Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[C:7]([N:10]2[CH2:13][CH:12]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11]2)[S:8][CH:9]=1)=[N+]=[N-].Cl[C:33]([O:35][CH3:36])=[O:34].C(N(CC)CC)C>CO.[OH-].[Pd+2].[OH-]>[Si:15]([O:14][CH:12]1[CH2:13][N:10]([C:7]2[S:8][CH:9]=[C:5]([CH2:4][NH:1][C:33]([O:35][CH3:36])=[O:34])[N:6]=2)[CH2:11]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(CN=[N+]=[N-])cs2)C1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)Cl
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)NCc1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
1-(4-Azidomethyl-1,3-thiazol-2-yl)-3-t-butyldiphenylsilyloxyazetidine (2.12 g, 4.71 mmol) (obtained as described in Reference Example 62(1)) in methanol (106 ml) was subjected to catalytic reduction in the presence of 20% palladium hydroxide (2.12 g) at room temperature. After checking the completion of the reaction, the reaction mixture was filtered in order to remove the catalyst and the filtrate concentrated under reduced pressure. The residue was dissolved in methylene chloride (100 ml). To the mixture were added methyl chloroformate (0.43 ml, 5.65 mmol) and triethylamine (0.79 ml, 5.65 mmol), and the mixture was stirred at room temperature for 2 hours. After checking the completion of the reaction, the mixture was distilled under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 3-t-butyldiphenylsilyloxy-1-[4-(methoxycarbonylamino-methyl)-1,3-thiazol-2-yl]azetidine (1.88 g, yield 45%) as pale yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=[N:19][NH:20][C:21]([NH:23][C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[C:26]([N+:34]([O-:36])=[O:35])[CH:25]=3)=[S:22])[CH3:18])[C:12]=2[OH:37])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=[N:19][NH:20][C:21]([NH:23][C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[C:26]([N+:34]([O-:36])=[O:35])[CH:25]=3)=[S:22])[CH3:18])[C:12]=2[OH:37])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(NC(=S)NN=C(C)c2nn(C)c(-c3ccc(C(C)(C)C)cc3)c2O)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)c([N+](=O)[O-])c1)c1nn(C)c(-c2ccc(C(C)(C)C)cc2)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.8 %

Procedure:
Methyl 4-{[(2-{1-[5-(4-t-butylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethylidene}hydrazino)-carbonothioyl]amino}-2-nitrobenzoate (100 mg, 0.19 mmol) synthesized in Synthetic Example 102 was dissolved in methanol (6.7 ml), and 1 M sodium hydroxide aqueous solution (0.96 ml, 0.96 mmol) was added thereto, following by stirring overnight at room temperature. After completion of the stirring, the reaction solution was washed with ethyl acetate, and to the aqueous layer, 1 M hydrochloric acid was added. The precipitated solid was filtered to obtain 27 mg of the desired product as a pale yellow solid (yield 28%).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:7][O:8][C:4]=2[CH:3]=1.[N+:16]([O-])([OH:18])=[O:17]>>[F:1][C:2]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:5]2[C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COC(=O)Cc1noc2cc(F)ccc12
Reactant: O=[N+]([O-])O
Product: COC(=O)Cc1noc2cc(F)c([N+](=O)[O-])cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methyl 6-fluoro-1,2-benzisoxazole-3-acetate (6.0 g, 28.7 mmol) is added portionwise to nitric acid (90%, 60 mL) at 0° C. The reaction mixture is stirred at 0° C. for 30 minutes and poured into an ice/water mixture. The aqueous mixture is extracted with methylene chloride. The organic extracts are combined, washed sequentially with water, saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a yellow oil. Flash column chromatography of the oil using silica gel and ether/petroleum ether solutions gives the title product as a pale yellow solid which is identified by 1HNMR spectral analysis.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])[CH:3]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[NH:61]1[CH2:64][CH:63]([NH:65][C:66](=[O:72])[O:67][C:68]([CH3:71])([CH3:70])[CH3:69])[CH2:62]1>CN(C=O)C>[F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([N:61]2[CH2:64][CH:63]([NH:65][C:66](=[O:72])[O:67][C:68]([CH3:70])([CH3:69])[CH3:71])[CH2:62]2)=[O:8])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])[CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: O=C(O)c1cc(F)c(F)cc1Nc1ccc(I)cc1F
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CN(C(=O)c2cc(F)c(F)cc2Nc2ccc(I)cc2F)C1
Reaction time: 0.25 h
Yield: 95.7 %

