Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][C@H:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:48][C:49]1[S:50][CH:51]=[CH:52][N:53]=1>C(Cl)Cl>[CH:28]1([CH2:33][C@H:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35]([NH:48][C:49]2[S:50][CH:51]=[CH:52][N:53]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2nccs2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
A solution of triphenylphosphine (3.35 g, 12.79 mmol) in methylene chloride (19 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (2.28 g, 12.79 mmol) in small portions. The reaction mixture was stirred at 0° C. for 30 min, and during this time period, the color of the reaction mixture changed from light yellow to a darker yellow then to a purple color. The cooled purple reaction mixture was then treated with 3-cyclopentyl-2(R)-(4-methanesulfonylphenyl)propionic acid (prepared as in Example 128, 2.23 g, 7.52 mmol). The resulting reaction mixture was then allowed to warm to 25° C. over 45 min. The reaction mixture was then treated with 2-aminothiazole (1.88 g, 18.81 mmol). The resulting reaction mixture was stirred at 25° C. for 12 h. The reaction mixture was then concentrated in vacuo to remove methylene chloride. The remaining black residue was diluted with ethyl acetate (300 mL). The organic layer was washed sequentially with a 10% aqueous hydrochloric acid solution (2×100 mL), a 5% aqueous sodium bicarbonate solution (3×100 mL), and a saturated aqueous sodium chloride solution (1×200 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 9/1, 3/1, and then 11/9 hexanes/ethyl acetate) afforded 3-cyclopentyl-2(R)-(4-methanesulfonylphenyl)-N-thiazol-2-yl-propionamide (2.10 g, 74%) as a white foam: mp 78–80° C. (foam to gel); [α]23589=−70.4° (c=0.027, chloroform); EI-HRMS m/e calcd for C18H22N2O3S2 (M+) 378.1072, found 378.1081.
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].[CH:7](=O)[CH2:8][CH2:9][CH2:10][CH3:11].O.C(O)(=O)C.[CH2:18]([NH:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH:19]([CH3:21])[CH3:20]>>[CH3:20][CH:19]([CH3:21])[CH2:18][N:22]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:23][CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)CNCC(C)C
Reactant: CCCCC=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O
Solvent: CC(=O)O
Product: CCCCCN(CC(C)C)CC(C)C
Temperature: 12.5 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To a suspension of magnesium sulfate (10.1 g) in diisobutylamine (72.0 g) was added dropwise valeraldehyde (24.6 g) at 0-5° C. under a nitrogen atmosphere, and it was stirred at 10-15° C. for 1 hour. After ice-cooling, water (60 ml) was added and it was stirred to dissolve the magnesium sulfate. After the removal of the aqueous layer, to the organic layer obtained was added a 9% (w/v) aqueous acetic acid solution (200 ml) at 0-5° C. and then stirred for 5 minutes. The aqueous layer was, then, removed again, a 0.5% (w/v) aqueous sodium hydroxide solution (60 ml) was added to the organic layer at 0-5° C., and stirred for 5 minutes. After stirring, the aqueous layer was removed to afford the title compound (51.3 g, yield: 80%, purity: 93.8%) as a colorless oil.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=O.[CH3:16][NH:17][C:18]1[CH2:22][S:21][C:20](=[O:23])[N:19]=1.CC(C)([O-])C.[K+]>C(O)C>[CH3:16][NH:17][C:18]1=[N:19][C:20](=[O:23])[S:21]/[C:22]/1=[CH:1]\[CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CNC1=NC(=O)SC1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: CNC1=NC(=O)S/C1=C\C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
tert-Butyl 4-formylpiperidine-1-carboxylate (1.61 g) and 4-(methylamino)-1,3-thiazol-2(5H)-one (1.18 g) were suspended in ethanol (10 mL), potassium tert-butoxide (1.02 g) was added, and the mixture was stirred at 80° C. for 8 hr. The reaction mixture was concentrated, saturated aqueous ammonium chloride solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (1.27 g).
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:5]=1[O:6][C:7]1[CH:23]=[CH:22][C:10]([O:11][CH:12]([CH3:21])[C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=1)([O-:3])=[O:2].[BH4-].[Na+]>C(O)C.C(Cl)Cl>[N+:1]([C:4]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:5]=1[O:6][C:7]1[CH:23]=[CH:22][C:10]([O:11][CH:12]([CH3:21])[CH:13]([OH:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CC(=O)C(C)Oc1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CC(O)C(C)Oc1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Reaction time: 0.33 h

