Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C@H:3]([OH:5])[CH3:4].[H-].[Na+].Cl[C:10]1[CH:11]=[CH:12][C:13]2[CH2:14][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:17][O:18][C:19]=2[N:20]=1.O>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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>[CH3:4][C@@H:3]([O:5][C:10]1[CH:11]=[CH:12][C:13]2[CH2:14][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:17][O:18][C:19]=2[N:20]=1)[CH:2]([CH3:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCOc2nc(Cl)ccc2C1
Reactant: CC(C)[C@@H](C)O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)[C@@H](C)Oc1ccc2c(n1)OCCN(C(=O)OC(C)(C)C)C2
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a solution of (2R)-3-methylbutan-2-ol (0.38 mL) in toluene (8 mL) was added sodium hydride (0.28 g), and the resulting mixture was stirred at 70° C. for 15 min under a nitrogen atmosphere. A mixture of tert-butyl 8-chloro-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (1.0 g), BINAP (0.066 g), Pd2(dba)3 (0.048 g) and toluene (8 mL) was added, and the resulting mixture was stirred at 100° C. for 2 hr under an argon atmosphere. The reaction solution was poured into water, and the resulting product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane) to give tert-butyl 8-{[(1R)-1,2-dimethylpropyl]oxy}-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.77 g, 65%) as a white powder.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[S:9][C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([CH3:20])[CH3:19])=[CH:13][CH:12]=2)=[N:7][CH:6]=1)[NH2:4].[O:21]=[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:31])[N:23]1[CH:32]([CH3:36])[C:33](Cl)=O.CO>N1C=CC=CC=1>[CH:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:8]2[S:9][C:5]([C:3]3[N:4]=[C:36]([CH:32]([N:23]4[C:24](=[O:31])[C:25]5[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=5)[C:22]4=[O:21])[CH3:33])[O:1][N:2]=3)=[CH:6][N:7]=2)=[CH:12][CH:13]=1)([CH3:20])[CH3:19]
Reactant: CC(C)Oc1ccc(Oc2ncc(C(N)=NO)s2)cc1
Reactant: CC(C(=O)Cl)N1C(=O)c2ccccc2C1=O
Solvent: c1ccncc1
Solvent: CO
Product: CC(C)Oc1ccc(Oc2ncc(-c3noc(C(C)N4C(=O)c5ccccc5C4=O)n3)s2)cc1
Temperature: 25 °C

Procedure:
To a solution of Example 40B (616 mg, 2.1 mmol) in pyridine (15 mL) was added 2-(1,3-dioxoisoindolin-2-yl)propanoyl chloride (CAS#5364-22-7) (598 mg, 2.52 mmol) and the solution was stirred for an hour at room temperature and then at reflux for an additional hour. The reaction mixture was cooled down, methanol was added, and after stirring for 15 minutes the solvent was removed under vacuum. The title compound was purified via silica-gel column chromatography using a gradient of 25 to 50% ethyl acetate in hexane to provide 855 mg, 1H NMR (300 MHz, CDCl3) δ ppm 7.84-7.96 (m, 3H) 7.73-7.83 (m, 2H) 7.15-7.24 (m, 2H) 6.86-6.99 (m, 2H) 5.68 (q, J=7.35 Hz, 1H) 4.43-4.63 (m, 1H) 1.98 (d, J=7.35 Hz, 3H) 1.35 (d, J=5.88 Hz, 6H). MS (DCI): m/z 477 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].Cl.Cl.[NH:38]1[CH:42]=[CH:41][N:40]=[C:39]1[CH2:43][NH2:44].C(N(CC)C(C)C)(C)C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:44][CH2:43][C:39]3[NH:38][CH:42]=[CH:41][N:40]=3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: NCc1ncc[nH]1
Reactant: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(NCc2ncc[nH]2)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 32.9 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide (20 mg, 0.04 mmol) in THF (3 mL) were added (1H-imidazol-2-ylmethyl)amine dihydrochloride (50 mg, 0.52 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.574 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM [90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (7 mg, 33%). LC-MS m/z 533 (M+H)+; 1H-NMR (MeOD) δ 1.26 (d, 6H), 2.26 (s, 3H), 4.12 (s, 2H), 4.23 (m, 1H), 4.36 (s, 2H), 6.88 (s, 2H), 7.10 (t, 2H), 7.48 (m, 2H), 7.69 (s, 1H), 7.85 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](Br)[C:9]2[N:10]([CH3:20])[C:11]3[C:16]([C:17]=2[C:18]=1[OH:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[C:22]([Cu])#[N:23].[OH-].[NH4+].Cl>CN1C(=O)CCC1.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:22]#[N:23])[C:9]2[N:10]([CH3:20])[C:11]3[C:16]([C:17]=2[C:18]=1[OH:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2c(c1O)c1ccccc1n2C
Reactant: N#C[Cu]
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(C#N)c2c(c1O)c1ccccc1n2C
Temperature: 120 °C
Yield: 38.8 %

