Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[OH:21].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.F[P-](F)(F)(F)(F)F.[Cu+].C(#N)C.C(#N)C.C(#N)C.C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:21][C:15]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=2[Cl:13])=[N:8][CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: Oc1cc(Cl)ccc1Cl
Reactant: CCOC(=O)c1cncnc1Cl
Agent: [Cu+]
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CCOC(=O)c1cncnc1Oc1cc(Cl)ccc1Cl

Procedure:
To a solution of 420 mg (2.25 mmol) 4-chloropyrimidine-5-carboxylic acid ethyl ester (commercially available, CAS RN 41103-17-7) and 440 mg (2.7 mmol) 2,5-dichlorophenol (commercially available, CAS RN 583-78-8) in 2.5 mL toluene were added 688 mg (5.17 mmol) cesium carbonate and 168 mg (0.45 mmol) tetrakis(acetonitrile) copper(I) hexafluorophosphate (commercially available, CAS RN 64443-05-6). The reaction was heated to reflux for 2.5 h. The solvent was evaporated and the crude reaction product extracted with ethyl acetate from an aqueous saturated solution of sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered and evaporated. The resulting product was purified by silica gel chromatography using a MPLC system (silica gel column, CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate yielding 620 mg (88%) of the desired compound as a light yellow viscous oil. MS (ESI): m/z=313.1 [M+H]+.
Reaction SMILES: 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.C(=O)([O-])[O-].[Cs+].[Cs+].[C:53]([N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54].[CH2:66]([C:73]1[C:77]2[CH:78]=[C:79]([CH3:83])[CH:80]=[C:81](Br)[C:76]=2[O:75][C:74]=1[C:84]#[N:85])[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:56]([O:55][C:53]([N:60]1[CH2:61][CH2:62][N:63]([C:81]2[C:76]3[O:75][C:74]([C:84]#[N:85])=[C:73]([CH2:66][C:67]4[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=4)[C:77]=3[CH:78]=[C:79]([CH3:83])[CH:80]=2)[CH2:64][CH2:65]1)=[O:54])([CH3:59])([CH3:58])[CH3:57]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc(Br)c2oc(C#N)c(Cc3ccccc3)c2c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2oc(C#N)c(Cc3ccccc3)c2c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 44.8 %

Procedure:
In an oven dried flask was added BINAP (racemic, 0.17 g, 0.913 mmol), cesium carbonate (0.35 g, 1.07 mmol), tris(dibenzylideneacetone)dipalladium (0.0207 g, 0.0226 mmol), 1-BOC-piperazine (0.17 g, 0.913 mmol) and 5 ml DMF. The flask was evacuated and refilled with nitrogen. 3-benzyl-7-bromo-5-methyl-benzofuran-2-carbonitrile (0.29 g, 0.90 mmol) in 5 ml DMF was added via syringe and the mixture heated to 80° C. overnight, then to 100° C. for another 24 hours. The mixture was concentrated on a rotary evaporator and purified by column chromatography (1:9 ethyl acetate/hexane) to give 4-(3-benzyl-2-cyano-5-methyl-benzofuran-7-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.174 g, 45% yield) as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[C:6]([CH2:19][CH2:20][CH3:21])[C:5]=1[OH:22])(=[O:3])[CH3:2].[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][CH2:31][CH2:32][NH2:33]>>[C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:33][CH2:32][CH2:31][CH2:30][CH2:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)=[O:16])=[C:6]([CH2:19][CH2:20][CH3:21])[C:5]=1[OH:22])(=[O:3])[CH3:2]
Reactant: NCCCCc1ccccn1
Reactant: CCCc1c(OCCCCCC(=O)O)ccc(C(C)=O)c1O
Product: CCCc1c(OCCCCCC(=O)NCCCCc2ccccn2)ccc(C(C)=O)c1O

