Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.N1C=CC=CC=1.Cl[C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20].O>ClCCl>[CH2:22]([O:21][C:19]([NH:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1)=[O:20])[CH:23]=[CH2:24]
Reactant: COC(=O)c1cnc(N)cn1
Reactant: C=CCOC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: C=CCOC(=O)Nc1cnc(C(=O)OC)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-aminopyrazine-2-carboxylate (2 g) in dichloromethane (20 mL) were added pyridine (36.4 mL) and allyl chloroformate (25.2 mL) in 4 divided portions respectively, under ice-cooling, followed by stirring at room temperature overnight. To the reaction mixture was added water under ice-cooling, followed by extraction with ethyl acetate. The organic layer was sequentially washed with 1 M hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The obtained solid was collected by filtration while washing with a solvent (hexane:ethyl acetate=3:1) to obtain methyl 5-{[(allyloxy)carbonyl]amino}pyrazine-2-carboxylate (481 mg) as a white solid.
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[CH:6]=[C:7]([NH:20][C:21]2[C:26]3[C:27]4[CH2:35][CH2:34][C:33]5[N:32]([CH2:36][CH2:37]O)[N:31]=[CH:30][C:29]=5[C:28]=4[S:39][C:25]=3[N:24]=[CH:23][N:22]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1.S(Br)([Br:42])=O>O>[Br:42][CH2:37][CH2:36][N:32]1[C:33]2[CH2:34][CH2:35][C:27]3[C:26]4[C:25](=[N:24][CH:23]=[N:22][C:21]=4[NH:20][C:7]4[CH:8]=[CH:9][C:10]([O:11][CH2:12][C:13]5[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=5)=[C:5]([Cl:4])[CH:6]=4)[S:39][C:28]=3[C:29]=2[CH:30]=[N:31]1
Reactant: OCCn1ncc2c1CCc1c-2sc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Reactant: O=S(Br)Br
Solvent: ClCCl
Solvent: O
Product: Fc1cccc(COc2ccc(Nc3ncnc4sc5c(c34)CCc3c-5cnn3CCBr)cc2Cl)c1
Temperature: 25 °C
Yield: 61.5 %

Procedure:
To 10 mL CH2Cl2 cooled to 0° C. was added 2-[6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-4,5-dihydro-3H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-3-yl]ethanol (295 mg, 0.57 mmol) followed by thionyl bromide (0.11 mL, 1.41 mmol), and the contents allowed to stir with warming to rt. After 4 h stirring at rt, the contents were diluted with H2O (10 mL). The layers were separated and the aqueous layer extracted with CH2Cl2 (3×10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was triturated from methanol to afford the final product (205 mg, 62%) as an off-white solid. 1H-NMR (DMSO-d6) δ 3.09 (t, 2H), 3.39 (t, 2H), 3.85 (m, 2H), 4.52 (m, 2H), 5.24 (s, 2H), 7.14-7.34 (m, 4H), 7.40-7.53 (m, 2H), 7.75 (s, 1H), 7.79 (d, 1H), 8.35 (s, 1H), 8.40 (s, 1H); LCMS RT=3.82 min; [M+H]+=584.0, 586.0.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C=O)C.[NH2:26][C:27]1[S:28][CH:29]=[CH:30][N:31]=1>S(Cl)(Cl)=O.C(Cl)Cl.N1C=CC=CC=1>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([NH:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: Nc1nccs1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The title B compound, 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionic acid (3.44 mmol, 1.02 g) is suspended in thionyl chloride (5 mL) with a catalytic amount of DMF and stirred for 12 h. The mixture is evaporated and then diluted with toluene and re-evaporated to afford an oil which is diluted with 4 mL of DCM and added to 2-aminothiazole (3.8 mmol, 0.4 g) in 10 mL of pyridine at 0° C. and then stirred for 12 h while warming to RT. The reaction mixture is evaporated, diluted with EtOAc and 0.1 N HCl and the organic solution is washed with brine, dried and evaporated to an oil. Chromatography on silica (eluent: 5%→25% EtOAc in hexanes) affords 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide: 1H NMR δ 11.7 (s, 1H), 7.86 (d, J=8, 2H), 7.55 (d, J=3.5, 1H), 7.53 (d, J=8, 2H), 7.10 (d, J=3.5, 1H), 3.81 (t, J=7.5, 1H), 3.03 (s, 3H), 1.1-2.2 (m, 