Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:5]2[CH:10]=[C:9]([CH2:11][O:12][CH2:13][CH:14]3[CH2:16][CH2:15]3)[N:8]=[C:7](Cl)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[N:27]1[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]1)[NH2:23].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:1]1([C:5]2[CH:10]=[C:9]([CH2:11][O:12][CH2:13][CH:14]3[CH2:16][CH2:15]3)[N:8]=[C:7]([NH:23][C:22]3[CH:24]=[CH:25][C:26]([N:27]4[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]4)=[C:20]([O:19][CH3:18])[CH:21]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: Clc1nc(COCC2CC2)cc(N2CCC2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(COCC3CC3)cc(N3CCC3)n2)ccc1-n1cnc(C)c1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 78.3 %

Procedure:
A mixture of 4-(azetidin-1-yl)-2-chloro-6-((cyclopropylmethoxy)methyl)pyrimidine (44 mg, 0.17 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (42 mg, 0.21 mmol), cesium carbonate (113 mg, 0.35 mmol), palladium acetate (5.84 mg, 0.03 mmol) and 2-(dicyclohexyl-phosphino)biphenyl (9 mg, 0.03 mmol) in dioxane (2 mL) was stirred under argon at 120° C. for 90 minutes in microwave reactor. The mixture was filtered through a short silica plug which was washed with 10% MeOH in EtOAc (75 mL). The solvent was removed in vacuum and the residue was purified by preparative HPLC to give the title compound as a solid 56 mg (77%).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12](Cl)(=[O:14])=[O:13])=[CH:4][CH:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>C1COCC1>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH:29][S:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([F:1])=[CH:3][CH:4]=2)(=[O:14])=[O:13])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=S(=O)(Cl)c1ccc(F)c2ccccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(F)c3ccccc23)CC1
Temperature: 25 °C

Procedure:
4-Fluoro-naphthalene-1-sulfonyl chloride 27 (10.0 g, 40.9 mmol) was dissolved in THF (100 mL) and stirred at room temperature. 4-Amino-piperidine-1-carboxylic acid tert-butyl ester (8.19 g, 40.9 mmol) and triethylamine (4.14 g, 5.75 mL, 40.9 mmol) were added and the reaction was stirred overnight at room temperature. The solvent was removed in vacuo. Dichloromethane (250 mL) was added and the solution was charged to a separatory funnel. The organic layer was washed twice with water and brine and dried over MgSO4. Filtration and concentration in vacuo afforded 28 as a yellow foam. Wt.: 15.1 g (90%). 1H NMR (300 MHz, CDCl3) δ 8.62 (d, 1H), 8.26 (m, 2H), 7.69 (m, 2H), 7.20 (m, 1H), 4.92 (d, 1H), 3.82 (m, 2H), 3.26 (m, 1H), 2.70 (m, 2H), 1.61 (m, 2H), 1.40 (s, 9H), 1.24 (m, 2H); LC/MS m/z 409 (M+H)+.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:9]([CH3:12])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].S(=O)(=O)(O)[OH:14].N([O-])=O.[Na+].C(OCC)C>C1COCC1.O.CO>[OH:14][C:2]1[CH:3]=[C:4]([C:9]([CH3:12])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(N)ccc1C
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(O)ccc1C
Reaction time: 0.33 h

Procedure:
4.6 g (28 mmol) of methyl 3-amino-6-methylbenzoate are dissolved in 50 ml of THF and 50 ml of 1M sulphuric acid and then the reaction medium is cooled to 0° C. A solution of sodium nitrite (2.3 g, 33.6 mmol) in 10 ml of water is then added dropwise and then the medium is stirred for 20 minutes. 15 ml of pure sulphuric acid are then added and the reaction medium is heated under reflux for 2 hours, poured into 500 ml of water and extracted with ethyl ether. The organic phases are dried, concentrated under reduced pressure and the residue obtained is dissolved in 100 ml of methanol. 3 ml of sulphuric acid are added and the reaction medium is heated under reflux for 14 hours, cooled, treated with water and ethyl ether. After extraction with ethyl ether, the organic phases are combined, dried over magnesium sulphate and concentrated under reduced pressure. After purification on a silica column (ethyl acetate 30-heptane 70), a brown oil is obtained (m=1.2 g; Y=25%).
Reaction SMILES: CO.[Na].[SH:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.Cl[C:12]1[C:13]([C:22]#[N:23])=[N:14][C:15]([C:20]#[N:21])=[C:16](Cl)[C:17]=1Cl>CC(C)=O>[N:8]1[CH:9]=[CH:10][C:5]([S:4][C:12]2[C:13]([C:22]#[N:23])=[N:14][C:15]([C:20]#[N:21])=[C:16]([S:4][C:5]3[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=3)[C:17]=2[S:4][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1nc(C#N)c(Cl)c(Cl)c1Cl
Reactant: Sc1ccncc1
Agent: [Na]
Solvent: CC(C)=O
Solvent: CO
Product: N#Cc1nc(C#N)c(Sc2ccncc2)c(Sc2ccncc2)c1Sc1ccncc1
Reaction time: 0.08 h
Yield: 45.7 %