Procedure:
6-(4-Acetyl-3-hydroxy-2-propylphenoxy)hexanoic acid was allowed to react with 2-pyridine butanamine according to procedure A and the product was purified by crystallization from ether-hexane to give 6-(4-acetyl-3-hydroxy-2-propylphenoxy)-N-[4-(2-pyridinyl)butyl]hexanamide, the title compound, mp 63°-66° in 76% yield,
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9]([C:11]1[C:20]([CH3:21])=[C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:30])[CH:17]=2)[CH:12]=1)=O>C1COCC1>[CH2:23]([O:22][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:30])[CH:17]=2)[CH:12]=[C:11]([CH2:9][OH:8])[C:20]=1[CH3:21])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1cc2ccc(F)cc2c(OCc2ccccc2)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(CO)cc2ccc(F)cc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
To a suspension of LiAlH4 (8.8 g, 235 mmol) in dry THF (120 mL) was added a solution of 4-benzyloxy-6-fluoro-3-methyl-naphthalene-2-carboxylic acid methyl ester (25.4 g, 78.4 mmol) in THF (180 mL) dropwise at 0° C. under nitrogen. The reaction mixture was stirred at room temperature for 3 hours. After this time, the reaction mixture was cooled to 0° C. and quenched carefully via addition of cold water (10 mL) followed by 15% NaOH solution (10 mL) and additional water. The resulting solution was stirred for one hour, then filtered through a sintered glass funnel. The filter pad was washed with THF (50 mL). The combined filtrates were dried over Na2SO4, filtered, and concentrated to afford (4-benzyloxy-6-fluoro-3-methyl-naphthalen-2-yl)-methanol (21.5 g, 92%, crude) as a white solid. The crude product was used in the next step without further purification. MS cald. for C19H16FO2 [(M−H)+]: 295, obsd. 294.9.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)[C:3]([OH:23])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(-c2ccncc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCC1)c1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
A solution of 3-cyclopentyl-2-(4-pyridin-4-yl-phenyl)-propionic acid methyl ester (240 mg, 0.78 mmol) in tetrahydrofuran (3 mL) was treated with a 0.8M aqueous lithium hydroxide solution (1.45 mL, 1.16 mmol). The resulting reaction mixture was stirred at 25° C. for 30 min and then heated under reflux for 15 h. The reaction mixture was allowed to cool to 25° C. and then partitioned between water (100 mL) and ethyl acetate (70 mL). The layers were separated, and the aqueous layer was further extracted with ethyl acetate (1×30 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a yellow oil that solidified upon sitting. The solid was collected to afford 3-cyclopentyl-2-(4-pyridin-4-yl-phenyl)-propionic acid (127 mg, 55%) as a yellow solid: mp 118-121° C.; FAB-HRMS m/e calcd for C19H21NO2 (M+H)+ 296.1650, found 296.1658.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:13])=O>CN(C=O)C>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:13])=[O:5]
Reactant: O=C(O)c1cccnc1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccnc1Cl

Procedure:
A mixture of 2.565 g (16.28 mmol) of 2-chloronicotinic acid, 20 ml of thionyl chloride and two droplets of DMF was heated under reflux for 2 hours. The resulting reaction solution was allowed to cool, and then concentrated under reduced pressure to obtain 2-chloronicotinoyl chloride. The compound thus obtained was dissolved in 15 ml of acetone. The solution thus obtained was then added dropwise to a solution of 1.363 g of ammonium thiocyanate in 15 ml of acetone with stirring in 5 minutes. After the termination of dropwise addition, the reaction mixture was heated to a temperature of 40° C. with stirring for 5 minutes to obtain a solution of 4-chloronicotinoyl isothiocyanate. To the solution thus obtained was then added dropwise a solution of 1.363 g of N-(2-hydroxyethyl)aniline in 15 ml of THF with stirring in 5 minutes. The reaction mixture was stirred at room temperature for 17 hours, and then poured into about 1,000 ml of ice-water. The resulting crystal was collected by filtration, washed with water, and then dried under reduced pressure. The resulting crude product was then recrystallized from ethanol to obtain 777 mg of 2-[N-(2-hydroxyethyl)-N-phenylamino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](I)=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:20]([O:24][C:25](=[O:28])[CH:26]=[CH2:27])([CH3:23])([CH3:22])[CH3:21].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](/[CH:27]=[CH:26]/[C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:28])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(I)c2cccnc12
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)/C=C/c1ccc(O[Si](C)(C)C(C)(C)C)c2ncccc12

Procedure:
A mixture of Example 201B (5.00 g, 13.0 mmol), tert-butylacrylate (2.00 g, 15.6 mmol), palladium(II) acetate (175 mg, 0.78 mmol), and tri-o-tolylphosphine (951 mg, 3.12 mmol) in a sealed tube with triethylamine (8 mL) and acetonitrile (38 mL) was heated to 120° C. for 16 hours and then concentrated. The concentrate was purified by flash column chromatography on silica gel with 10-100% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH:4]=[CH2:5].[NH2:7][CH2:8][CH:9]1[O:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[O:11][CH2:10]1>CO>[CH3:1][O:2][C:3]([CH2:4][CH2:5][N:7]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:6])[CH2:8][CH:9]1[O:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[O:11][CH2:10]1)=[O:6]
Reactant: NCC1COc2ccccc2O1
Reactant: C=CC(=O)OC
Solvent: CO
Product: COC(=O)CCN(CCC(=O)OC)CC1COc2ccccc2O1
Reaction time: 16 h
Yield: 95 %

