Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@@H:11]([NH:25][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([Cl:34])[C:27]=1[CH3:35])[C:12]1[O:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)=[N:15][N:16]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[Cl:34][C:28]1[C:27]([CH3:35])=[C:26]([NH:25][C@@H:11]([C:12]2[O:13][C:14]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=3)=[N:15][N:16]=2)[CH2:10][CH2:9][OH:8])[CH:33]=[CH:32][C:29]=1[C:30]#[N:31]
Reactant: Cc1c(N[C@H](CCO[Si](C)(C)C(C)(C)C)c2nnc(-c3ccc(C#N)cc3)o2)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(N[C@H](CCO)c2nnc(-c3ccc(C#N)cc3)o2)ccc(C#N)c1Cl
Temperature: -40 °C
Yield: 0 %

Procedure:
To a 25 mL round bottom flask equipped with a magnetic stirrer and a septum was added (R)-4-(3-(tert-butyldimethylsilyloxy)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2-chloro-3-methylbenzonitrile (900 mg, 177 mmol), which was then dissolved in anhydrous THF (50 mL) under an atmosphere of nitrogen and cooled to −40° C. To this was added the tetrabutylammonium fluoride as a 1M solution in THF (2.13 mL, 2.13 mmol) producing an instant color change to yellow. The mixture was then allowed to warm to −20° C. over a period of 2 h, at which point TLC analysis suggested the reaction was complete. The solvent was then removed under reduced pressure to yield a dark brown residue. This residue was taken up in EtOAc (40 mL) and washed with water (2×25 mL), brine (1×25 mL) and dried over Na2SO4. The solution was then filtered and concentrated under reduced pressure using rotary evaporation to reveal a yellow solid (1.08 g). Purification by flash column chromatography [EtOAc-hexanes (1:1) as eluent] afforded the title compound as a white crystalline solid (0.605 mg, 87%): 1H NMR (400 MHz, Acetone-d6, δ in ppm) 8.21 (d, J=9 Hz, 2H), 7.99 (d, J=9 Hz, 2H), 7.48 (d, J=9 Hz, 1H), 6.92 (d, J=9 Hz, 1H), 6.41 (d, J=9 Hz, 1H), 5.4 (m, 1H), 4.28-4.26 (m, 1H), 3.97-3.77 (m, 1H), 2.58-2.38 (m, 2H), 2.37.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.C[Si]([CH:22]=[N+:23]=[N-:24])(C)C>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:5](=[O:7])[CH:22]=[N+:23]=[N-:24])[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: [N-]=[N+]=CC(=O)c1ccc(Cl)c(Br)c1
Temperature: -5 °C

Procedure:
To a mixture of 3-bromo-4-chlorobenzoic acid (1.51 g, 6.4 mmol, 1.00 eq.) in DCM (25 mL) cooled at −5° C., oxalylchlorid (0.8 mL, 9.6 mmol, 1.50 eq.) and 4 drops of DMF were added. The reaction mixture was warmed to r.t. over 20 hours. The mixture was concentrated in vacuo. The resulting oil was dissolved in THF (50 mL) and cooled to −5° C. (Trimethylsilyl)diazomethane solution (2.0 M in hexanes, 7.2 mL, 14.4 mmol, 2.25 eq.) was added and the mixture was allowed to warm to r.t. over 18 hours. The mixture was concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 60 fractions of 45 mL, Heptane to Heptane+20% AcOEt) to yield 1-(3-bromo-4-chloro-phenyl)-2-diazo-ethanone as a yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([S:14]([NH:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][S:32]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([N:41](C(OC(C)(C)C)=O)[C:42]([NH2:51])=[N:43]C(OC(C)(C)C)=O)[CH:36]=3)(=[O:34])=[O:33])[CH:26]=2)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[C:8]1([S:14]([NH:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][S:32]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([NH:41][C:42]([NH2:51])=[NH:43])[CH:36]=3)(=[O:34])=[O:33])[CH:26]=2)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:15])=[O:16])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)CC(NS(=O)(=O)c1ccccc1)c1cccc(NS(=O)(=O)c2cccc(N(C(=O)OC(C)(C)C)C(N)=NC(=O)OC(C)(C)C)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC(NS(=O)(=O)c1ccccc1)c1cccc(NS(=O)(=O)c2cccc(NC(=N)N)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.6 %

Procedure:
2 ml of trifluoroacetic acid were added to a solution of 246 mg of (1g) in 2 ml of methylene chloride. The reaction was stirred at room temperature for 4 h and the solvent was then removed on a rotary evaporator. 100 mg of a viscous oil were obtained by means of chromatographic purification (dichloromethane/methanol 1:1).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]1=[N:12][NH2:13].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[CH:15]=1.[OH-].[Na+]>C(O)(=O)C>[CH3:2][N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5]/[C:4]/1=[N:12]/[N:13]=[CH:20][C:16]1[CH:17]=[CH:18][CH:19]=[N:14][CH:15]=1
Reactant: Cn1c(=NN)sc2ccccc21
Reactant: O=Cc1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cn1/c(=N\N=Cc2cccnc2)sc2ccccc21

