Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:7]=3[C:6]=2[C:5]([Cl:17])=[CH:4][CH:3]=1.[H-].[Na+].CC1C=CC(S(O[CH2:31][CH2:32][C:33]2[CH:34]=[N:35][C:36]([CH3:39])=[CH:37][CH:38]=2)(=O)=O)=CC=1>CN(C=O)C>[Cl:1][C:2]1[C:10]2[N:9]([CH2:31][CH2:32][C:33]3[CH:34]=[N:35][C:36]([CH3:39])=[CH:37][CH:38]=3)[C:8]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:7]=3[C:6]=2[C:5]([Cl:17])=[CH:4][CH:3]=1
Reactant: CN1CCc2[nH]c3c(Cl)ccc(Cl)c3c2CC1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C)nc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(CCn2c3c(c4c(Cl)ccc(Cl)c42)CCN(C)CC3)cn1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7,10-dichloro-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole (200 mg, 0.746 mmol) in DMF (2 mL), sodium hydride (90 mg, 2.25 mmol) was added. After stirring at 60° C. for 30 min., 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (543 mg, 1.86 mmol) was added to the reaction mixture and the reaction mixture was stirred at the same temperature for 40 min. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to obtain the residue that was purified by reverse phase HPLC to obtain 7,10-dichloro-1,2,3,4,5,6-hexahydro-3-methyl-6-(2-(6-methylpyridin-3-yl)ethyl)azepino[4,5-b]indole. 1H NMR TFA: —CD3OD: 8.4 (s, 1H), 8.1 (d, 1H), 7.75 (d, 1H), 7.0 (q, 2H), 4.8 (m, 1H), 4.0 (m, 1H), 3.8 (m, 2H), 3.4 (m, 3H), 3.3 (m, 2H), 3.2 (t, 3H), 3.0 (s, 3H), 2.7 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[NH3:13].CCO>>[NH2:13][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:12])=[CH:5][CH:4]=1
Reactant: N
Reactant: O=C(O)Cc1ccc(CBr)cc1
Solvent: CCO
Product: NCc1ccc(CCO)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a stirred solution of NH3/EtOH (170 mL) was added (4-Bromomethyl-phenyl)-acetic acid (1.61 g, 7.01 mmol). The resultant solution was stirred at room temperature for 2 h. The mixture was concentrated in vacuo, and redissolved with anhydrous THF (10 mL). To the solution, BH3.Me2S was added, and the mixture was stirred for 1 h at 70° C., and at room temperature for 2 d. The reaction was concentrated in vacuo, 6 N HCl (10 mL) was added, and the mixture was stirred at 70° C. for 1 h. Water (20 mL) was added, and it was neutralized with 1 N NaOH to pH˜7. The solution was concentrated to dryness under high vacuum, washed with MeOH/CH2Cl2, and filtered. The crude product was purified by flash chromatography on silica gel (5:3:92 CH3OH—NH3 H2O—CH2Cl2) to afford the title compound (820 mg, 77%) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1Br.[C:10]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].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.CC(C)([O-])C.[Na+]>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:13]([O:12][C:10]([N:17]1[CH2:22][CH2:21][N:20]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])[CH2:19][CH2:18]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1cccc(Cl)c1Br
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2c(Cl)cccc2Cl)CC1
Temperature: 110 °C

Procedure:
2,6-dichlorobromobenzene (2.26 g, 10 mmole), N-Boc-piperazine (2.05 g, 11 mmole), Pd2(dba)3 (92 mg, 1 mol %), BINAP (187 mg, 3 mol %), and sodium tert-butoxide (1.15 g, 12 mmole) were charged in a microwave vessel. The vessel was capped, purged with nitrogen, and 20 mL toluene added. The reaction mixture was heated to 110° C. for 30 minutes in the microwave and then the mixture was filtered through celite, rinsing with EtOAc. The filtrate was evaporated and then filtered through a pad of silica gel, eluting with dichloromethane. Evaporation gave crude 4-(2,6-Dichloro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester as an orange oil that was taken on to the next step without further purification.
Reaction SMILES: C([Si]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[F:17])(C)C)(C)(C)C.CN(C)CCN(C)CCN(C)C.C([Li])CCC.CN(C)[CH:37]=[O:38]>O1CCCC1.CCCCCCC.O>[F:17][C:10]1[C:9]([OH:8])=[CH:14][C:13]([O:15][CH3:16])=[CH:12][C:11]=1[CH:37]=[O:38]
Reactant: COc1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(O)c(F)c(C=O)c1
Temperature: -72 °C
Reaction time: 3 h
Yield: 80.8 %

