Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]([NH:23]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(NCC)C>[NH2:23][C@H:18]([C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:17][CH:16]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1ccc(OCCNC(=O)OC(C)(C)C)cc1
Solvent: CCNCC
Product: COC(=O)[C@H](N)c1ccc(OCCNC(=O)OC(C)(C)C)cc1
Yield: 71.3 %

Procedure:
A solution of 1.695 g (3.10 mmol) of methyl (2R)-(4-{2-[(tert-butoxycarbonyl)amino]ethoxy}phenyl){[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-ethanoate in 10 mL of diethylamine was stirred at room temperature for 2 h and then concentrated in vacuo. The residue was chromatographed on silica gel eluting with a gradient starting with ethyl acetate/hexanes (1:2) and ending with chloroform/methanol (9:1) to provide 0.717 g of methyl (2R)-amino(4-{2-[(tert-butoxycarbonyl)amino]-ethoxy}phenyl)ethanoate as a colorless oil. Electrospray Mass Spec 325.2 (M+H)+
Reaction SMILES: [CH2:1]([C:3]([C:17]1[CH:30]=[CH:29][C:20]([O:21][CH2:22][C:23]([OH:28])([CH2:26][CH3:27])[CH2:24][CH3:25])=[C:19]([CH3:31])[CH:18]=1)([C:6]1[S:10][C:9]2[CH:11]=[C:12]([O:15]C)[CH:13]=[CH:14][C:8]=2[CH:7]=1)[CH2:4][CH3:5])[CH3:2].CN(C=O)C>C(OCC)C>[CH2:1]([C:3]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:8]=2[CH:7]=1)([C:17]1[CH:30]=[CH:29][C:20]([O:21][CH2:22][C:23]([CH2:24][CH3:25])([OH:28])[CH2:26][CH3:27])=[C:19]([CH3:31])[CH:18]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(O)(CC)COc1ccc(C(CC)(CC)c2cc3ccc(OC)cc3s2)cc1C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCC(O)(CC)COc1ccc(C(CC)(CC)c2cc3ccc(O)cc3s2)cc1C
Temperature: 100 °C
Yield: 86.3 %

Procedure:
To a solution of 3-{4-[1-ethyl-1-(6-methoxy-benzo[b]thiophen-2-yl)-propyl]-2-methyl-phenoxymethyl}-pentan-3-ol (0.80 g, 1.82 mmol) and DMF (10 mL) is added NaSEt (1.53 g, 18.15 mmol). The resulting solution is heated at 100° C. overnight, diluted with diethyl ether (50 mL), washed with water (3×50 mL), brine (50 mL), dried with MgSO4, filtered and concentrated. The resulting residue is purified by silica gel chromatography (10% to 40% EtOAc gradient) to give the title compound (0.67 g, 1.57 mmol, 87%). 1H NMR (CDCl3), δ 0.75 (t, J=7.2 Hz, 6H), 0.95 (t, J=7.4 Hz, 6H), 1.67 (q, J=15.1, 7.4 Hz, 4H), 2.12-2.24 (m, 7H), 3.82 (s, 2H), 6.73 (d, J=8.6 Hz, 1H), 6.79 (dd, J=9.0, 2.6 Hz, 1H), 6.79 (dd, J=9.0, 2.6 Hz, 1H), 7.00 (s, 1H), 7.05 (d, J=2.2 Hz, 1H), 7.08 (dd, J=8.2, 2.6 Hz, 1H), 7.11 (d, J=2.2 Hz, 1H), 7.49 (d, J=9.0 Hz, 1H). LC/MS (m/z): calcd. for C26H35O3S (M+H)+: 427.2; found: 427.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[O:23]([C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([NH:33][C:32]2[CH:34]=[CH:35][CH:36]=[C:30]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:31]=2)=[O:21])=[CH:18][CH:19]=1
Reactant: Nc1cccc(Oc2ccccc2)c1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)Nc4cccc(Oc5ccccc5)c4)cc3)c2)o1

