Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC2N=C(N3CCN(C[C:16]4[CH:17]=[C:18]([OH:23])[CH:19]=[C:20](C)[CH:21]=4)CC3)SC=2C=1.[C:26]([O:29][CH2:30][CH2:31]Br)(=[O:28])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O.C(OCC)(=O)C>[C:26]([O:29][CH2:30][CH2:31][O:23][C:18]1[CH:17]=[CH:16][CH:21]=[CH:20][CH:19]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OCCBr
Reactant: Cc1cc(O)cc(CN2CCN(c3nc4ccc(Cl)cc4s3)CC2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1ccccc1
Temperature: 50 °C
Reaction time: 17 h

Procedure:
A mixture of 3-{[4-(6-chlorobenzothiazole-2-yl)piperazine-1-yl]methyl}-5-methylphenol (0.50 g; 1.34 mmol), bromoethyl acetate (0.22 ml; 2.01 mmol) and cesium carbonate (0.65 g; 2.01 mmol) in anhydrous N,N-dimethylformamide (5 ml) was stirred at 50° C. for 17 hours. Water and ethyl acetate were added to the reaction solution and extracted. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was purified by column chromatograph on silica gel (hexane:ethyl acetate=2:1) to give {3-[[4-(6-chlorobenzothiazole-2-yl)piperazine-1-yl]methyl]-5-methyl}+phenoxyethyl acetate as pale yellow oil (0.48 g; 78%).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=O.C(Cl)(=O)C(Cl)=O.NCCN[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].[CH3:27][CH2:28][N:29](CC)CC>C(Cl)Cl.CN(C=O)C>[C:22]([O:21][C:20]([CH2:27][CH2:28][NH:29][C:4](=[O:6])/[CH:3]=[CH:2]/[C:1]([O:8][CH3:9])=[O:7])=[O:26])([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CCN(CC)CC
Reactant: COC(=O)/C=C/C(=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)/C=C/C(=O)NCCC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 65.3 %

Procedure:
Mono methyl fumarate (1.7 g, 13.1 mmol) was taken up in 20 mL of CH2Cl2 along with oxalyl chloride (1.1 mL, 13.1 mmol). After a few drops of DMF were added, the reaction mixture was stirred at room temperature until all the solids had dissolved and all gas evolution had ceased (1 h). This freshly prepared solution of the acid chloride was added dropwise at 0° C. to a solution containing tert-butyl 2-aminoethylcarbamate (2.1 g, 13.1 mmol) and Et3N (2.8 mL, 19.6 mmol) in 200 mL of CH2Cl2. The resulting reaction mixture was warmed to room temperature and stirred for 2 h. It was then washed with brine, dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography (CH2Cl2) afforded 2.2 g of (E)-methyl 4-(2-(tert-butoxycarbonyl)ethylamino)-4-oxobut-2-enoate (62% yield). (E)-Methyl 4-(2-(tert-butoxycarbonyl)ethylamino)-4-oxobut-2-enoate (2.2 g, 8.1 mmol) was taken up in 10 mL of 4 M HCl in dioxane. The resulting reaction mixture was allowed to stand at room temperature for 1 h, then diluted with 50 mL of EtOAc and concentrated under reduced pressure to afford the HCl salt of (E)-methyl 4-(2-aminoethylamino)-4-oxobut-2-enoate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.[C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)#[CH:36]>O1CCCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:36]#[C:35][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1ccccc1
Reactant: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: C(#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1)c1ccccc1
Yield: 60.4 %

