Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]=[C:10]=[O:11])[CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[C:20]([F:25])[C:21]=1[O:22][CH2:23][CH3:24])[N:18]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[N:17]=[C:16]2[NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>ClCCl>[C:37]([O:36][C:34]([NH:33][C:16]1[C:15]2[C:19](=[C:20]([F:25])[C:21]([O:22][CH2:23][CH3:24])=[C:13]([NH:12][C:10]([NH:9][CH2:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[O:11])[CH:14]=2)[N:18]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[N:17]=1)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: CCOc1c(N)cc2c(NC(=O)OC(C)(C)C)nn(C(=O)OC(C)(C)C)c2c1F
Reactant: O=C=NCc1cccc(F)c1
Solvent: ClCCl
Product: CCOc1c(NC(=O)NCc2cccc(F)c2)cc2c(NC(=O)OC(C)(C)C)nn(C(=O)OC(C)(C)C)c2c1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.5 %

Procedure:
4.3 120 mg of 1-fluoro-3-isocyanatomethylbenzene (0.79 mmol) are added to 270 mg of tert-butyl 5-amino-3-tert-butoxycarbonylamino-6-ethoxy-7-fluoroindazole-1-carboxylate (0.66 mmol), dissolved in 10 ml of dichloromethane, and the mixture is stirred at RT for 24 hours. The reaction solution is evaporated, and the residue is purified by column chromatography on silica gel (eluent: 100% heptane->60% heptane/40% ethyl acetate), giving 250 mg of tert-butyl 3-tert-butoxycarbonylamino-6-ethoxy-7-fluoro-5-[3-(3-fluorobenzyl)ureido]indazole-1-carboxylate (68%), MS-FAB (M+H+)=562.
Reaction SMILES: [C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:8]=1)[CH3:5])([OH:3])=O.[CH3:22][NH:23][CH3:24]>>[CH3:22][N:23]([CH3:24])[C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:8]=1)[CH3:5])=[O:3]
Reactant: CC(Oc1ncn(-c2ccc(C(F)(F)F)cc2)n1)C(=O)O
Reactant: CNC
Product: CC(Oc1ncn(-c2ccc(C(F)(F)F)cc2)n1)C(=O)N(C)C

Procedure:
Three g of the product of Example 65 was reacted with 4 ml of 45% aqueous dimethylamine, substantially as shown in Example 60, to obtain 1.2 g of the desired product, m.p. 102°-104°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:37].[CH3:38][N:39]([CH3:43])[CH2:40][CH2:41][NH2:42]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:42][CH2:41][CH2:40][N:39]([CH3:43])[CH3:38])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:37]
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CN(C)CCN
Product: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(NCCN(C)C)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound was prepared from 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide and N,N-dimethyl-1,2-ethanediamine by following the procedures in Example 79c. LC-MS m/z 562 (M+H)+; 1H-NMR (MeOD) 2.15 (m, 6 H), 2.36 (m, 4 H), 2.65 (m, 1 H), 3.27 (m, 2 H), 6.38 (d, J=8.4 Hz, 1 H), 7.17 (m, 1 H), 7.25 (m, 2 H), 7.49 (m, 2 H), 7.59 (m, 2 H), 8.00 (s, 1 H), 8.11 (d, J=8.0 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[C:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17](Cl)=[CH:16][CH:15]=1)=[C:5]2[Cl:21].[Cl:22]C1C=C(C=CC=1)CC(C(O)=O)C(O)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[C:6]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:22])[CH:15]=1)=[C:5]2[Cl:21]
Reactant: Clc1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1
Reactant: O=C(O)C(Cc1cccc(Cl)c1)C(=O)O
Product: Clc1cccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)c1

Procedure:
The title compound was prepared by substituting 2-(4-chlorobenzyl)malonic acid (Intermediate 3: step b) with 2-(3-chlorobenzyl)malonic acid (Intermediate 5: step b) then following the procedure described for the preparation of 6-bromo-2,4-dichloro-3-(4-chlorobenzyl)quinoline (Intermediate 3: step c).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[NH:9][C:10]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[C:18](=NO)[CH2:17][CH2:16]4)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=[O:33]>ClCCl>[N:1]1([CH2:7][C:8]2[NH:9][C:10]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:33])[CH2:17][CH2:16]4)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: ON=C1CCc2cc(-c3nc(CN4CCNCC4)[nH]c3-c3ccncc3)ccc21
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CCc2cc(-c3nc(CN4CCNCC4)[nH]c3-c3ccncc3)ccc21

