Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C1C=C(C=CC=1)C=O.[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][NH:24][CH2:25]2)[CH2:21][CH2:20]1)=[O:17].[CH:34]1([CH:40](C2CCCCC2)[C:41](N[C@@H]2[C@H]3[C@H](CNC3)CC2)=O)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][N:24]([CH2:41][CH2:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:25]2)[CH2:21][CH2:20]1)=[O:17]
Reactant: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21)c1ccccc1
Agent: O=Cc1cccc(C(F)(F)F)c1
Product: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CN(CCc3ccccc3)C[C@@H]21)c1ccccc1

Procedure:
The title compound was prepared by substituting 2-phenylacetaldehyde for 3-(trifluoromethyl)benzaldehyde and 3-methyl-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]-2-phenylbutanamide from Example 83 Step A for 2,2-dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide in the procedure described for Example 54: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.57 (dd, J=5.2, 12.0, 1H), 7.65 (t, J=7.1, 2H), 7.38-7.23 (m, 8H), 4.40-4.29 (m, 1H), 3.23 (d, J=10.5, 1H), 3.00 (dd, J=2.6, 9.0, 0.5H), 2.80 (t, J=7.8, 1H), 2.75-2.70 (m, 1H), 2.70-2.61 (m, 1H), 2.61-2.52 (m, 1H), 2.52-2.46 (m, 1H), 2.43 (dd, J=7.6, 8.7, 0.5H), 2.38 (dd, J=2.7, 8.8, 1H), 2.34 (dd, J=2.7, 8.5, 1H), 2.26 (d, J=8.3, 0.5H), 2.24-2.18 (m, 1H), 2.12 (td, J=6.4, 12.4, 0.5H), 1.91-1.82 (m, 1H), 1.76 (dt, J=6.2, 18.7, 0.5H), 1.70-1.61 (m, 0.5H), 1.46-1.26 (m, 2H), 1.23 (dd, J=6.5, 13.5, 3H), 0.97-0.83 (m, 1H), 0.71 (dd, J=2.7, 6.7, 3H); MS (ESI+) m/z 391 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH2:3]1[C:13]2[CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[CH:8]([CH2:18][CH2:19][OH:20])[C:7]=2[CH2:6][CH:5]=[CH:4]1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>O.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl>[CH2:14]1[C:10]2[CH2:11][CH2:12][C:13]3[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=3[CH:8]([CH2:18][CH2:19][O:20][S:28]([C:25]3[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=3)(=[O:30])=[O:29])[C:9]=2[CH2:17][CH:16]=[CH:15]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCC1C2=C(CC=CC2)CCc2ccccc21
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCC2C3=C(CC=CC3)CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 664 g of sodium hydroxide in 996 ml of water is added to a solution, stirred at room temperature, of 87.5 g of crude 4,5,10,11-tetrahydro-1H-dibenzo[a,d]cycloheptene-5-ethanol, 103.7 g of p-toluenesulfochloride and 7.2 g of benzyltriethylammonium chloride in 1440 ml of methylene chloride and the mixture is stirred at room temperature overnight. The mixture is treated with 2 l of ice-water and extracted with 3 l of methylene chloride. The organic extracts are washed neutral with water. The aqueous extracts remaining are subsequently back-extracted three times with 2 l of methylene chloride each time. The organic extracts are combined, dried over magnesium sulfate and evaporated. After four-fold recrystallization of the solid residue from toluene, there is obtained pure 2-(4,5,10,11-tetrahydro-1H-dibenzo[a,d]cyclohepten-5-yl)ethyl-p-toluenesulfonate of melting point 150°-151°.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]([C@H:14]([C@@:20]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)([NH:22][CH:23]([CH3:25])[CH3:24])[CH3:21])[CH2:15][CH2:16][C:17]([OH:19])=O)[CH:11]=[CH:12][CH:13]=1.CN(C=O)C>C1C=CC=CC=1>[Cl:7][C:8]1[CH:9]=[C:10]([C@@H:14]2[C@:20]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:21])[N:22]([CH:23]([CH3:24])[CH3:25])[C:17](=[O:19])[CH2:16][CH2:15]2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)N[C@](C)(c1ccc(Cl)cc1)[C@H](CCC(=O)O)c1cccc(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@@]1(C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Oxalyl chloride (˜0.38 M in benzene, 0.617 mL, 0.234 mmol) was added to a room temperature solution of (4R,5S)-4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-(isopropylamino)hexanoic acid (Example 418, Step G, 84 mg, 0.213 mmol) in benzene (3 mL) followed by a drop of DMF. The reaction solution was stirred at room temperature for 25 minutes then heated to 80° C. After 3.5 hours the reaction was removed from heat and saturated aqueous sodium bicarbonate solution was added. The organic phase was diluted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with brine, then dried with anhydrous magnesium sulfate and concentrated to afford a red-orange oil. The product was isolated by chromatography on silica (12 g RediSep Rf cartridge) eluting with 20-40% ethyl acetate gradient in hexane to afford the title compound as a pale yellow film. [α]D=+ 89.33° (T=24.0° C.; c=1, CHCl3)
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=1[O:16][CH3:17].[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.O>C(Cl)(Cl)Cl.CO>[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=1[N:27]1[CH2:28][CH2:29][N:30]([C:11]([C:10]2[CH:14]=[CH:15][C:7]([N:3]3[CH2:4][CH2:5][CH2:6][S:2]3(=[O:1])=[O:18])=[C:8]([O:16][CH3:17])[CH:9]=2)=[O:13])[CH2:31][CH2:32]1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: COc1cc(C(=O)O)ccc1N1CCCS1(=O)=O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)N2CCN(c3ccc(C)cc3C)CC2)ccc1N1CCCS1(=O)=O
Temperature: 25 °C
Yield: 88.6 %

