Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH2:6]([O:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17](Br)=[CH:16][C:15]=1[C:29]1[O:33][N:32]=[C:31]([CH3:34])[C:30]=1[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[C:44]([O:46][CH3:47])=[O:45]>O1CCCC1>[CH3:47][O:46][C:44](=[O:45])[C:17]1[CH:16]=[C:15]([C:29]2[O:33][N:32]=[C:31]([CH3:34])[C:30]=2[C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:14]([O:13][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:19][C:18]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)Cl
Reactant: COc1ccc(-c2c(C)noc2-c2cc(Br)c(OCc3ccccc3)cc2OCc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2onc(C)c2-c2ccc(OC)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (1001 μl) was added to a solution of 5-(2,4-bis-benzyloxy-5-bromo-phenyl)-4-(4-methoxy-phenyl)-3-methyl-isoxazole (154 mg, 0.28 mmol) in tetrahydrofuran (2.5 ml) under a nitrogen atmosphere at −78° C. Solution stirred at −70° C. for 30 minutes to give an orange solution. The ion was quenched with methyl chloroformate (100 μl, 3 eq) and allowed to warm to room temperature for 30 minutes. The solution was quenched with saturated aqueous ammonium chloride (5 ml). The mixture was extracted with ethyl acetate (3×5 ml). The combined extracts were washed with water (2×5 ml) and saturated aqueous sodium chloride solution (5 ml). The solution was dried over anhydrous magnesium sulphate and concentrated. The crude products were purified by column chromatography, silica, eluting with ethyl acetate in hexane (gradient 20% to 60% ethyl acetate) to give 2,4-Bis-benzyloxy-5-[4-(4-methoxy-phenyl)-3-methyl-isoxazol-5-yl]-benzoic acid methyl ester (72 mg).
Reaction SMILES: [OH-].[Na+].C1C=[C:7]([C:9]2[C:23]3C(=C(Br)C([O-])=C(Br)C=3)OC3[C:10]=2C=C(Br)C(C=3Br)=O)[C:6]([C:29]([O-:31])=[O:30])=CC=1.[Na+].[Na+].C(=[S:37])([O-])[O-].[Na+].[Na+]>O>[SH:37][CH:6]([CH2:7][CH:9]([CH3:23])[CH3:10])[C:29]([OH:31])=[O:30]
Reactant: [O-]C([O-])=S
Reactant: O=C([O-])c1ccccc1-c1c2cc(Br)c(=O)c(Br)c-2oc2c(Br)c([O-])c(Br)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)CC(S)C(=O)O
Reaction time: 24 h
Yield: 34 %

Procedure:
A total of 1.25 g. (6.5 mmoles) of the product prepared above is taken up in 2 ml. of water. Sufficient 1 N sodium hydroxide is added to dissolve the bromo acid. To this mixture, there is added 5 ml. of 40% sodium thiocarbonate and the vessel is closed and allowed to stand at room temperature for 24 hours. At the end of this period, the solution is acidified with 18 N. sulfuric acid, and extracted with 2 10 ml. portions of ethyl ether. The combined extracts are dried over anhydrous magnesium sulfate and filtered. The filtrate is concentrated to approximately half its volume and chromatographed on a silica gel column (2.2×30 cm). The original solution is eluted with 150 ml. of ethyl ether, and the product recovered by evaporation of the solvent in the eluate. The yield is approximately 34%. The Rf values (TLC) are 0.88 and 1.0 on silica gel and cellulose plates (n-butanol/acetic acid/water-12/3/5).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([CH2:7][P:8](=[O:15])([O:12]CC)[O:9]CC)=[CH:5][CH:4]=1>Cl.CCO>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([CH2:7][P:8](=[O:9])([OH:12])[OH:15])=[CH:5][CH:4]=1
Reactant: CCOP(=O)(Cc1ccc(C(F)(F)F)cc1)OCC
Agent: Cl
Solvent: CCO
Product: O=P(O)(O)Cc1ccc(C(F)(F)F)cc1