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(3-phenoxyphenyl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 3-phenoxyaniline using method I. LCMS; retention time 3.85 min, MH+ 462.
Reaction SMILES: N1C2C(=NC=CC=2)N([N:10]2[C:14](/[CH:15]=[C:16]3\[C:17](=[O:26])[NH:18][C:19]4[C:24]\3=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)=[C:13]([CH3:27])[C:12]([C:28]([O-:30])=O)=[C:11]2[CH3:31])N=1.[CH3:32][CH2:33][N:34](C(C)C)C(C)C.[CH3:41][N:42]([CH:44]=[O:45])C>>[O:45]=[C:44]1[C@@H:33]([NH:34][C:28]([C:12]2[C:13]([CH3:27])=[C:14](/[CH:15]=[C:16]3\[C:17](=[O:26])[NH:18][C:19]4[C:24]\3=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[NH:10][C:11]=2[CH3:31])=[O:30])[CH2:32][CH2:41][NH:42]1
Reactant: Cc1c(C(=O)[O-])c(C)n(-n2nnc3cccnc32)c1/C=C1\C(=O)Nc2ccc(F)cc21
Reactant: CN(C)C=O
Reactant: CCN(C(C)C)C(C)C
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)N[C@H]1CCNC1=O
Temperature: 25 °C
Yield: 27 %

Procedure:
To the solution of A4 (334 mg, 0.8 mmol) and DIEA (1 mL) in 20 mL of DMF was added 25b (120 mg, 1.28 mmol). The reaction mixture was stirred at room temperature for several hours. LC/MS was applied to determine completion of the reaction. DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine/methanol (10 mL). The precipitate was collected by filtration, washed with ethanol and dried in vacuum to give title compound as an orange solid (83 mg, 27% yield). 1H NMR (300 MHz, DMSO-d6): δ=13.68 (s, 1H), 10.89 (s, 1H), 7.71-7.82 (m, 4H), 6.82-6.96 (m, 2H), 4.47-4.56 (q, 1H), 3.18-3.25 (m, 2H), 2.42-2.45 (ds, 6H), 2.27-2.39 (m, 1H), 1.92-2.00 (q, 1H). LC/MS: 383.0 [M+H]+.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([N:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[N+]([C:18]1C=CC=CC=1)([O-])=O.[CH3:24][O:25][S:26]([O:29]C)(=[O:28])=[O:27]>>[CH3:24][O:25][S:26]([O-:29])(=[O:28])=[O:27].[CH3:18][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[N:13]=[C:14]1[C:5]([CH:4]=[CH:3][CH:2]=[CH:1]1)=[NH+:6]2
Reactant: c1ccc2nc3ccccc3nc2c1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: COS(=O)(=O)OC
Product: COS(=O)(=O)[O-]
Product: Cc1cccc2[nH+]c3ccccc3nc12
Temperature: 100 °C
Reaction time: 48 h
Yield: 67 %

Procedure:
1.76 g (0.011 mol) of phenazine and 33.5 ml of dry nitrobenzene are heated to boiling, cooled to 100° C., added with 12.2 g (0.011 mol) of freshly distilled dimethylsulphate and heated for 7 minutes at the temperature of 100° C. Then the reaction mixture is cooled with ice and allowed to stand for 48 hours at the temperature of 4° C. in a refrigerator. The formed precipitate is filtered off, washed with 30 ml of ethyl ether and recrystallized from 15 ml of ethanol. 2.0 g of 9-methylphenazinium methylsulphate (67%) are thus obtained in the form of yellowish crystals melting at 155°-157° C.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8](Cl)[C:7]([Cl:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:12][C:13]1[NH:17][N:16]=[C:15]([NH2:18])[CH:14]=1.CCN(C(C)C)C(C)C>CCO>[Cl:1][C:2]1[N:9]=[C:8]([NH:18][C:15]2[CH:14]=[C:13]([CH3:12])[NH:17][N:16]=2)[C:7]([Cl:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(Cl)c(Cl)nc1Cl
Reactant: Cc1cc(N)n[nH]1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(Cl)c(C#N)cc2Cl)n[nH]1
Temperature: 55 °C
Yield: 59.8 %