Procedure:
4,5-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (100 mg, 0.25 mmol) was taken into DMF (1 mL) followed by addition of PyBOP (137 mg, 0.26 mmol) and the mixture was stirred for 15 minutes then NMM (60 μL, 0.5 mmol) and commercially available 1,1-dimethylethyl azetidin-3-ylcarbamate (43 mg, 0.25 mmol) were subsequently added. The mixture was allowed to stir for 12 hours at room temperature then partitioned with ethyl acetate and water. The organic phase was washed three times with additional water then brine and dried over anhydrous sodium sulfate. Filtration and concentration followed by silica gel flash chromatography of the residue using hexanes:ethyl acetate 3:1 as eluent afforded 1,1-dimethylethyl [1-({4,5-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]carbamate (131 mg) as a colorless oil. The oil was taken into trifluoroacetic acid (1 mL) and allowed to stand at room temperature for 5 minutes then concentrated in vacuo. The residue was portioned with ethyl acetate and saturated aqueous sodium bicarbonate and the organic phase washed with brine then dried over anhydrous sodium sulfate. The organic solution was filtered and concentrated then the residue taken into methanol (1 mL) followed by addition of 4 N HCl in dioxane until the solution was acidic. The solution was concentrated and the residue triturated with ethyl ether to give a thick precipitate. The solid was collected by filtration and dried in vacuo to give 1-({4,5-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine hydrochloride (67 mg, 55% overall yield). 1H-NMR (400 MHz, D6-DMSO): 9.02 (s, 1H), 8.54 (br s, 3H), 7.68 (dd, 1H), 7.53-7.47 (m, 2H), 7.22 (tr, 1H), 7.16 (dd, 1H), 4.60 (br s, 1H), 4.23 (br s, 2H), 4.03 (br m, 2H). MS (EI) for C16H13F3IN3O: 448 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[C:13]#[C:14][CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH:39]=O)=[N:31]1>CO.N1CCCCC1>[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](/[CH:39]=[C:8]2\[O:9][C:5]3[C:4]([C:13]#[C:14][CH2:15][CH2:16][CH:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:31]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: COc1ccc2c(c1C#CCCC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1C#CCCC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
A solution of tert-butyl 4-[4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)but-3-ynyl]piperidine-1-carboxylate (0.0500 g, 0.125 mmol) in methanol (5 mL) was added with 1H-indazole-3-carboxaldehyde (0.0166 g, 0.114 mmol) and piperidine (7 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/ethyl acetate) to obtain tert-butyl (Z)-4-(4-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}but-3-ynyl)piperidine-1-carboxylate (0.0507 g, 84%).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17]([C:19]1[NH:20][C:21]2[CH2:22][CH2:23][CH2:24][CH2:25][C:26]=2[C:27]=1[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=O>N1CCCCC1.C(O)C>[O:16]=[C:12]1[C:11](=[CH:17][C:19]2[NH:20][C:21]3[CH2:22][CH2:23][CH2:24][CH2:25][C:26]=3[C:27]=2[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:10]2[C:14](=[CH:15][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)[NH:13]1
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Reactant: O=Cc1[nH]c2c(c1CCC(=O)O)CCCC2
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C(O)CCc1c(C=C2C(=O)Nc3cc(-c4ccccc4)ccc32)[nH]c2c1CCCC2
Reaction time: 4 h
Yield: 33.3 %

Procedure:
A mixture of 90 mg 6-phenyl-2-oxindole, 95 mg 3-(2-formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid and piperidine (3 drops) in ethanol (2 mL) was held in a sealed tube at 90° C. for 4 hrs. The reaction mixture was concentrated and acidified with 6 N hydrochloric acid. The precipitate was collected by filtration and washed with water and hexane to give 59 mg of 3-[2-(2-oxo-6-phenyl-1,2-dihydro-indol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionic acid as a brown solid (31% yield).
Reaction SMILES: ClC1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=O)[CH:3]=1.[CH2:12]([N:14]1C(CCC(C)=C)=[N:17][N:16]=[N:15]1)[CH3:13].S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:12]([N:14]1[C:7]([CH2:6][CH2:5][C:4]2([CH3:3])[CH2:8][O:10]2)=[N:17][N:16]=[N:15]1)[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)CCc1nnnn1CC
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCn1nnnc1CCC1(C)CO1
Temperature: 25 °C
Reaction time: 21 h
Yield: 115.3 %