Procedure:
The diethyl 4-trifluoromethylbenzylphosphonate (3.0 g, 10 mmol) was dissolved in a mixture of 50 mL of conc hydrochloric acid and 5 mL of EtOH and heated at reflux for 17 hours. After cooling the mixture in an ice bath, white crystalline material was collected. Recrystallization of the solid from H2O gave 1.80 g, 75% of the analytically pure product: mp=163°-164° C.; D.C.I.M.S. [MH+, 241].
Reaction SMILES: [C:1]([NH:8][NH2:9])([O:3][C:4](C)(C)[CH3:5])=[O:2].CCN(C(C)C)C(C)C.C(Cl)(OCC1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=O>C(Cl)Cl>[CH:34]1[C:35]2[CH:5]([CH2:4][O:3][C:1]([NH:8][NH2:9])=[O:2])[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]=2[CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NNC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
Boc-hydrazine (10.0 g, 75.6 mmol) and DIPEA (12.95 ml, 75.6 mmol) were dissolved in dry CH2Cl2 (200 ml) and cooled to 0° C. FmocCl (19.6 g, 75.8 mmol), dissolved in dry CH2Cl2 (100 ml), was then added over the course of 30 minutes, and the mixture was stirred overnight at room temperature. The organic phase was extracted with water (200 ml) and evaporated to a volume of about 100 ml. Trifluoroacetic acid (100 ml) was then carefully added at 0° C., and the mixture was stirred for 1.5 hours. The product was precipitated by careful addition of saturated Na2CO3 solution (300 ml) and dried, giving a colourless solid (18.02 g, 70.8 mmol, 94%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:15][C:16]1[NH:20][CH:19]=[N:18][CH:17]=1.O>CN(C=O)C>[Br:15][C:16]1[N:20]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:19]=[N:18][CH:17]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Brc1cnc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1nccc(-n2cncc2Br)n1
Temperature: 0 °C
Yield: 23.1 %

Procedure:
To a solution of 2,4-dichloropyrimidine (0.447 g, 3 mmol) in anhydrous DMF (4 ml) was added potassium carbonate (0.415 g, 3 mmol). The reaction mixture was cooled (0° C.) under an inert atmosphere before the addition of 5-bromo-1-H-imidazole (0.441 g, 3 mmol) as solution in DMF (2 ml). The reaction was then allowed to stir at this temperature for a further 3 hours whereupon water (3 ml) was added. The resultant white precipitate was removed from the mixture by filtration and washed with water before being dried to give the title compound as a white solid (0.18 g, 23%) which was suitably pure to be used without further purification. m/z (LC-MSW, ESP):259.2,261.2 (bromine isotopes) [M+H]+, R/T=3.47 mins.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:13]2[N:21](S(C3C=CC=CC=3)(=O)=O)[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH:14]=2)=[CH:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:13]2[NH:21][C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH:14]=2)=[CH:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C=C(c1cccc(Cl)c1)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)C=C(c1cccc(Cl)c1)c1cc2cccnc2[nH]1
Temperature: 70 °C
Reaction time: 16 h
Yield: 76.8 %