Procedure:
7.57 g (88 mmol) of acrylic acid methyl ester are added to a solution of 6.61 g (40 mmol) of 2-aminomethylbenzo-1,4-dioxan [J. Augustin et al., J. Med. Chem. 8, 446 (1965)] in 80 ml of methanol and the whole is stirred for 16 hours at 50°. After cooling, the reaction mixture is concentrated by evaporation in vacuo. 12.82 g (95%) of N,N-bis(2-methoxycarbonylethyl)-N-(benzo-1,4-dioxan-2-ylmethyl)-amine are obtained in the form of a reddish oil.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1Br.[CH:13]([C:15]1[S:19][C:18](B(O)O)=[CH:17][CH:16]=1)=[O:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OC(=O)C)C.CC([O-])=O.CC([O-])=O.[Pd+2].O>[F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:18]1[S:19][C:15]([CH:13]=[O:14])=[CH:16][CH:17]=1
Reactant: O=Cc1ccc(B(O)O)s1
Reactant: FC(F)(F)Oc1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(-c2ccccc2OC(F)(F)F)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-trifluoromethoxy-1-bromobenzene (0.21 mL) and 5-formyl-2-thiophene boronic acid (0.23 g) in DME (11 mL) were added Pd(OAc)2 (0.014 g) and Ph3P (0.033 g) followed by 2M sodium carbonate (1 mL) and water (1 mL). The mixture was stirred at rt for 3 h. The reaction was diluted with ethylacetate (20 mL) and washed with water and brine, and then dried (sodium sulfate). The crude product was purified by flash-chromatography using acetone-hexanes (1:4) to give the desired 5-(2-trifluoromethoxyphenyl)thiophene-2-aldehyde as an oil [MS data: m/e 273 (M+1)+]. The aldehyde (0.15 g), thus obtained, was then condensed with 2,4-thiazolidine-2,4-dione in the presence of benzoic acid and piperidine under the conditions described in EXAMPLE 5 to give the title compound 5-(5-(2-trifluoromethoxyphenyl)thienylidene)thiazolidine-2,4-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27](O)=[O:28])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1.[CH:37]1([NH2:40])[CH2:39][CH2:38]1.C(P(=O)(OCC)OCC)#N>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([NH:40][CH:37]3[CH2:39][CH2:38]3)=[O:28])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1
Reactant: Cn1cc(C(=O)O)cc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1n[nH]c2ccc(Cl)cc12
Reactant: NC1CC1
Agent: CCOP(=O)(C#N)OCC
Product: Cn1cc(C(=O)NC2CC2)cc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1n[nH]c2ccc(Cl)cc12

Procedure:
This compound was synthesized by the reaction of 5-[2-[(5-chloro-1H-indazol-3-yl)methyl]-7-(cyclopropylmethyl)-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carboxylic acid and cyclopropylamine using diethyl cyanophosphonate as a coupling reagent Mass: 547.19 (M+H).
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][NH:3]1.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][N:3]=1
Reactant: COC(=O)c1c[nH]c(=O)c2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cnc(Cl)c2ccccc12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of the product from part 3 (12.5 g) in 50 ml of POCl3 is stirred at 100° C. for about two hours then cooled and concentrated under vacuum. The residue is dissolved in 300 ml of CHCl3, and the resulting solution is washed with aqueous NaHCO3 and water, dried over Na2SO4, filtered and then concentrated to give the title compound, m.p. 53–55° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([C:8](O)([CH3:10])[CH3:9])[CH:7]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.FC1C=CC(O)=C(C(C2C=C(F)C=CC=2OC)(C)C)C=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:12][CH3:13])([CH3:10])[CH3:9])[CH:16]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: COc1ccc(Cl)cc1C(C)(C)O
Agent: COc1ccc(F)cc1C(C)(C)c1cc(F)ccc1O
Product: COc1ccc(Cl)cc1C(C)(C)c1cc(Cl)ccc1O