Procedure:
A solution of the product of Step 1 (0.350 g, 0.74 mmol) in dichloromethane (10 ml) and trifluoroacetic acid (5 ml) was stirred at room temperature for 3 hours. The solution was concentrated and the residue co-evaporated with dichloromethane. The residue was dissolved in water (10 ml) and the solution was neutralised with sodium carbonate solution. The solvent was evaporated in vacuo and the resulting solid was dried over phosphorus pentoxide to give title compound which was used in the next step; MS(AP+) m/e 374 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[N:10]1[C:15]([CH3:16])=[CH:14][C:13]([OH:17])=[CH:12][C:11]1=[O:18].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[F:30][C:31]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:32]=1[CH2:33]Br>C([O-])(O)=O.[Na+]>[F:30][C:31]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:32]=1[CH2:33][O:17][C:13]1[CH:14]=[C:15]([CH3:16])[N:10]([C:3]2[CH:4]=[C:5]([CH2:8][OH:9])[CH:6]=[CH:7][C:2]=2[F:1])[C:11](=[O:18])[CH:12]=1
Reactant: Cc1cc(O)cc(=O)n1-c1cc(CO)ccc1F
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccc(F)cc2F)cc(=O)n1-c1cc(CO)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 100 mL roundbottomed flask (nitrogen purged) was charged with 1-[2-fluoro-5-(hydroxymethyl)phenyl]-4-hydroxy-6-methylpyridin-2(1H)-one (1.2 g, 4.82 mmol) and N,N-dimethyl formamide (10 mL). Potassium carbonate (0.6 g, 4.4 mmol) and 2,4-difluorobenzyl bromide (0.56 mL, 4.4 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with saturated aqueous NaHCO3 and extracted with ethyl acetate. The organic layer was concentrated in vacuo and the residue was chromatographed on silica (9:1 methylene chloride: ethanol). The impure oil (0.3 g, 17%) was carried on without further purification. 1H NMR (400 MHz, CD3OD) δ 7.54 (m, 2H), 7.30 (m, 2H), 7.02 (m, 2H), 6.17 (dd, J=1 and 2.8 Hz, 1H), 6.03 (d, j=2.8 Hz, 1H), 5.14 (s, 2H), 4.62 (s, 2H), 2.14 (s, 3H) ppm. 19F NMR (400 MHz, CD3OD) δ −111.35 (1F), −115.97 (1F), −127.31 (1F) ppm. LC/MS, tr=5.05 minutes (5 to 95% acetonitrile/water over 8 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 375 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:36]=[CH:35][C:17]4[N:18]=[C:19]([NH:21][C@H:22]5[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]5)[S:20][C:16]=4[CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:4]=[N:3]1.O1CCOCC1>Cl>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:36]=[CH:35][C:17]4[N:18]=[C:19]([NH:21][C@H:22]5[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]5)[S:20][C:16]=4[CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cc(Oc3ccc4nc(N[C@H]5CCCN(C(=O)OC(C)(C)C)C5)sc4c3)ccn2)cn1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(Oc3ccc4nc(N[C@H]5CCCNC5)sc4c3)ccn2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
(S)-tert-butyl 3-(6-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)piperidine-1-carboxylate (9.6 mg, 19 μmol) was dissolved in 1 ml of 4M HCl in dioxane (4 mmol). The reaction solution was stirred at room temperature for 1 hour. The crude reaction solution was evaporated in vaccuo to give (S)-6-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-N-(piperidin-3-yl)benzo[d]thiazol-2-amine (7.6 mg, 18 μmol) as white solid. ES/MS m/z 407.1 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>>[N+:12]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[OH:1])([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc2ccccc2c1
Product: O=[N+]([O-])c1c(O)ccc2ccccc12