Procedure:
A solution of 2-(1-(3-chloro-phenyl)-3-methyl-but-1-enyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (2.5 g, 5.7 mmol) in ethanol (45 mL) and tetrahydrofuran (90 mL) was treated with a 10% aqueous sodium hydroxide solution (15 mL). The reaction was stirred at 70° C. for 16 h. The solvent was removed in vacuo and the obtained precipitate was filtered and washed with water (3×50 mL) and ethyl acetate (20 mL) to afford 2-(1-(3-chloro-phenyl)-3-methyl-but-1-enyl)-1H-pyrrolo[2,3-b]pyridine (1.3 g, 77%) as a white solid: 1H NMR (300 MHz, d6-DMSO) δ ppm 11.57 (s, 1H), 8.17 (dd, 1H, J1=4.5 Hz, J2=1.5 Hz), 7.93 (dd, 1H, J1=8.4 Hz, J2=1.8 Hz), 7.31 (m, 2H), 7.21 (m, 1H), 7.15 (m, 1H), 7.05 (m, 1H), 6.40 (s, 1H), 6.21 (d, 1H, J=9.9 Hz), 2.57 (m, 1H), 1.03-1.01 (m, 6H).
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][C:20]1[C:21]([NH2:26])=[N:22][CH:23]=[CH:24][CH:25]=1>>[CH3:19][C:20]1[C:21]([NH:26][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1cccnc1N
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Product: Cc1cccnc1NC(=O)c1cccc(S(=O)(=O)N2CCCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 3-methylpyridine-2-amine as the starting materials.
Reaction SMILES: Cl[C:2]1[N:21]=[C:5]2[C:6]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:20][S:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:35][C:32]3[CH:33]=[CH:34][C:29]([CH:26]4[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]4)=[CH:30][CH:31]=3)[N:21]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)c1ccccc1Nc1cccn2nc(Cl)nc12
Reactant: CN1CCC(c2ccc(N)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCC(c2ccc(Nc3nc4c(Nc5ccccc5S(C)(=O)=O)cccn4n3)cc2)CC1

Procedure:
N(8)-(2-Methanesulfonyl-phenyl)-N(2)-[4-(1-methyl-piperidin-4-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonyl-phenyl)-amine (75.0 mg, 0.232 mmol) and 4-(1-methyl-piperidin-4-yl)-phenylamine (53.0 mg, 0.279 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.063 g, 57%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.47 (s, 1H), 8.13 (d, J=6.8 Hz, 1H), 7.98 (dd, J=7.8, 1.2 Hz, 1H), 7.58-7.48 (m, 4H), 7.29-7.25 (m, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.14-7.09 (m, 1H), 6.83-6.77 (m, 2H), 3.14 (s, 3H), 3.01-2.94 (m, 2H), 2.50-2.40 (m, 1H), 2.33 (s, 3H), 2.10-2.00 (m, 2H), 1.87-1.73 (m, 4H). MS=477 (MH)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:7]2[CH:8]=[CH:9][C:10]([C:12]([CH3:25])=[CH:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)=[CH:11][C:6]=2[S:5][CH2:4][CH2:3]1.[OH-].[K+].Cl>C(O)C.O>[CH3:1][C:2]1([CH3:26])[C:7]2[CH:8]=[CH:9][C:10]([C:12]([CH3:25])=[CH:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:23][CH:24]=3)=[CH:11][C:6]=2[S:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C=C(C)c2ccc3c(c2)SCCC3(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=Cc1ccc(C(=O)O)cc1)c1ccc2c(c1)SCCC2(C)C
Temperature: 50 °C
Yield: 65 %

Procedure:
1 g of the thus-obtained ester was dissolved in 20 ml of ethanol and treated with a solution of 1.6 g of potassium hydroxide in 10 ml of water. After heating to 50° C. for 2 hours, the mixture was poured on to ice, acidified with 2N hydrochloric acid and extracted repeatedly with ethyl acetate. The crystalline residue obtained after evaporation was recrystallized from acetic acid. There was obtained 0.6 g of p-[2-(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-7-yl)propenyl]benzoic acid, m.p. 255°-257° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10].N1C=CN=C1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.CCCCCC>[Si:20]([O:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CCCCC1CCO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OCCC1CCCCC1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 53.3 %

