Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[N:12][NH:13][N:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].O[CH2:16][C:17]([CH3:23])([CH3:22])[C:18]([O:20][CH3:21])=[O:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[N:12][N:13]([CH2:16][C:17]([CH3:23])([CH3:22])[C:18]([O:20][CH3:21])=[O:19])[N:14]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(-c2nn[nH]n2)cc1
Reactant: COC(=O)C(C)(C)CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)Cn1nnc(-c2ccc(C(C)C)cc2)n1
Reaction time: 2 h
Yield: 30 %

Procedure:
To a solution of crude 5-(4-isopropylphenyl)-2H-tetrazole (1.0 g, ˜5.3 mmol), methyl 3-hydroxy-2,2-dimethylpropanoate (830 mg, 8.0 mmol), and PPh3 (2.1 g, 8.0 mmol) in THF (5 mL) was added DEAD (1.35 mL, 8.0 mmol) dropwise. The reaction mixture was stirred for 2 h. LC/MS indicated the reaction was complete. The reaction mixture was filtered and purified on RP-HPLC using a mixture of acetonitrile and H2O to give methyl 3-(5-(4-isopropylphenyl)-2H-tetrazol-2-yl)-2,2-dimethylpropanoate (480 mg, 32% for two steps). LRMS (M+H+) m/z 303.2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)=[CH:29][CH:28]=1)[C:10]([NH:12][C@@H:13]([CH:23]([CH3:25])[CH3:24])[CH2:14][O:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>C1COCC1.CO>[NH2:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C:10]([NH:12][C@@H:13]([CH:23]([CH3:25])[CH3:24])[CH2:14][O:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:11])=[CH:28][CH:29]=1
Reactant: CCOC(=O)CCOC[C@@H](NC(=O)[C@@H](Cc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1)NC(=O)OC(C)(C)C)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)[C@@H](COCCC(=O)O)NC(=O)[C@@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
355.0 mg (0.52 mmol) of ethyl 3-((S)-2-{(R)-2-tert-butoxycarbonylamino-3-[4-(9H-fluoren-9-ylmethoxycarbonylamino)phenyl]propionylamino}-3-methylbutoxy)propionate were dissolved in a mixture of 9 ml of THF and 3 ml of MeOH. 1.29 ml (1.29 mmol) of an aqueous 1M LiOH solution were added, and the resulting reaction mixture was stirred at room temp. for 1 h. After the reaction was complete, the mixture was neutralized by adding a little aqueous 1N HCl solution, concentrated under reduced pressure and codistilled with toluene. The product obtained in this way (225.0 mg) was employed crude in the next reaction.
Reaction SMILES: C([Mg]Br)(C)C.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.COCN[C:17](=[O:27])[CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[O:27]=[C:17]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25]
Reactant: Brc1cccnc1
Reactant: COCNC(=O)CNC(=O)OC(C)(C)C
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)c1cccnc1
Reaction time: 1 h
Yield: 78 %

Procedure:
Isopropylmagnesium bromide (15.5 ml, 2M in THF) was added to a solution of 3-bromopyridine (4.92 g) in THF (30 ml) at 0° C. and stirred for 1 h. A solution of the product from step (a) (2.18 g) in THF (20 ml) was then added and the reaction mixture was stirred at room temperature for 40 h. The mixture was quenched by the addition of saturated ammonium chloride solution (250 ml) and extracted with ethyl acetate. The organic layer was washed with brine and dried (MgSO4). The solvent was evaporated off and the residue purified by chromatography (silica, 20% ethyl acetate/dichloromuethane as eluent) to give the sub-title compound (1.84 g) as a white solid.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([O:8][C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([CH:18]([C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=3)[CH2:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[NH:15][C:12]2=[N:13][CH:14]=1)([CH3:7])[CH3:6])C.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[CH:20]1([CH2:19][CH:18]([C:16]2[NH:15][C:12]3=[N:13][CH:14]=[C:9]([O:8][C:5]([CH3:6])([CH3:7])[CH2:4][OH:3])[CH:10]=[C:11]3[CH:17]=2)[C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)C(C)(C)Oc1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(CO)Oc1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
To a stirred solution of 2-{2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-2-methyl-propionic acid ethyl ester (prepared as in Example 26, 300 mg, 0.6 mmol) in dry tetrahydrofuran (10 mL) at −78° C. was added diisobutylaluminum hydride (3.0 mL, 3.01 mmol). The mixture was then warmed to room temperature and stirred for 1 h. The reaction was quenched with a saturated aqueous potassium sodium tartrate solution at 0° C. After stirring at 0° C. for 30 min, the mixture was filtered and washed with tetrahydrofuran (100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-{2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-2-methyl-propan-1-ol (236 mg, 86.1%) as a white solid: LC/MS m/e calcd for C25H32N2O4S [M+H]+ 457.61, observed 457.1; 1H NMR (400 MHz, CD3OD) δ ppm 7.87-7.92 (m, 3H), 7.59-7.64 (m, 3H), 6.36 (s, 1H), 4.31 (t, J=7.8 Hz, 1H), 3.56 (s, 2H), 3.10 (s, 3H), 2.25-2.34 (m, 1H), 2.07-2.15 (m, 1H), 1.62-1.89 (m, 6H), 1.45-1.57 (m, 2H), 1.02-1.42 (m, 6H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.[C:24]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:25]([C:30]([NH:32][C:33]2[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][C:34]=2[O:42][CH3:43])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=1.[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>C(Cl)Cl>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:37]([C:36]3[CH:40]=[CH:41][C:33]([NH:32][C:30]([C:25]4[C:24]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:31])=[C:34]([O:42][CH3:43])[CH:35]=3)=[O:38])[CH2:6][C:5]=12
Reactant: COc1cc(C(=O)Cl)ccc1NC(=O)c1ccccc1-c1ccccc1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Agent: [Mg+2]
Agent: [O-][Si]([O-])([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1NC(=O)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.1 %