Procedure:
A mixture of 1-bromo-4-hydroxy-9-methyl-9H-beta-carboline-3-carboxylic acid ethyl ester (256 mg), CuCN (132 mg) in NMP (N-methyl 2-pyrrolidinone, 2 mL) was heated at 120° C. for 67 min. The mixture was poured into a stirring mixture of EtOAc and diluted ammonium hydroxide solution, then acidified with conc. HCl; then the organic phase was separated from aqueous and washed with sat. NaCl solution, dried over anhydrous sodium sulfate, filtered, concentrated; the residue was purified with column to give the desired product (84 mg). The title compound, ESI MS (m/z): 296 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([N:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]3=[O:20])[CH:11]=[CH:12][C:5]=2[N:4]=1)[CH3:2].[F:21][C:22]1[S:26][C:25]([CH2:27]O)=[CH:24][CH:23]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([N:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:27][C:25]4[S:26][C:22]([F:21])=[CH:23][CH:24]=4)=[CH:15][C:14]3=[O:20])[CH:11]=[CH:12][C:5]=2[N:4]=1)[CH3:2]
Reactant: OCc1ccc(F)s1
Reactant: CCc1nc2ccc(-n3ccc(O)cc3=O)cc2n1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCc1nc2ccc(-n3ccc(OCc4ccc(F)s4)cc3=O)cc2n1C
Temperature: 60 °C
Reaction time: 4 h
Yield: 6.9 %

Procedure:
To a solution of 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (224 mg), (5-fluorothiophen-2-yl)methanol (100 mg) and tributylphosphine (750 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (956 mg), and the mixture was stirred at 60° C. for 4 h. The reaction mixture was concentrated in vacuo, and diluted with DCM. The mixture was washed with water and brine successively, dried over Na2SO4, concentrated in vacuo and purified by silica gel column chromatography (MeOH/DCM) followed by preparative HPLC to afford the title compound (20 mg) as a white solid.
Reaction SMILES: C[N:2]([C@@H:10]([CH3:26])[C:11](=[O:25])[NH:12][C@H:13]1[CH2:19][O:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[NH:15][C:14]1=[O:24])[C:3](=O)OC(C)(C)C.Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1>>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][N:15]2[C:14](=[O:24])[C@@H:13]([NH:12][C:11](=[O:25])[C@@H:10]([NH:2][CH3:3])[CH3:26])[CH2:19][O:18][C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]2=3)=[CH:30][CH:31]=1
Reactant: C[C@@H](C(=O)N[C@H]1COc2ccccc2NC1=O)N(C)C(=O)OC(C)(C)C
Reactant: Clc1ccc(CBr)cc1
Product: CN[C@@H](C)C(=O)N[C@H]1COc2ccccc2N(Cc2ccc(Cl)cc2)C1=O
Yield: 61.2 %

Procedure:
In a similar manner to that described for Example 45 except in Step 2 the material obtained after chromatography was not triturated, tert-butyl methyl((S)-1-oxo-1-((S)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)propan-2-yl)carbamate (173 mg, 476 iumol) and 1-(bromomethyl)-4-chlorobenzene (103 mg, 500 μmol) were converted to the title compound (113 mg) as an off-white foam. HRMS: calcd. for C20H22N3O3Cl: (MH+) 388.1422. found 388.1423.
Reaction SMILES: [F-:1].[K+].[F:3][C:4]([F:12])([C:8]([F:11])([F:10])[F:9])[C:5](F)=[O:6]>C(#N)C>[F:1][C:4]([F:12])([F:3])[C:5]([C:8]([F:11])([F:10])[F:9])([OH:6])[C:4]([F:12])([F:3])[C:8]([F:11])([F:10])[F:9]
Reactant: [F-]
Reactant: O=C(F)C(F)(F)C(F)(F)F
Agent: [K+]
Solvent: CC#N
Product: OC(C(F)(F)F)(C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: -196 °C