Procedure:
To a flask, tert-butyl(2-fluoro-5-methoxyphenoxy)dimethylsilane (6.00 g, 23 mmol), N,N,N′,N″,N″-pentamethyldiethylenetriamine (4.87 g, 28 mmol), and tetrahydrofuran (48.0 mL) were added, and the resulting mixture was cooled to −72° C. under nitrogen atmosphere. To the solution, n-butyllithium (10.2 mL, 28 mmol, 2.76 M, in hexane) was added dropwise, and the resulting mixture was stirred at −56° C. for 3 hours. To the solution, a solution of N,N-dimethylformamide (3.42 g, 47 mmol) in tetrahydrofuran (6.0 mL) was added, and the resulting mixture was warmed to 10° C., after which water was added thereto, and the two-layer reaction solution was stirred overnight at room temperature. Heptane was added to the reaction mixture, and the aqueous layer was collected. Toluene was added to the aqueous layer. To the resulting mixture, 5 N hydrochloric acid was added to adjust the pH to 2, and the resulting mixture was extracted. The organic layer was washed with water and concentrated under reduced pressure, after which a mixture of toluene and ethyl acetate was added to the resulting concentration residue, and the resulting mixture was purified by suspension. The purified product obtained was filtered and dried to obtain the captioned compound (3.16 g) as a light brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][O:12][C:11](=[O:14])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Cl:21]>>[Cl:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:10]1[C@@H:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[CH2:13][O:12][C:11]1=[O:14]
Reactant: ClCCCCCBr
Reactant: O=C1N[C@@H](c2ccc(F)c(F)c2)CO1
Product: O=C1OC[C@H](c2ccc(F)c(F)c2)N1CCCCCCl

Procedure:
Prepared by Procedure G and Scheme C1 using (4S)-4-(3,4-difluorophenyl)-1,3-oxazolidin-2-one and 1-bromo-5-chloropentane.
Reaction SMILES: C([C:4]1[C:13]([CH2:14][O:15][C:16](=[O:18])[CH3:17])=[N+:12]([O-:19])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N+:5]=1[O-:20])(=O)C.Cl.[CH3:22]O>>[CH3:22][O:18][C:16]1([CH3:17])[C:4]2=[N+:5]([O-:20])[C:6]3[C:11]([N+:12]([O-:19])=[C:13]2[CH2:14][O:15]1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: CC(=O)OCc1c(C(C)=O)[n+]([O-])c2ccccc2[n+]1[O-]
Reactant: CO
Agent: Cl
Product: COC1(C)OCc2c1[n+]([O-])c1ccccc1[n+]2[O-]
Yield: 63 %

Procedure:
A suspension of 30.0 g. (0.11 mol.) of 2-acetyl-3-acetoxymethylquinoxaline 1,4-dioxide in 300 ml. of methanol, saturated with dry hydrogen chloride, was stirred at ambient temperature for 2 days. The tan solid was collected by filtration, and then it was recrystallized from methanol, to give 17.0 g. (63% yield) of 1-methoxy-1-methyl-1,3-dihydrofuro[3,4-b]quinoxaline 4,9-dioxide, m.p. 201°-202° C.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6][C:7]2[CH:12]=[C:11](Cl)[N:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:18]=1[NH2:19].Cl>C(O)CCC>[OH:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6][C:7]2[CH:12]=[C:11]([NH:19][C:18]3[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:17]=3[Cl:16])[N:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: Cc1ccc(Cl)c(N)c1
Agent: Cl
Solvent: CCCCO
Product: Cc1ccc(Cl)c(Nc2cc(Nc3ccc(O)cc3)ncn2)c1
Yield: 84 %