Procedure:
In dry DMF (200 ml) was dissolved 2-(2-hydroxyethyl)cyclohexanone (7.86 g) followed by addition of imidazole (9.53 g) and tert-butyldimethylchlorosilane (10 g), and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with hexane (500 ml), washed successively with aqueous sodium hydrogen carbonate, diluted hydrochloric acid, aqueous sodium hydrogen carbonate, and aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was further subjected to vacuum distillation to give 7.55 g of 2-[2-(tert-butyldimethylsilyloxy)ethyl]cyclohexanone as a colorless oil.
Reaction SMILES: [Li+].[OH-].Br[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]3[N:16]=[C:17]([O:27][C@H:28]4[C@H:32]5[O:33][CH2:34][C@@H:35]([OH:36])[C@H:31]5[O:30][CH2:29]4)[N:18]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:13]3=[CH:12][C:11]=2[Cl:37])=[CH:6][CH:5]=1.[C:38]1(B(O)O)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O1CCOCC1.O>[Cl:37][C:11]1[CH:12]=[C:13]2[N:18]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:17]([O:27][C@H:28]3[C@H:32]4[O:33][CH2:34][C@@H:35]([OH:36])[C@H:31]4[O:30][CH2:29]3)=[N:16][C:14]2=[N:15][C:10]=1[C:7]1[CH:8]=[CH:9][C:4]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:5][CH:6]=1
Reactant: OB(O)c1ccccc1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(Br)cc3)c(Cl)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Temperature: 80 °C

Procedure:
LiOH (1.3 ml, 3.90 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (107.7 mg, 0.132 mmol) were added to a stirred solution of (3R,3aR,6R,6aR)-6-[5-(4-bromophenyl)-6-chloro-1-(2-trimethylsilylethoxymethyl)-imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (776.2 mg, 1.332 mmol) and phenylboronic acid (201.9 mg, 1.656 mmol) in dioxane (10.5 ml) and water (1.3 ml). The reaction mixture was degassed (3×) and placed under nitrogen before being heated to 80° C. for 20 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc (100 ml) and water (100 ml). The aqueous layer was extracted with EtOAc (2×50 ml). The organic layers were combined, washed with brine (1×30 ml), dried over MgSO4, filtered, and evaporated under reduced pressure to give an amber residue. This material was purified by flash chromatography, utilizing a 40 g silica RediSep Rf® column and employing a 0-70% EtOAc/hexane gradient followed by 70% EtOAc/hexane. The product fractions were combined, evaporated under reduced pressure, and lyophilized from ethanol and benzene to give the title compound as a yellow solid. LC-MS: calculated for C30H34ClN3O5Si 579.2 observed m/e: 580.24 (M+H)+ (Rt 1.36/2 min).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:21][CH2:22][CH2:23]Br>CS(C)=O.CCOC(C)=O>[Cl:21][CH2:22][CH2:23][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cnn(CCCl)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.0 G, 5.2 mmol) in 30 mL of DMSO was added cesium carbonate (6.73 G, 20.6 mmol) and 2-chloroethylbromide (0.854 mL, 10.3 mmol). This reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was then diluted with a large volume of EtOAc. The organic was washed with water×1, saline×1, then dried over Na2SO4 and conc. to give 1-(2-chloroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a solid.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([S:7][CH3:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH:15]O>C(O)(=O)C>[NH2:1][C:2]1[S:6][C:5]([S:7]([CH3:8])=[O:15])=[N:4][C:3]=1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CSc1nc(-c2ccccc2)c(N)s1
Reactant: OO
Solvent: CC(=O)O
Product: CS(=O)c1nc(-c2ccccc2)c(N)s1
Yield: 87 %

