Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1.[O:29]1[CH2:33][C:32](=O)[N:31]=[C-:30]1.N[C@@H]1CCCC[C@H]1N.[O-:43]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I.O>[F:1][C:2]1[CH:7]=[C:6]([N:31]2[CH2:32][CH2:33][O:29][C:30]2=[O:43])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1
Reactant: COc1cn(-c2ccc(I)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reactant: O=P([O-])([O-])[O-]
Reactant: O=C1CO[C-]=N1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cn(-c2ccc(N3CCOC3=O)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Yield: 71.1 %

Procedure:
A suspension of 1-(2-fluoro-4-iodophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (244 mg, 0.5 mmol), 2-oxazolidone (52.2 mg, 0.6 mmol), CuI (9.5 mg, 0.05 mmol), trans-1,2-diaminocyclohexane (0.012 mL, 0.1 mmol), and K3PO4 (212 mg, 1.0 mmol) in 1,4-dioxane (2 mL) was refluxed for 1.5 h under Ar atmosphere. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was washed with AcOEt and recrystallized from MeOH/H2O to give the title compound (159 mg, 71% yield) as a pale yellow solid: mp 218-220° C.; 1H NMR (300 MHz, CDCl3): ppm 3.90 (3H, s), 4.03-4.08 (2H, m), 4.51-4.56 (2H, m), 6.42 (1H, t, J=9.0 Hz), 7.01 (1H, ddd, J=1.1, 2.3, 9.0 Hz), 7.30 (1H, d, J=1.9 Hz), 7.35-7.45 (5H, m), 7.66 (1H, dd, J=2.3, 13.6 Hz), 7.78 (2H, d, J=1.9 Hz). LC-MS (ESI) m/z 448 [M+H]+. Anal. Calcd for C23H18FN5O4: C, 61.74; H, 4.06; N, 15.65. Found: C, 61.48; H, 4.07; N, 15.54.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C(Cl)Cl.[C:32](Cl)(=[O:41])[CH:33]=[CH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C1C=CN=CC=1.CCOCC>[CH:12]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([CH:16]3[CH2:17][CH2:18][N:19]([C:32](=[O:41])[CH:33]=[CH:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:20][CH2:21]3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: C1=Cc2ccccc2C(C2CCNCC2)c2ccccc21
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(C=Cc1ccccc1)N1CCC(C2c3ccccc3C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
1.42 grams (5.15 millimoles) of 4-(5H-dibenzo[a,d]cyclohepten-5-yl)piperidine, 1.56 grams (15.45 millimoles0 of triethylamine, 0.06 gram (0.51 millimoles) of 4-dimethylaminopyridine and 25 milliliters of methylene chloride were stirred together for 5 minutes and to the stirred solution, 0.86 gram (5.15 millimole) of cinnamoyl chloride was added in one portion. The resulting mixture was stirred for 0.5 hour at room temperature, then diluted with 200 milliliters of ether and the ethereal solution washed successively with two 200 milliliter portions of 2N hydrochloric acid, one 200 milliliter portion of sodium bicarbonate solution and one 300 milliliter portion of brine. The washed solution was dried over magnesium sulfate, and the solvent vaporized in vacuo from the dried solution to obtain as residue 1.6 grams of 4-(5H-dibenzo[a,d]cyclohepten-5-yl)-1-cinnamoylpiperidine.
Reaction SMILES: Br[C:2]1[C:14]([NH2:15])=[C:13](Br)[C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[CH:17](=O)[C:18]1[CH:23]=CC=C[CH:19]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)[C:40]2C=CC=[CH:42][C:41]=2[C:46]2C(OC)=CC=CC=2OC)CCCCC1>C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[CH3:23][C:18]([CH3:17])=[CH:19][C:2]1[C:14]([NH2:15])=[C:13]([CH:40]=[C:41]([CH3:46])[CH3:42])[C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: Nc1c(Br)cc2c(oc3ccccc32)c1Br
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)=Cc1cc2c(oc3ccccc32)c(C=C(C)C)c1N
Temperature: 25 °C
Yield: 511.9 %