Procedure:
The title compound was prepared in a similar manner to that of Reference Example 4 from 4-(4-hydroxyanilino)-6-chloropyrimidine (Reference Example 5) by reaction with 2-chloro-5-methylaniline in butan-1-ol in the presence of catalytic concentrated hydrochloric acid. The mixture was heated at reflux for 18 hours, concentrated and the residue purified by column chromatography eluting with DCMN:MeOH: concentrated ammonia (94:5:1). Yield 84%. NMR: 2.26 (3H, s), 5.85 (1H, s), 6.68 (2H, d), 6.93 (1H, d), 7.19 (2H, d), 7.32 (1H, d), 7.46 (1H, s), 8.09 (1H, s), 8.44 (1H, s), 8.69 (1H, s), 9.11 (1H, s); m/z 327 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[C:13]1[N:18]=[CH:17][N:16]=[C:15]([NH:19][C@H:20]([CH3:24])[CH2:21][O:22][CH3:23])[C:14]=1[NH2:25].[C:26](OCC)(=[O:30])[C:27]([CH3:29])=O>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:10])([F:12])[F:11])[CH:5]=[CH:4][C:3]=1[C:13]1[C:14]2[N:25]=[C:27]([CH3:29])[C:26](=[O:30])[N:19]([C@H:20]([CH3:24])[CH2:21][O:22][CH3:23])[C:15]=2[N:16]=[CH:17][N:18]=1
Reactant: COC[C@@H](C)Nc1ncnc(-c2ccc(OC(F)(F)F)cc2Cl)c1N
Reactant: CCOC(=O)C(C)=O
Solvent: CCO
Product: COC[C@@H](C)n1c(=O)c(C)nc2c(-c3ccc(OC(F)(F)F)cc3Cl)ncnc21
Reaction time: 18 h

Procedure:
(R)-6-(2-Chloro-4-trifluoromethoxy-phenyl)-N4-(2-methoxy-1-methyl-ethyl)-pyrimidine-4,5-diamine (0.20 g, 0.53 mmol) was diluted in ethanol (6 ml) and ethyl pyruvate was added (0.59 ml, 5.3 mmol). The mixture was stirred for 18 hours at which time the solution was concentrated. After concentrating the solution the product was purified by reverse phase HPLC to yield 4.0 mg of (R)-4-(2-chloro-4-trifluoromethoxy-phenyl)-8-(2-methoxy-1-methyl-ethyl)-6-methyl-8H-pteridin-7-one (Example 1067a). 1H NMR (300 MHz, CDCl3) δ ppm 9.02 (s, 1 H), 7.49 (d, J=8.42 Hz, 1 H), 7.39 (d, J=1.10 Hz, 1 H), 7.26 (dd, J=8.42, 1.10 Hz, 1 H), 5.95 (s, 1 H), 4.36 (t, J=9.52 Hz, 1 H), 3.68 (dd, J=10.07, 5.31 Hz, 1 H), 3.30 (s, 3 H), 2.48 (s, 3 H), 1.58 (d, J=6.96 Hz, 3 H).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([CH2:11][CH2:12][CH2:13][CH2:14]O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(Cl)Cl>[C:5]1([CH2:11][CH2:12][CH2:13][CH2:14][Cl:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: OCCCCc1ccccc1
Solvent: ClCCl
Product: ClCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 2.2 ml (20 mmol) amount of thionyl chloride was added dropwise to a methylene chloride solution (30 ml) containing 3 g (20 mmol) of 4-phenyl-1-butanol and stirred overnight at room temperature. The reaction solution was washed with water, an aqueous 50% sodium hydrogen carbonate solution, water, 1N hydrochloric acid and water in that order, and then the solvent was dried with anhydrous magnesium sulfate. After distillation under reduced pressure, 3.62 g of a crude 4-phenylbutyl chloride was obtained. This material was used in the next reaction without being further purified.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[SH:13].[C:14](=S)=[S:15].[OH-].[K+]>CCO>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[CH:5][C:4]2[S:13][C:14]([SH:15])=[N:2][C:3]=2[CH:8]=1
Reactant: S=C=S
Reactant: Nc1cc(C(F)(F)F)ccc1S
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: FC(F)(F)c1ccc2sc(S)nc2c1
Temperature: 25 °C
Yield: 72.6 %