Procedure:
4-(1,1-Dioxo-1λ6-isothiazolidin-2-yl)-3-methoxybenzoic acid (285 mg) described in Preparation Example 21 and 1-(2,4-dimethylphenyl)piperazine (199 mg) were dissolved in a solution of chloroform (2.1 mL) and methanol (2.1 mL), 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (349 mg) was added, and the mixture was stirred at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give the title compound (411 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:6][CH3:7])[C:3](O)=O.C(Cl)(=O)C(Cl)=O.CN(C=O)C.CC(C)(CC)C(Cl)=O.Cl.[NH2:29][NH:30][C:31]([NH2:33])=[O:32].[OH-].[Na+].[NH4+].[Cl-]>C(Cl)Cl.O1CCOCC1.O>[C:2]([C:3]1[NH:33][C:31](=[O:32])[NH:30][N:29]=1)([CH2:6][CH3:7])([CH3:8])[CH3:1]
Reactant: CCC(C)(C)C(=O)O
Reactant: NNC(N)=O
Agent: CCC(C)(C)C(=O)Cl
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)(C)c1n[nH]c(=O)[nH]1
Temperature: 0 °C
Reaction time: 12 h
Yield: 53.2 %

Procedure:
2,2-Dimethylbutyric acid (1 g, 8.6 mmol) was dissolved in DCM (10 mL) and cooled to 0° C. The solution was treated with oxalyl chloride (1.2 mL, 13.8 mmol) and DMF (0.07 mL, 0.87 mmol), allowed to warm to RT, and stirred for 2 h for complete conversion to 2,2-dimethylbutyric acid chloride. The solution was cooled to 0° C. and added to a stirred solution of semicarbazide hydrochloride (1.4 g, 12.9 mmol) and NaOH (1.4 g, 34.4 mmol) in a mixture of dioxane (10 mL) and water (2.0 mL) at 0° C. The reaction mixture was allowed to warm to RT and stirred for 12 h. Organic solvent was evaporated in vacuo, and the resultant slurry was diluted with 2 M NaOH (aq) (50 mL, 100 mmol). The suspension was stirred at 100° C. for 24 h. The aqueous solution was saturated with solid NH4Cl and extracted with EtOAc (5×50 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo to afford 3-(tert-pentyl)-1H-1,2,4-triazol-5(4H)-one (0.71 g, 53.1%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.17 (s, 1H), 11.02 (s, 1H), 1.49 (q, J=7.5 Hz, 2H), 1.11 (s, 6H), 0.68 (t, J=7.4 Hz, 3H); MS (ESI) m/z: 156.1 (M+H+).
Reaction SMILES: [Na].[CH2:2]([O:9][CH2:10][C:11]([NH2:13])=[NH:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O:16][CH:17]=[C:18]([C:24](OCC)=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>CCO>[CH2:2]([O:9][CH2:10][C:11]1[N:13]=[C:17]([OH:16])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][N:12]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N=C(N)COCc1ccccc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1cnc(COCc2ccccc2)nc1O