Procedure:
By operating as in the above examples, 0.26 g of KF (4.5 mmol) was charged to the reactor, and then 4.0 ml of anhydrous acetonitrile was injected through the pierceable cap; the whole was then cooled down to -196° C. with the residual air being evacuated; then, 2.0 mmol of pentafluoropropionyl fluoride
Reaction SMILES: [OH:1][NH:2][CH2:3][CH2:4][CH2:5][P:6](=[O:9])([OH:8])[OH:7].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[S:22](Cl)([CH3:25])(=[O:24])=[O:23].C>O.ClCCl.C(N(CC)CC)C>[OH:1][N:2]([CH2:3][CH2:4][CH2:5][P:6](=[O:8])([OH:7])[OH:9])[S:22]([CH3:25])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: O=P(O)(O)CCCNO
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N(O)CCCP(=O)(O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 26 %

Procedure:
A mixture of 3-(N-hydroxyamino)propylphosphonic acid (820 mg), bis(trimethylsilyl)acetamide (5.0 g), triethylamine (1.01 g) and dichloromethane (40 ml) was stirred at ambient temperature for 2.5 hours. The reaction mixture was cooled to 0°-5° C. and mesyl chloride (1.15 g) was added dropwise with stirring. The reaction mixture was stirred for 1.25 hours and then concentrated under reduced pressure to give a residue, which was dissolved in water (50 ml). The solution was subjected to a column chromatography using activated charcoal. After the column was washed with water, the object compound was eluted with 70% aqueous acetone. The eluate was collected and evaporated to dryness to give powdery 3-(N-hydroxy-N-mesylamino)-propylphosphonic acid (320 mg). This powder was dissolved in ethanol (20 ml). To the solution was added conc. aqueous ammonia (0.4 ml) to give precipitates, which were separated by filtration and dried to give crystalline monoammonium salt of 3-(N-hydroxy-N-mesylamino)-propylphosphonic acid (220 mg). Mp 103°-105° C. (dec.).
Reaction SMILES: C[Mg]Br.O1CCC[CH2:5]1.C[Mg]Br.C(OCC)C.[CH2:17]([O:24][C@@H:25]1[C@@H:29]([CH2:30][O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:28][C@H:27]([O:39][CH3:40])[C:26]1=[O:41])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH2:17]([O:24][C@@H:25]1[C@@H:29]([CH2:30][O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:28][C@H:27]([O:39][CH3:40])[C@:26]1([CH3:5])[OH:41])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C1CCOC1
Reactant: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)C1=O
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@]1(C)O
Temperature: 0 °C

Procedure:
92 mL of a 1 mol/L methyl magnesium bromide/tetrahydrofuran solution and 23 mL of a 3 mol/L methyl magnesium bromide/diethyl ether solution were added dropwise to a solution of 23.2 g of (2S,4R,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-2-methoxyoxolane-3-one in 100 mL of tetrahydrofuran at −40° C., and the obtained mixture was then stirred at the same temperature as described above for 30 minutes. Thereafter, the temperature of the reaction mixture was increased to 0° C. over 1 hour, and 500 mL of a saturated ammonium chloride aqueous solution and 500 mL of ethyl acetate were then added to the mixture. The organic layer was fractionated, and it was washed with 300 mL of a saturated sodium chloride aqueous solution and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography, so as to obtain 12.0 g of (2S,3R,4R,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-2-methoxy-3-methyloxolan-3-ol in the form of a colorless oily product.
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)([O-:3])=[O:2].[Br:13][C:14]1[CH:22]=[C:21]2[C:17]([CH:18]=[CH:19][NH:20]2)=[CH:16][CH:15]=1>CO>[Br:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18]([CH:5]([C:6]3[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=3)[CH2:4][N+:1]([O-:3])=[O:2])=[CH:19][NH:20]2)=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(Cl)cc1
Reactant: Brc1ccc2cc[nH]c2c1
Solvent: CO
Product: O=[N+]([O-])CC(c1ccc(Cl)cc1)c1c[nH]c2cc(Br)ccc12
Temperature: 80 °C
Reaction time: 16 h
Yield: 45.2 %