Procedure:
In a 500 ml single-neck flask equipped with a magnetic stirrer and a reflux condenser fitted with a calcium chloride drying tube were placed 250 ml of methanol and 2.30 g (0.10 mol) of sodium metal. After all of the sodium had reacted, 11.11 g (0.10 mol) of 4-mercaptopyridine was added and the solution was allowed to stir for five minutes. To the resulting thiolate solution, 7.65 g (0.033 mol) of 3,4,5-trichloro-2,6-pyridinedicarbonitrile was added. The reaction mixture immediately became cloudy and orange in color. The reaction mixture was heated to reflux and then cooled. The methanol was removed in vacuo leaving a red-orange gum. Mixing of the gum with acetone, filtering off the solid and drying the latter afforded 6.89 g of the title compound as a yellow to orange powder, m.p. 186°-189° C (dec.). A 1.00 g sample was recrystallized from absolute ethanol to give a 0.25 g analytical sample as small, yellow-orange crystals, m.p. 186°-189° C (dec.). Anal. % Calcd. for C22H12N6S3 : C, 57.87; H, 2.65; N, 18.41. Found: C, 57.64; H, 2.59; N, 18.22.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][N:13]=[CH:14]2)=[CH:9][CH:8]=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].C(=[NH:38])(C1C=CC=CC=1)C1C=CC=CC=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:14]1[C:15]2[C:10](=[CH:9][CH:8]=[C:7]([NH2:38])[CH:16]=2)[CH:11]=[CH:12][N:13]=1
Reactant: O=S(=O)(Oc1ccc2ccncc2c1)C(F)(F)F
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Nc1ccc2ccncc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.6 %

Procedure:
A mixture of isoquinolin-7-yl trifluoromethanesulfonate (Description 117, 1.04 g, 3.75 mmol), cesium carbonate (1.6 g, 4.88 mmol), benzophenone imine (747 mg, 4.13 mmol), BINAP (100 mg, 0.16 mmol) and palladium acetate (18 mg, 0.08 mmol) in tetrahydrofuran (15 ml) was degassed (N2×3) then heated at reflux for 18 h. More BINAP (100 mg, 0.16 mmol) and palladium acetate (18 mg, 0.08 mmol) were added and the reaction heated for a further 24 h. The reaction was then cooled to room temperature and partitioned between ethyl acetate (100 ml) and water (100 ml). The aqueous layer was extracted with more ethyl acetate (50 ml) and the combined organic layers were evaporated. The residue was taken up in tetrahydrofuran (40 ml) and 2N hydrochloric acid (aq. 10 ml) was added. After 2 h, the THF was evaporated, 3N hydrochloric acid (aq. 100 ml) was added and the mixture washed with ethyl acetate (2×75 ml). The aqueous layer was then basified by addition of 47% aqueous sodium hydroxide solution and extracted with dichloromethane (3×50 ml). The combined organic layers were dried (Na2SO4) and evaporated to give crude isoquinolin-7-amine (198 mg) which was reacted directly with [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61 to give the title compound (100 mg, 8%). m/z (ES+) 346 (M+H)+.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[OH:8][C:9]([CH3:17])([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:10][SH:11].C(NC(C)C)(C)C>C(Cl)Cl>[CH2:12]([C:9]1([CH3:17])[O:8][C:4](=[O:5])[CH:3]([CH2:2][C:1]([OH:6])=[O:7])[S:11][CH2:10]1)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=C1C=CC(=O)O1
Reactant: CCCCCC(C)(O)CS
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CCCCCC1(C)CSC(CC(=O)O)C(=O)O1
Reaction time: 0.25 h