Procedure:
Into a 25 ml round bottomed flask were added 2-amino-4-(trifluoromethyl)benzenethiol hydrochloride (107 mg, 0.43 mmol), CS2 (331 mg, 4.35 mmol), aqueous KOH (127 mg, 2.3 mmol), and EtOH (5 ml). The solution was refluxed under Ar for 2 h, cooled to rt, then treated with Amberlite IR-120(H+) (2 g, 3.8 mmol). The solution was filtered and concentrated to afford the title compound as a white crystalline solid (73.4 mg, 67%). 1H NMR (DMSO-d6) δ=7.46 (s, 1H), 7.61 (d, 1H), 7.93 (d, 1H), 13.99 (br s, 1H); ESIMS: m/z 234 (M−H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14](Br)=[C:13]([O:18][CH3:19])[CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[N:34][CH:35]=1>>[C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:32]2[CH:33]=[N:34][CH:35]=[C:30]([F:29])[CH:31]=2)=[C:13]([O:18][CH3:19])[CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(C(=O)C(NC(=O)OC(C)(C)C)c2ccc(Cl)c(Cl)c2)ccc1Br
Reactant: OB(O)c1cncc(F)c1
Product: COc1cc(C(=O)C(NC(=O)OC(C)(C)C)c2ccc(Cl)c(Cl)c2)ccc1-c1cncc(F)c1

Procedure:
The title compound was prepared from rac-[2-(4-bromo-3-methoxy-phenyl)-1-(3,4-dichloro-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and 5-fluoropyridine-3-boronic acid in analogy to Example 1b): MS (ISN): 503.0 (M−H)− and 429.01 ((M-tBuOH)−H)−.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][N:17](C)[CH2:16][CH2:15]1.C([O-])(O)=O.[Na+].O>O1CCOCC1>[Cl:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([N:17]2[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]2)[N:11]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: CN1CCN(C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CN1CCN(c2nc(Cl)c3ccccc3n2)CC1
Temperature: 150 °C
Yield: 51.3 %

Procedure:
2,4-Dichloroquinazoline (2.00 g, 10.1 mmol, prepared as described in Prasad, M., et al. Org. Process Res. Dev. 2004, 8, 330-340) was slurried in 1,4-dioxane (20.0 mL). 1,4-Dimethylpiperazine (1.44 mL, 10.6 mmol) was added. The mixture was heated in a CEM microwave at about 150° C. for about 5 min. The material was poured into saturated aqueous NaHCO3/water (1:1, 150 mL). The mixture was extracted with EtOAc (5×100 mL). 20 g of silica gel was added to the combined organics and the volatiles were removed under reduced pressure. The resulting solid was purified by silica gel chromatography eluting with a gradient of 2-10% MeOH/DCM to afford 4-chloro-2-(4-methylpiperazin-1-yl)quinazoline (1.36 g, 52%): LC/MS (Table 1, Method n) Rt=0.51 min; MS m/z 263 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.Cl>N1C=CC=CC=1>[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([NH:4][C:3]2[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=2[CH3:1])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cccc(C)c1N
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2c(C)cccc2C)cc1
Yield: 136.2 %

Procedure:
A solution of 23.4 g (0.12 mole) of 2,6-dimethylaniline and 40.5 g (0.19 mole) of p-toluenesulfonyl chloride in 75 ml of pyridine was heated at reflux for three hours. The mixture was cooled and poured into vigorously stirred 2N hydrochloric acid. The crude product was recrystallized from ethanol to give 45 g of the title compound. Structure assignment was supported by the nmr spectrum and by elemental analysis.
Reaction SMILES: [I:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1>ClCCl.[O-2].[Mn+2]>[I:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1
Reactant: OCc1ccc(I)nc1
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ccc(I)nc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 73.9 %