Procedure:
2-(5-chloro-2-hydroxyphenyl)-2-(5-chloro-2-methoxyphenyl) propane (m.p. 137° C.) was prepared from 2-(5-chloro-2-methoxyphenyl)propan-2-ol and 4-chlorophenol following the method described in Example 3 for the preparation of 2-(5-fluoro-2-hydroxyphenyl)-2-(5-fluoro-2-methoxyphenyl)propane.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C:14](=[O:15])[C@@H:13]([CH3:16])[CH2:12][N:11]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:27]1COCC1.C[Mg]Cl>>[C:1]([O:5][C:6]([NH:8][C@H:9]1[C@@:14]([OH:15])([CH3:27])[C@@H:13]([CH3:16])[CH2:12][N:11]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:10]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)C1=O
Reactant: C1CCOC1
Agent: C[Mg]Cl
Product: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@]1(C)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.6 %

Procedure:
Benzyl (3R,5S)-3-[(tert-butoxycarbonyl)amino]-5-methyl-4-oxopiperidine-1-carboxylate (466 mg, 1.29 mmol) was added to an oven-dried vial equipped with a magnetic stirring bar. The vial was sealed with a PTFE-lined septum and kept under an N2 atmosphere. A solution of LaCl3.2LiCl in THF (from Aldrich, 0.6 M, 6.50 mL, 3.90 mmol) was added. The reaction mixture was stirred at room temperature for 1 h, and then cooled to −10° C. A solution of methylmagnesium chloride in THF (3.0 M; 1.30 mL, 3.90 mmol) was added slowly. After stirring at −10° C. for 1.5 h, the reaction was quenched with saturated aq. NH4Cl and the solution was extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.05% TFA, at flow rate of 30 mL/min.) to afford benzyl (3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxy-4,5-dimethylpiperidine-1-carboxylate as a colorless oil (81 mg, 17%), Retention time 2.085 min.: LCMS calc. for C20H30N2NaO5 (M+Na)+: m/z=401.2. found 401.0; and benzyl (3R,4S,5S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxy-4,5-dimethylpiperidine-1-carboxylate as a colorless oil (100 mg, 21%), retention time: 2.247 min., LCMS calc. for C20H30N2NaO5(M+Na)+: m/z=401.2. found 401.0.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][NH:18][O:19][CH3:20].C(N(CC)CC)C>O1CCCC1>[CH3:20][O:19][N:18]([CH3:17])[C:10](=[O:11])[C:9]1[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=1[S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccccc1Sc1ccccc1
Reactant: CNOC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccccc1Sc1ccccc1
Reaction time: 8 h

Procedure:
A solution of 3.7 parts of 2-(phenylthio)-benzoylchloride in 50 parts of tetrahydrofuran was added to a cold (~5°) stirred solution of 1 part N,O-dimethyl hydroxylamine and 1.6 parts triethylamine in 75 parts of tetrahydrofuran. The mixture was stirred for 8 hrs. and the temperature was allowed to rise to room temperature. Removal of the precipitated triethylamine hydrochloride by filtration and concentration of the filtrate under vacuum gave 3.3 parts of N-methoxy N-methyl 2-(phenylthio)-benzamide as a very viscous oil. NMR (CDCl3) 3.3δ(S,3H,N-CH3), 3.5δ(S,3H,-O-CH3), 7.3δ(m,9H,Aromatic H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH3:10].[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[S:16](Cl)(=[O:18])=[O:17].N1C=CC=CC=1>C(Cl)Cl>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:16]([C:12]2[S:11][CH:15]=[CH:14][CH:13]=2)(=[O:18])=[O:17])=[C:3]([O:9][CH3:10])[CH:4]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COc1cc(Cl)ccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(Cl)ccc1NS(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.5 %

Procedure:
A mixture of 2-amino-5-chloroanisole (157 mg, 1 mmol), thiophene-2-sulfonyl chloride (183 mg, 1 mmol), and pyridine (0.25 mL, 3 mmol) in methylene chloride (3 mL) was stirred at room temperature for 16 hours. The mixture was then partitioned between methylene chloride and water. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum to provide 290 mg (96%) of the title compound. MS (ESI) m/e 304 (M+H)+.
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][N:7]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:6][CH:5]1[OH:14])=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH:4]1[CH2:9][CH2:8][N:7]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:6][CH:5]1[OH:14]
Reactant: CS(=O)(=O)N1CCC(N=[N+]=[N-])C(O)C1
Agent: [Pd]
Solvent: CCO
Product: CS(=O)(=O)N1CCC(N)C(O)C1