Procedure:
1-((1E)-2-Nitrovinyl)-4-chlorobenzene (0.206 g, 1.12 mmol) was added to a solution of 6-bromoindole (0.200 g, 1.02 mmol) in methanol (5 mL), followed by the addition of sufamic acid (39.6 mg, 0.40 mmol). The mixture was stirred at 80° C. for 16 hours. The mixture was concentrated then diluted with EtOAc (15 mL) and washed with H2O (15 mL). The organic layer was dried (Na2SO4), filtered and concentrated. The crude product was purified by silica gel chromatography, eluting with EtOAc/hexane (0-50%) to give 6-bromo-3-(1-(4-chlorophenyl)-2-nitroethyl)-1H-indole (0.175 g, 45.2%). 1H NMR (CDCl3, 400 MHz) δ 8.12 (s, 1H), 7.51 (s, 1H), 7.28 (d, J=8.5 Hz, 2H), 7.25-7.20 (m, 3H), 7.17 (d, J=8.5 Hz, 1H), 7.15 (s, 1H), 5.12 (t, 1H), 5.01 (q, 1H), 4.88 (q, 1H).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[Cl:23])[N:19]([CH:24]1[CH2:26][CH2:25]1)[CH:18]=[C:17]([C:27]([OH:29])=[O:28])[C:16]2=[O:30])=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[Cl:23])[N:19]([CH:24]1[CH2:26][CH2:25]1)[CH:18]=[C:17]([C:27]([OH:29])=[O:28])[C:16]2=[O:30]
Reactant: CC(C)(C)OC(=O)NCCCNc1cc2c(=O)c(C(=O)O)cn(C3CC3)c2cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCNc1cc2c(=O)c(C(=O)O)cn(C3CC3)c2cc1Cl
Yield: 133.7 %

Procedure:
A solution of intermediate 11 (100 mg) in 10% TFA/DCM (1 mL) was stirred at room temperature for 2 h. The solvent was partially evaporated under reduced pressure. For five times the residual was diluted in DCM (2 mL) and concentrated under reduced pressure. Final solvent evaporation afforded the title compound (103 mg).
Reaction SMILES: [BrH:1].C(O)(=O)C.C1(OC)C=CC=CC=1.C(OC([N:24]1[CH2:30][CH2:29][CH2:28][N:27]([NH:31][C:32](=[O:40])[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH2:26][CH2:25]1)=O)C1C=CC=CC=1>C(OCC)C>[BrH:1].[N:27]1([NH:31][C:32](=[O:40])[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH2:28][CH2:29][CH2:30][NH:24][CH2:25][CH2:26]1
Reactant: O=C(NN1CCCN(C(=O)OCc2ccccc2)CC1)c1ccc(F)cc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: COc1ccccc1
Product: O=C(NN1CCCNCC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 25% hydrogen bromide-acetic acid (1.5 ml) and anisole (0.09 ml) was added N-(4-benzyloxycarbonyl-1-homopiperazinyl)-p-fluorobenzamide (529 mg) dropwise for 3 minutes under nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 3.5 hours and diluted with diethyl ether. The resulting precipitate was collected and washed with diethyl ether to give N-(l-homopiperazinyl)-4-fluorobenzamide hydrobromide (606 mg). This product was used for next step without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[F:15][CH:16]([F:29])[CH2:17][O:18][C:19]1[CH:20]=[C:21]([CH:26]([NH2:28])[CH3:27])[CH:22]=[C:23]([CH3:25])[CH:24]=1>>[Cl:13][C:12]1[C:3]2[CH2:2][N:28]([CH:26]([C:21]3[CH:22]=[C:23]([CH3:25])[CH:24]=[C:19]([O:18][CH2:17][CH:16]([F:15])[F:29])[CH:20]=3)[CH3:27])[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: Cc1cc(OCC(F)F)cc(C(C)N)c1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(OCC(F)F)cc(C(C)N2Cc3c(ccnc3Cl)C2=O)c1
Yield: 85 %