11H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[CH:29]1[C:34]([NH2:35])=[CH:33][CH:32]=[C:31]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([NH:43][C:44]3[CH:49]=[CH:48][C:47]([NH2:50])=[CH:46][CH:45]=3)=[CH:39][CH:38]=2)[CH:30]=1>Cl>[CH:26]1[C:25]([NH2:28])=[CH:24][CH:23]=[C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([NH:14][C:11]3[CH:10]=[CH:9][C:8]([NH:7][C:4]4[CH:5]=[CH:6][C:1]([NH:35][C:34]5[CH:29]=[CH:30][C:31]([NH:36][C:37]6[CH:42]=[CH:41][C:40]([NH:43][C:44]7[CH:49]=[CH:48][C:47]([NH:50][C:1]8[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=8)=[CH:46][CH:45]=7)=[CH:39][CH:38]=6)=[CH:32][CH:33]=5)=[CH:2][CH:3]=4)=[CH:13][CH:12]=3)=[CH:16][CH:17]=2)[CH:27]=1
Reactant: Nc1ccc(Nc2ccc(Nc3ccc(N)cc3)cc2)cc1
Reactant: Nc1ccc(Nc2ccc(Nc3ccc(Nc4ccccc4)cc3)cc2)cc1
Agent: Cl
Product: Nc1ccc(Nc2ccc(Nc3ccc(Nc4ccc(Nc5ccc(Nc6ccc(Nc7ccc(Nc8ccc(N)cc8)cc7)cc6)cc5)cc4)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ferric chloride hexahydrate 5.4 g (0.02 mole) was dissolved in 20 ml 0.1 M HCl at room temperature. The tetraaniline in the leucoemeraldine oxidation state from Example 3 above 3.66 g (0.01 mole) was suspended in 250 ml 0.1 M HCl solution with magnetic stirring for 0.5 hours at room temperature. The ferric chloride solution was added very quickly (within 1~2 seconds) to the tetraaniline suspension with strong stirring. The suspension was then stirred magnetically for 2 hours. The reaction mixture was filtered, washed and neutralized following the general procedure described herein.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[C:5]([F:10])[C:4]=1[C@@H:11]([NH2:13])[CH3:12].C([O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[C:42]3[C:37](=[CH:38][C:39]([C:43](O)=[O:44])=[CH:40][CH:41]=3)[C:36]([CH3:46])=[C:35]2[CH3:47])=[CH:29][CH:28]=1)=[O:20])(C)(C)C>>[CH3:47][C:35]1[N:34]([CH2:33][C:30]2[CH:31]=[CH:32][C:27]([C:22]3[C:21]([C:19]([OH:20])=[O:18])=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:28][CH:29]=2)[C:42]2[C:37]([C:36]=1[CH3:46])=[CH:38][C:39]([C:43](=[O:44])[NH:13][C@H:11]([C:4]1[C:5]([F:10])=[CH:6][CH:7]=[C:8]([F:9])[C:3]=1[F:2])[CH3:12])=[CH:40][CH:41]=2
Reactant: C[C@H](N)c1c(F)ccc(F)c1F
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Agent: Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3c(F)ccc(F)c3F)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(2,3,6-trifluorophenyl)ethanamine hydrochloride and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 557 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]#[N:8].C(=O)([O-])[O-].[K+].[K+].I[CH2:16][CH2:17][CH2:18][C:19]#[C:20][Si:21]([CH3:24])([CH3:23])[CH3:22].O>CN(C=O)C.C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:6]([CH2:16][CH2:17][CH2:18][C:19]#[C:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:5]=[CH:4][C:3]=1[C:7]#[N:8]
Reactant: N#Cc1cn[nH]c1N
Reactant: C[Si](C)(C)C#CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: C[Si](C)(C)C#CCCCn1ncc(C#N)c1N
Temperature: 25 °C
Reaction time: 48 h
Yield: 20.4 %

Procedure:
A suspension of 5-amino-4-cyanopyrazole (10 g) and finely ground anhydrous potassium carbonate (38 g) in dry DMF (100 ml) was treated with 5-iodo-1-trimethylsilyl-1-pentyne (25 g) and the mixture was stirred under nitrogen for two days at room temperature. The reaction mixture was then poured into water and the product extracted into ethyl acetate. The extract was washed with water and then with brine, dried over Na2SO4, and evaporated to give a semisolid brown residue. This solid was taken up in chloroform and filtered through a short plug of silica gel. Evaporation of the chloroform left a tan solid comprising a mixture of the isomeric compounds 5-amino-4-cyano-1-(5-trimethylsilyl-4-pentynyl)pyrazole and 3-amino-4-cyano-1-(5-trimethylsilyl-4-pentynyl)pyrazole. Fractional recrystallization from ethyl acetate/hexane gave 4.66 grams of the desired 5-amino-4-cyano-1-(5-trimethylsilyl-4-pentynyl)pyrazole: mp 125°-127°.