Procedure:
Into a mixture consisting of 10 g of maleic acid anhydride, 8.5 g of 2-hydroxy-2-methylheptane-1-thiol and 105 ml of methylene chloride, 1 ml of diisopropylamine, dissolved in 5 ml of methylene chloride is dropped. During this step the temperature is maintained at equal to or less than 30°. An additional 8.5 g of 2-hydroxy-2-methylheptane-1-thiol, dissolved in 5 ml of methylene chloride is added. After 15 minutes the usual work-up is performed. (Usual working up refers to the following procedure throughout the examples: washing of the organic phase with 1% aqueous sulphuric acid and with water; drying of the organic phase over MgSO4 ; distilling off the solvent; and chromatographic purification of the residue on silica gel with chloroform or ether:petroleum ether = 2:8 as elution agent.) 6-pentyl-6-methyl-2-oxo-1,4-oxathiane-3-acetic acid is obtained: NMR: 3.88 (q), 1.54 (s), 0.9 (t).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=3)[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[NH4+].[OH-:28]>C(O)(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:26])=[O:28])=[CH:21][CH:20]=3)[NH:11][C:12]=2[C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CSc1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
To a solution of 4-(4-fluorophenyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)-1H-imidazole (0.80 g, 2.2 mmol) [See Ex. 17 above] in glacial acetic acid (15 mL) was added a solution of K2S2O8 (0.72 g, 2.6 mmol) in H2O (20 mL). Additional glacial acetic acid (15 mL) was added to ensure homogeneity, and the resulting solution was stirred at rt for 18 h. The mixture was then poured into H2O, and the pH was adjusted to neutral by the addition of conc. NH4OH. The solid which formed was collected by filtration to afford the title compound (0.65 g, 78%) as a tan solid, which was recrystallized from MeOH: mp 250-252° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][O:23][CH3:24])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:31].[Na+]>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:31])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][O:23][CH3:24])[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: [BH3-]C#N
Reactant: COCCN1CCN(c2c(C(C)=O)cc(Cl)c3cccnc23)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: COCCN1CCN(c2c(C(C)N)cc(Cl)c3cccnc23)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-8-[4-(2-methoxyethyl)piperazin-1-yl]quinolin-7-yl}ethanone (22 mg, 0.063 mmol) and ammonium acetate (48.8 mg, 0.632 mmol) in methanol (0.36 mL) and acetonitrile (0.36 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling, sodium cyanoborohydride (7.95 mg, 0.126 mmol) was added to the resultant mixture. The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature, quenched with saturated sodium bicarbonate, and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness (22 mg, 99%). The residue was used directly in the next step. LCMS calculated for C18H26ClN4O(M+H)+: m/z=349.2; found: 349.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O[C@@H:10]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:19]=[C:20]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH:21]=[CH:22][CH:23]=2)[CH2:14][CH2:13]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C@H:10]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:19]=[C:20]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH:21]=[CH:22][CH:23]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(C[C@@H](O)c3ccccc3)CC2)c1
Reactant: Oc1ccc(F)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@H](Oc3ccc(F)cc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure B and Scheme B1 using 4-fluorophenol and N-(3-{1-[(2S)-2-hydroxy-2-phenylethyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 461.2 (M+H)+.
Reaction SMILES: C[C:2](=[CH2:25])[CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:9][CH2:8]2.[O:26]=[O+][O-]>>[O:26]=[C:2]([CH3:25])[CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:9][CH2:8]2
Reactant: O=[O+][O-]
Reactant: C=C(C)COc1ccc2c(c1)CCN(CCCc1ccccc1)C2=O
Product: CC(=O)COc1ccc2c(c1)CCN(CCCc1ccccc1)C2=O