Procedure:
86 g (987 mol) of manganese (II) oxide are added to a solution of 23.2 g (98.7 mmol) of (6-iodopyrid-3-yl)methanol in 800 mL of dichloromethane. The reaction mixture is stirred at room temperature for 22 hours. The reaction mixture is filtered through Celite and rinsed with dichloromethane. The filtrate is evaporated under vacuum to give 17 g (74%) of 6-iodopyridine-3-carbaldehyde in the form of a yellow solid.
Reaction SMILES: CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH3:23][O:24][C:25](=[O:41])[C@@H:26]([NH:30][C:31](=[O:40])[C:32]1[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=1[Cl:39])[CH2:27][CH:28]=[CH2:29].I[C:43]1[CH:48]=[CH:47][C:46]([N:49]([CH3:56])[C:50]2[N:55]=[CH:54][CH:53]=[CH:52][N:51]=2)=[CH:45][CH:44]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[CH3:23][O:24][C:25](=[O:41])[C@@H:26]([NH:30][C:31](=[O:40])[C:32]1[C:33]([Cl:39])=[CH:34][CH:35]=[CH:36][C:37]=1[Cl:38])[CH2:27]/[CH:28]=[CH:29]/[C:43]1[CH:48]=[CH:47][C:46]([N:49]([CH3:56])[C:50]2[N:51]=[CH:52][CH:53]=[CH:54][N:55]=2)=[CH:45][CH:44]=1
Reactant: CN(c1ccc(I)cc1)c1ncccn1
Reactant: C=CC[C@H](NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](C/C=C/c1ccc(N(C)c2ncccn2)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 66.4 %

Procedure:
Under an argon atmosphere, palladium acetate (93.2 mg) and tris(2-methylphenyl)phosphine (121.2 mg) were added to a suspension of (S)-2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (1.20 g), N-(4-iodophenyl)-N-methylpyrimidin-2-amine (1.24 g) and potassium carbonate (824 mg) in DMF (20 ml), and the resulting mixture was stirred at 80° C. for 3 hours. After cooling the reaction solution to room temperature, ethyl acetate was added thereto, and the resulting mixture was washed twice with water and once with saturated brine, followed by drying the organic layer over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent:cyclohexane/chloroform=1/1 chloroform). The obtained crudely purified product was purified again by column chromatography (silica gel, eluent:cyclohexane/ethyl acetate=4/1→2/1) to obtain (S,E)-2-(2,6-dichlorobenzamido)-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (1.28 g).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:4]=2[CH:3]=1.[NH2:14][NH2:15]>N1C=CC=CC=1>[NH:14]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:4]=2[CH:3]=1)[NH2:15]
Reactant: Clc1cc2c(nn1)CCCCCC2
Reactant: NN
Solvent: c1ccncc1
Product: NNc1cc2c(nn1)CCCCCC2

Procedure:
3-Chloro-5,6,7,8,9,10-hexahydrocycloocta[c]pyridazine (1.36 g) was treated with anhydrous pyridine (10 mL) and anhydrous hydrazine (3 mL) at 100° C. for 5.5 h. The solvent was removed under vacuum and the residue was partitioned between chloroform and saturated aqueous potassium carbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to provide 3-hydrazinyl-5,6,7,8,9,10-hexahydrocycloocta[c]pyridazine; 1H NMR (CDCl3, 300 MHz) 6.71 (s, 1H), 3.01 (m, 2H), 2.68 (m, 2H), 1.70-1.85 (m, 4H), 1.40 (m, 4H) ppm; MS (ES) 193 (M+H).
Reaction SMILES: Cl.C(OC([N:12]1[CH2:16][CH:15]([N:17]([CH3:19])[CH3:18])[CH2:14][N:13]1[C:20](=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=O)C1C=CC=CC=1>CO.[Pd]>[CH3:19][N:17]([CH3:18])[CH:15]1[CH2:14][N:13]([C:20](=[O:29])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[NH:12][CH2:16]1
Reactant: CN(C)C1CN(C(=O)Cc2ccc(F)cc2)N(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN(C)C1CNN(C(=O)Cc2ccc(F)cc2)C1

Procedure:
4-dimethylamino-2-[2-(4-fluorophenyl)acetyl]-pyrazolidine-1-carboxylic acid benzyl ester HCl salt, 21, (4.22 g, 10 mmol) is dissolved in methanol and Pd/C (100 mg) is added. The solution is then hydrogenated of a Parr® Hydrogenation Apparatus 18 hours after which time the catalyst is removed by filtration and the filtrate concentrated in vacuo to afford the desired product.
Reaction SMILES: [CH2:1](O)[CH3:2].[C:4]1([CH3:14])[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:4]1([CH3:14])[CH:5]=[CH:6][C:7]([CH2:10][C:11]([O:13][CH2:1][CH3:2])=[O:12])=[CH:8][CH:9]=1
Reactant: CCO
Reactant: Cc1ccc(CC(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(C)cc1
Yield: 94.7 %