Procedure:
Fluorination can be accomplished by nitrating 2-hydroxynaphthalene (Formula I) with one equivalent of nitric acid in an inert organic solvent, to form 1-nitro-2-hydroxynaphthalene, reacting this with dimethyl sulfate in dilute alkali to form 1-nitro-2-methoxynaphthalene, hydrogenating the methyl ether over Raney nickel, for example, to form 1-amino-2-methoxynaphthalene, diazotizing this in aqueous fluoroboric acid to yield the 1-diazonium fluoroborate, and thermally decomposing the latter in the presence of copper powder to yield 1-fluoro-2-methoxynaphthalene (Formula IV).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:17]([OH:19])=[O:18])=[CH:8][N:9]2[CH:14]2[CH2:16][CH2:15]2)=[CH:4][C:3]=1[F:21].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>O1CCOCC1>[C:12]([C:11]1[C:2]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:3]([F:21])[CH:4]=[C:5]2[C:10]=1[N:9]([CH:14]1[CH2:16][CH2:15]1)[CH:8]=[C:7]([C:17]([OH:19])=[O:18])[C:6]2=[O:20])#[N:13]
Reactant: N#Cc1c(Cl)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: C1CCNC1
Solvent: C1COCCO1
Product: N#Cc1c(N2CCCC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
3.05 g of the product from Example 1 and 2.5 ml of pyrrolidine are boiled in 50 ml of dioxane for 3 hours. The mixture is concentrated in vacuo and the residue is taken up in water. The mixture is rendered neutral with 1N HCl. The solid which has precipitated out is filtered off with suction, dried and stirred with acetonitrile. 1.8 g of the title compound with a melting point of 274°-276° C. are obtained.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[N:17]=[CH:16][C:15]([C:18]2[N:23]3[N:24]=[C:25]([NH:27][C:28]([CH:30]4[CH2:32][CH2:31]4)=[O:29])[N:26]=[C:22]3[CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1>C1COCC1>[CH2:1]([O:8][C:12]1[N:17]=[CH:16][C:15]([C:18]2[N:23]3[N:24]=[C:25]([NH:27][C:28]([CH:30]4[CH2:31][CH2:32]4)=[O:29])[N:26]=[C:22]3[CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=C(Nc1nc2cccc(-c3ccc(Cl)nc3)n2n1)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1nc2cccc(-c3ccc(OCc4ccccc4)nc3)n2n1)C1CC1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
At 0° C. and under N2 atmosphere, benzyl alcohol (2 eq) in a solution of THF was treated with NaH 60% in mineral oil (4 eq) for 30 min. Then cyclopropanecarboxylic acid [5-(6-chloro-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amide prepared by method A was added to the solution and the mixture was stirred at 70° C. for 3 hours. The reaction was completed. The reaction mixture was quenched with water and the compound was extracted with EtOAc. The compound was washed with brine, dried on MgSO4, filtrated and concentrated. Compound was purified on Prep HPLC.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][C:8]([OH:10])=[O:9].OS(O)(=O)=O.[CH2:16](O)[CH3:17]>>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][C:8]([O:10][CH2:16][CH3:17])=[O:9]
Reactant: CCO
Reactant: O=C(O)CC1CCCC1=O
Agent: O=S(=O)(O)O
Product: CCOC(=O)CC1CCCC1=O

Procedure:
To a solution of 2-(2-oxocyclopentyl)acetic acid (23.6 g, 166 mmol) in absolute ethanol (400 mL) was added H2SO4 (16.28 g, 166 mmol). The resultant solution was heated under reflux overnight. The reaction mixture was concentrated and the liquid residue was added into ice-water (200 mL). The aqueous mixture was extracted with DCM (3×200 mL). The combined organic layers were washed with H2O (300 mL), brine (300 mL), dried over Na2SO4, decanted, concentrated and dried under vacuum to afford the title compound as a light yellow liquid (27.2 g). LCMS m/z=171.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.19 (t, J=7.14 Hz, 3H), 1.50-1.62 (m, 1H), 1.65-1.80 (m, 1H), 1.92-2.02 (m, 1H), 2.12 (dd, J=16.7, 8.86 Hz, 1H), 2.19-2.29 (m, 2H), 2.30-2.44 (m, 2H), 2.65 (dd, J=15.12, 2.6 Hz, 1H), 4.07 (q, J=7.14 Hz, 2H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:46][C:47]1[N:52]=[C:51](O)[CH:50]=[CH:49][CH:48]=1>O.C1COCC1>[Cl:46][C:47]1[N:52]=[C:51]([O:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)[CH:50]=[CH:49][CH:48]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1cccc(Cl)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.7 %