Procedure:
To a solution of ethyl 4-[4-(2-nitro-4-chlorophenoxy)phenoxy]-3-oxopentanoate (600 mg) in absolute ethanol (10 ml) is added at 0°, NaBH4 (300 mg). After addition is complete, the reaction mixture is stirred for about 20 minutes. Then the solution is taken up in CH2Cl2, washed with brine, dried and evaporated to give ethyl 4-[4-(2-nitro-4-chlorophenoxy)phenoxy]-3-hydroxypentanoate.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([CH2:9][OH:10])=[CH:7][N:6]=[C:5]([S:11][CH3:12])[N:4]=1.O.O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+]>C(O)(=O)C>[CH3:1][NH:2][C:3]1[C:8]([CH:9]=[O:10])=[CH:7][N:6]=[C:5]([S:11][CH3:12])[N:4]=1
Reactant: CNc1nc(SC)ncc1CO
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CNc1nc(SC)ncc1C=O
Reaction time: 2 h
Yield: 30.2 %

Procedure:
4-Methylamino-2-methylsulfanyl-5-pyrimidinemethanol (2.40 g, 13.0 mmol) in 7 mL of acetic acid was added to a solution of sodium dichromate-dihydrate (1.30 g, 4.4 mmol) in 6 mL of acetic acid. After 2 hours at room temperature, additional sodium dichromate-dihydrate (0.3 g, 1.0 mmol) in 1 mL of acetic acid was added. After a total reaction time of 3.5 hours, the bright yellow solid was removed by filtration. Water (30 mL) was added to the filtrate, followed by aqueous ammonium hydroxide until basic (pH 9.0). The mixture was cooled in the refrigerator for 30 minutes. The precipitate was collected and dissolved in ethyl acetate, and the solution was dried over MgSO4. Filtration and concentration in vacuo gave 0.72 g (30%) of 4-methylamino-2-methylsulfanyl-5-pyrimidinecarboxaldehyde; mp 99-101° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:17]2[CH2:21][NH:20][C:19](=[O:22])[CH2:18]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:24]1[CH:25]=[C:26]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:28][CH:29]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CN(C=O)C>[Cu]I.O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:17]2[CH2:21][N:20]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)[C:19](=[O:22])[CH2:18]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(I)c1
Reactant: COc1ccc(C2CNC(=O)C2)cc1OCc1ccccc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1ccc(C2CC(=O)N(c3cccc([N+](=O)[O-])c3)C2)cc1OCc1ccccc1
Temperature: 110 °C
Yield: 56.7 %

Procedure:
To a round bottom flask was added 4-(3-benzyloxy-4-methoxyphenyl)-pyrrolidin-2-one (1.76 g, 5.9 mmol), 3-iodonitrobenzene (2.64 g, 10.6 mmol), K3PO4 (2.79 g, 13 mmol), trans-cyclohexanediamine (50 μL), DMF (8 mL) and dioxane (8 mL). The mixture was stirred under N2 for 5 min before the addition of CuI (150 mg). After heating to 110° C. for 20 h, the mixture was cooled to r.t. After filtration, the reaction mixture was diluted with EtOAc (100 mL), washed with saturated NH4Cl, brine and dried over Na2SO4. Concentration and purification by column chromatography on silica gel (EtOAc:hexane=1:3) gave 1.4 g of the desired product. Yield: 57%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([OH:26])/[CH:21]=[CH:22]/[CH2:23][CH2:24][CH3:25].O[C:28]1[S:29][C:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:41][CH:40]=3)=[CH:35][CH:34]=2)=[CH:31][CH:32]=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:20]([O:26][C:28]1[S:29][C:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:40]=[CH:41][C:42]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:43][CH:44]=3)=[CH:35][CH:34]=2)=[CH:31][CH:32]=1)/[CH:21]=[CH:22]/[CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCc1ccc(-c2ccc(-c3ccc(O)s3)cc2)cc1
Reactant: CCC/C=C/CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC/C=C/COc1ccc(-c2ccc(-c3ccc(CCCCCC)cc3)cc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.3 %

Procedure:
Triphenylphosphine (1.4 g) is added in small portions to a solution of (E)-hex-2-en-1-ol (0.60 g), 2-hydroxy-5-(4′-hexylbiphenyl-4-yl)thiophene (0.50 g), diethylazodicarboxylate (0.80 g) in dry tetrahydrofuran (100 cm3) at 0° C. under an atmosphere of nitrogen. The reaction mixture is stirred at room temperature overnight. The solvent is removed under reduced pressure and the crude product was purified by column chromatography on silica gel using a 4:1 petroleum (40-60° C.) ether/ethyl acetate mixture as eluent, followed by recrystallisation from ethanol to yield 0.12 g of 2-[(E)-hex-2-enyloxy]-5-(4′-hexylbiphenyl-4-yl)thiophene.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:13][C:12]([NH:14][C:15](=[O:17])[CH3:16])=[N:11][C:10]=1[CH3:18])(=[O:8])=[O:7])(C)(C)C>C(O)(C(F)(F)F)=O>[NH2:5][S:6]([C:9]1[S:13][C:12]([NH:14][C:15](=[O:17])[CH3:16])=[N:11][C:10]=1[CH3:18])(=[O:7])=[O:8]
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)NC(C)(C)C)s1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1nc(C)c(S(N)(=O)=O)s1
Reaction time: 24 h