Procedure:
Sodium (4.6 g, 200 mmol) was added to EtOH (500 mL) and the mixture was stirred until a clear solution was obtained. Then, step B product, 2-c, (20.1 g, 100 mmol) and diethyl 2-(ethoxymethylene)malonate (21.6 g, 100 mmol) were added to the clear mixture, respectively. The reaction mixture was refluxed overnight and then concentrated under vacuum, washed with EA. The wet cake was then dried to afford compound 2-d (40.0 g, crude). LC-MS: (M+H)+ 289. The crude was directly used to next step without further purification.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:14][OH:15])[O:7][C:6]2=[N:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][N:5]2[CH2:4][CH2:3]1.[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1.[H-].[Na+]>>[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][O:15][CH2:14][C@:2]2([CH3:1])[O:7][C:6]3=[N:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][N:5]3[CH2:4][CH2:3]2)=[CH:19][CH:18]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: C[C@]1(CO)CCn2cc([N+](=O)[O-])nc2O1
Agent: [H-]
Agent: [Na+]
Product: C[C@]1(COCc2ccc(Br)cc2)CCn2cc([N+](=O)[O-])nc2O1
Yield: 57 %

Procedure:
Alkylation of (R)-alcohol 159 with 4-bromobenzyl bromide (1.3 equiv.) and NaH (1.5 equiv.) as in Example 2UU above for 3 h, followed by chromatography of the product on silica gel, eluting with CH2Cl2 (foreruns) and then with 1% EtOAc/CH2Cl2, gave (7R)-7-{[(4-bromobenzyl)oxy]methyl}-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (160) (349 mg, 57%) as a white solid: mp (CH2Cl2/hexane) 157-159° C.; 1H NMR (CDCl3) δ 7.46 (dt, J=8.3, 2.0 Hz, 2H), 7.39 (s, 1H), 7.12 (br d, J=8.3 Hz, 2H), 4.50 (s, 2H), 4.09 (ddd, J=12.5, 6.9, 6.0 Hz, 1H), 4.01 (ddd, J=12.5, 7.0, 6.0 Hz, 1H), 3.62 (d, J=10.2 Hz, 1H), 3.58 (d, J=10.2 Hz, 1H), 2.37 (ddd, J=14.4, 7.0, 6.0 Hz, 1H), 2.10 (ddd, J=14.4, 6.9, 6.1 Hz, 1H), 1.46 (s, 3H); [α]D27 30.0° (c 1.00, CHCl3); HRFABMS calcd for C15H17BrN3O4 m/z [M+H]+ 384.0382, 382.0402. found 384.0385, 382.0398.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:27][NH:28][O:29][CH3:30].C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>C(Cl)Cl>[CH3:30][O:29][N:28]([CH3:27])[C:11](=[O:13])[C@@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH3:10]
Reactant: CNOC
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C1c2ccccc2C(=O)C1(O)O
Solvent: ClCCl
Product: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N-Boc-L-alanine (1.0 Kg, 5.29 mol, 1.0 equiv), in DCM (15 L) was added carbonyldiimidazole (943 g, 5.81 mol, 1.1 equiv) and the resultant mixture was stirred for 1 h at rt. To this reaction mixture was added N,O-dimethylhydroxylamine hydrochloride (577 g, 5.92 mol, 1.12 equiv) and stirred at rt for 16 h. The reaction was monitored using TLC (Note: for TLC, ninhydrin stain was used to visualize the product). Another 800 g batch was combined with this batch prior to the work up. Upon completion DCM was evaporated in vacuo. The crude residue thus obtained was partitioned between EtOAc (30 L) and water (10 L). The organic layer was then washed with 1 N HCl (2×10.0 L), aq satd. NaHCO3 (2×15.0 L), brine (5 L), and dried over Na2SO4. The aq layer was back extracted with EtOAc (3×15.0 L) and the work up procedure was repeated. Evaporation of solvent in vacuo afforded (S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate as a white solid.
Reaction SMILES: [CH3:1][Mg]Cl.[O:4]=[C:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1.[Cl-].[NH4+]>O1CCCC1>[OH:4][C:5]1([CH3:1])[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:9][CH2:10]1
Reactant: C[Mg]Cl
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(O)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 79 %