Procedure:
Diethyl azodicarboxylate (11 ml, 40% Tol solution) was dropwise added to a THF (30 ml) solution containing tert-butyl 4-hydroxypiperidine-1-carboxylate (4.6 g), triphenylphosphine (6.1 g) and 6-chloro-2-pyridinol (2.0 g) at 0° C., followed by stirring at room temperature for 24 hours. Water was added to the reaction solution, followed by extraction with EtOAc. The organic layer was washed with an aqueous 1 M sodium hydroxide solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=10:1 (v/v)) to obtain tert-butyl 4-[(6-chloro-2-pyridinyl)oxy]-1-piperidinecarboxylate (3.8 g).
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([S:35]([NH:38][C:25](=[O:26])[CH:24]=[CH:23][C:20]2[CH:21]=[CH:22][C:17]([C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:9][CH3:10])=[CH:18][CH:19]=2)(=[O:36])=[O:37])=[CH:33][CH:34]=1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 4-chlorobenzenesulfonamide in accordance with Procedure 1, Method B described hereinabove. Yield (22%); 1H NMR (d6-DMSO) δ 12.31 (br s, 1H), 7.90 (d, J=8.4 Hz, 2H), 7.66 (d, J=8.4 Hz, 2H), 7.39–7.07 (m, 13H), 6.84 (d, J=8.0 Hz, 2H), 6.40 (d, J=15.7 Hz, 1H), 2.35 (q, J=7.4 Hz, 2H), 0.82 (t, J=7.4 Hz, 3H); APcI m/z: 527 (M−H−).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:19](=[O:20])[N:18]2[CH:13]1[S:14][CH2:15][N:16]([S:31]([C:34]([F:37])([F:36])[F:35])(=[O:33])=[O:32])[CH:17]2[C:21]([O:23]CC1C=CC=CC=1)=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(OC)C=CC=CC=1.C(OCC)(=O)C.Cl>C(Cl)Cl.[N+](C)([O-])=O>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:19](=[O:20])[N:18]2[CH:13]1[S:14][CH2:15][N:16]([S:31]([C:34]([F:35])([F:36])[F:37])(=[O:32])=[O:33])[CH:17]2[C:21]([OH:23])=[O:22])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C1SCN(S(=O)(=O)C(F)(F)F)C2C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C[N+](=O)[O-]
Product: O=C(COc1ccccc1)NC1C(=O)N2C1SCN(S(=O)(=O)C(F)(F)F)C2C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
To a solution of benzyl 7-phenoxyacetamido-8-oxo-3-trifluoromethanesulfonyl-5-thia-1,3-diazabicyclo[4,2,0]octane-2-carboxylate (2.19 g.) and anisole (6.3 ml.) in methylene chloride (20 ml.) was added a solution of alminum trichloride (2.6 g.) in nitromethane (10 ml.) at 0° C. over a period of 5 minutes. The resultant deep red solution was stirred at 0° C. for 30 minutes. After the reaction mixture was poured into a mixture of ice and ethyl acetate (120 ml.), it was acidified to pH 1 with 3 N hydrochloric acid. The organic layer was separated, washed twice with an aqueous solution of sodium chloride and hydrochloric acid and then extracted with a chilled dilute aqueous solution of sodium bicarbonate (once with 50 ml. and twice with 30 ml.). These aqueous extracts were combined, acidified to pH 1 with 3 N hydrochloric acid, saturated with sodium chloride and then extracted three times with chloroform. Drying over magnesium sulfate and removal of the solvent afforded an amorphous solid (1.75 g.) of 7-phenoxyacetamido-8-oxo-3-trifluoromethanesulfonyl-5-thia-1,3-diazabicyclo[4,2,0]octane-2-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]([C:14]([OH:16])=O)=[C:9]([O:10][CH:11]([CH3:13])[CH3:12])[C:5]=2[CH:4]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:29][CH3:30])(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]([C:14]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([O:29][CH3:30])(=[O:28])=[O:27])=[CH:22][CH:21]=3)=[O:16])=[C:9]([O:10][CH:11]([CH3:12])[CH3:13])[C:5]=2[CH:4]=1
Reactant: COS(=O)(=O)c1ccc(N)cc1
Reactant: COc1ccc2sc(C(=O)O)c(OC(C)C)c2c1
Product: COc1ccc2sc(C(=O)Nc3ccc(S(=O)(=O)OC)cc3)c(OC(C)C)c2c1
Yield: 56 %

Procedure:
Following a procedure analogous to Example 12, 5-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxylic acid (300 mg, 1.1 mmol) and 402 mg, 1.8 mmol) methyl 4-aminobenzenesulfonate [obtained by catalytic hydrogenation of methyl 4-nitrobenzenesulfonate (Aldrich) followed by salt formation] provides 295 mg (56%) of product; mp 176.5°-177° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]4[N:22]([CH2:27][CH3:28])[N:23]=[C:24]([CH3:26])[CH:25]=4)=[O:20])=[CH:14][CH:13]=3)[CH:8]=2)[NH:3]1.[CH:29](OCC)=[O:30].[O-]CC.[Na+].Cl>C(O)C>[OH:30][CH:29]=[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:11][C:12]3[CH:13]=[CH:14][C:15]([NH:18][C:19]([C:21]4[N:22]([CH2:27][CH3:28])[N:23]=[C:24]([CH3:26])[CH:25]=4)=[O:20])=[CH:16][CH:17]=3)[CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCn1nc(C)cc1C(=O)Nc1ccc(Cc2ccc3c(c2)CC(=O)N3)cc1
Reactant: CCOC=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCn1nc(C)cc1C(=O)Nc1ccc(Cc2ccc3c(c2)C(=CO)C(=O)N3)cc1
Temperature: 78 °C
Yield: 46.8 %