Procedure:
The azide (300 mg, 1.36 mmol, Example 304) was dissolved in ethanol and hydrogenated at 45 psi under the catalyst of 10% palladium on carbon (30 mg) for 1 hour. The mixture was filtered and the filtrate was concentrated to give a white solid. 245 mg, 93%. The compound was used directly for the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[O:17][N:16]=[C:15]([CH3:18])[CH:14]=1)=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C-:25]#[N:26].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC#N>[CH3:18][C:15]1[CH:14]=[C:13]([C:6]2[C:7](=[O:12])[NH:8][C:9]3[C:4]([C:5]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:3][C:2]([C:25]#[N:26])=[CH:11][CH:10]=3)[O:17][N:16]=1
Reactant: [C-]#N
Reactant: Cc1cc(-c2c(-c3ccccc3)c3cc(Br)ccc3[nH]c2=O)on1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CC#N
Product: Cc1cc(-c2c(-c3ccccc3)c3cc(C#N)ccc3[nH]c2=O)on1
Temperature: 100 °C

Procedure:
A flask was charged with 6-bromo-3-(3-methyl-isoxazol-5-yl)-4-phenyl-1H-quinolin-2-one (30 mg, 0.077 mmol)(example 39), Pd(PPh3)4 (5 mg, 5 mol %), NaCN (8 mg, 0.16 mmol), Cul (1.5 mg, 10 mol %), and 0.7 mL CH3CN and heated in a sealed tube in a microwave reactor at 100° C. for 1 hr. The title compound was obtained by elution from a 10 g SPE with 50% EtAc/hex to give 13 mg (50%) of a white solid. 1H NMR (400 MHz, CD3OD) δ 7.78 (dd, 1H), 7.50 (m, 5H), 7.28 (m, 2H), 6.42 (s, 1H), 2.20 (s, 3H). Mass spectrum (ESI, m/z) calcd. for C20H13N3O2 327.1, found 328.1 (M+H).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[Cl:17][C:18]1[CH:19]=[C:20]([O:27][CH3:28])[CH:21]=[C:22]2[C:26]=1[NH:25][CH2:24][CH2:23]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:25]2[C:26]3[C:22](=[CH:21][C:20]([O:27][CH3:28])=[CH:19][C:18]=3[Cl:17])[CH2:23][CH2:24]2)[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=1
Reactant: COc1cc(Cl)c2c(c1)CCN2
Reactant: CC[C@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Agent: Cl
Product: CC[C@H](C1CC1)n1cc(Cl)nc(N2CCc3cc(OC)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 7-chloro-5-methoxyindoline hydrochloride as the starting materials. mp 118-120° C.; 1H NMR (300 MHz, CDCl3): δ 6.93 (s, 1 H), 6.71 (s, 2 H), 4.34-4.24 (m, 2 H), 4.09-4.01 (m, 1 H), 3.76 (s, 3 H), 3.08 (t, J=7.7 Hz, 2 H), 1.93-1.74 (m, 2 H), 1.06-0.98 (m, 1 H), 0.95-0.81 (m, 3 H), 0.79-0.72 (m, 1 H), 0.54-0.44 (m, 2 H), 0.34-0.22 (m, 1 H); HRMS (ESI) calcd for C19H22N3O2Cl2 (M+H)+: 394.1089; found m/z 394.1099.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1.[CH:16]([CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCl.CO>[C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([C@@H:4]2[CH2:5][C@H:3]2[NH:2][CH2:16][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:20][CH2:19]2)=[CH:7][CH:8]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)Nc1ccc([C@@H]2C[C@H]2N)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CO
Product: CC(=O)Nc1ccc([C@@H]2C[C@H]2NCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 0.08 h
Yield: 58.5 %

Procedure:
To a solution of N-(4-((trans)-2-aminocyclopropyl)phenyl)acetamide, hydrochloride (150 mg, 0.662 mmol) in a mixture of dichloromethane (10 mL) and methanol (5 mL) was added tert-butyl 4-formylpiperidine-1-carboxylate (141 mg, 0.662 mmol) and stirred for 5 min, then Na(OAc)3BH (210 mg, 0.992 mmol) was added and stirred for 30 min. The crude was diluted with DCM (100 mL) and poured into sat NaHCO3 solution (50 mL). The separated organic layer was washed with water (20 mL), brine solution (20 mL) and the organic layer was dried over any sodium sulphate and concentrated. The crude was purified using silica gel (100-200 mesh) column chromatography, eluting with MeOH in DCM. Compound eluted in 4% MeOH in DCM to afford tert-butyl 4-((((trans)-2-(4-acetamidophenyl)cyclopropyl)amino)methyl)piperidine-1-carboxylate (150 mg, 0.387 mmol, 58.5% yield). LCMS (ES) m/e 387.96 (M+H), 95.06%