Procedure:
m-Chloroperbenzoic acid (1.97 g, 7.99 mmol) was gradually added to a solution of 1-ethyl-5-(3-methyl-3-butenyl)-1H-tetrazole (0.95 g, 5.71 mmol) in methylene chloride (20 ml) while cooling in an ice-bath, and the mixture was stirred at room temperature for 21 hours. To the reaction mixture, sodium thiosulfate aqueous solution and sodium hydrogencarbonate aqueous solution were added, and the resulting mixture was filtered. The organic layer was separated, washed with sodium hydrogencarbonate aqueous solution, dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 1-ethyl-5-[2-(2-methyl-2-oxiranyl)ethyl]-1H-tetrazole (1.2 g, quantitative) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[O:8][N:9]=[C:10]([OH:11])[C:5]2=[CH:4][CH:3]=1.[CH3:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19](Cl)=[O:20])[CH2:15][CH2:14]1>>[CH3:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:11][C:10]2[C:5]3[C:6](=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[O:8][N:9]=2)=[O:20])[CH2:15][CH2:14]1
Reactant: CC1CCN(C(=O)Cl)CC1
Reactant: Oc1noc2nc(Cl)ccc12
Product: CC1CCN(C(=O)Oc2noc3nc(Cl)ccc23)CC1

Procedure:
In analogy to example 1, 55 mg (0.32 mmol) of 6-chloroisoxazolo[5,4-b]pyridin-3-ol were reacted with 62.7 mg (0.39 mmol) of 4-methylpiperidine-1-carbonyl chloride. Yield: 22 mg (24%), M+H+: 296.04.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21](OC)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:25]([C:28]2[CH:33]=[C:32]([F:34])[C:31]([F:35])=[C:30]([F:36])[CH:29]=2)(=[O:27])=[O:26])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.O>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([CH2:21][OH:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:25]([C:28]2[CH:29]=[C:30]([F:36])[C:31]([F:35])=[C:32]([F:34])[CH:33]=2)(=[O:27])=[O:26])[CH2:16][CH2:15]4)=[CH:6][CH:7]=1
Reactant: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1cc(F)c(F)c(F)c1)C2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(c1cc(F)c(F)c(F)c1)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(CO)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
To a solution of (R)-methyl 1-(4-fluorophenyl)-6-((3,4,5-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate (1.0 g, 1.918 mmol) in anhydrous dichloromethane (30 mL) at −78° C. under a nitrogen atmosphere was added diisobutyl aluminium hydride (DIBAL-H) (1 M in Heptane) (7.67 ml, 7.67 mmol) dropwise over 10 minutes. The reaction mixture was stirred at −78° C. for 1 hour. Water (10 mL) was then added and the reaction mixture stirred at −78° C. for 5 minutes, then warmed to room temperature over 15 minutes. The solution was partitioned between ethyl acetate (150 mL) and Rochelle's salt (150 mL). The organic layer was washed with Rochelle's salt (150 mL), brine (100 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give an off white solid. The crude product was purified by chromatography on silica gel (gradient: 0-90% ethyl acetate in isohexane) to afford (R)-(1-(4-fluorophenyl)-6-((3,4,5-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)methanol (680 mg) as a white solid. LCMS (Method F, ES-API): RT 2.58 min, m+H=494.2.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[O:11])[C:3]=1[C:4]#[N:5].[NH4+:20].[OH-]>CO.CCO>[NH2:20][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[O:11])[C:3]=1[C:4]#[N:5]
Reactant: COc1cccc(S(=O)c2cccc(F)c2C#N)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: COc1cccc(S(=O)c2cccc(N)c2C#N)c1
Temperature: 130 °C