Procedure:
To a 25-ml, round-bottom flask, was added 2,5,6-trichloronicotinonitrile (Method 44, 1 g, 4.8 mmol), 5-methyl-1H-pyrazol-3-amine (466 mg, 4.8 mmol), DIEA (1.1 ml, 6.3 mmol), and EtOH (5 ml) and set to heat at 55° C. for 16 hours. The resulting mixture was then purified by silica gel chromatography (Biotage Horizon System) using 25-75% EtOAc/hexanes to give 770 mg of the title compound. 1H NMR: 12.36 (s, 1H) 9.68 (s, 1H) 8.39 (s, 1H) 6.32 (s, 1H) 2.29 (s, 3H). MS: Calcd.: 268. Found: [M+H]+ 267/269.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH2:14][NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH2:14][N:13]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:12]2=[O:23])[CH2:24][CH2:25]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)NCN2c1ccc(F)cc1
Reactant: BrCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(Cc1ccccc1)CN2c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Combine 8-tert-butoxycarbonyl-1-(4-fluoro-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]decane (12 mmol) and DMF (20 mL). Cool in an ice bath. Add NaH (18 mmol) in several portions. After the addition is complete, add benzyl bromide (18 mmol). Allow the reaction mixture to warm to ambient temperature. After 3 h, cool the reaction vessel using an ice bath and cautiously add 10% aqueous citric acid (20 mL). When gas evolution has ceased, pour into an additional 20 mL of 10% aqueous citric acid and extract using ethyl acetate (3×60 mL). Extract the combined organics with saturated aqueous NaCl, dry over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Purify to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:9]([F:11])[F:10])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[C:18]1([CH2:24][SH:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.CCOC(C)=O>[CH2:24]([S:25][C:6]1[CH:7]=[C:2]([Br:1])[C:3]([CH:9]([F:11])[F:10])=[N:4][CH:5]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:24]([S:25][C:2]1[C:3]([CH:9]([F:11])[F:10])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: FC(F)c1ncc(Br)cc1Br
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FC(F)c1ncc(Br)cc1SCc1ccccc1
Product: FC(F)c1ncc(SCc2ccccc2)cc1Br
Temperature: 25 °C
Reaction time: 14 h
Yield: 26.1 %
Yield: 20.3 %