Procedure:
A 20 ml microwave vial was charged with 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1; 440 mg, 1.35 mmol), DBU (1230 mg, 8.08 mmol) and ethynylbenzene (413 mgs, 4.04 mmol) in tetrahydrofuran (5 ml) to produce an orange solution. The mixture was purged with nitrogen and dichlorobis(triphenylphosphine)palladium(II) (47.3 mg, 0.067 mmol) and copper(I) iodide (25.6 mg, 0.135 mmol) were added before the whole was subjected to microwave radiation for 1 hour at 80° C. Upon cooling, the resulting mixture was diluted with ethyl acetate and washed with brine and the organic layer was purified by silica chromatography (eluting with 0-30% ethyl acetate-petrol) to yield 3,4-bis(benzyloxy)-6-(phenylethynyl)pyridazine (320 mg, 0.815 mmol, 61% yield).
Reaction SMILES: [CH2:1]([P:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[Cl:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][Cl:23])[CH:17]=1>C1(C)C=CC=CC=1>[Cl-:14].[Cl:23][CH2:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][P+:5]([CH2:6][CH2:7][CH2:8][CH3:9])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCP(CCCC)CCCC
Reactant: ClCc1cccc(CCl)c1
Solvent: Cc1ccccc1
Product: CCCC[P+](CCCC)(CCCC)Cc1cccc(CCl)c1
Product: [Cl-]
Temperature: 25 °C

Procedure:
A mixture of tri-n-butylphosphine (18.9 g, 103.8 mmol) in toluene (50 mL) was added dropwise to a mixture of α,α'-dichloro-m-xylene (7.0 g, 34.6 mmol) in toluene (200 mL) under argon gas. The reaction mixture was allowed to stir for several days at room temperature under argon, after which time the tri-n-butylphosphonium chloride salt had crystallized out of solution and TLC examination showed completion of reaction. The white crystals were filtered and washed several times with toluene and hexanes, and then dried. 1H NMR (CDCl3) δ 0.93 (t, 9H), 1.45 (m, 12H), 2.41 (m, 6H), 4.40 (d, 2H), 4.57 (s, 2H), 7.36 (m, 2H), 7.42 (d, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23]C(=O)OC(C)(C)C)[CH2:18]2)=[C:4]2[C:10]([NH:11][C:12](=[O:16])[CH2:13][C:14]#[N:15])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:39]>>[ClH:39].[NH2:23][C@@H:19]1[CH2:20][CH2:21][CH2:22][N:17]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:16])[CH2:13][C:14]#[N:15])[C:4]=23)[CH2:18]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)CC#N)c23)C1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: N#CCC(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](N)C3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
(R)-tert-Butyl 1-(5-bromo-3-(2-cyanoacetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.050 g, 0.10 mmol) was placed in DCM (3 mL) at room temperature. TFA (1 mL) was then added. The reaction was stirred at room temperature for 1 hour and then concentrated to dryness. The resulting residue was then purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 5-50% CH3CN/water). The resulting product was next dissolved in minimal DCM (with MeOH to aid solubility) and added to a stirring solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to give (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-cyanoacetamide hydrochloride (0.035 g, 74% yield) as a solid. 1H NMR (400 MHz, D2O) δ 8.24 (s, 1H), 7.32 (s, 1H), 3.83 (s, 2H), 3.73-3.70 (m, 1H), 3.56-3.54 (m, 1H), 3.32-3.29 (m, 1H), 3.24-3.13 (m, 2H), 2.10-2.07 (m, 1H), 1.83-1.79 (m, 1H), 1.67-1.55 (m, 2H). LCMS (APCI+) m/z 377, 379 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[F:34][C:35]1[CH:36]=[C:37]([S:42](Cl)(=[O:44])=[O:43])[CH:38]=[CH:39][C:40]=1[CH3:41].O>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([S:42]([C:37]4[CH:38]=[CH:39][C:40]([CH3:41])=[C:35]([F:34])[CH:36]=4)(=[O:43])=[O:44])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1F
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2c(=O)n(-c3ccc(C(C)(C)C#N)cc3)c3c4cc(Br)ccc4ncc32)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 50 mg, 0.12 mmol) and triethylamine (24.4 mg, 0.24 mmol) in dichloromethane (6 ml) was added 3-fluoro-4-methylbenzene-1-sulfonyl chloride (37.5 mg, 0.18 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 36 mg (50%); 1H NMR (DMSO-d6, 300 MHz): δ 9.4 (s, 1H), 7.92-7.98 (m, 3H), 7.784-7.7.812 (d, 2H, J=8.4 Hz), 7.67-7.74 (m, 3H), 7.59-7.64 (m, 1H), 6.72-6.726 (d, 1H, J=1.8 Hz), 2.17 (s, 3H), 1.74 (s, 6H); MS: m/z 579 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH:6]=[C:7]([CH:12]3[CH2:14][CH2:13]3)[NH:8]2)=[CH:4][CH:3]=1.Br[C:16]1[CH:17]=[N:18][N:19]([CH2:21][CH3:22])[CH:20]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH:6]=[C:7]([CH:12]3[CH2:14][CH2:13]3)[N:8]2[C:16]2[CH:17]=[N:18][N:19]([CH2:21][CH3:22])[CH:20]=2)=[CH:4][CH:3]=1
Reactant: CCn1cc(Br)cn1
Reactant: Fc1c(Cl)ccc2cc(C3CC3)[nH]c12
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCn1cc(-n2c(C3CC3)cc3ccc(Cl)c(F)c32)cn1
Temperature: 140 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
To a solution of compound 3 (4.3 g, 20.5 mmol) in toluene (50 mL) were added 4-bromo-1-ethyl-1H-pyrazole 4 (4.0 g, 22.8 mmol), potassium phosphate (11.0 g, 51.2 mmol), N,N′-dimethylethylenediamine (722 mg, 8.2 mmol) and Cu(I)I (390 mg, 2.0 mmol) at RT under inert atmosphere. The reaction solution was purged with argon for 15 min and then sealed the tube. The reaction mixture was heated to 140° C. and stirred for 16 h. After completion of the reaction by TLC, the reaction mixture was cooed to RT, diluted with EtOAc (50 mL) and filtered. The filtrate was washed with water (40 mL), brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified (silica gel chromatography; 9% EtOAc/Hexanes) to afford compound 5 (3.9 g, 63%) as a pale brown solid. 1H NMR (400 MHz, CDCl3): δ 7.64 (s, 1H), 7.60 (s, 1H), 7.16 (d, J=8.4 Hz, 1H), 7.01 (dd, J=8.4, 6.4 Hz, 1H), 6.12 (s, 1H), 4.25 (q, J=7.2 Hz, 2H), 1.69-1.62 (m, 1H), 1.56 (t, J=7.2 Hz, 3H), 0.92-0.87 (m, 2H), 0.76-0.72 (m, 2H); LC-MS (ESI): 98.6%; m/z 304.3 (M+H+); (column: X Select C-18, 50×3.0 mm, 3.5 μm); RT 4.23 min; 5 mM NH4OAc: ACN; 0.8 mL/min).
Reaction SMILES: [F:1][CH:2]([F:33])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][C:21]([CH:24]([NH:29][CH3:30])[C:25]([F:28])([F:27])[F:26])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[O:7]C1(C)C)=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[F:33][CH:2]([F:1])[C:3]([NH:5][C@H:9]([CH2:10][F:11])[C@H:8]([OH:7])[C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:19]=[N:20][C:21]([CH:24]([NH:29][CH3:30])[C:25]([F:28])([F:26])[F:27])=[CH:22][CH:23]=2)=[CH:16][CH:17]=1)=[O:4]
Reactant: CNC(c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(c1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc2)cn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.4 %