Procedure:
To a degassed toluene (40 mL), 2,4-dibromodibenzofuran-3-amine (1.5 g, 4.4 mmol), benzaldehyde (0.47 g, 4.4 mmol) 4,4,5,5-tetramethyl-2-(2-methylprop-1-enyl)-1,3,2-dioxaborolane (3.2 g, 17.6 mmol), potassium phosphate (6.08 g, 26 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.28 g, 0.704 mmol), Pd2(bda)3 (0.161 g, 0176 mmol) and water (6 mL) were sequentially added. The solution was refluxed for overnight in an atmosphere of nitrogen and then allowed to cool to room temperature. The reaction was diluted with ethyl acetate and the organic phase was separated from the aqueous phase. The organic phase was dried over sodium sulfate and the solvent was removed under vacuum. The product was chromatographed using silica gel with ethylacetate and hexanes as the eluent. The solvent was removed to give 1.05 g (82% yield) of title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>C(OC(C)C)(C)C>[CH:12]1([NH:15][C:10]([NH:9][C:4]2[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=2)=[O:11])[CH2:14][CH2:13]1
Reactant: NC1CC1
Reactant: Cc1cc(C)cc(N=C=O)c1
Solvent: CC(C)OC(C)C
Product: Cc1cc(C)cc(NC(=O)NC2CC2)c1

Procedure:
14.7 g of 3,5-dimethylphenylisocyanate were slowly added by a dropper upon stirring at a temperature of 28° C. to a solution of 5.7 g of cyclopropylamine in 200 ml diisopropylether. The formed precipitate was removed by suction after an hour, was washed with a small amount of diisopropylene and finally dried. There were thus obtained 18.9 g of 1-cyclopropyl-3-(3,5-dimethylphenyl)-urea (92.5% of the theoretical value) having a melting point of 169° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][OH:8].C(O)(=[O:12])C=C.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][CH:3]([OH:12])[CH2:4][O:5][CH2:6][CH2:7][OH:8]
Reactant: C=CC(=O)O
Reactant: COCCOCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(O)COCCO

Procedure:
682 grams Methyl Carbitol (diethylene glycol monomethyl ether, Union Carbide) were azeotropically esterified with 598.9 grams acrylic acid in 272 grams toluene in the presence of 22.8 grams p-toluenesulfonic acid and inhibitors until no more water was collected. Conditions were 95°-98° C., nitrogen sparge in vacuo. On completion, the product was washed and neutralized with sodium carbonate. 1,300 ppm p-methoxyphenol were added and solvent removed at 80° C. at maximum vacuum with an air sparge. Filter aid was added and the product filtered to clarity at 50° C. The final product was a clear, light yellow liquid, viscosity 6 cps with a Gardner 1 color.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](=[O:30])[N:8]2[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([NH:22]C(=O)OC(C)(C)C)[CH2:18][CH2:17]1)#[N:2].C(C1C=C2C(C=CC(=O)N2CCN2CCC(NC(=O)OC(C)(C)C)CC2)=C(F)C=1)#N.FC(F)(F)C(O)=O.NC1CCN(CCN2C3C(=CC=C(F)C=3)N=CC2=O)CC1>ClCCl>[NH2:22][CH:19]1[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][N:8]2[C:9]3[C:10](=[C:11]([F:13])[CH:12]=[C:3]([C:1]#[N:2])[CH:4]=3)[CH:5]=[CH:6][C:7]2=[O:30])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3c(C#N)cc(F)cc32)CC1
Agent: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3c(F)cc(C#N)cc32)CC1
Agent: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(F)c2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Yield: 92 %