Procedure:
2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(2-oxo-2,3-dihydro-1H-indol-5-ylmethyl)-phenyl]-amide (0.140 g, 0.374 mmol) and ethyl formate (0.060 mL, 0.816 mmol) were dissolved in anhydrous ethanol (0.250 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (0.42 mL, 1.12 mmol). This reaction mixture was heated at 78° C. for 0.5-1 h, producing a viscous, dark reddish colored oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 3 with dropwise addition of 1M HCl(aq) causing the formation of a grey precipitate. The suspension was filtered yielding a grey solid as the pure product (0.070 g, 0.175 mmol, 47%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]([NH:14][C:15](=[O:39])[CH2:16][CH:17]([C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[NH:18][S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1)(=[O:21])=[O:20])[CH2:9][CH2:8][CH2:7]2)(=O)[CH3:2].[CH2:40]([NH2:44])[CH:41]([CH3:43])[CH3:42].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[F:38][C:35]1[CH:36]=[CH:37][C:32]([CH:17]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:29])[F:31])[CH:23]=2)(=[O:21])=[O:20])[CH2:16][C:15]([NH:14][CH:10]2[C:11]3[C:6](=[CH:5][C:4]([CH:1]([NH:44][CH2:40][CH:41]([CH3:43])[CH3:42])[CH3:2])=[CH:13][CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:39])=[CH:33][CH:34]=1
Reactant: CC(=O)c1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccc(F)cc1
Reactant: CC(C)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)CNC(C)c1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of N-(6-acetyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-3-(4-fluoro-phenyl)-3-(3-trifluoromethyl-benzenesulfonylamino)-propionamide (161 mg, 0.286 mmol, 1.0 eq), isobutylamine (Aldrich, 126 mg, 1.72 mmol, 6.0 eq), NaBH(OAc)3 (Aldrich, 182 mg, 0.858 mmol, 3.0 eq) and glacial HOAc (J, T. Baker, 34 mg, 0.572 mmol, 2.0 eq) in ClCH2—CH2Cl (3 mL) was stirred at RT for 5 days. The reaction was quenched with saturated NaHCO3 (60 mL). The crude was extracted with CH2Cl2 (60 mL×3). The extract phase was washed with saturated NaCl, dried over Na2SO4, filtered and concentrated. Flash column chromatography (silica gel, 0-10% MeOH—CH2Cl2) afforded the title compound as a colorless thin film. MS (ESI, pos. ion) m/z: 620 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:21]([CH3:23])[CH3:22])[C@@H:13]([OH:20])[CH2:14][C:15](OCC)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O)(=O)=O.[C:40]([SiH:44]([CH3:46])[CH3:45])([CH3:43])([CH3:42])[CH3:41].O>O1CCCC1>[Si:44]([O:20][C@H:13]1[CH2:14][CH2:15][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[C@H:12]1[CH:21]([CH3:22])[CH3:23])([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:46])[CH3:45]
Reactant: C[SiH](C)C(C)(C)C
Reactant: CCOC(=O)C[C@H](O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Solvent: O
Product: CC(C)[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution (10 mL) of ethyl (3S,4S)-4-{[(benzyloxy)carbonyl]amino}-3-hydroxy-5-methylhexanoate (700 mg) in tetrahydrofuran were added 2,6-lutidine (0.504 mL) and tert-butyldimethylsilane trifluoromethanesulfonate (0.596 mL), and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with 1 mol/L hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a solution of the residue in tetrahydrofuran (5 mL)-ethanol (1 mL) was added lithium borohydride (94 mg), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a solution (10 mL) of the residue in tetrahydrofuran were added triethylamine (0.602 mL) and methanesulfonyl chloride (0.25 mL), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with 1 mol/L hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL), potassium tert-butoxide (363 mg) was added thereto under ice-cooling, and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with 0.1 mol/L hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=9:1→5:1) to give the title compound (yield: 441 mg) as a pale-yellow oil.