Procedure:
To a solution of 3,5-dibromo-2-(difluoromethyl)pyridine (3.00 g, 10.5 mmol) in DMF (100 mL) was added K2CO3 (1.45 g, 10.5 mmol) at 0° C. Phenylmethanethiol (1.30 g, 10.5 mmol) in DMF (50 mL) was added through addition funnel over a period of 0.5 h and the reaction mixture was stirred at ambient temperature for 14 h. The reaction mixture was dissolved in EtOAc (300 mL) and washed with ice cold water (2×150 mL). The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by CombiFlash Isco (REDISEP®, SiO2, 12 g, 0-13% EtOAc/petroleum ether) to obtain a mixture of both regioisomers. Both regioisomers were separated by preparative HPLC (Condition B-16 described in general methods) to obtain 5-(benzylthio)-3-bromo-2-(difluoromethyl)pyridine (0.700 g, 20.3%) as a colorless liquid and 3-(benzylthio)-5-bromo-2-(difluoromethyl)pyridine (0.900 g, 26.1%) as a pale yellow liquid.
Reaction SMILES: [I:1]I.[I-].[K+].[CH3:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[CH3:15].[CH3:16][N:17]1[CH2:21][CH2:20][NH:19][C:18]1=[S:22]>O.CO>[IH:1].[CH3:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([S:22][C:18]2[N:17]([CH3:16])[CH2:21][CH2:20][N:19]=2)=[C:7]1[CH3:15]
Reactant: CN1CCNC1=S
Reactant: Cc1cc2ccccc2n1C
Reactant: II
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1c(SC2=NCCN2C)c2ccccc2n1C
Product: I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 12.7 g of iodine and 25 g of potassium iodide in 100 ml of water is added dropwise to a mixture of 7.25 g of 1,2-dimethylindole in 60 ml methanol and 5.8 g of 1-methyl-2-imidazolidinethione in 100 ml methanol. The reaction mixture is stirred for 2 hours at room temperature. The crystalline precipitate formed was filtered and recrystallized from a mixture of methanol, ethyl acetate and ether to yield 1,2-dimethyl-3-(1-methyl-2-imidazolin-2-ylthio)-indole hydriodide which melts at 250°-251° (with decomposition).
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][C@H:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1C=CC=CC=1>[CH3:3][C@H:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:5][NH:2][CH3:1]
Reactant: C[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: CN
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CNC[C@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
6.00 ml methylamine solution (2 M in tetrahydrofuran) are added to 1.73 g tert.butyl ((S)-1-methyl-2-oxoethyl)-carbamate in 20 ml benzene with stirring at ambient temperature. Then 2.50 g anhydrous sodium sulphate are added and the reaction mixture is stirred overnight at ambient temperature. The sodium sulphate is suction filtered and washed again with benzene. The filtrate is evaporated down, taken up in 20 ml of methanol and combined with 397 mg sodium cyanoborohydride with stirring at ambient temperature. After 2.5 hours the reaction mixture is acidified by dropwise addition of approx. 20 ml 2 N citric acid and extracted with tert.-butylmethylether. The aqueous phase is made alkaline with 10 M sodium hydroxide solution and extracted with a methylene chloride/methanol mixture. The combined organic phases are dried over magnesium sulphate and evaporated down.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[C:3]=1[CH3:27].[O:28]1[CH2:33][CH2:32][N:31]([C:34]2[C:39]([NH2:40])=[CH:38][C:37]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[CH:36][N:35]=2)[CH2:30][CH2:29]1>C1(C)C=CC=CC=1>[O:28]1[CH2:33][CH2:32][N:31]([C:34]2[C:39]([NH:40][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=4[F:12])[N:5]=[C:4]([N:14]4[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]4)[C:3]=3[CH3:27])=[CH:38][C:37]([N:41]3[CH2:42][CH2:43][O:44][CH2:45][CH2:46]3)=[CH:36][N:35]=2)[CH2:30][CH2:29]1
Reactant: Cc1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Solvent: Cc1ccccc1
Product: Cc1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
Essentially prepared according to Procedure H using tert-butyl 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)piperazine-1-carboxylate (240.0 mg, 0.60 mmol) and 2,5-dimorpholinopyridin-3-amine in toluene to give tert-butyl 4-(4-(2,5-dimorpholinopyridin-3-ylamino)-5,7-difluoro-3-methylquinolin-2-yl)piperazine-1-carboxylate. 1H NMR (CDCl3) δ ppm 7.62 (1H, d, J=2.7 Hz), 7.57 (1H, d, J=11.2 Hz), 7.31 (1H, d, J=7.6 Hz), 6.80 (1H, ddd, J=13.4, 8.8, 2.5 Hz), 6.25 (1H, d, J=2.5 Hz), 3.88-3.94 (4H, m), 3.72-3.83 (4H, m), 3.62 (4H, br. s.), 3.36 (4H, br. s.), 3.15 (4H, br. s.), 2.90-3.04 (4H, m), 2.11 (3H, s), 1.48-1.56 (9H, m). Mass Spectrum (ESI) m/e=626.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([CH:8]2[CH2:15][C:11]3[S:12][CH:13]=[CH:14][C:10]=3[C:9]2=O)=O)=[CH:4][CH:3]=1.O.[NH2:20][NH2:21].C(O)(=O)C>C(O)C>[Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]2[C:8]3[CH2:15][C:11]4[S:12][CH:13]=[CH:14][C:10]=4[C:9]=3[NH:21][N:20]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Br)cc1)C1Cc2sccc2C1=O
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Brc1ccc(-c2n[nH]c3c2Cc2sccc2-3)cc1
Temperature: 25 °C
Yield: 96.8 %

Procedure:
5-(4-Bromo-benzoyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (8.0 g, 25 mmol), hydrazine monohydrate (4.8 mL, 150 mmol), glacial acetic acid (1.8 mL) and ethanol (45 mL) was heated at 100° C. under nitrogen for 4 hr. The mixture was cooled to 25° C. and concentrated under reduced pressure to give a solid which was recrystallized from ethanol to provide the corresponding 6-(4-Bromo-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (7.6 g, 24.2 mmol) as white solid in 97% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH3:16]C1C=CC=C(C)C=1O>>[CH3:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: Cc1cccc(C)c1O
Reactant: Cc1ccccc1OCCCCC(=O)O
Product: Cc1cccc(C)c1OCCCCC(=O)O