Procedure:
A mixture of tert-butyl {1-[2-(5-cyano-7-fluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate and tert-butyl {1-[2-(7-cyano-5-fluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediates 173 and 174, 170 mg, 0.41 mmol) was reacted with trifluoroacetic acid in dichloromethane as described for Intermediate 140 to give 120 mg (92% yield) of the mixture of regioisomers as an oil. This mixture was carried on without further purification to the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:15]=[CH:14][C:13](F)=[N:12][C:8]=2[N:9]=[CH:10][N:11]=1.Cl.[CH3:21][NH:22][CH3:23].CCN(CC)CC>CCO>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:15]=[CH:14][C:13]([N:22]([CH3:23])[CH3:21])=[N:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: CNC
Reactant: Fc1ccc2c(Nc3cccc(Br)c3)ncnc2n1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C)c1ccc2c(Nc3cccc(Br)c3)ncnc2n1
Yield: 84 %

Procedure:
Reaction of 4-(3-bromoanilino)-7-fluoropyrido[2,3-d]pyrimidine (see a previous experimental) (0.12 g, 0.38 mmol) with dimethylamine hydrochloride (92 mg, 1.13 mmol) and Et3N (0.18 mL, 1.32 mmol) in EtOH (15 mL) at 100° C. for 18 h in a pressure vessel, followed by evaporation of the solvent and workup, gives 4-(3-bromoanilino)-7-(dimethylamino)pyrido[2,3-d]pyrimidine (0.11 g, 84%). 1H NMR (DMSO) δ 9.58 (1H, brs), 8.56 (1H, d, J=9.3 Hz), 8.54 (1H, s), 8.18 (1H, t, J=1.9 Hz), 7.84 (dt, Jd=8.0, Hz, Jt=1.9 Hz), 7.33 (1H, dd, J=8.1, 8.0 Hz) 7.25 (1H, dt, Jd=9.3, Hz, Jt=1.9 Hz), 7.10 (1H, d, J=9.3 Hz), 3.18 (6H, s).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[C:11]1(=O)NCCCCC1>O>[CH3:11][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1=[O:9]
Reactant: COC(=O)CCCCCN
Reactant: O=C1CCCCCN1
Solvent: O
Product: CN1CCCCCC1=O
Yield: 5.8 %

Procedure:
A solution of 18.28% of methyl 6-aminocaproate and 5.75% of caprolactam in water was pumped through a 40 ml tube reactor at 300° C. and 100 bar with a residence time of 15 minutes. The exit stream contained according to quantitative gas chromatography 15.09% by weight of caprolactam, corresponding to a yield of 65.6%, based on methyl 6-aminocaproate. N-methylcaprolactam was formed as a by-product in a 5.8% yield.
Reaction SMILES: S(Cl)(C1C=[CH:9][C:7]([CH3:8])=[CH:6]C=1)(=O)=O.[F:12][C:13]1(C(O)=O)[CH:18]=[CH:17][CH:16]=[CH:15][NH:14]1.N1C=CC=CC=1.[C:28]([O-:31])(O)=[O:29].[Na+]>CC(O)(C)C>[F:12][C:13]1[N:14]=[C:15]([C:28]([O:31][C:7]([CH3:9])([CH3:8])[CH3:6])=[O:29])[CH:16]=[CH:17][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C([O-])O
Reactant: O=C(O)C1(F)C=CC=CN1
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)c1cccc(F)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Tosyl chloride (915 mg, 4.8 mmol) was added to a solution of 2-fluoro-picolinic acid (254 mg, 2 mmol) and pyridine (1.08 mL, 13.4 mmol) in 3.6 mL of t-BuOH at 0° C. The reaction was then stirred at room temperature for 12 hours. An aqueous solution of NaHCO3 was then added and the mixture was extracted with ethyl acetate (3 times). The combined organic phases were washed with brine and dried over Na2SO4. The crude compound was purified by flash chromatography using SiO2 (Petroleum Ether/EtOAc 100:0 to 90:10). The product 120A was obtained as a white solid (m=326 mg, 83%): 1HNMR (ppm, CDCl3) 1.6 (s, 9H), 7.05-7.11 (m, 1H), 7.85-7.93 (m, 2H).
Reaction SMILES: BrBr.[F:3][C:4]([F:14])([F:13])[O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1.[S-:15][C:16]#[N:17].[K+].N>C(O)(=O)C.O>[NH2:17][C:16]1[S:15][C:11]2[CH:12]=[C:6]([O:5][C:4]([F:13])([F:14])[F:3])[CH:7]=[CH:8][C:9]=2[N:10]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: BrBr
Agent: N
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc2ccc(OC(F)(F)F)cc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
A solution of 77 g of bromine in 220 ml of acetic acid is added drop by drop, in a period of one hour, to a solution of 84 g of 4-trifluoromethoxy-aniline and 187 g of potassium thiocyanate in 500 ml of acetic acid. The mixture is stirred overnight at the ambient temperature. The reaction mixture is then poured into 2 liters of water. The resulting mixture is cooled in an icebath and neutralized by addition of ammonia. The insoluble material is separated by filtration, washed with water, then recrystallized in an ethanol-water mixture (50--50). 77 g of 2-amino-6-trifluoromethoxy-benzothiazole, which melts at 119° C., are thus obtained.
Reaction SMILES: [C:1]1([C:7]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][N:16]3[C:20](=[O:21])[C:19]([CH3:32])([C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=[CH:24][CH:23]=4)[NH:18][C:17]3=[O:33])[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49].[H-].[Na+]>CN(C)C=O>[CH2:51]([O:50][C:48](=[O:49])[CH2:47][N:18]1[C:19]([CH3:32])([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:20](=[O:21])[N:16]([CH2:15][CH2:14][CH2:13][C:11]2[N:10]=[CH:9][N:8]([C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:12]=2)[C:17]1=[O:33])[CH3:52]
Reactant: CC1(c2cccc3ccccc23)NC(=O)N(CCCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)C1=O
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)N(CCCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)C(=O)C1(C)c1cccc2ccccc12
Reaction time: 1 h
Yield: 97.1 %