Procedure:
Treatment of 6-(2-methyl-2-propenyloxy)-2-(3-phenylpropyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline with ozone under conditions of ozonolysis described in example 1 yields 6-(2-oxopropyloxy)-2-(3-phenylpropyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([OH:12])=[C:6]2[C:13]1[CH:24]=[CH:23][C:16]([C:17](N(OC)C)=[O:18])=[CH:15][N:14]=1)#[N:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.C(OCC)(=O)C>[CH:17]([C:16]1[CH:23]=[CH:24][C:13]([C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=3)[NH:8][C:7]=2[OH:12])=[N:14][CH:15]=1)=[O:18]
Reactant: CON(C)C(=O)c1ccc(-c2c(O)[nH]c3ccc(C#N)cc23)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1ccc2[nH]c(O)c(-c3ccc(C=O)cn3)c2c1
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To an icecold suspension of 50 mg (0.16 mmol) of 6-(5-cyano-2-hydroxy-1H-indol-3-yl)-N-methoxy-N-methylnicotin-amide from example 1.2 in THF (4 mL) were added 19.4 mg (0.51 mmol) of LiAlH4 as a solid in small portions. The resulting mixture was stirred at that temperature for further 30 min. After diluting with ethyl acetate the reaction was quenched by adding 4.2 mL of a 0.35 M solution of KHSO4. The resulting solution was stirred for further 60 min, the phases were separated, and the precipitate in the organic layer was collected by filtration, washed with water and ethyl acetate, and dried in a vacuum oven yielding a red solid. Amount 28 mg. Yield 68%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][S:11][C:12]=2[CH:13]=O)=[CH:4][CH:3]=1.C(OP([CH2:23][C:24]([O:26]CC)=[O:25])(OCC)=O)C.[H-].[Na+].Cl>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[N:10][S:11][C:12]=2/[CH:13]=[CH:23]/[C:24]([OH:26])=[O:25])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1snnc1-c1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)/C=C/c1snnc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.1 %

Procedure:
A mixture of 4-(4-fluorophenyl)-1,2,3-thiadiazole-5-carbaldehyde (180 mg), ethyl diethylphosphonoacetate (450 mg), sodium hydride (60% in oil, 40 mg) and N,N-dimethylformamide (3 ml) was stirred at room temperature for 2 hrs. The reaction mixture was poured into a 1N aqueous hydrochloric acid solution and the mixture was extracted with ethyl acetate. The ethyl acetate layer was concentrated, and a 6N aqueous hydrochloric acid solution (3 ml) and acetic acid (3 ml) were added to the residue. The mixture was stirred for 3 hrs. with heating under reflux. The reaction mixture was concentrated and poured into water. The precipitated solids were collected by filtration, washed with water and dried to give (2E)-3-[4-(4-fluorophenyl)-1,2,3-thiadiazol-5-yl]acrylic acid (130 mg, yield 60%) as a pale-yellow solid.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([Br:10])[CH:9]=1.[C:12]1([CH3:18])[CH:17]=CC=C[CH:13]=1.BrCCCCC>O.[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1>[Br:3][C:4]1[CH:5]=[C:6]([O:11][CH2:13][CH:12]([CH3:18])[CH3:17])[CH:7]=[C:8]([Br:10])[CH:9]=1
Reactant: Oc1cc(Br)cc(Br)c1
Reactant: Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CCCCCBr
Product: CC(C)COc1cc(Br)cc(Br)c1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
Potassium hydroxide (15.9 g; 284 mmol) was dissolved in water (300 ml) and 3,5-dibromo-phenol (47 g; 188.5 mmol) was added. Benzyl tributylammoniumchloride (17.7 g; 56.8 mmol) and toluene (200 ml) was added and the reaction mixture was heated to 85° C. Bromoethylpropan (32.3 g; 325.7 mmol) was added over 5 hours and the reaction mixture was stirred at 85° C. for additional 16 h. The reaction mixture was cooled to room temperature and the phases were separated. Toluene (100 ml) was added to the organic phase which was washed with 0.2 N aqueous HCl (200 ml×2) and water (200 ml×2). The organic phase was evaporated to give the crude product which was purified by distillation (0.7. mm Hg; Bp: 98° C.); Yield: 43 g (colourless oil).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:33]([F:36])([F:35])[F:34])[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4([F:32])[CH2:24][N:23]([C:25]([CH:27]5[CH2:30][S:29](=[O:31])[CH2:28]5)=[O:26])[CH2:22]4)=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[OH:37]OS([O-])=O.[K+]>CO.O>[Cl:9][C:6]1[CH:5]=[C:4]([C:10]2([C:33]([F:35])([F:36])[F:34])[O:14][N:13]=[C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:21]4([F:32])[CH2:22][N:23]([C:25]([CH:27]5[CH2:28][S:29](=[O:37])(=[O:31])[CH2:30]5)=[O:26])[CH2:24]4)=[CH:19][CH:20]=3)[CH2:11]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[F:8]
Reactant: O=S([O-])OO
Reactant: O=C(C1CS(=O)C1)N1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(C1CS(=O)(=O)C1)N1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidin-1-yl)(1-oxidothietan-3-yl)methanone (30 mg) in methanol (2 mL) was added to a solution of oxone (160 mg) in water (1 mL) cooled with an ice bath. Reaction allowed to warm slowly to ambient then stirred at ambient temperature for 16 hours. Majority of methanol removed under reduced pressure then remaining aqueous extracted with DCM (2×5 mL). Organic phase collected and condensed. The crude material was adsorbed on silica and chromatographed on a 4 g silica column, eluting with a gradient of 0% to 100% ethyl acetate in heptane. Fractions containing the desired material were combined and concentrated. Placing the flask on high vacuum overnight resulted in formation of a white foam. Yield 15.7 mg (51%). 1H NMR (DMSO-D6) δ 7.82 (m, 4H), 7.69 (m, 2H), 4.67 (d, 2H), 4.46-4.29 (m, 8H), 3.56-3.43 (m, 1H). LC/MS retention time=3.455 minutes, MS calculated for (C23H17Cl2F5N2O4S), 582.02; nd M+H+.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]([NH:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1.[Li+].[OH-]>O>[C:20]([O:19][C:17]([NH:16][CH2:15][CH2:14][NH:13][CH:4]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)[C:3]([OH:24])=[O:2])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)C(NCCNC(=O)OC(C)(C)C)c1cccc(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: COc1cccc(C(NCCNC(=O)OC(C)(C)C)C(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
To a solution of (2-tert-butoxycarbonylamino-ethylamino)-(3-methoxy-phenyl)-acetic acid methyl ester (10.4 mmol) in TiAF:H2O (3:1, 40 mL) was added LiOH (10.9 mmol) and the reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was concentrated in vacuo then diluted with H20 and neutralised with 2M HCl solution and the resulting precipitate was collected by filtration to afford the title compound in 46% yield.
Reaction SMILES: C([N:8]1[CH2:13][C@@H:12]([O:14][C:15]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])[CH2:11][C@H:10]([C:22]([O:24][CH3:25])=[O:23])[C@H:9]1[C:26]([O:28]CC1C=CC=CC=1)=[O:27])C1C=CC=CC=1.CO.[H][H]>[Pd]>[CH3:25][O:24][C:22]([C@H:10]1[CH2:11][C@H:12]([O:14][C:15]([N:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)=[O:16])[CH2:13][NH:8][C@@H:9]1[C:26]([OH:28])=[O:27])=[O:23]
Reactant: [H][H]
Reactant: COC(=O)[C@H]1C[C@H](OC(=O)N2CCCC2)CN(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H]1C[C@H](OC(=O)N2CCCC2)CN[C@@H]1C(=O)O