Procedure:
Methylmagnesium chloride (9.53 mL, 3.0M tetrahydrofuran solution) was added to tetrahydrofuran (45.5 mL). Benzyl 4-oxopiperidine-1-carboxylate (5.00 g) was dissolved in tetrahydrofuran (8.8 mL), and added dropwise to a solution of ice-cooled methylmagnesium chloride in tetrahydrofuran, and the mixture was stirred at room temperature for 14 hr. The reaction mixture was ice-cooled, aqueous ammonium chloride solution (ammonium chloride 1.41 g, water 15 mL) was added dropwise, and the mixture was partitioned and extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was dried over magnesium sulfate, and purified by NH-silica gel column chromatography [developing solvent; hexane:ethyl acetate=80:20 (volume ratio)→60:40 (volume ratio)]. The obtained solid was washed with isopropyl ether, and dried under reduced pressure to give the title compound (4.20 g, yield 79%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[CH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[S:29]([NH:20][C:4]1[CH:5]=[C:6]([Cl:19])[C:7]([CH2:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:2]([Cl:1])[CH:3]=1)(=[O:31])=[O:30]
Reactant: Nc1cc(Cl)c(Cc2cnc3ccccc3c2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)c(Cc2cnc3ccccc3c2)c(Cl)c1)c1ccc(Cl)cc1Cl

Procedure:
2,4-Dichloro-N-(3,5-dichloro-4-quinolin-3-ylmethyl-phenyl)-benzenesulfonamide was synthesized (63%) from 3,5-dichloro-4-quinolin-3-ylmethyl-phenylamine (230), 2,4-dichlorobenzenesulfonyl chloride (Maybridge) and pyridine (EM) in a similar manner as described in Examples 70-91. 1H NMR (400 MHz, DMSO-d6) δ 11.34 (br s, 1H), 8.78 (d, J=2.0 Hz, 1H), 8.13 (d, J=8.6 Hz, 1H), 7.97 (d, J=8.6 Hz, 1H), 7.93 (d, J=1.8 Hz, 1H), 7.88 (d, J=7.9 Hz, 1H), 7.80 (s, 1H), 7.73-7.68 (m, 2H), 7.58 (t, J=7.5 Hz, 1H), 7.21 (s, 2H), 4.34 (s, 2H). MS (EI): m/z 509 (M−H).
Reaction SMILES: C(=O)([O-])[O-:2].[K+].[K+].F[B-](F)(F)F.[Cl:12][C:13]1[CH:27]=[C:26]([F:28])[C:25]([N:29]2[C:33](=[O:34])[N:32]([CH:35]([F:37])[F:36])[C:31]([CH3:38])=[N:30]2)=[CH:24][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([N+]#N)=[CH:18][N:17]=1>FC(F)(F)C(O)=O.O>[Cl:12][C:13]1[C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:2])=[CH:18][N:17]=2)=[CH:24][C:25]([N:29]2[C:33](=[O:34])[N:32]([CH:35]([F:36])[F:37])[C:31]([CH3:38])=[N:30]2)=[C:26]([F:28])[CH:27]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1nn(-c2cc(Oc3ccc([N+]#N)cn3)c(Cl)cc2F)c(=O)n1C(F)F
Agent: F[B-](F)(F)F
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1nn(-c2cc(Oc3ccc(O)cn3)c(Cl)cc2F)c(=O)n1C(F)F
Temperature: 25 °C
Yield: 177.8 %