Procedure:
The title compound is prepared in 85% yield (177 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(3-(2,2-difluoroethoxy)-5-methylphenyl)ethanamine hydrochloride (143 mg, 0.57 mmol, Amine-30, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: C([Li])CCC.[Br-].[OH:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[N:29]1[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][CH:30]=1>CCCCCC.C1COCC1>[OH:7][CH:8]=[CH:9][CH2:35][C:32]1[CH:31]=[CH:30][N:29]=[CH:34][CH:33]=1
Reactant: OCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccncc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC=CCc1ccncc1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
n-Butyllithium (25 ml of a 1.6M solution in hexane, 40 mmol) was added dropwise to a stirred suspension of 2-hydroxyethyltriphenylphosphonium bromide (7.74 g, 20 mmol) in THF (50 ml) at −70° C. and the mixture allowed to warm to −30° C. and stirred for 2 hours. 4-Pyridinecarboxaldehyde (2.16 g, 20 mmol) was added to the resulting red solution and the mixture stirred for 1 hour at −30° C. and then cooled to −70° C. n-Butyllithium (12.5 ml of a 1.6M solution in hexane, 20 mmol) was added and the reaction mixture stirred at −70° C. for 1 hour. The mixture was quenched with isopropanol and allowed to warm to ambient temperature. Saturated aqueous ammonium chloride solution was added, the organic layer separated and the aqueous layer extracted with ethyl acetate (3×50 ml). The combined extracts were washed with brine and dried (MgSO4) and the volatiles removed by evaporation. The residue was purified by column chromatography eluting with ethyl acetate to give 4-(3-hydroxyprop-2-en-1-yl)pyridine
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH3:10][NH:11][CH2:12][CH2:13][NH:14][CH3:15]>C1C=CC=CC=1>[CH3:10][N:11]1[CH2:12][CH2:13][N:14]([CH3:15])[CH:7]1[C:4]1[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=1
Reactant: CNCCNC
Reactant: Cc1ccc(C=O)cc1
Solvent: c1ccccc1
Product: Cc1ccc(C2N(C)CCN2C)cc1

Procedure:
Using the method of Birch and Dastur, Austral. J. Chem., 26, 1364 (1973), a solution of 48 g of p-tolualdehyde in 185 ml of benzene was added dropwise to a stirred solution of 25 g of sym-dimethylethylenediamine in 95 ml of benzene, and heated at 60° for 2 hrs. Evaporation and distillation at 52° (0.1 mm) afforded 48 g, identified by nmr.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH:23]3[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH3:30])[C:24]3=[O:31])[CH:20]=2)[N:15]([CH2:32][CH2:33][CH3:34])[CH:14]=1)[C:6](O)=[O:7].Cl.CN(C)CCCN=C=NCC.[CH3:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[S:54]([NH2:57])(=[O:56])=[O:55].Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH:23]3[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH3:30])[C:24]3=[O:31])[CH:20]=2)[N:15]([CH2:32][CH2:33][CH3:34])[CH:14]=1)[C:6]([NH:57][S:54]([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[CH3:47])(=[O:55])=[O:56])=[O:7]
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: CCCN1CCC(Cc2ccc3c(c2)c(Cc2ccc(C(=O)O)cc2OC)cn3CCC)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCN1CCC(Cc2ccc3c(c2)c(Cc2ccc(C(=O)NS(=O)(=O)c4ccccc4C)cc2OC)cn3CCC)C1=O
Reaction time: 18 h
Yield: 95.2 %