Procedure:
0.082 g(0.14 mmol) of 3-[3-(1-triphenylmethyl-imidazol-4-yl)-propyl]-5-methyl-5-naphthalen-1-yl-imidazolidin-2,4-dione prepared in Example 1-1) and 0.023 ml(0.21 mmol) of ethyl bromoacetate were dissolved in 5 ml of dimethylformamide. 0.017 g(0.21 mmol) of sodium hydride [NaH] was added thereto and the resulting solution was stirred for one hour. Dimethylformamide was removed under reduced pressure and the residue was dissolved in ethyl acetate and then washed with saturated sodium chloride solution. Removal of ethyl acetate under reduced pressure provided 0.092 g(Yield: 99%) of title compound.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([NH2:29])[CH3:28])=[CH:23][CH:22]=1>>[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([NH:29][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)[CH3:28])=[CH:23][CH:22]=1
Reactant: Cc1ccc([C@H](C)N)cc1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: Cc1ccc([C@H](C)Nc2nccc(-n3cnc4ccccc43)n2)cc1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with (S)-1-(4-methylphenyl)ethylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 330.3 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.53 (s, 1H); 8.39 (d, J=5.3 Hz, 1H), 7.84 (d, J=8.3 Hz, 1H); 6.78 (d, J=5.5 Hz, 1H); 5.75 (br s, 1H); 5.20 (br s, 1H); 2.36 (s, 3H); 1.63 (d, J=6.8 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[CH3:23].CC1(C)C(C)(C)OB([C:32]2[CH:36]=[CH:35][N:34](C(OC(C)(C)C)=O)[CH:33]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([CH3:23])=[C:2]([C:32]4[CH:36]=[CH:35][NH:34][CH:33]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(C)sc2n1
Reactant: CC(C)(C)OC(=O)n1ccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3cc[nH]c3)c(C)sc2n1
Temperature: 100 °C
Yield: 20.4 %