Procedure:
To a solution of 0.73 g (2.7 mmol) of 2-fluoro-6-[(3-methoxyphenyl)sulfinyl]benzonitrile (Example 16) in 65 ml of MeOH/EtOH (2.5:4) was added 20 mL of concentrated NH4OH. This mixture was sealed in a glass-lined bomb and heated at 130° C. for 3 h. After solvent removal, the resultant concentrate was purified by flash column chromatography on silica gel with 5% MeOH in methylene chloride as the eluent. This resulted in 0.36 g (53%) of 2-amino-6-[(3-methoxyphenyl)sulfinyl]benzonitrile as a solid: mp 110°-114° C.; NMR. (Me2SO-d6, 200 MHz): δ 3.8 (s, 3H), 6.5 (br s, 2H); 7.1 (apparent d, 1H), 7.0 (apparent d, 2H), 7.2-7.3 (m, 2H), 7.5 (apparent t, 2H); mass spec (CI) 273 (M+ +1, 100%). Anal. Calc. for C14H12N2O2S: C, 61.75; H, 4.44; N, 10.29; S, 11.77. Found: C 61.65; H, 4.46; N, 10.21; S, 11.69.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][NH:11][C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:23]([CH:27](OC)[OH:28])([F:26])([F:25])[F:24].ClCCl>O>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[C:13]([CH:27]([OH:28])[C:23]([F:26])([F:25])[F:24])=[CH:12][NH:11][C:10]=1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(O)C(F)(F)F
Reactant: Cc1[nH]ccc(=O)c1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: Cc1[nH]cc(C(O)C(F)(F)F)c(=O)c1OCc1ccccc1
Yield: 24 %

Procedure:
A mixture of 3-benzyloxy-2-methyl-1H-pyridin-4-one (10.0 g, 46.4 mmol), potassium carbonate (19 g, 138 mmol), and CF3CH(OH)OCH3 (35 mL, 0.35 mol) in a 500 mL 3-necked round bottom flask equipped with a mechanical stirrer was heated to reflux for 6 days. The progress of the reaction was monitored by HPLC Method 3 (Example 24). Analysis of the HPLC data indicated that there was about 42% conversion. The reaction was stopped, and dichloromethane and deionized water were added. The organic fraction was collected, washed with brine, dried over Na2SO4, filtered and concentrated to dryness. Purification of the residue by column chromatography on silica (methanol/dichloromethane 2/100 to 5/100 v:v) afforded 3-benzyloxy-2-methyl-5-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one as a solid product (3.5 g, 24% yield, HPLC Method 3 (Example 24), RT=14.3 min). 1H NMR (DMSO-d6) δ ppm: 11.68 (br s, 1H), 7.58 (s, 1H), 7.35, (m, 5H), 5.34 (q, J=7.3 Hz, 1H), 5.06 (m, 2H), 2.08 (s, 3H); MS-ESI (m/z) 313.7 [M+1]+, 206.1, 91.1 (100%).
Reaction SMILES: C[O:2][C:3]1[C:12]([O:13]C)=[CH:11][C:10]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].O>CC(O)=O.Br.[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-]>[OH:2][C:3]1[C:12]([OH:13])=[CH:11][C:10]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(S(=O)(=O)c2ccc(C)cc2)cc(OC)c1OC
Agent: Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)c2cc(O)c(O)c(C(=O)O)c2)cc1
Temperature: 140 °C
Reaction time: 20 h

Procedure:
Methyl 2,3-dimethoxy-5-(toluene-4-sulfonyl)-benzoate (1.3 g, 4.036 mmol) was dissolved in 5 mL AcOH to which HBr (15 mL of a 33% solution in AcOH) and Bu4NBr (1.1 g, 3.4 mmol, 0.85 eq.) were added. The reaction mixture was stirred at 140° C. for 20 h, then H2O was slowly added and the mixture was extracted with EtOAc. The organic layer was washed twice with saturated NaCl solution, dried over MgSO4 and evaporated in vacuo. The crude product was purified using flash chromatography (silica gel, hexane/EtOAc/AcOH 3:2:0.2→1:3:0.2) to yield the desired product as an orange solid.
Reaction SMILES: C([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:27])(=[N:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])=[CH:15][CH:14]=2)=[CH:5][C:4]=1[N:28]=[CH:29][N:30]([CH3:32])C)#N.[NH2:33][C:34]1[S:35][CH:36]=[N:37][N:38]=1.ClCCl.CO>CO>[CH2:25]([O:24][C:22]([N:21]=[S:19]([CH3:27])([C:16]1[CH:15]=[CH:14][C:13]([CH2:12][O:11][C:6]2[CH:5]=[C:4]3[C:3]([C:32]([NH:33][C:34]4[S:35][CH:36]=[N:37][N:38]=4)=[N:30][CH:29]=[N:28]3)=[CH:8][C:7]=2[O:9][CH3:10])=[CH:18][CH:17]=1)=[O:20])=[O:23])[CH3:26]
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(COc2cc(N=CN(C)C)c(C#N)cc2OC)cc1
Reactant: Nc1nncs1
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)N=S(C)(=O)c1ccc(COc2cc3ncnc(Nc4nncs4)c3cc2OC)cc1
Yield: 40 %