Procedure:
A mixture of 3-methoxy-4-[1-propyl-5-(1-propyl-2-oxopyrrolidin-3-ylmethyl)indol-3-ylmethyl]-benzoic acid (0.3 g), 4-dimethylaminopyridine (0.095 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.149 g), and 2-methylbenzenesulfonamide (0.122 g) was dissolved in methylene chloride (10 ml), and the solution was stirred under a nitrogen atmosphere for 18 h. The mixture was poured into 1M hydrochloric acid, extracted with ethyl acetate (twice), and the extract washed with 1M hydrochloric acid, water, and brine. The dried (MgSO4) solution was evaporated and the residue precipated from a mixture of methanol and lM hydrochloric acid to give 3-methoxy-N-(2-methylphenylsulfonyl)-4-[1-propyl-5-(1-propyl-2-oxopyrrolidin-3-ylmethyl)indol-3-ylmethyl]-benzamide (0.38 g, 95%) as an off-white solid; mp 98-115°.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH2:7][C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([OH:6])=[O:5].[H][H]>C(O)(=O)C.[C].[Pd]>[CH3:1][C:2]([CH3:16])([CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: [H][H]
Reactant: CC(C)(CC(=O)O)CC(=O)c1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(CCc1ccccc1)CC(=O)O
Yield: 89.2 %

Procedure:
3,3-Dimethyl-5-oxo-5-phenylpentanoic acid (17.0 g, 77.2 mmol) was subjected to hydrogen catalytic reduction in acetic acid (170 ml) by using 10% palladium-carbon as a catalyst. After completion of the reaction, the catalyst was filtered off and the solvent was distilled off under reduced pressure to obtain 14.2 g of 3,3-dimethyl-5-phenylpentanoic acid.
Reaction SMILES: [Li].[C:2]([O:6][C:7](=[O:26])[N:8]([CH:11]([CH3:25])[CH2:12][C:13]1[CH:24]=[CH:23][C:16]2[O:17][CH:18]([C:20](=O)[NH2:21])[O:19][C:15]=2[CH:14]=1)[CH2:9][CH3:10])([CH3:5])([CH3:4])[CH3:3]>C1COCC1>[C:2]([O:6][C:7](=[O:26])[N:8]([CH:11]([CH3:25])[CH2:12][C:13]1[CH:24]=[CH:23][C:16]2[O:17][CH:18]([CH2:20][NH2:21])[O:19][C:15]=2[CH:14]=1)[CH2:9][CH3:10])([CH3:3])([CH3:4])[CH3:5]
Reactant: CCN(C(=O)OC(C)(C)C)C(C)Cc1ccc2c(c1)OC(C(N)=O)O2
Agent: [Li]
Solvent: C1CCOC1
Product: CCN(C(=O)OC(C)(C)C)C(C)Cc1ccc2c(c1)OC(CN)O2
Temperature: -60 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
A flask containing 20 mL of freshly distilled THF was cooled to −60° C., and 615 mg (16.2 mmol) of lithium aluminun hydride (LAH) was added To the reaction mixture, a solution of 1.8 g (5.13 mmol) 2E in 20 mL of freshly distilled THF was added dropwise under argon atmosphere. The reaction mixture was allowed to stir at −60° C. for 20 minutes, 45 minutes at 0° C. and 2 hours at room temperature. The reaction was quenched with 430 μL of 15% NaOH and 3 mL of water and allowed to stir at room temperature for 10 minutes. The resulting solution was filtered through CELITE and the residue was washed with 100 mL of THF. The filtrate was concentrated to dryness under reduced pressure and purified by silica gel column chromatography using ethyl acetate as eluent to give 1.3 g (3.86 mmol, 75%) of 2F as a colorless gum (M+Na, 359).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[N:17]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]3[N:11]=[C:12]([C:15]#[N:16])[N:13]=[CH:14][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26]1>C1COCC1>[C:15]([C:12]1[N:13]=[CH:14][C:9]2[CH:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:25](=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:24][CH:23]=3)[N:17]([CH2:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:10]=2[N:11]=1)#[N:16]
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)(C)Cn1c(Cc2ccc(N)cc2)cc2cnc(C#N)nc21
Solvent: C1CCOC1
Product: CC(C)(C)Cn1c(Cc2ccc(NC(=O)CCC(=O)O)cc2)cc2cnc(C#N)nc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6-(4-amino-benzyl)-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (0.626 mmol) in THF (3 ml), succinic anhydride (0.626 mmol) is added. The reaction mixture is stirred at room temperature for 16 h. The reaction mixture is concentrated under vacuum. Purification of the residue by silica gel column chromatography affords the title compound in quantitative yield.