Procedure:
To a solution of 0.70 g of 10, 11-dihydro-5H-pyrrolo [2, 1-c][1, 4]benzodiazepine and 0.56 g of N, N-diisopropylethylamine in 50 ml of methylene chloride is added 1.35 g of 4-[([1, 1'-biphenyl]-2-carbonyl)amino]-3-methoxybenzoyl chloride followed by stirring at room temperature for 18 hours. The reaction mixture is washed with water and saturated aqueous NaHCO3 and the organic layer dried(Na2SO4). The organic layer is passed through hydrous magnesium silicate and the filtrate concentrated in vacuo to give a residue which is dissolved in methylene chloride and passed through a pad of hydrous magnesium silicate two additional times to give upon concentration in vacuo to give 1.5 g of amorphous solid. M+=512.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:16][CH:17]=[C:18](Cl)[CH3:19])([CH2:13][CH2:14][CH3:15])[C:8]2=[O:12])=[CH:4][C:3]=1[CH2:21][CH2:22][C:23]([OH:25])=[O:24].S(=O)(=O)(O)[OH:27].O>C(Cl)Cl>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:16][CH2:17][C:18](=[O:27])[CH3:19])([CH2:13][CH2:14][CH3:15])[C:8]2=[O:12])=[CH:4][C:3]=1[CH2:21][CH2:22][C:23]([OH:25])=[O:24]
Reactant: CCCC1(CC=C(C)Cl)Cc2cc(CCC(=O)O)c(Cl)c(Cl)c2C1=O
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: CCCC1(CCC(C)=O)Cc2cc(CCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 5 °C
Reaction time: 1 h

Procedure:
3-[6,7-Dichloro-2-(3-chloro-2-butenyl)-2,3-dihydro-1-oxo-2-propyl-1H-inden-5-yl]propionic acid (6.8 g, 0.0168 mole) dissolved in methylene chloride (65 ml) was added over 15 minutes to a mixture of sulfuric acid (75 ml) and methylene chloride (35 ml) at 5° C., stirred at 5° C. for 1 hour, poured over ice and water, and extracted with methylene chloride. The organic extracts were washed with water, dried over MgSO4 and concentrated under vacuum. The residue was recrystallized from butyl chloride to obtain the product mp 131°-3° C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([CH3:14])([CH3:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:34]=[CH:33][C:25]([C:26]([NH:28][CH:29]5[CH2:32][NH:31][CH2:30]5)=[O:27])=[CH:24][C:23]=4[O:35][CH3:36])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C=O.[C:39]([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>CO.Cl>[CH:1]1([N:6]2[CH2:12][C:11]([CH3:13])([CH3:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:34]=[CH:33][C:25]([C:26]([NH:28][CH:29]5[CH2:32][N:31]([CH3:39])[CH2:30]5)=[O:27])=[CH:24][C:23]=4[O:35][CH3:36])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)NC2CNC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Product: COc1cc(C(=O)NC2CN(C)C2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.4 %