Procedure:
According to GWP 5, the reaction of N′-(2-cyano-5-{4-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzyloxy}-4-methoxyphenyl)-N,N-dimethylformimidamide (85 mg, 0.19 mmol) with 2-amino-1,3,4-thiadiazole (23 mg, 0.22 mmol) and chromatographic purification (silica gel, dichloromethane/methanol: 0→30% methanol) gives the desired product in 40% yield (38 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:17][C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])[S:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1>[C:26]([N:23]1[CH2:24][CH2:25][CH:20]([C:18]([NH:17][C:8]2[S:9][C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[N:7]=2)=[O:19])[CH2:21][CH2:22]1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)C1CCNCC1
Solvent: c1ccncc1
Product: CC(=O)N1CCC(C(=O)Nc2nc(-c3ccco3)c(N3CCOCC3)s2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.7 %

Procedure:
Compound 44 (145 mg, 0.400 mmol) was dissolved in pyridine (5 mL), acetic anhydride (0.19 mL, 2.00 mmol) was added thereto, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (ethyl acetate:methanol=9:1) to afford the entitled Compound 54 (40.0 mg, 25%).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:20])[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[O:30]1COCO[CH2:31]1>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:20])[C@@H:15]([CH2:31][OH:30])[CH2:16][CH:17]([CH3:18])[CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1OCOCO1
Reactant: CC(C)CCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C[C@H](CO)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 0 °C
Yield: 98.3 %

Procedure:
Intermediate (2a) (14.5 g, 46.3 mmol) was dissolved in DCM (151 mL, 2.4 mol) and stirred at 0° C. under nitrogen. 1 M titanium tetrachloride in DCM (48.6 mL) was added and stirred for 15 minutes. DIPEA (8.9 mL, 51.0 mmol) was added dropwise at 0° C. and the mixture was stirred for 75 minutes. 1,3,5-Trioxane (4.6 g, 51.0 mmol) in DCM (30 mL) was then added. After 10 minutes a second equivalent of 1 M titanium tetrachloride in DCM (48.6 mL) was added and the mixture stirred at 0° C. for 5 hours. The reaction was then quenched with 250 mL of saturated ammonium chloride. Water and DCM were added, and the aqueous phase was extracted twice more with DCM. The organic layers were combined, dried over MgSO4, filtered and concentrated. The resulting material was purified by silica gel chromatography (0-60% EtOAc:hexanes) to provide intermediate (2b) (13.9 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:13]=1[OH:21])=[O:10]>CN(C)C=O.C(OCC)(=O)C>[N+:18]([C:14]1[C:13]2[O:21][CH2:8][C:9](=[O:10])[NH:11][C:12]=2[CH:17]=[CH:16][CH:15]=1)([O-:20])=[O:19]
Reactant: O=C(CCl)Nc1cccc([N+](=O)[O-])c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1COc2c(cccc2[N+](=O)[O-])N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Potassium carbonate (4.10 g, 29.7 mmol) was added to a solution of 2-chloro-N-(2-hydroxy-3-nitrophenyl)acetamide obtained (5.70 g, 24.7 mmol) in N,N-dimethylformamide (150 mL) while cooling in ice, and the mixture was stirred at room temperature for 5 hr. The mixture was diluted with ethyl acetate, washed with water and brine, and then dried over anhydrous sodium sulfate. The desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was powdered with chloroform and collected by filtration to afford 8-nitro-2 H-1,4-benzoxazin-3(4 H)-one as a pale orange powder (4.32 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[C:4]([CH3:28])[CH:3]=1.Cl.[NH2:30][OH:31].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=2)[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:30]\[OH:31])=[C:4]([CH3:28])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(CO)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(CO)cc1

Procedure:
In analogy to example 151, step 3, 5-(3-(4-chloro-2-methylphenyl)-3-(4-(hydroxymethyl)phenyl)propanoyl)-1-methylpyridin-2(1H)-one was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a colourless solid, MS (ESI+): m/z=411.2 [M+H]+.