Procedure:
Toluene (100 ml), ethanol (9.20 g, 199.77 mmol) and p-tolylacetic acid (25 g, 166.48 mmol) was added into a 200-ml flask in this order at room temperature and then p-toluenesulfonic acid monohydrate (4.75 g, 24.97 mmol) was charged thereto. The solution was gently heated and subjected to reflux dehydration for 3 to 5 hours. After reflux dehydration, the solution was cooled to around room temperature, added with triethylamine (4.21 g, 41.62 mmol) at room temperature, stirred and then added with silica gel. After stirring for a while, the silica gel was filtered off. After the solvent of the filtrate was removed in vacuum distillation, ethyl p-tolylacetate (28.09 g, 95%) was isolated in distillation.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:14][C:15]1[C:16]([CH3:23])=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O>>[Br:14][C:15]1[C:16]([CH3:23])=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(Br)cccc1C=O
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: Cc1c(Br)cccc1CN1CCN(c2cc(=O)[nH]cn2)CC1

Procedure:
6-[4-(3-Bromo-2-methyl-benzyl)-piperazin-1-yl]-3H -pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 3-bromo-2-methylbenzaldehyde (which may be prepared as described in N. Subasinghe et al. WO 2003099805). 1H NMR (400 MHz, CDCl3) δ 2.45-2.50 (m, 7H), 3.48-3.54 (m, 6H), 5.36 (s, 1H), 6.97-7.01 (m, 1H), 7.16-7.21 (m, 1H), 7.47-7.49 (m, 1H), 7.82 (s, 1H), 11.95 (br s, 1H). Mass spectrum (ES) MH+=363.
Reaction SMILES: [C:1]([CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]2[O:14][CH2:15][O:16][C:9]=12)C(O)=O)#[N:2].CN(C)C(=O)C>O>[C:1]([CH2:3][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]2[O:14][CH2:15][O:16][C:9]=12)#[N:2]
Reactant: N#CC(Cc1cccc2c1OCO2)C(=O)O
Solvent: CC(=O)N(C)C
Solvent: O
Product: N#CCCc1cccc2c1OCO2
Temperature: 150 °C
Yield: 87 %

Procedure:
60.6 g of acid prepared in Stage B are mixed with 115 ml of N,N-dimethylacetamide and the mixture is heated at 150° C. for approximately 2 hours and then allowed to cool, taken up in water and extracted with diethyl ether. The ethereal phases are washed with a sodium hydrogen carbonate solution and then with water and dried to yield the desired compound in the form of an oil.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:16][NH:17][C@H:18]([CH3:33])[CH2:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24]([C:29]([O:31][CH3:32])=[O:30])=[CH:23]3)=[CH:11][C:10]=1[CH2:42][OH:43])C1C=CC=CC=1>[Pd].C(O)C>[Si:35]([O:34][C@H:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([CH2:42][OH:43])[CH:11]=1)[CH2:16][NH:17][C@H:18]([CH3:33])[CH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([C:29]([O:31][CH3:32])=[O:30])=[CH:23]2)([C:38]([CH3:41])([CH3:39])[CH3:40])([CH3:37])[CH3:36]
Reactant: COC(=O)c1cc2cc(C[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(OCc4ccccc4)c(CO)c3)ccc2[nH]1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cc2cc(C[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c(CO)c3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.8 %

Procedure:
A suspension of methyl 5-{(2R)-2-[((2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]propyl}-1H-indole-2-carboxylate (Preparation 13, 0.38 g, 0.63 mmol) and 10% palladium on carbon (78 mg) in ethanol (20 ml) was stirred under an atmosphere of hydrogen (60 psi) at room temperature for 16 hours. The catalyst was filtered off through arbocel and the solvent removed in vacuo to give the title compound as a pale pink foam (316 mg), which was used without further purification.