Procedure:
To 5-amino-2-(methylsulfanyl)-4-phenylthiazole (305 mg, 1.37 mmol) in acetic acid (3.0 ml) was added aqueous hydrogen peroxide (660 μl, 30% wt, 6.9 mmol) dropwise at ambient temperature. After 4 hr the mixture was partitioned between dichloromethane (60 ml) and water (60 ml). The organic phase was separated, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography on silica gel (ethyl acetate/hexanes) yielded pure 5-amino-2-(methylsulfinyl)-4-phenylthiazole (285 mg, 87%).
Reaction SMILES: C[O-].[Na+].[O:4]=[C:5]1[C:13]2[S:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[N:10][C:9]=2[CH2:8][CH2:7][CH2:6]1.[CH:18](OCC)=[O:19].Cl>CN(C)C=O.C1C=CC=CC=1>[CH:18]([CH:6]1[CH2:7][CH2:8][C:9]2[N:10]=[C:11]([NH:14][C:15](=[O:17])[CH3:16])[S:12][C:13]=2[C:5]1=[O:4])=[O:19]
Reactant: CCOC=O
Reactant: CC(=O)Nc1nc2c(s1)C(=O)CCC2
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(=O)Nc1nc2c(s1)C(=O)C(C=O)CC2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
20 g (0.37 mol) sodium methoxide are suspended in 50 mL dimethylformamide, a suspension of 21 g (0.1 mol) N-(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide in 100 mL dimethylformamide is added dropwise. The mixture is stirred for 15 minutes, then cooled to 0° C. A mixture of 29.9 mL (0.37 mol) ethyl formate and 60 mL benzene is added dropwise and the reaction mixture is diluted with another 100 mL benzene. A precipitate gradually settles out and stirring is continued at 0° C. for 3.5 hours. The suspension is hydrolysed with 370 mL 1 molar hydrochloric acid, the solid precipitated is suction filtered. The two phases of the mother liquor are separated, the aqueous phase is extracted with dichloromethane. The resulting organic phase is dried and evaporated to dryness. The solid and the residue from the extraction are recrystallised from acetonitrile. Yield: 20 g
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:13][C:14]1[O:18][C:17]([C:19](Cl)=[O:20])=[CH:16][CH:15]=1>ClCCl>[Br:13][C:14]1[O:18][C:17]([C:19]([N:10]2[CH2:11][CH2:12][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]2)=[O:20])=[CH:16][CH:15]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)c1ccc(Br)o1
Solvent: ClCCl
Product: O=C(c1ccc(Br)o1)N1CCN(c2ccccc2)CC1
Reaction time: 2.5 h
Yield: 77.1 %

Procedure:
N-Phenylpiperazine (1.3 ml, 8.51 mmol) is added to a mixture of 5-bromofuran-2-carbonyl chloride (1.5 g, 7.16 mmol), piperidinomethylpolystyrene (2.2 g, 3.5 mmol/g, 7.7 mmol) in anhydrous dichloromethane (30 mL) and stirred for 2.5 hr. The reaction mixture is diluted with dichloromethane and filtered through silica gel. The filtrate is concentrated to afford (5-bromo-furan-2-yl)-(4-phenyl-piperazin-1-yl)-methanone as a white solid (1.85 g, 77% yield); MS: m/e=336 (M+H). 1H-NMR (CDCl3, δ ppm) 7.03 (m, 6H); 6.45 (d, 1H); 3.96 (s, 4H); 3.28 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][Si:8]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.O1CCCC1.C([Li])CCC.[C:30]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH:35]=[O:36])#[N:31]>[Cl-].[NH4+].C(OCC)(=O)C>[OH:36][CH:35]([C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][Si:8]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1)[C:34]1[CH:33]=[C:32]([CH:39]=[CH:38][CH:37]=1)[C:30]#[N:31]
Reactant: CC(C)[Si](OCc1ccc(Br)cc1)(C(C)C)C(C)C
Reactant: N#Cc1cccc(C=O)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)[Si](OCc1ccc(C(O)c2cccc(C#N)c2)cc1)(C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 74.4 %