Procedure:
Under nitrogen, N-(3-bromo-2,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 61) (100 mg, 0.232 mmol) was dissolved in 1,4-dioxane (2.5 mL) and water (1 mL). 1,1-Dimethylethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1-carboxylate (102 mg, 0.347 mmol), bis(triphenylphosphine)palladium(II) chloride (16.26 mg, 0.023 mmol) and potassium carbonate (96 mg, 0.695 mmol) were added and the mixture heated in a microwave at 100° C. for 10 min. The solution was then concentrated, ethyl acetate (10 mL) added and the mixture washed with water (2×5 mL). The organic layer was dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified by normal phase chromatography, eluting with a gradient of 0-30% ethyl acetate in cyclohexane and then further purified by MDAP (acidic conditions), to give the title compound (19.8 mg). LCMS (A) m/z: 416 [M−1]−, Rt 1.47 min (acidic).
Reaction SMILES: [C:1]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].Cl>C(Cl)Cl>[C:4]([O:3][C:1]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:11][CH2:10]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
4-(N—BOC amino) piperidine (17 kg, 84.88 mol) was dissolved in DCM (90 kg), triethylamine (10.14 kg, 100.16 mol) was added, and the resulting solution was cooled to 0-5° C. Benzyl chloroformate (16.51 kg, 96.76 mol) was added over 45 minutes while keeping the temperature at <25° C., after which the solution was aged for 30 minutes at 20° C. 2 M HCl (61 kg, 118.13 mol) was then added over 10 minutes while keeping the temperature at <25° C. The mixture was agitated for 10 minutes and then the agitation was stopped and the phases were allowed to separate. The phases were then separated from each other, and the organic phase was distilled in vacuo to a volume of 35 L. Isopropyl acetate (89 kg) was then added, and the batch was concentrated by vacuum distillation at less than 35° C. to a volume of 50 L to crystallize the title product. Heptane (47 kg) was then added over 10 minutes, and the resulting slurry cooled to and aged at 20° C. for 20 minutes, after which the aged slurry was filtered, washed with heptane (17 kg), and dried by N2 sweep on the filter to give the title product as a white solid (24.7 kg, 87%). 1H NMR (CDCl3) 7.33 (5H, m), 5.13 (2H, s), 4.47 (1H, m), 4.11 (2H, m), 3.61 (1H, m), 2.93 (2H, m), 1.94 (2H, m), 1.45 (9H, s) and 1.30 (2H, m).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH3:11])=[CH:4][CH:3]=1.O[CH2:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:26][C@@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3[C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])=[CH:22][CH:23]=2)=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(O)cc1)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 50.7 %

Procedure:
To a stirred mixture of 4-(1-(4-hydroxylphenyl)-2-phenylbut-1-enyl)phenol (500 mg, 1.0 eq), (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (480 mg, 1.5 eq) and PPh3 (625 mg, 1.5 eq) in 25 mL anhydrous THF under nitrogen was added DIAD (480 mg, 1.5 eq) dropwise at 0° C. The reaction was stirred for 48 h at rt. Then the reaction was quenched with water and extracted with EtOAc. The extract was dried, concentrated and purified by column chromatography to give the desired product (400 mg, 51% yield, Z/E=1/1).
Reaction SMILES: [C:1]1([C:7](=[N+]=[N-])[C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)(OC(C)(C)C)=O.FC(F)(F)C(O)=O>CC(C(C)C)C.CCCCCCCCCCCCC1C=CC(S(N2[C@H](C(O)=O)CCC2)(=O)=O)=CC=1.CCCCCCCCCCCCC1C=CC(S(N2[C@H](C(O)=O)CCC2)(=O)=O)=CC=1.CCCCCCCCCCCCC1C=CC(S(N2[C@H](C(O)=O)CCC2)(=O)=O)=CC=1.CCCCCCCCCCCCC1C=CC(S(N2[C@H](C(O)=O)CCC2)(=O)=O)=CC=1.[Rh].[Rh]>[CH3:11][O:10][C:8]([C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C@@H:22]1[NH:21][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCCCC1
Reactant: COC(=O)C(=[N+]=[N-])c1ccccc1
Agent: [Rh]
Agent: CC(C)C(C)C
Agent: CCCCCCCCCCCCc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](c1ccccc1)[C@H]1CCCCN1
Yield: 49 %