Reaction SMILES: C([O:5][C:6](=[O:42])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][N:31]([C:33]([C:35]1[CH:39]=[C:38]([Cl:40])[S:37][C:36]=1[Cl:41])=[O:34])[CH3:32])(C)(C)C.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:41][C:36]1[S:37][C:38]([Cl:40])=[CH:39][C:35]=1[C:33]([N:31]([CH2:30][C:10]1[CH:11]=[C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])[CH:13]=[CH:14][C:9]=1[CH2:8][CH2:7][C:6]([OH:42])=[O:5])[CH3:32])=[O:34]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CN(C)C(=O)c2cc(Cl)sc2Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)O)c(CN(C)C(=O)c2cc(Cl)sc2Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
A solution of 3-{2-{[(2,5-dichloro-thiophene-3-carbonyl)-methyl-amino]-methyl}-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid tert butyl ester (50 mg, 0.079 mmol) in CH2Cl2 (2 mL) was treated with anisole (1.0 mL) then TFA (0.6 mL). The solution was stirred at ambient temperature 2 h, and more TFA (1.0 mL) was added. After 15 min, the reaction was concentrated and co-evaporated with CCl4 (3×). The residue was triturated with hexanes to yield a foam (43 mg, 95%). 1H NMR (400 MHz, CDCl3) δ 2.36 (s, 3H), 2.48 (t, 0.6H, J=7.8 Hz), 2.58 (t, 1.4H, J=7.8 Hz), 2.72 (t, 0.6H, J=7.8 Hz), 2.84 (s, 2H), 2.90 (t, 1.4H, J=7.8 Hz), 2.93 (s, 1H), 2.98 (brs, 2H), 4.17 (t, 2H, J=6.4 Hz), 4.47 (s, 0.6H), 4.71 (s, 1.4H), 6.61 (brs, 0.3H), 6.71-6.76 (m, 2H), 6.79 (s, 0.7H), 7.04 (d, 0.3H, J=8.3 Hz), 7.08 (d, 0.7H, J=8.3 Hz), 7.41-7.43 (m, 3H), 7.94 (brs, 2H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.CN(OC)[C:15]([C@@H:17]1[CH2:21][C:20](=[O:22])[N:19]([C@@H:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:24])[CH2:18]1)=[O:16].Cl>O1CCCC1>[C:25]1([C@H:23]([N:19]2[CH2:18][C@H:17]([C:15]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[O:16])[CH2:21][C:20]2=[O:22])[CH3:24])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Brc1ccccn1
Reactant: CON(C)C(=O)[C@@H]1CC(=O)N([C@H](C)c2ccccc2)C1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1C[C@H](C(=O)c2ccccn2)CC1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.7 %

Procedure:
In an atmosphere of nitrogen and at −78° C., n-butyl lithium (1.5 mol/l tetrahydrofuran solution; 13.2 ml, 19.9 mmol) was added dropwise to a tetrahydrofuran solution (40 ml) of 2-bromopyridine (1.94 ml, 19.9 mmol), and then the mixture was stirred for 10 minutes. At −78° C., to this was further added dropwise a tetrahydrofuran solution (20 ml) of N-methyl-N-methoxy-1-(1-(R)-phenylethyl]-5-oxopyrrolidine-3-(R)-carboxamide (3.66 g, 13.2 mmol), and the mixture was stirred for 30 minutes. The reaction solution was mixed with 1 mol/l hydrochloric acid (200 ml), warmed up to room temperature and then extracted with diethyl ether (200 ml×2). The resulting organic layer was washed with saturated brine (100 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure and the residue was applied to a silica gel column chromatography (silica gel 100 g). By eluting with a n-hexane:ethyl acetate system of from (3:1) to (1:1), 1.97 g (52%) of the title compound was obtained as a light yellow oil. 1H-NMR (400 MHz, CDCl3) δ: 1.54 (3H, d, J=7.08 Hz), 2.80-2.83 (2H, m), 3.35 (1H, t, J=9.37 Hz), 3.61 (1H, dd, J=6.35, 9.37 Hz), 4.49-4.54 (1H, m), 5.54 (1H, q, J=7.08 Hz), 7.25-7.38 (5H, m), 7.47-7.50 (1H, m), 7.86 (1H, dt, J=1.71, 7.81 Hz), 8.08 (1H, d, J=7.81 Hz), 8.64-8.65 (1H, m).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:15][CH:14]([NH:16][CH3:17])[CH2:13]2)[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:18][C:19]1[N:20]=[C:21]([C:26]([OH:28])=O)[NH:22][C:23]=1[CH2:24][CH3:25].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[Cl:18][C:19]1[N:20]=[C:21]([C:26]([N:16]([CH3:17])[CH:14]2[CH2:13][N:12]([C:4]3[S:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[N:3]=3)[CH2:15]2)=[O:28])[NH:22][C:23]=1[CH2:24][CH3:25]