Procedure:
To a solution of 2,2-Difluoro-1-((4S,5R)-4-fluoromethyl-2,2-dimethyl-5-{4-[6-(2,2,2-trifluoro-1-methylamino-ethyl)-pyridin-3-yl]-phenyl}-oxazolidin-3-yl) ethanone (0.12 g, 0.235 mmol) in CH2Cl2 (2 mL) is added trifluroacetic acid (0.5 mL) at 0° C. then is stirred to room temperature for 2 hours. Reaction solvent evaporated in vacuo then diluted with sodium bicarbonate solution and extract with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by combiflash eluting in 5% Methanol in CH2Cl2 to afford the title compound (0.028 g). 1H-NMR (400 MHz, DMSO) δ: 2.25 (d, J=5.84 Hz, 3H), 3.00-3.04 (m, 1H), 4.31-4.35 (m, 1.5H), 4.41-4.46 (m, 1.5H), 4.55-4.56 (m, 0.5H), 4.65-4.68 (m, 0.5H), 4.90 (m, 1H), 5.93 (d, J=4.36 Hz, 1H), 6.19 (d, J=53.72 Hz, 1H), 7.46 (d, J=8.32 Hz, 2H), 7.95-7.98 (dd, J1=1.96 HzHz, J2=8.32 Hz, 1H), 8.03 (d, J=8.32 Hz, 1H), 8.06 (d, J=8.48 Hz, 2H), 8.71 (d, J=1.88 Hz, 1H), 8.84 (d, J=8.72 Hz, 1H). LC-MS (m/z): [M+H]=436.0.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](Cl)=[N:8][C:4]=2[CH:3]=1.[Cl:12][C:13]1[C:14]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:15][CH:16]=[CH:17][CH:18]=1.C(N(CC)C(C)C)(C)C>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([N:22]3[CH2:23][CH2:24][N:19]([C:14]4[C:13]([Cl:12])=[CH:18][CH:17]=[CH:16][N:15]=4)[CH2:20][CH2:21]3)[NH:8][C:4]=2[CH:3]=1
Reactant: Clc1cccnc1N1CCNCC1
Reactant: Clc1nc2cc(Br)ccc2[nH]1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cccnc1N1CCN(c2nc3ccc(Br)cc3[nH]2)CC1