Procedure:
A solution of N-{5-[(tert-butylamino)sulfonyl]-4-methyl-1,3-thiazol-2-yl}acetamide (1.1 g) in TFA (10 ml) was stirred at room temperature for 3 d. The mixture was evaporated, redissolved in TFA (10 ml) and stirred for a further 1 d. On evaporation the resulting oil was azeotroped with DCM (×2) and triturated with Et2O to give the subtitle compound as a beige solid. Yield 0.7 g.
Reaction SMILES: BrC[C:3]1[C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[N-]=[N+]=[N-].[Na+].CCOCC>CN(C=O)C>[S:11]1[C:7]2[CH:6]=[CH:5][CH:4]=[CH:3][C:8]=2[N:9]=[CH:10]1
Reactant: BrCc1cccc2scnc12
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: c1ccc2scnc2c1
Reaction time: 0.08 h
Yield: 90.7 %

Procedure:
A solution of 4-Bromomethyl benzothiazole (20.4 g, 89.9 mmol) in 272 mL of dry DMF was treated with NaN3 (7.00 g, 108 mmol) at 20° C. and stirred at the same temperature for 5 min. The resulting mixture was quenched by addition of NaCl (5 g in 150 mL of H2O) at 0° C., diluted with Et2O (200 mL) and extracted with Et2O (200 mL×6). The organic phase was washed with NaCl (2 g in 100 mL of H2O) twice and brine (100 mL). The resulting solution was dried over MgSO4 and concentrated in vacuo. The residue was submitted to silica gel column chromatography with toluene:Et2O=50:3 to 50:5 as eluate to afford 4-azidemethyl benzothiazole as a colorless oil (15.5 g, 81.5 mmol, 91%). Rf=0.48 (toluene:Et2O=10:1); 1H NMR (400 MHz, CDCl3) δ 9.03 (1H, s), 7.95 (1H, d, J=7.7 Hz), 7.49 (2H, m), 5.01 (2H, s); 13C NMR (99.5 MHz, CDCl3) δ 154.2, 151.7, 134.3, 130.6, 126.0, 125.7, 122.1, 51.6.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[C:32](Cl)(=[O:35])[CH2:33][CH3:34]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:31][CH2:30][N:29]([C:32](=[O:35])[CH2:33][CH3:34])[CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CCNC1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f9) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH2:6]O)=[C:4]([F:11])[CH:3]=1.C(Br)(Br)(Br)[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH2:6][Br:13])=[C:4]([F:11])[CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cc(F)c(Br)cc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1cc(CBr)c(F)cc1Br
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To a solution of 2 g (8.44 mmol) of 4-bromo-2,5-difluorobenzoic acid (prepared according to the procedure of Ishikawa et al., Kogyo Kagaku Zasshi, pg 972-979, 1970) in 20 mL of tetrahydrofuran was added 40 mL of a 1M solution of borane-tetrahydrofuran complex. The solution was heated under reflux for 64 h, cooled to ambient temperature and 100 mL of methanol was added. The reaction was then heated for a further 2 h, cooled and concentrated in vacuo. Purification by flash chromatography (silica gel, 9:1 hexane:ethyl acetate) afforded 1.6 g of 4-bromo-2,5-difluorobenzyl alcohol. To a solution of 1.3 g (5.6 mmol) of 4-bromo-2,5-difluorobenzyl alcohol in 20 mL of dichloromethane at 0° C. was added 2.27 g (6.7 mmol) of carbon tetrabromide and 1.8 g (6.7 mmol) of triphenylphosphine. The reaction was stirred for 2 h at this temperature, the solvent was removed in vacuo and the residue stirred with 100 mL of diethyl ether. The solution was filtered, concentrated in vacuo, and purified by flash chromatography (silica gel, 9:1 hexane:ethyl acetate) to afford 1.5 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14])[CH2:6][C:5]2([CH3:20])[CH3:19].N1C=CC=CC=1.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][S:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[F:27])(=[O:36])=[O:35])[CH2:6][C:5]2([CH3:20])[CH3:19]
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(Cl)cc21
Reactant: O=S(=O)(Cl)c1ccccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2ccccc2F)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)aniline (100 mg, 0.35 mmol) in dichloromethane (5 mL) was added pyridine (0.6 mL) and 2-fluorobenzenesulfonyl chloride (68 mg, 0.35 mmol) at ice-bath. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed by brine, dried over anhydrous sodium sulfate, concentrated in vacuo. The residue was purified by HPLC to give N-[2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-2-fluoro-benzenesulfonamide. LC/MS m/e obsd. (ESI+) [(M+H)+] 445.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[CH:9]1([CH2:12]Br)[CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH:9]1([CH2:12][S:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:11][CH2:10]1
Reactant: BrCC1CC1
Reactant: Sc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(SCC2CC2)cc1