Procedure:
4-(9-cyclopentyl-6,7,8,9-tetrahydro-5,7,7-trimethyl-6-oxo-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(azetidin-3-yl)-3-methoxybenzamide (69 mg, 0.14 mmol) was dissolved in methanol (1.5 ml). 37% aqueous formaldehyde (66 μl, 0.84 mmol) and sodium cyanoborohydride (26 mg, 0.42 mmol) were successively added. The reaction mixture was stirred at room temperature for 2 hours. The crude mixture was diluted with 2N HCl then, basified with a saturated solution of NaHCO3. The mixture was extracted twice with ethyl acetate. The combined organic phases were dried (MgSO4 and concentrated in vacuo. The title compound (33 mg) was obtained as a white solid after crystallization from ethyl acetate. NMR DMSO D6 1.10 (6H, s), 1.55-1.69 (4H, m), 1.69-1.80 (2H, m), 1.82-1.95 (2H, m), 2.28 (3H, s), 3.01 (2H, t), 3.38 (2H, s), 3.57 (2H, t), 3.95 (3H, s), 4.39-4.50 (1H, m), 5.12-5.25 (1H, m), 7.43-7.52 (2H, m), 7.71 (1H, s), 8.00 (1H, s), 8.38 (1H, d), 8.63 (1H, d); HPLC rt(min): 9.60; MS (ES+) 508, (ES−) 506.
Reaction SMILES: C[Si](C)(C)Cl.[CH2:6]([O:8][P:9](C(OCC)(OCC)C)([CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:10])[CH3:7].ClCCl>C(O)C>[CH2:6]([O:8][PH:9]([CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:10])[CH3:7]
Reactant: CCOC(C)(OCC)P(=O)(CC1CCCCC1)OCC
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCO
Product: CCO[PH](=O)CC1CCCCC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
150 g of trimethylchlorosilane are added to a solution of 213 g of 1,1-diethoxyethyl(cyclohexylmethyl)phosphinic acid ethyl ester in 600 ml of a mixture of dichloromethane and ethanol (90:10% by volume) and the batch is stirred for 2 to 3 days at room temperature. The solvent is removed and the residue is distilled under reduced pressure to give P-(cyclohexylmethyl)phosphinic acid ethyl ester having a boiling point of 50° (2×10-4 mbar).
Reaction SMILES: C[O-].[Na+].[F:4][C:5]([F:16])([F:15])[C:6](=O)[CH:7]=[CH:8][NH:9][CH:10]=[CH:11][C:12]#[N:13].O.CCCCCC.C(OCC)(=O)C>CO>[C:12]([C:11]1[CH:10]=[N:9][CH:8]=[CH:7][C:6]=1[C:5]([F:16])([F:15])[F:4])#[N:13]
Reactant: N#CC=CNC=CC(=O)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cnccc1C(F)(F)F
Yield: 47.2 %

Procedure:
To a solution of 28% sodium methoxide (290 mg, 1.5 mmol), a solution prepared by dissolving 3-[(4,4,4-trifluoro-3-oxo-1-butenyl)amino]-2-propenenitrile (a high-polar compound IIb; 190 mg, 1.0 mmol) in methanol (2 ml) was added at room temperature and then, the mixture was refluxed for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over magnesium sulfate and then concentrated. The resulting residue was purified by thin layer chromatography (a developing solvent: hexane/ethyl acetate=3/1) to obtain 81.0 mg (yield 47.2%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH2:21][CH2:22]Cl)[N:9]=2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C([O-])([O-])=O.[K+].[K+].CO.CCOC(C)=O>CC#N.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH2:21][CH2:22][N:34]3[CH2:33][CH2:32][N:31]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[F:24])[CH2:36][CH2:35]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(Cl)cc3)nn2CCCCl)C1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)N1CCc2c(c(-c3ccc(Cl)cc3)nn2CCCN2CCN(c3ccccc3F)CC2)C1
Temperature: 25 °C
Reaction time: 168 h
Yield: 40.3 %