Reactant: CCOC(=O)c1sc(N2CC(NC)C2)nc1C
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCOC(=O)c1sc(N2CC(N(C)C(=O)c3nc(Cl)c(CC)[nH]3)C2)nc1C
Yield: 90.1 %

Procedure:
The same operation as in Example (217c) was performed using ethyl 4-methyl-2-[3-(methylamino)azetidin-1-yl]-1,3-thiazole-5-carboxylate obtained in Example (226b) (114 mg, 0.45 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (78 mg, 0.45 mmol), WSC hydrochloride (256 mg, 1.34 mmol), 1-hydroxybenzotriazole (60 mg, 0.45 mmol) and N-methylmorpholine (0.10 mL, 0.89 mmol), to obtain 167 mg of the title compound as a white solid (91%).
Reaction SMILES: [Br-].[C:2]([CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:4][CH2:5][CH3:6])=[O:3].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:39]([CH2:47][CH2:48][C:49]1[CH:56]=[CH:55][C:52]([CH:53]=O)=[CH:51][CH:50]=1)[Si](C(C)(C)C)(C)C.O>O1CCCC1>[CH2:5]([O:4][C:2]([CH2:7][CH2:8][CH:9]=[CH:53][C:52]1[CH:51]=[CH:50][C:49]([CH2:48][CH2:47][OH:39])=[CH:56][CH:55]=1)=[O:3])[CH3:6]
Reactant: CCOC(=O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(C=O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CCC=Cc1ccc(CCO)cc1
Reaction time: 4 h

Procedure:
To a solution of 4-(2-t-butyldimethylsiloxyethyl)bromobenzene (4.29 g) in tetrahydrofuran (30 ml) was added n-butyllithium (1.64 mol/l solution in tetrahydrofuran, 9.0 ml) at -78° C., and the mixture was stirred at the same temperature for 15 minutes. To the reaction mixture was added N,N-dimethylformamide (1.3 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, and the mixture was extracted with diethyl ether. The extract was concentrated to dryness under reduced pressure to give 4-(2-t-butyldimethylsiloxyethyl)benzaldehyde(3.59 g)To a solution of ethyl triphenylphosphranylidenebutylate (2.22 g), which was prepared from (3-carboethoxypropyl)triphenylphosphonium bromide and sodium bis(trimethylsilyl)amide, in tetrahydrofuran (25 ml) was added 4-(2-t-butyldimethylsiloxyethyl)benzaldehyde (1.57 g) at -78° C., and the mixture was stirred at the same temperature for 4 hours and allowed to stand at room temperature for 12 hours. The reaction mixture was poured into water, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over anhydrous MgSO4, and the solvent was removed under reduced pressure. To a solution of the residue in acetonitrile (80 ml) was added a 47% hydrofluoric acid (1 ml), and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure. The residue was dissolved in chloroform, the solution was washed with a saturated aqueous NaHCO3 solution, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure. The residue was purified by medium pressure liquid column chromatography on a silica gel column using a mixture of methylene chloride, diethyl ether and methanol (1:1:1) as eluent to give 2-[4-(4-ethoxycarbonyl-1-butenyl)phenyl]ethyl alcohol (0.35 g).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:19]([CH2:20][OH:21])=[C:18](I)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1COCC1.C([Mg]Cl)(C)C.CO[B:35]1[O:39][C:38]([CH3:41])([CH3:40])[C:37]([CH3:43])([CH3:42])[O:36]1.[NH4+].[Cl-]>>[Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:19]([CH2:20][OH:21])=[C:18]([B:35]3[O:39][C:38]([CH3:41])([CH3:40])[C:37]([CH3:43])([CH3:42])[O:36]3)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COB1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2ncc(I)c2CO)CC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnn([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)c2CO)OC1(C)C
Reaction time: 1 h

Procedure:
To a solution of [1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-4-iodo-1H-pyrazol-5-yl]methanol (40.0 mg, 0.0916 mmol) in THF (2 mL, 20 mmol) at rt was added 1.3 M of isopropylmagnesium chloride in THF (0.28 mL, 0.37 mmol), and the mixture was stirred for 1 h. The reaction was quenched with 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.075 mL, 0.46 mmol), and allowed to stir at rt for 1 h. Sat. NH4Cl was added, and the organic solvent was removed in vacuo. The material was extracted with DCM and water. The organic layer was concentrated in vacuo to afford the title compound as a white solid. The material was used in the next step without further purification. MS (ES+): m/z=437.29 (100) [MH+]. HPLC: tR=1.94 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C)C=O>[Br:2][CH2:3][CH2:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:7][CH:6]=1
Reactant: CCOC(=O)CBr
Reactant: Nc1ccc(CCBr)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1ccc(CCBr)cc1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of 4-(2-bromoethyl)aniline hydrobromide (9.15 g) in N,N-dimethylformamide (65 ml) were added potassium carbonate (4.95 g) and ethyl bromoacetate (3.97 ml), and the mixture was stirred for 36 hours at room temperature. The reaction mixture was poured into ice-water, and collection of the resulting precipitates by filtration gave ethyl N-[4-(2-bromoethyl)phenyl]aminoacetate (8.39 g)
Reaction SMILES: [C:1]([C:4]1[C:5]([F:13])=[C:6]([CH:9]=[C:10]([F:12])[CH:11]=1)[C:7]#[N:8])(=[O:3])[CH3:2].[Br:14]Br>C(Cl)(Cl)Cl>[Br:14][CH2:2][C:1]([C:4]1[C:5]([F:13])=[C:6]([CH:9]=[C:10]([F:12])[CH:11]=1)[C:7]#[N:8])=[O:3]
Reactant: CC(=O)c1cc(F)cc(C#N)c1F
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: N#Cc1cc(F)cc(C(=O)CBr)c1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred mixture of 6.85 g of 3-acetyl-2,5-difluorobenzonitrile and 220 mL of CHCl3 heated at reflux is added dropwise over 75 minutes a solution of 2.1 mL of Br2 in 50 mL of CHCl3. The mixture is boiled for another 15 minutes, cooled to 25° C., washed sequentially with saturated NaHCO3 and H2O (200 mL each), dried with Na2SO4 and stripped in vacuo to 10.26 g of brown oil. The oil which contains 78% of 3-bromoacetyl-2,5-difluorobenzonitrile by NMR analysis is satisfactory for the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15]Br)=[C:11]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Na+].[I-].[CH3:29][C:30]([SH:33])([CH3:32])[CH3:31]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][S:33][C:30]([CH3:32])([CH3:31])[CH3:29])=[C:11]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)S
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)cc3)c(=O)c2CBr)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)SCc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 60.2 %

Procedure:
A 0° C. solution of the 2-(4-fluorophenyl)-4-bromomethyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone prepared in Example 194F (92.5 mg, 0.212 mmol) in acetone (2.5 mL) was treated with NaI (35 mg, 0.233 mmol), and after 5 minutes, the cooling bath was removed and the reaction warmed to 23° C. After 30 minutes, conversion to the 2-(4-fluorophenyl)-4-iodomethyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone was complete (thin layer chromatography, ethyl acetate/hexanes 4:1). The NaBr and residual NaI were filtered off through a pad of Celite®. Additional acetone (2 mL) was added along with 2-methyl-2-propanethiol (20.5 mg, 0.227 mmol), and the solution cooled to 0° C. before addition of Ag2CO3 (63 mg, 0.227 mmol). After 5 minutes, the cooling bath was removed and the solution warmed to 23° C. for 5 hours. The reaction mixture was filtered through Celite® and concentrated in vacuo. The residue was chromatographed (flash silica gel, ethyl acetate/hexanes gradient 1:1 to 3:2) to provide the product (yield: 57 mg, 60%). mp 50-70° C. 1H NMR (300 MHz, CDCl3) δ 1.34 (s, 9H), 3.14 (s, 3H), 3.65 (s, 2H), 7.13-7.21 (m, 2H), 7.63-7.70 (m, 2H), 7.79 (s, 1H), 7.84 (d, J=8.7 Hz, 2H), 8.13 (d, J=8.7 Hz, 2H). MS (APCI+) m/z 447 (M+H)+. Anal. calc. for C22H23FN2O3S2: C, 59.17; H, 5.19; N, 6.27. Found: C, 59.48; H, 5.36; N, 5.90.