Procedure:
4-Bromothiophenol (106.12 g, 561 mmol), cyclopropylmethyl bromide (83.3 g, 617 mmol) and potassium carbonate (85.2 g, 617 mmol) were stirred in DMF (400 mL) overnight. The mixture was diluted with water (1.5 L) and the product extracted into hexanes (2×1 L). The combined organic extracts were dried (MgSO4) and concentrated to give 4-bromophenyl cyclopropylmethyl sulphide as an oil (130.7 g, quantitative). The aforementioned sulphide (10 g, 41 mmol) was dissolved in THF (400 mL) and cooled to −78° C. n-Butyllithium (51 mL of a 1.6 M solution in hexanes) was added dropwise. On completion of addition, the mixture was stirred for a further 15 min before dropwise addition of DMF. The reaction mixture was stirred for 18 h, allowing to warm to room temperature. The reaction was quenched by addition of satd. NH4Cl(aq) followed by water. The product was extracted into diethyl ether (×2) and the combined organic layers were dried (MgSO4) and concentrated. Purification by chromatography on silica eluting with 5 to 10% ethyl acetate in hexane gave the title compound (5.50 g, 70% yield). 1H NMR δ (360 MHz, CDCl3) δ 9.92 (1H, s), 7.76 (2H, d, J=8.4 Hz), 7.38 (2H, d, J=8.2 Hz), 2.97 (2H, d, J=7.0 Hz), 1.14-1.08 (1H, m), 0.67-0.62 (2H, m) 0.35-0.30 (2H, m).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[CH3:16])\[CH3:7])[CH3:2].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[CH3:16])\[CH2:7][Br:18])[CH3:2]
Reactant: CCOC(=O)/C=C(\C)Oc1cccc(C)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C(\CBr)Oc1cccc(C)c1C
Yield: 30.9 %

Procedure:
To a stirred mixture of (E)-3-(2,3-dimethyl-phenoxy)-but-2-enoic acid ethyl ester (7.19 g, 0.031 mol) in carbon tetrachloride (40 mL) under a nitrogen atmosphere was added N-bromosuccinimide (8.19 g, 0.046 mol) and benzoyl peroxide (730 mg, 0.003 mol). Nitrogen gas was bubbled through the mixture for 5 min, and the resulting mixture was heated to reflux for 4 h. The reaction mixture was then placed in the refrigerator overnight. The solids formed were removed by filtration and the filtrate concentrated in vacuo. The crude product obtained was purified using flash column chromatography (silica gel (100-200 mesh), ethyl acetate/hexanes) to afford (E)-4-bromo-3-(2,3-dimethyl-phenoxy)-but-2-enoic acid ethyl ester (3.00 g, 31%) as a yellow oil.
Reaction SMILES: C(O)(=O)C.[BH3-]C#N.[Na+].[Cl:9][C:10]1[C:11]([CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[C:12]([CH:16]=O)[CH:13]=[N:14][CH:15]=1.[CH3:26][C:27]1([CH3:34])[O:31][CH:30]([CH2:32][NH2:33])[CH2:29][O:28]1>CO>[Cl:9][C:10]1[C:11]([CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[C:12]([CH2:16][NH:33][CH2:32][CH:30]2[CH2:29][O:28][C:27]([CH3:34])([CH3:26])[O:31]2)[CH:13]=[N:14][CH:15]=1
Reactant: CC1(C)OCC(CN)O1
Reactant: O=Cc1cncc(Cl)c1COC1CCCCO1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC1(C)OCC(CNCc2cncc(Cl)c2COC2CCCCO2)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetic acid (133 μL) and NaBH3CN (14.8 mg, 0.235 mmol) were added to a stirred solution of 5-chloro-4-(tetrahydro-pyran-2-yloxymethyl)-pyridine-3-carbaldehyde (40 mg, 0.157 mmol) and 2,2-dimethyl-1,3-dioxolane-4-methanamine (203 μL, 1.57 mmol) in MeOH (1 mL). After stirring for 2 h at room temperature the solvent was removed in vacuo and the residue was partitioned between DCM (10 mL) and saturated NaHCO3 solution (10 mL). After extraction of the aqueous layer with DCM (2×10 mL) the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting title compound was used for the next reaction without purification. MS (m/z): 370.9 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:28]2[CH:32]=[N:31][N:30]=[N:29]2)=[C:6]([CH:27]=1)[CH2:7][NH:8][C:9]([C@H:11]1[N:15]([C:16](=[O:26])[C@@H:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[OH:18])[N:14]=[CH:13][CH2:12]1)=[O:10].N1C=CC=CC=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>ClCCl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:28]2[CH:32]=[N:31][N:30]=[N:29]2)=[C:6]([CH2:7][NH:8][C:9]([C@H:11]2[N:15]([C:16](=[O:26])[C@H:17]([O:18][C:39](=[O:41])[CH3:40])[C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[N:14]=[CH:13][CH2:12]2)=[O:10])[CH:27]=1
Reactant: O=C(NCc1cc(Cl)ccc1-n1cnnn1)[C@@H]1CC=NN1C(=O)[C@H](O)c1ccc(F)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O[C@@H](C(=O)N1N=CC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cnnn1)c1ccc(F)cc1
Reaction time: 4 h
Yield: 90.7 %