Procedure:
1-[3-(4-Chloro-phenyl)-1-(3-chloro-propyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (0.053 g, 0.15 mmol) was dissolved in CH3CN (0.5 mL) and a solution of 1-(2-fluorophenyl)piperazine (0.053 g, 0.30 mmol) in CH3CN (0.5 mL) was added, followed by K2CO3 (0.031 g, 0.22 mmol) and Bu4NI (0.018 g, 0.05 mmol). The mixture was stirred at room temperature for 7 d. Preparative TLC (silica, 5% MeOH/EtOAc) afforded 30 mg (41%) of the title compound. MS (electrospray): exact mass calculated for C27H31ClFN5O, 495.22; m/z found, 496.3 [M+H]+. 1H NMR (500 MHz, CDCl3, a mixture of 1:1 rotamers): 7.60 (d, J=8.3 Hz, 1H), 7.54 (d, J=8.3 Hz, 1H), 7.39 (d, J=8.3 Hz, 1H), 7.35 (d, J=8.3 Hz, 1H), 7.06-6.90 (m, 4H), 4.77 (s, 1H), 4.60 (s, 1H), 4.10 (t, J=6.8 Hz, 2H), 3.92 (t, J=5.7 Hz, 1H), 3.74 (t, J=5.7 Hz, 1H), 3.08 (br s, 4H), 2.83 (t, J=5.6 Hz, 1H), 2.77 (t, J=5.7 Hz, 1H), 2.58 (br s, 4H), 2.41-2.38 (m, 2H), 2.19 (s, 1.5H), 2.13 (s, 1.5H), 2.10-2.07 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[N:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11].[C:31](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[N:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][N:27]([CH3:31])[CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11]
Reactant: CC(Oc1cc(-c2cn(C3CCNCC3)nn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(Oc1cc(-c2cn(C3CCN(C)CC3)nn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reaction time: 8 h

Procedure:
3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-2-aminopyridine (451 mg, 1 mmol) in the above mentioned Example 2 was added to N,N-dimethyl formamide (10 mL), potassium carbonate (276 mg, 2 mmol) and iodomethane (425.7 mg, 3 mmol) were added, and the reaction was performed overnight at room temperature. The resultant mixture was washed with water for several times, dried over anhydrous sodium sulfate, filtered, the filtrate was rotatedly concentrated to dryness to yield a solid, which was purified via silica gel column chromatography (dichloromethane/methanol=10:1) to yield the target product as white solid powder.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:25])=[CH:7][C:5]=2[N:6]=1.CCN(CC)CC.C(O)=O>C(#N)C>[Br:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=3)=[C:9]([C@H:18]([OH:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:25])=[CH:7][C:5]=2[N:6]=1
Reactant: CCOC(=O)C(=O)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)[C@@H](O)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
A 100 mL flask was charged with ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-oxoacetate (2.4 g, 5.5 mmol, 1.0 equiv) and sealed with a rubber septum. The flask was purged with argon and to this was charged ACN (11 mL) and NEt3 (1.9 mL, 13.6 mmol, 2.5 equiv) and stirring was initiated. The solution was cooled to 0° C. and then HCO2H (0.63 mL, 16.7 mmol, 3.0 equiv) was added to the solution at a rate to maintain an internal temperature not more than 20° C. Upon completion of the addition, the solution was allowed to cool back to 0° C. Argon was then bubbled through the solution using a porous gas dispersion unit. To the stirring solution at 0° C. was charged the prepared catalyst solution (0.5 mL, 0.05 equiv) from the catalyst preparation above. The solution was stirred at 0° C. with the bubbling of argon through the solution until TLC indicated complete consumption of starting material (10-18 h). The reaction was quenched with H2O then diluted with EtOAc and allowed to warm to room temperature. The layers were separated and the organic extract was washed once more with H2O. The organic extract was then dried over Na2SO4, filtered through a small pad of silica gel eluting with EtOAc, and concentrated in vacuo. The resulting crude residue was chromatographed using a 80 g RediSep normal phase silica gel cartridge (EtOAc/Hex, 5%→20%) on a CombiFlash system to give the desired product. TLC (20% EtOAc/Hex) Rf=0.27; 1H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.53-7.43 (m, 2H), 7.37 (m, 2H), 5.23 (d, J=2.2 Hz, 1H), 4.19 (m, 2H), 3.29 (d, J=2.2 Hz, 1H), 2.48 (d, J=0.5 Hz, 3H), 1.21 (t, J=7.1 Hz, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([CH3:8])[N:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:5](=[O:16])[C:4]=1[CH:17]1[CH2:19][CH2:18]1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>C(#N)C.O.CCOC(C)=O>[CH:17]1([C:4]2[C:5](=[O:16])[N:6]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[N:7]([CH3:8])[C:3]=2[CH2:2][O:27][C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)[CH2:19][CH2:18]1
Reactant: Oc1ccc(F)cc1
Reactant: Cn1c(CBr)c(C2CC2)c(=O)n1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cn1c(COc2ccc(F)cc2)c(C2CC2)c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.1 %