Procedure:
Stir a solution of (4-bromo-benzyloxy)-triisopropyl-silane (72 g, 209.7 mmol) and tetrahydrofuran (500 mL) at −78° C. Add a 1.6 M solution of n-butyllithium in hexanes (143 mL) over 10 min. After addition, allow the reaction mixture to reach −20° C. and stir for 5 minutes. Cool the reaction mixture to −78° C. In another flask, stir a solution of 3-cyanobenzaldehyde (25 g, 190.6 mmol) and tetrahydrofuran (250 mL) at −78° C. Add the lithium anion solution to the aldehyde solution via large canula at a rate such that the internal aldehyde temperature does not rise above −50° C. After addition is complete, stir the reaction mixture 18 hours at room temperature. Dilute the reaction mixture with aqueous saturated ammonium chloride (500 mL) and ethyl acetate (200 mL). Separate the layers, and extract the aqueous layer with ethyl acetate (3×100 mL). Combine the organic layers, dry over anhydrous magnesium sulfate, filter, and concentrate. Purify the residue via silica gel chromatography eluting with hexanes to 9:1 hexanes:ethyl acetate to afford the title compound (56.1 g, 75%) as a colorless oil. LCMS (m/z) 396 M+1.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[NH:10][C@@H:11]([CH3:14])[CH:12]=[CH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B1C2CCCC1CCC2.C1C[O:28]CC1>>[CH2:1]([O:8][C:9](=[O:15])[NH:10][C@@H:11]([CH3:14])[CH2:12][CH2:13][OH:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C[C@H](C)NC(=O)OCc1ccccc1
Reactant: C1CCOC1
Agent: B1C2CCCC1CCC2
Product: C[C@@H](CCO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
(1-(S)-Methyl-allyl)-carbamic acid benzyl ester (1.96 g, 9.56 mmol) was taken up in THF (200 mL). 9-BBN 0.5M in THF (38 mL, 19.0 mmol) was added slowly to the reaction mixture. The solution was allowed to stir at rt for 16 h. Quenched with H2O (65 mL), followed by 1.0M NaOH(aq) (20 mL). The solution was cooled to 0° C. in an ice bath and H2O2 30% in H2O (7.0 mL) was slowly added. The reaction was partitioned between Et2O and H2O. The layers were separated and the aqueous washed with Et2O. The combine organics were dried over Na2SO4. Solids were filtered and the solvent removed under reduced pressure. (3-hydroxy-1-(S)-methyl-propyl)-carbamic acid benzyl ester (1.85 g, 87%) was isolated by silica gel chromatography as a white solid.
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]([S:6]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)[C:13]([CH2:29][N:30]1[CH2:35][CH2:34][C:33](=[O:36])[CH:32]([CH3:37])[CH2:31]1)=[C:12]2[C:38]([O:40]C)=[O:39])(=[O:8])=[O:7])[CH3:5]>CO.O1CCCC1>[CH3:5][CH:4]([S:6]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)[C:13]([CH2:29][N:30]1[CH2:35][CH2:34][C:33](=[O:36])[CH:32]([CH3:37])[CH2:31]1)=[C:12]2[C:38]([OH:40])=[O:39])(=[O:7])=[O:8])[CH3:3]
Reactant: COC(=O)c1c(CN2CCC(=O)C(C)C2)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(=O)(=O)C(C)C)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1CN(Cc2c(-c3cccc(C(F)(F)F)c3)nc3ccc(S(=O)(=O)C(C)C)cc3c2C(=O)O)CCC1=O
Temperature: 50 °C
Yield: 78.6 %

Procedure:
Sodium hydroxide (11.02 mL of a 2M solution, 22.04 mmol) was added to a yellow solution of methyl 6-[(1-methylethyl)sulfonyl]-3-[(3-methyl-4-oxo-1-piperidinyl)methyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.24 g, 2.204 mmol) in methanol (11.02 mL) and tetrahydrofuran (11.02 mL). The mixture was heated to 50° C. for 20 h. The mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was diluted with water (5 mL), and the solid precipitate was collected by filtration, washed with water (2×1 mL), and dried in a vacuum oven at 40° C. to afford 6-[(1-methylethyl)sulfonyl]-3-[(3-methyl-4-oxo-1-piperidinyl)methyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.95 g, 72% yield). 1H NMR (400 MHz, DMSO-d6) δ8.53 (d, J=1.76 Hz, 1H), 8.10-8.18 (m, 2H), 7.96-8.05 (m, 2H), 7.83 (d, J=7.81 Hz, 1H), 7.72 (t, J=7.68 Hz, 1H), 3.71 (s, 2H), 3.49 (dt, J=6.77, 13.41 Hz, 1H), 2.68-2.78 (m, 2H), 2.08-2.32 (m, 3H), 1.92-2.03 (m, 2H), 1.22 (s, 3H), 1.20 (s, 3H), 0.70 (d, J=6.55 Hz, 3H); MS (m/z) 549.2 (M+H+).