Procedure:
5-(2,6-Dimethylphenoxy)pentanoic acid 26c was prepared in the same manner as 26b, except that 2,6-dimethylphenol was used as the starting material. 1H NMR: (400 MHz, CDCl3): 7.0-7.1 (m, 3H), 3.83 (t, 2H, J=6 Hz), 2.37 (t, 2H, J=6 Hz), 2.73 (s. 6H), 1.92 (m, 4H). MS (ESI): 223 [M+H]+; 245 [M+Na]+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]([NH:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[CH:10]2)(=O)=O.[CH3:30][N:31]1[CH:35]=[C:34]([C:36]2[CH:37]=[CH:38][C:39]3[N:40]([C:42]([SH:45])=[N:43][N:44]=3)[CH:41]=2)[CH:33]=[N:32]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>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]>[Si:21]([O:20][CH2:19][CH2:18][NH:17][C:11]1[CH:12]=[N:13][C:14]2[C:9]([CH:10]=1)=[CH:8][C:7]([S:45][C:42]1[N:40]3[CH:41]=[C:36]([C:34]4[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=4)[CH:37]=[CH:38][C:39]3=[N:44][N:43]=1)=[CH:16][CH:15]=2)([C:24]([CH3:25])([CH3:26])[CH3:27])([CH3:22])[CH3:23]
Reactant: Cn1cc(-c2ccc3nnc(S)n3c2)cn1
Reactant: CC(C)(C)[Si](C)(C)OCCNc1cnc2ccc(OS(=O)(=O)C(F)(F)F)cc2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2ccc3nnc(Sc4ccc5ncc(NCCO[Si](C)(C)C(C)(C)C)cc5c4)n3c2)cn1
Temperature: 110 °C
Reaction time: 1 h
Yield: 42.4 %

Procedure:
A mixture of Intermediate Q28 (0.2 g, 0.444 mmol), Intermediate E (0.103 g, 0.444 mmol), xantphos (0.051 g, 0.089 mmol), Pd2(dba)3 (0.041 g, 0.044 mmol) and DIPEA (0.155 ml, 0.888 mmol) in DMF (10 ml) was bubbled with Ar gas for 10 min and then the reaction mixture was stirred under MW radiation at 110° C. for 1 h. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH=40/1) to afford the title compound as brown oil (0.1 g, 42.4% yield). LCMS (method B): [M+H]+=532, tR=2.74 min.
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH:9]=C)[C:3]([O:5][CH2:6][CH3:7])=[O:4].N1C(C)=CC=CC=1C.C(Cl)Cl.[O:22]1CCOCC1>O.[Os](=O)(=O)(=O)=O>[CH3:1][CH:2]([CH2:8][CH:9]=[O:22])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: C1COCCO1
Reactant: C=CCC(C)C(=O)OCC
Agent: O=[Os](=O)(=O)=O
Solvent: ClCCl
Solvent: O
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)C(C)CC=O
Temperature: 25 °C
Reaction time: 20.5 h

Procedure:
A colorless solution of ethyl 2-methylpent-4-enoate (5.000 g; 35.16 mmol) in dioxane (260 ml) and water (85 ml) was treated successively with 2,6-lutidine (7.536 g; 70.32 mmol), a solution of osmium tetroxide (2.5 wt. % in 2-methylpropan-2-ol; 0.45 ml), and NaIO4 (30.083 g; 140.65 mmol). The resulting beige heterogeneous reaction mixture was further stirred at rt, under nitrogen, for 20.5 h. The resulting milky mixture was treated with water (100 ml) and DCM (500 ml). The layers were separated, and the aq. layer was further extracted with DCM (200 ml/150 ml). The mixed slightly yellow organic layers were then washed with brine (200 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure to give crude ethyl 2-methyl-4-oxobutanoate as a dark-yellow/slightly brown oil which was directly used for the next step without additional purification.
Reaction SMILES: [CH:1]1([NH:6][C:7](=[O:23])[NH:8][C@H:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([O:12]C(C)(C)C)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([NH:6][C:7](=[O:23])[NH:8][C@H:9]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:10]([OH:12])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)[C@H](NC(=O)NC1CCCC1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC1CCCC1)N[C@@H](C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.2 %