Procedure:
To a solution of 5-bromomethyl-4-cyclopropyl-2-(4-fluoro-phenyl)-1-methyl-1,2-dihydro-pyrazol-3-one (0.130 g) in acetonitrile (5 mL), was added 4-fluorophenol (0.045 g), caesium carbonate (0.13 g) and potassium iodide (3 crystals). The reaction was stirred overnight at ambient temperature and was then diluted with water and EtOAc. The phases were separated and the aqueous was extracted with further EtOAc. The combined organic phases were washed with further HCl solution, brine and dried with sodium sulfate. Filtration and evaporation of the volatiles in vacuo and purification of the residue via ISCO Combiflash chromatography (using EtOAc/heptane) afforded the desired 4-cyclopropyl-5-(4-fluoro-phenoxymethyl)-2-(4-fluoro-phenyl)-1-methyl-1,2-dihydro-pyrazol-3-one (0.023 g) as a light beige solid. MS (ESI+): 357.0 ([M+H]+).
Reaction SMILES: Br[C:2]1[C:10]2[S:9](=[O:12])(=[O:11])[N:8]=[C:7]([NH2:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[O:11]=[S:9]1(=[O:12])[C:10]2[C:2]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:3][CH:4]=[CH:5][C:6]=2[C:7]([NH2:13])=[N:8]1
Reactant: OB(O)c1ccccc1
Reactant: NC1=NS(=O)(=O)c2c(Br)cccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: NC1=NS(=O)(=O)c2c1cccc2-c1ccccc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 24.4 %

Procedure:
170 mg of 7-bromo-1,1-dioxo-1H-1λ6-benzo[d]isothiazol-3-ylamine, 119 mg of phenylboronic acid, 10 mg of palladium(II)acetate, 21 mg of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl and 415 mg of potassium phosphate are suspended in 5 ml of toluene. The mixture is stirred under an argon athmosphere at 100° C. for 16 h. The reaction mixture is poured into water and extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and evaporated. Chromatographie of the residue with cyclohexane—ethyl acetate (1:1) affords 41 mg of 1,1-dioxo-7-phenyl-1H-1λ6-benzo[d]isothiazol-3-ylamine (P1.5).
Reaction SMILES: O=[C:2]([CH3:16])[CH:3]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][C:5]([O:7]C)=[O:6].S(=O)(=O)(O)O>C(OC(=O)C)(=O)C>[C:11]([C:10]1[O:15][C:2]([CH3:16])=[C:3]([CH2:4][C:5]([OH:7])=[O:6])[N:9]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(=O)CC(NC(=O)C(C)(C)C)C(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1oc(C(C)(C)C)nc1CC(=O)O
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
Methyl 4-oxo-3-pivaloylaminovalerate was dissolved in acetic anhydride (15 ml), and concentrated sulfuric acid (1.2 ml) was added dropwise with stirring. The mixture was allowed to stand at room temperature for 20 minutes and heated at 80° C. for 5 minutes. The acetic anhydride was distilled off under reduced pressure and the residue was poured into 50 ml of ice water. The mixture was neutralized with potassium carbonate and extracted with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the oily residue (2.5 g) was stirred in a mixture of ethanol (13 ml) and 2N sodium hydroxide (13 ml) at room temperature for 30 minutes. The reaction mixture was diluted with water, adjusted to pH 2 with hydrochloric acid and extracted with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was treated with hexane to give 2-tert-butyl-5-methyl-4-oxazoleacetic acid as crystals; yield 1.50 g (60.2%). Recrystallization from isopropyl ether gave colorless prisms melting at 121°-122° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:7]([Cl:11])=[C:8]([Cl:10])[CH:9]=1)=[O:4].[CH3:21][O:22][C:23](=[O:28])[CH2:24][C:25](Cl)=[O:26]>>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:25](=[O:26])[CH2:24][C:23]([O:22][CH3:21])=[O:28])[C:7]([Cl:11])=[C:8]([Cl:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(Cl)c(Cl)n1NCc1ccc(F)cc1
Reactant: COC(=O)CC(=O)Cl
Product: COC(=O)CC(=O)N(Cc1ccc(F)cc1)n1c(C(=O)OC)cc(Cl)c1Cl

Procedure:
Prepared according to the acylation condition used in Example 2 step f) from 4,5-dichloro-1-(4-fluoro-benzylamino)-1H-pyrrole-2-carboxylic acid methyl ester and chlorocarbonyl-acetic acid methyl ester (1.5 eq.). 1H NMR (CDCl3, δ in ppm): 7.1-6.8 (m, 5H), 4.88 (d, 1H, J=14.6 Hz), 4.75 (d, 1H, J=14.0 Hz), 3.72 (s, 3H), 3.67 (s, 3H), 3.17 (dd, 2H).