Yield: 50.6 %

Procedure:
To solution of (4-nitro-phenoxy)-acetic acid (50 mg, 0.25 mmol), 2-amino isonicotinamide (52 mg, 0.37 mmol) and DMAP (62 mg, 0.5 mmol) in DMF 6 ml was added PyBOP (684 mg, 1.31 mmol), and stirred room temperature. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by PLC (EtOAc:n-Hexane:MeOH=1:2:1˜1:2:2) to afford 2-[2-(4-nitro-phenoxy)-acetylamino]-isonicotinamide as a colorless solid (0.04 g, 50% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)(=[O:17])=[O:16])[CH2:9][CH2:10][NH:11][C:12](=[O:14])[O-])=[C:4]([CH2:28][C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=2[F:36])[CH:3]=1.[CH3:37][NH2:38]>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:9][CH2:10][NH:11][C:12]([NH:38][CH3:37])=[O:14])[S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)(=[O:17])=[O:16])=[C:4]([CH2:28][C:29]2[C:30]([F:36])=[CH:31][CH:32]=[CH:33][C:34]=2[F:35])[CH:3]=1
Reactant: CN
Reactant: COc1ccc(S(=O)(=O)N(CCNC(=O)[O-])c2ccc(Cl)cc2Cc2c(F)cccc2F)cc1OC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CNC(=O)NCCN(c1ccc(Cl)cc1Cc1c(F)cccc1F)S(=O)(=O)c1ccc(OC)c(OC)c1

Procedure:
To 0.42 g of phenyl(2-{[4-chloro-2-(2,6-difluorobenzyl)phenyl][(3,4-dimethoxyphenyl)sulfonyl]amino}ethylcarbamate in 1.2 ml of dimethyl sulfoxide is added, at room temperature, 0.053 ml of an aqueous solution of methylamine, and the mixture is left at room temperature for 18 hours. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel to give 0.326 g of the expected product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][S:8][C:9]2[N:13]=[CH:12][NH:11][N:10]=2)=[CH:5][CH:4]=1.[N+](=[CH2:18])=[N-]>CO.CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C:9]2[N:10]([CH3:18])[N:11]=[CH:12][N:13]=2)=[CH:14][CH:15]=1
Reactant: C=[N+]=[N-]
Reactant: COc1ccc(CSc2nc[nH]n2)cc1
Solvent: CO
Solvent: CCOCC
Product: COc1ccc(CSc2ncnn2C)cc1
Reaction time: 1 h

Procedure:
To a solution of 3-p-methoxybenzylthio-1,2,4-triazole (10.0 g : 45.2 mMol.) in methanol (100 ml) is added under ice cooling a solution of diazomethane in ether (prepared from 15 g of N-nitrosomethylurea), and the mixture is stirred for 1 hour. The reaction mixture is concentrated and purified by Lobar column chromatography (toluene : ethyl acetate=1:2 to 1:3) to give 3-p-methoxybenzylthio-2-methyl- 1,2,4-triazole [5.17 g : NMR δ(CDCl3) ppmi 3.63(s, 3H), 3.79(s, 3H), 4.34(s, 2H), 6.80-6.84, 7.19-7.24(A2B2, 4H), 7.88(s, 1H). IR ν(CHCl3) cm-1 : 1611, 1511, 1476, 1464, 1440, 1360, 1302 Yield: 49%]and 3-p- methoxybenzylthio-1-methyl-1,2,4-triazole [3.60 g : NMR δ(CDCl3) ppmi 3.78(s, 3H), 3.87(s, 3H), 4.31(s, 2H), 6.80-6.85, 7.30- 7.34(A2B2, 4H), 7.99(s, 1H). IR ν(CHCl ) cm-1 : 1612, 1512, 1465, 1440, 1421, 1356, 1302. Yield : 34%].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][C:12]([C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[N:11]2)=[CH:4][CH:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1>>[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:21]([C:17]2[S:16][C:15]([C:12]3[CH:13]=[CH:14][N:10]([CH2:9][CH2:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:11]=3)=[N:19][C:18]=2[CH3:20])=[O:23])[CH:25]=1
Reactant: Nc1cccnc1
Reactant: Cc1nc(-c2ccn(CCc3ccc(F)cc3)n2)sc1C(=O)O
Product: Cc1nc(-c2ccn(CCc3ccc(F)cc3)n2)sc1C(=O)Nc1cccnc1

Procedure:
The title compound was prepared from 2-{1-[2-(4-fluoro-phenyl)-ethyl]-1H-pyrazol-3-yl}-4-methyl-thiazole-5-carboxylic acid and pyridine-3-ylamine as describe in Example 88 and isolated as a yellow solid (0.085 g, 71% yield). 1H NMR (400 MHz, CDCl3) δ 8.63 (d, J=2.27 Hz, 1H), 8.40 (d, J=4 Hz, 1H), 8.23 (d, J=4 Hz, 1H), 7.61 (s, 1H), 7.32-7.36 (m, 1H), 7.18 (d, J=2 Hz, 1H), 6.91-7.05 (m, 4H), 6.76 (d, J=2 Hz, 1H), 4.37 (t, J=7 Hz, 2H), 3.19 (t, J=7 Hz, 2H), 2.81 (s, 3H); MS (M+H)+=408.1; Rt=1.32 min; HRMS (M+H)+=408.13.