Procedure:
The 5-bromo-2-chloro-1H-benzoimidazole (0.115 g, 0.5 mmol, Example 23b), 1-(3-chloropyridin-2-yl)piperazine (0.198 g, 1 mmo, Example 3b) and N,N-diisopropylethylamine (0.35 mL, 2 mmol, Aldrich) were reacted under the conditions of Example 3c to give the title compound as a white solid. M.p. 207-208° C. MS (ESI; pos.,ion) m/z: 394 (M+1).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH3:7][C:8]([CH3:41])([CH2:39][CH3:40])[CH2:9][C:10]1[N:11]=[C:12]([C:21]([OH:38])([CH3:37])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[S:35][CH3:36])=[CH:25][CH:24]=2)[N:13]([S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:14]=1>C(O)C.O>[CH3:7][C:8]([CH3:41])([CH2:39][CH3:40])[CH2:9][C:10]1[N:11]=[C:12]([C:21]([OH:38])([CH3:37])[CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[S:35]([CH3:36])=[O:2])=[CH:27][CH:28]=2)[N:13]([S:15]([N:18]([CH3:19])[CH3:20])(=[O:16])=[O:17])[CH:14]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(-c3ccccc3SC)cc2)n1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(-c3ccccc3S(C)=O)cc2)n1
Temperature: 25 °C

Procedure:
Sodium periodate (40 mg, 0.19 mmol) was added to an ambient temperature solution of 4-(2,2-dimethylbutyl)-2-{1-hydroxy-1-methyl-2-[2′-(methylthio)biphenyl-4-yl]ethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide (65 mg, 0.13 mmol) in ethanol/water (1:1) (5 mL). After stirring at ambient temperature until no further reaction (LCMS), the reaction mixture was quenched with saturated aqueous sodium thiosulfate and extracted with methylene chloride. Combined extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-30% acetone/methylene chloride afforded 4-(2,2-dimethylbutyl)-2-{1-hydroxy-1-methyl-2-[2′-(methylsulfinyl)biphenyl-4-yl]ethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: [CH:1]1([N:7]([CH3:29])[C:8]([C:10]2[CH:11]=[N:12][N:13]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)[C:14]=2[S:15][CH2:16][CH2:17][CH3:18])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([N:7]([CH3:29])[C:8]([C:10]2[CH:11]=[N:12][N:13]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=3)[C:14]=2[S:15][CH2:16][CH2:17][CH3:18])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCSc1c(C(=O)N(C)C2CCCCC2)cnn1-c1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCSc1c(C(=O)N(C)C2CCCCC2)cnn1-c1ccc(C(=O)O)cc1
Reaction time: 18 h