Procedure:
A solution of 2-benzyl 3-methyl(2S,3S,5S)-1-benzyl-5-[(pyrrolidin-1-ylcarbonyl)oxy]piperidine-2,3-dicarboxylate (144 mg, 0.000300 mol) in methanol (3.0 mL, 0.074 mol) was hydrogenated in the presence of 10% Pd/C, under balloon pressure of hydrogen, overnight. After filtered off the catalyst, the filtration was concentrated to dry to provide crude product, which was used directly in next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=2[CH:21]=[O:22])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[N:24]1[C:33]2[C:28](=[CH:29][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:30]3[CH:29]=[C:28]4[C:33](=[CH:32][CH:31]=3)[N:24]=[CH:25][CH:26]=[CH:27]4)=[CH:16][C:15]=2[CH:21]=[O:22])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CC1(C)OB(c2ccc3ncccc3c2)OC1(C)C
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(Br)cc2C=O)c1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3ccc4ncccc4c3)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: (4′-bromo-2′-formyl-6-methoxy-biphenyl-3-yl)-acetic acid ethyl ester and 6-quinolineboronic acid pinacol ester.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:25]([O:32][C:33](ONC(=O)CCC(N)=O)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[CH2:25]([O:32][C:33]([N:12]1[CH2:13][CH2:14][CH2:15][CH:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:17][CH:16]=2)[CH2:11]1)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NC(=O)CCC(=O)NOC(=O)OCc1ccccc1
Reactant: O=C(NCC1CCCNC1)c1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCC1CCCN(C(=O)OCc2ccccc2)C1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 4-hydroxy-N-piperidin-3-ylmethyl-benzamide (135 mg, 0.580 mmol) in tetrahydrofuran (5 mL) was added triethylamine (100 μL) and N-benzyloxycarbonyloxysuccinamide (144 mg, 0.580 mmol) and the mixture stirred at rt for 3 h. The reaction was concentrated in vacuo and chromatographed on silica using 50–100% ethyl acetate/hexane to give 3-[(4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester as a foam.