Procedure:
As shown above in Scheme V and Table III, Rh2 (S-DOSP)4 7 catalyzed decomposition of methyl phenyldiazoacetate 9a in the presence of N-BOC-piperidine (15, 4 equiv) in 2,3-dimethylbutane at room temperature followed by treatment with trifluoroacetic acid resulted in the formation of a mixture of threo and erythro methyphenidate, 16 and 17, in 49% yield. However, the threo isomer 16 was the minor diastereomer and was formed in only 34% ee. The combined yield of 16 and 17 was improved to 86% by using the N-BOC-peperidine as the limiting reactant. This result is different to what was observed with N-BOC-pyrrolidine, which gave bis C—H insertion when an excess of phenyldiazoacetate was used. A major improvement in enantioselectivity and diastereoselectivity was achieved by carrying out the reaction with the Rh2 [bridged(S-TBSP)2]2 8 catalyst. The ratio of 16:17 (73% yield) was improved to 2.5:1 and (2R, 2′R)-threo isomer 16 was formed in 86% ee and 52% isolated yield. As shown in Table III, Rh2 [bridged(S-TBSP)2]2 8 results in opposite asymmetric induction to Rh2 (S-DOSP)4 7, and, in the reaction of 9a and 15 catalyzed by 8, the biologically active enantiomer of threo-methylphenidate is formed.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:13]3[N:14]=[CH:15][C:16]([CH:18]=O)=[CH:17][C:12]=3[C:11]3=[N:20][CH:21]=[N:22][N:10]3[C:9]2=[O:23])=[CH:5][CH:4]=1.[CH:26]12[CH2:32][CH:29]([NH:30][CH2:31]1)[CH2:28][O:27]2.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C(#N)C>[CH:26]12[CH2:32][CH:29]([N:30]([CH2:18][C:16]3[CH:15]=[N:14][C:13]4[N:8]([CH2:7][C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:25][CH:24]=5)[C:9](=[O:23])[N:10]5[N:22]=[CH:21][N:20]=[C:11]5[C:12]=4[CH:17]=3)[CH2:31]1)[CH2:28][O:27]2
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3cc(C=O)cnc32)cc1
Reactant: C1OC2CNC1C2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: CO
Product: COc1ccc(Cn2c(=O)n3ncnc3c3cc(CN4CC5CC4CO5)cnc32)cc1
Reaction time: 0.17 h
Yield: 55.8 %

Procedure:
6-(4-Methoxybenzyl)-5-oxo-5,6-dihydropyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine-9-carbaldehyde (49 mg, 0.15 mmol), 2-oxa-5-azabicyclo[2.2.1]heptane (49 mg, 0.36 mmol), ACN (1 mL), TEA (0.051 mL, 0.37 mmol) and acetic acid (0.040 mL, 0.69 mmol) were combined and stirred for 10 minutes. Sodium cyanoborohydride (18 mg, 0.29 mmol) was added and the mixture was stirred for 18 h at room temperature. The mixture was diluted with methanol, filtered, and purified by preparative HPLC to afford the title compound (35 mg, 45%) as the trifluoroacetic acid salt as a white solid. 1H NMR (400 MHz, CDCl3) δ 2.25 (d, J=11.42 Hz, 1H), 2.43 (br s, 1H), 3.44-3.63 (m, 2H), 3.76 (s, 3H), 3.91 (d, J=10.42 Hz, 1H), 4.37-4.53 (m, 3H), 4.56-4.65 (m, 1H), 4.73 (s, 1H), 5.74 (s, 2H), 6.76-6.91 (m, 2H), 7.60 (d, J=8.78 Hz, 2H), 8.38 (s, 1H), 8.83 (s, 1H), 9.08 (s, 1H). [M+H]=419.2.