Procedure:
Methyl 4-[4-(cyclohexyl-methyl-carbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoate (Intermediate #4) (162 mg, 0.39 mmol) was dissolved in methanol (10 mL) and treated at ambient temperature with 2M aqueous sodium hydroxide solution (0.96 mL, 1.95 mmol). The mixture was stirred at ambient for 18 h. Methanol was removed by evaporation under reduced pressure and the clear solution diluted with water (25 ml). 2M HCl was added to pH4 and the mixture extracted with ethyl acetate (2×25 mL). The combined extracts were washed with water (2×10 mL) and brine (10 mL), dried (MgSO4) and evaporated to give the title compound as a white solid foam (150 mg, 96%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1)([O-])=O.C.[H][H]>[Pd].CO>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1
Reactant: O=[N+]([O-])c1ccccc1-n1cccn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1-n1cccn1
Yield: 90 %

Procedure:
Into a Parr hydrogenation apparatus is successively added 20 g. (0.106 M.) of 1-(o-nitrophenyl)-pyrazole and 150 ml. of methanol and the resultant solution is hydrogenated in the presence of 1.0 g. of hydrogenation catalyst (10% Pd on active charcoal) at between 40 and 50 p.s.i. of hydrogen pressure at room temperature. After the theoretical uptake of hydrogen is achieved, the reaction mixture is filtered to remove the palladium and the solvent is removed on a rotary evaporator. Ether is then added to the resultant mixture and after removing the precipitated solids by filtration, the solvent is evaporated to yield a light amber colored oil (Yield: 90%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13](=[O:18])[CH2:14][CH2:15][S:16][CH3:17])[C:9]1=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(C)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH:13]([OH:18])[CH2:14][CH2:15][S:16][CH3:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSCCC(=O)C1CCN(C(=O)OC(C)(C)C)C1=O
Solvent: C1CCOC1
Solvent: CSC
Product: CSCCC(O)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 166.6 %

Procedure:
3-(3-Methylsulfanylpropionyl)-2-oxo-pyrrolidine-1-carboxylic acid t-butyl ester (188 mg, 654 μmol) was dissolved in THF (531 μL) under nitrogen. 2M BH3.Me2S in THF (981 μL) was added via syringe over 15 minutes. The mixture was stirred at room temperature for 1 hour, then heated at 65° C. for 1 hours, then cooled to room temperature. The mixture was cooled on an ice bath and the reaction was slowly quenched with cold MeOH (100 mL). The mixture was stirred overnight and then diluted with EtOAc (30 mL) and washed with saturated aqueous NaHCO3 (2×50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated by rotary evaporation to yield a yellow oil (300 mg), which was used without further purification. LCMS m/z: [M+H]+ calcd for C13H25NO3S, 275.40. found 276.4.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[CH:5]=[CH:4][N:3]=1.Cl.[CH3:17][S:18]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24])(=[O:20])=[O:19].COC1C=CC=CC=1C1C=CN=C(NC2C=CC=C([N+]([O-])=O)C=2)C=1>>[CH3:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:24][C:23]2[CH:25]=[CH:26][CH:27]=[C:21]([S:18]([CH3:17])(=[O:20])=[O:19])[CH:22]=2)[CH:7]=1
Reactant: COc1ccccc1-c1ccnc(Cl)c1
Reactant: CS(=O)(=O)c1cccc(N)c1
Agent: COc1ccccc1-c1ccnc(Nc2cccc([N+](=O)[O-])c2)c1
Agent: Cl
Product: COc1ccccc1-c1ccnc(Nc2cccc(S(C)(=O)=O)c2)c1

Procedure:
F1 was prepared from A1 (281 mg, 1.28 mmol) and 3-(methylsulfonyl)aniline hydrochloride (267 mg, 1.28 mmol) following the procedure reported for C1. Yield: 210 mg (46%). 1H NMR (400 MHz, d6-DMSO, 300K) δ 3.18 (s, 3H), 3.80 (s, 3H), 7.02-7.08 (m, 2H), 7.12-7.18 (m, 2H), 7.35-7.45 (m, 2H), 7.50-7.53 (m, 1H), 7.53-7.62 (m, 1H), 7.92 (d, J=8.0 Hz, 1H), 8.12-8.19 (m, 2H), 10.05 (bs, 1H). MS (ES) C19H18N2O3S requires: 354. found: 355 (M+H)+.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]#[N:13])(=O)OCC)C.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][C:16]1=O>C(COC)OC>[CH3:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][C:16]=1[CH2:11][C:12]#[N:13]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC1C(=O)CCc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC1=C(CC#N)CCc2ccccc21
Temperature: 40 °C
Reaction time: 0.75 h