Procedure:
To a stirred, cold (ice bath) solution of 0.67 g (0.0048 mole) of potassium carbonate in 20 mL of trifluoroacetic acid was added 4.7 g (0.097 mole) of 2-[2-chloro-4-fluoro-5-(4-difluoromethyl-4,5-dihydro -3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]pyridine-5-diazonium tetrafluoroborate. The reaction mixture was allowed to warm to room temperature and was then heated at reflux for 5.5 hours. The mixture was cooled to room temperature, diluted with 50 mL of water, and the whole was extracted with four portions of methylene chloride. The extracts were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure to give a red oil which was purified by column chromatography on silica gel. Elution with n-hexane:ethyl acetate (2:1) gave 3.3 g of 1-[4-chloro-2-fluoro-5-(5-hydroxypyridin-2-yloxy)-phenyl]-4-difluoromethyl-4,5-dihydro -3-methyl,1,2,4-triazol-5(1H)-one as a solid, m.p. 179°-181° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[N:19]=[CH:18][C:17]=2[C:31]#[N:32])=[CH:12][CH:11]=1>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:23][CH:22]=3)[N:19]=[CH:18][C:17]=2[C:31]#[N:32])=[CH:12][CH:11]=1
Reactant: OB(O)c1ccco1
Reactant: CS(=O)(=O)c1ccc(-n2ncc(C#N)c2-c2ccc(Br)cc2)cc1
Product: CS(=O)(=O)c1ccc(-n2ncc(C#N)c2-c2ccc(-c3ccco3)cc2)cc1

Procedure:
The title compound was prepared according to the procedure of Example 1 using 2-furanboronic acid instead of thiophen-3-boronic acid and 4-[5-[4-Bromophenyl]-4-cyano-1-[4-(methylsulfonyl)phenyl]-1H-pyrazole instead of 1-[4-(Methylsulfonyl)phenyl]-5-(4-bromophenyl)-3-trifluoromethyl-1H-pyrazole in step 2.
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8]2.[Cl:23][CH2:24][C:25](=O)[CH2:26]Cl.CN(C)C(=O)C>O>[Cl:23][CH2:24][C:25]1[N:13]=[C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[CH:4][C:3]=3[N:2]([CH3:1])[S:15]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)(=[O:17])=[O:16])[S:14][CH:26]=1
Reactant: O=C(CCl)CCl
Reactant: CN(c1cccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(c1cccc2cc(-c3nc(CCl)cs3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 80 °C
Reaction time: 2 h
Yield: 81.1 %

Procedure:
A mixture of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.46 g), 1,3-dichloro-2-propanone (0.33 g) and N,N-dimethylacetamide (6 mL) was stirred at 80° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (0.45 g, yield 85%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio). melting point 153-154° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11](SC)=[C:12]([S:15]([CH3:18])(=[O:17])=[O:16])[C:13]#[N:14])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:21][C:22]([NH2:26])([CH3:25])[CH2:23][CH3:24]>>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]([NH:26][C:22]([CH3:25])([CH3:21])[CH2:23][CH3:24])=[C:12]([S:15]([CH3:18])(=[O:16])=[O:17])[C:13]#[N:14])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CSC(Nc1ccc2ncsc2c1)=C(C#N)S(C)(=O)=O
Reactant: CCC(C)(C)N
Product: CCC(C)(C)NC(Nc1ccc2ncsc2c1)=C(C#N)S(C)(=O)=O
Yield: 33 %