Procedure:
To (5S)—N-[5-chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-(4-fluorophenyl)-2-hydroxyacetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide (Example 1) (483 mg, 1.05 mmol) in dichloromethane (10 mL) was added pyridine (2 mL) and acetic anhydride (100 μL, 1.06 mmol). The mixture was stirred for 4 h. Another portion of acetic anhydride (600 μL, 6.34 mmol) and DMAP (23 mg, 0.19 mmol) was added and the mixture was stirred for another 15 h. The solvents were removed by evaporation and the residue was purified by HPLC (MeCN gradient 0 to 100% in aqueous 0.1 M NH4OAc buffer containing 5% MeCN, C8 column: 50×300 mm). The relevant fractions were collected, combined and freeze dried to give the title compound (476 mg, 90%) as a solid material.
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Br.[OH:13][C:14]1[CH:18]=[C:17]([N:19]2[C:27]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[N:21]=[CH:20]2)[S:16][C:15]=1[C:28]([O:30][CH3:31])=[O:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][O:13][C:14]1[CH:18]=[C:17]([N:19]2[C:27]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[N:21]=[CH:20]2)[S:16][C:15]=1[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)c1sc(-n2cnc3cnccc32)cc1O
Reactant: FC(F)Oc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1ccccc1OC(F)F

Procedure:
In a similar manner as described for example B18, 207.7 mg of 2-(difluoromethoxy)benzyl bromide, 200 mg of methyl 3-hydroxy-5-(1H-imidazo[4,5-c]pyridin-1-yl)thiophene-2-carboxylate, 110.9 mg of potassium carbonate in 6 ml anhydrous DMF yield the title compound.
Reaction SMILES: [S:1]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[O-:12]I(=O)(=O)=O.[Na+]>O.[Cl-].[Na+].O>[S:1]([CH2:2][C:3]([O:5][CH3:6])=[O:4])([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:12]
Reactant: COC(=O)CSCC(=O)OC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COC(=O)CS(=O)CC(=O)OC
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To the mixture of dimethyl 2,2′-thiodiacetate (4.54 g, 25.5 mmol, 1 eq) in water (50 mL) at 0° C. was added sodium (meta)periodate (5.786 g, 1.05 eq) and the resulting reaction mixture was stirred overnight. The mixture was then diluted with brine and extracted with CHCl3 (5×). All organics were combined and dried with anhydrous sodium sulfate. The solution was decanted, concentrated under reduced pressure, and the clear oily residue was subject to column chromatography (EtOAc-Hex 1:5 to 1:1) giving dimethyl 2,2′-sulfinyldiacetate as a clear oil (4.522 g).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][S:20]([C:17]1[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=1)(=[O:22])=[O:21]
Reactant: Nc1ccccc1C(F)(F)F
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)Nc2ccccc2C(F)(F)F)cc1
Yield: 75.5 %

Procedure:
Using 2-trifluoromethylaniline (1.39 g, 8.55 mmol) and 4-methoxybenzenesulfonyl chloride (1.78 g, 8.55 mmol), the procedure of Reference Example 2 was repeated to obtain 2.14 g (75.5%) of the title compound in the form of colorless solid.