Procedure:
To a stirred solution of (R)-tert-butyl 2-(3-cyclopentylureido)-2-phenylacetate (1.31 g, 4.10 mmol) in CH2Cl2 (25 mL) was added TFA (4 mL) and trietheylsilane (1.64 mL; 10.3 mmol) dropwise, and the resulting solution was stirred at room temperature for 6 hours. The volatile components were removed under reduced pressure and the crude product was recrystallized in ethyl acetate/pentanes to yield (R)-2-(3-cyclopentylureido)-2-phenylacetic acid as a white solid (0.69 g, 64%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.17-1.35 (m, 2H) 1.42-1.52 (m, 2H) 1.53-1.64 (m, 2H) 1.67-1.80 (m, 2H) 3.75-3.89 (m, 1H) 5.17 (d, J=7.93 Hz, 1H) 6.12 (d, J=7.32 Hz, 1H) 6.48 (d, J=7.93 Hz, 1H) 7.24-7.40 (m, 5H) 12.73 (s, 1H). LCMS: Anal. Calcd. for C14H18N2O3: 262.31; found: 263.15 (M+H)+. HPLC XTERRA® C-18 3.0×50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.2% H3PO4, B=10% water, 90% methanol, 0.2% H3PO4, RT=1.24 min, 100% homogeneity index.
Reaction SMILES: [C:1]1([CH:7]2[C:16]3[C:11]4=[C:12]([CH:21]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:22][CH2:23][N:10]4[CH2:9][CH2:8]2)[CH:13]=[C:14]([CH2:17][C:18]([OH:20])=O)[CH:15]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:30]([NH2:32])[CH3:31].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl>[CH2:30]([NH:32][C:18](=[O:20])[CH2:17][C:14]1[CH:13]=[C:12]2[C:11]3=[C:16]([CH:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:8][CH2:9][N:10]3[CH2:23][CH2:22][CH:21]2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:15]=1)[CH3:31]
Reactant: CCN
Reactant: O=C(O)Cc1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCNC(=O)Cc1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.7 %

Procedure:
To a solution of 2-(1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-yl)acetic acid (16), (85 mg, 0.229 mmol) in dichloromethane (10 mL) were added Ethyl amine (0.015 mL, 0.229 mmol), EDCl (103 mg, 0.538 mmol), followed by HOBt (72 mg, 0.538 mmol) under argon at 0° C. The reaction mixture was then stirred at room temperature for overnight. The reaction was quenched with water (30 mL). The residue was isolated in a typical aqueous workup and purified by MPLC (medium pressure liquid chromatography) using silica gel column with 5% MeOH:CH2Cl2 to give N-ethyl-2-(1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-yl)acetamide (371), (27 mg, 29%).
Reaction SMILES: [C:1]([NH:4][C:5](=[CH2:10])[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].S[CH:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15].C(N(CC)CC)C.O[O:27][S:28]([O-:30])=O.[K+]>CO>[C:1]([NH:4][C@H:5]([C:6]([O:8][CH3:9])=[O:7])[CH2:10][S:28]([CH:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])(=[O:30])=[O:27])(=[O:3])[CH3:2]
Reactant: C=C(NC(C)=O)C(=O)OC
Reactant: CCCC(S)CCC
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCC(CCC)S(=O)(=O)C[C@H](NC(C)=O)C(=O)OC
Reaction time: 0.75 h

Procedure:
Methyl 2-acetamidoacrylate (LXXX, 5.0 g, 34 mmole) and 4-mercaptoheptane (4.6 g, 34 mmole) in methanol (50 ml) are mixed. Triethylamine (3.6 g, 36 mmole) is added and the mixture is stirred at 20–25° for 45 minutes. The reaction vessel is then treated with oxone (47.2 g, 77 mmole). After 90 minutes HPLC indicated complete oxidation to the desired sulfone (LXXXII). The reaction mixture is filtered and concentrated under reduced pressure. The residue is partitioned between ethyl acetate and water and the organic phase is separate and is washed with saline, dried over sodium sulfate, and concentrated under reduced pressure to give methyl N-acetyl-3-[(1-propylbutyl)sulfonyl]alaninate (LXXXII), M+H=308 g/m.