Procedure:
3-(Benzothiazol-6-ylamino)-2-methylsulfonyl-3-methylsulfanyl-propenenitrile (0.167 g, 0.5 mmol) was stirred in 1,1-dimethylpropylamine (0.5 ml) for 17 h at 100° C. under nitrogen in a sealed flask. Work-up as described in EXAMPLE 17, 2) without chromatography gave 60 mg (33%) of the title compound. Mp 112-114° C. 1H NMR (200 MHz, CDCl3): δ=1.00 (t, 3H), 1.39 (s, 6H), 1.65 (q, 2H), 3.12 (s, 3H) 7.29 (dd, 1H), 7.70 (d, 1H), 8.13 (d, 1H), 9.0 (s, 1H); EI SP/MS: 364 (M+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]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.[C:44]([C:48]1[CH:64]=[CH:63][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:64]=[CH:63][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(Cl)cc2)cc1
Reactant: O=C(O)c1cccc2cc[nH]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
Solvent: O
Product: CC(C)(C)c1ccc(CN(CCc2ccc(Cl)cc2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95.9 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 4 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 91 mg (0.3 mmol) (4-tert-butyl-benzyl)-[2-(4-chloro-phenyl)-ethyl]-amine in 1 ml DMF was added. After stirring for 3 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The yellow solid foam was purified by column chromatography (8 g silica gel; heptane/EtOAc 9:1) to give 128 mg (86%) of a white solid. MS (ISP) 445.4 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][N:7]=[C:8]([C:14](=[O:16])[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].S(Cl)([Cl:20])(=O)=O>C(O)(=O)C>[Cl:20][CH2:15][C:14](=[O:16])[C:8](=[N:7][O:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOCCON=C(C(C)=O)C(=O)OCC
Solvent: CC(=O)O
Product: CCOCCON=C(C(=O)CCl)C(=O)OCC
Yield: 88.7 %

Procedure:
ethyl 2-(2-ethoxyethoxyimino)-3-oxobutyrate (syn isomer 56 g.), sulfuryl chloride (32.7 g.) and acetic acid (56 ml.) were treated in a similar manner to that of Example A-(2) to give ethyl 4-chloro-2-(2-ethoxyethoxyimino)-3-oxobutyrate (syn isomer, 57.1 g.).
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]1([O:10][C:11]2[CH:12]=[C:13]([C:21]3[N:38]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:24]4[CH:25]=[N:26][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:28](=[O:29])[C:23]=4[C:22]=3[CH:47]=O)[CH:14]=[CH:15][C:16]=2[O:17][CH:18]([F:20])[F:19])[CH2:9][CH2:8]1.O1[CH2:53][CH2:52][CH2:51][CH2:50]1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CCC>[CH:7]1([O:10][C:11]2[CH:12]=[C:13]([C:21]3[N:38]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:24]4[CH:25]=[N:26][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:36])([CH3:37])[CH3:35])[C:28](=[O:29])[C:23]=4[C:22]=3[CH:47]=[CH:50][CH2:51][CH2:52][CH3:53])[CH:14]=[CH:15][C:16]=2[O:17][CH:18]([F:19])[F:20])[CH2:9][CH2:8]1
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(C=O)c(-c3ccc(OC(F)F)c(OC4CC4)c3)n2COCC[Si](C)(C)C)c1=O
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CCCC=Cc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To 10 ml of tetrahydrofuran solution containing 1.20 g (3.00 mmol) of butyltriphenylphosphonium bromide was added 0.38 g (3.40 mmol) of potassium tert-butoxide under room temperature, and the mixture was stirred at the same temperature for 30 minutes. Then, to the mixture was added 0.62 g (1.00 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-formyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in the same method as in Example 15-(a), and the mixture was stirred for further 4 hours. After completion of the reaction, the reaction suspension was filtered, and the filtrate was concentrated under reduced pressure. The residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=1:3 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 0.35 g of the title compound as a slightly yellowish oil. (Yield: 53%).