Procedure:
To a stirred suspension of 7.2 g (0.15 mole) of sodium hydride (50% in oil dispersion) in 200 ml of dimethoxyethane was added dropwise 28.1 g (0.15 mole) of diethylcyanomethylphosphonate [(C2H5O)2P(O)CH2CN]. The addition was complete in ten minutes while the reaction temperature rose to 44° C. The reaction mixture was stirred for 45 minutes and then 25.0 g (0.14 mole) of 1-methyl-2-tetralone was added dropwise over a 30 minute period. The reaction mixture was then warmed at 40° C. for two hours and poured into ice-water. The product was extracted with ether, and the ether extracts were dried over anhydrous magnesium sulfate and concentrated to a yellow oil (31.3 g). The latter was crystallized from ether-hexane to give 3,4-dihydro-1-methyl-2-naphthaleneacetonitrile as a light yellow solid, m.p. 48°-49° C.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C@@H:11]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.[Cl:47][C:48]1[N:53]=[CH:52][C:51]([S:54](Cl)(=[O:56])=[O:55])=[CH:50][CH:49]=1>C(Cl)Cl>[Cl:47][C:48]1[N:53]=[CH:52][C:51]([S:54]([N:13]2[CH2:14][CH2:15][N:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:29])([F:31])[F:30])[C:24]([F:26])([F:25])[F:27])=[CH:19][CH:18]=3)[C@@H:11]([CH2:10][S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])[CH2:12]2)(=[O:56])=[O:55])=[CH:50][CH:49]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)[C@@H](CS(=O)(=O)c2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(C[C@H]1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.8 %

Procedure:
A 20 mL vial was charged with tert-butyl (3R)-3-((phenylsulfonyl)methyl)-4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinecarboxylate (0.038 g, 0.065 mmol), TFA (0.50 mL, 6.5 mmol, Sigma-Aldrich, St. Louis, Mo.) and DCM (1 mL). The mixture was stirred at rt for 10 min. The volatile was removed and the residue was taken into DCM (1 mL). TEA (0.10 mL, 0.78 mmol) was added and the mixture was stirred at rt for 5 min. At this time, 6-chloropyridine-3-sulfonyl chloride (0.016 g, 0.073 mmol, Organic Process Research & Development 2009, 13, 875) was added and the mixture was stirred at rt for 10 min. The reaction mixture was directly purified by column chromatography (10 g of silica, 0 to 50% EtOAc in hexanes) to afford 2-(4-((2R)-4-((6-chloro-3-pyridinyl)sulfonyl)-2-((phenylsulfonyl)methyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.026 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]2[CH2:22][F:23])[C:9]2[C:4](=[C:5]([O:24][CH3:25])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>CN(C)C=O>[ClH:1].[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:2]2[N:11]=[C:10]([N:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]3[CH2:22][F:23])[C:9]3[C:4](=[C:5]([O:24][CH3:25])[CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:29][CH:28]=1
Reactant: COc1cccc2c(N3CCc4ccccc4C3CF)nc(Cl)nc12
Reactant: Nc1ccc(F)cc1
Solvent: CN(C)C=O
Product: COc1cccc2c(N3CCc4ccccc4C3CF)nc(Nc3ccc(F)cc3)nc12
Product: Cl
Yield: 14.5 %

Procedure:
In accordance with the same procedures as in Example 18, except that to a mixture of 3.3 g of the compound (9 mM) prepared in Example 9 and 15 ml of dimethylform-amide, 1.9 ml of 4-fluoroaniline(20.0 mM) was added, 0.61 g of the title compound was prepared.