Procedure:
1.50 g (6.42 mmol) of 2,3-dihydro-3-methyl-2-benzothiazolone hydrazone hydrochloride and 0.69 g (6.42 mmol) of 3-pyridinecarboxaldehyde in 10% acetic acid were stirred at room temperature for 30 minutes. The mixture was then made slightly alkaline with 2N sodium hydroxide solution and the precipitate was suction-filtered off, washed with water and dried under vacuum.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH3:6].[CH3:7][C:8]1[CH:9]=[C:10]([SH:15])[CH:11]=[C:12]([CH3:14])[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[CH2:5]([O:4][CH2:3][CH2:2][S:15][C:10]1[CH:11]=[C:12]([CH3:14])[CH:13]=[C:8]([CH3:7])[CH:9]=1)[CH3:6]
Reactant: Cc1cc(C)cc(S)c1
Reactant: CCOCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCCSc1cc(C)cc(C)c1
Temperature: 25 °C
Yield: 76.2 %

Procedure:
To a solution of 1-chloro-2-ethoxyethane (5.90 mL, 54.3 mmol) and 3,5-dimethylbenzenethiol (5.00 g, 36.2 mmol) in N,N-dimethylformamide (140 mL) were added potassium carbonate (5.50 g, 39.8 mmol) and potassium iodide (0.90 g, 5.43 mmol) under stirring at room temperature, and the mixture was stirred at 80° C. for 5 hr. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with diethyl ether. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane/ethyl acetate=10/1) to give the title compound (5.80 g, yield 76%) as a colorless oil.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH2:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]1[C@H:22]1[NH:27][C:26](=[O:28])[C@@H:25]([C@@H:29]([CH3:32])[CH2:30][CH3:31])[N:24]([CH:33]([C:44]2[N:45]=[C:46]([CH3:49])[O:47][CH:48]=2)[C:34](NC2C=CC=CC=2O)=[O:35])[C:23]1=[O:50]>ClCCl>[CH2:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13][CH:14]1[C@H:22]1[NH:27][C:26](=[O:28])[C@@H:25]([C@@H:29]([CH3:32])[CH2:30][CH3:31])[N:24]([CH:33]([C:44]2[N:45]=[C:46]([CH3:49])[O:47][CH:48]=2)[C:34]([OH:35])=[O:2])[C:23]1=[O:50]
Reactant: CC[C@H](C)[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1C(C(=O)Nc1ccccc1O)c1coc(C)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1C(C(=O)O)c1coc(C)n1
Reaction time: 16 h
Yield: 38.4 %

Procedure:
Carbonyldiimidazole (352 mg, 1.6 equiv.) was added to a solution of 2-{(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinyl}-N-(2-hydroxyphenyl)-2-(2-methyl-1,3-oxazol-4-yl)acetamide (11.8 g pre-dried in vacuo over P4O10 for 24 hours) in dichloromethane (20 mL) and the solution was left at room temperature for 16 hr. The mixture was evaporated and the residue dissolved in acetone (20 ml) and water (20 ml) added, followed by addition of 2NHCl (2 ml) and the mixture left at room temperature for 4.5 hr. This was extracted with ethylacetate (2×30 ml) and the combined organic phase dried via a hydrophobic frit and evaporated. The residue was taken up in ethylacetate (30 ml) washed with 2NHCl (2×10 ml) and then extracted with saturated sodium bicarbonate solution (2×15 ml). The combined aqueous phase was acidifed with 2NHCl and extracted with ethylacetate (2×20 ml) and the combined organic phase washed with brine dried via a hydrophobic frit and evaporated to give {(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinyl}(2-methyl-1,3-oxazol-4-yl)acetic acid (0,355 mg, 73%) as a white solid.
Reaction SMILES: O[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Cl:18])[CH:11]=2)[C:5]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][N:3]=1.CCN(C1C=CC=CC=1)CC.P(Cl)(Cl)([Cl:37])=O>O>[Cl:37][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Cl:18])[CH:11]=2)[C:5]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc(O)nc1NCc1ccc(OC)c(Cl)c1
Solvent: O
Solvent: CCN(CC)c1ccccc1
Product: CCOC(=O)c1cnc(Cl)nc1NCc1ccc(OC)c(Cl)c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-hydroxy-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine (prepared in Example 92) 500 mg, diethylaniline 2 ml and phosphoryl chloride 4 ml is stirred at 80° C. for 30 minutes and then at 100° C. for 5 hours. After cooling, the reaction solution is poured into water in ice and the mixture is stirred at room temperature for 30 minutes. The product is extracted with ethyl acetate and the organic layer is washed with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by silica gel chromatography (silica gel 7 g, solvent; chloroform) to give 2-chloro-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine as a slightly yellow crystalline powder, 375 mg. mp 114–115° C. MS(m/z): 356(M+H)+
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([CH3:53])([CH3:52])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:47])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[N:29][C:30]([O:36]CC4C=CC(OC)=CC=4)=[C:31]([O:33][CH2:34][CH3:35])[CH:32]=3)=[C:23]([F:46])[CH:22]=2)=[CH:14][C:13]=1[C:48]([F:51])([F:50])[F:49])(C(C)(C)C)(C)C.Cl>>[CH2:34]([O:33][C:31]1[C:30](=[O:36])[NH:29][CH:28]=[C:27]([C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:19]([NH:18][C:15]3[CH:16]=[CH:17][C:12]([CH2:11][C:10]([CH3:52])([CH3:53])[CH2:9][OH:8])=[C:13]([C:48]([F:50])([F:51])[F:49])[CH:14]=3)=[O:47])=[CH:22][C:23]=2[F:46])[CH:32]=1)[CH3:35]
Reactant: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(CC(C)(C)CO[Si](C)(C)C(C)(C)C)c(C(F)(F)F)c3)cc2F)cnc1OCc1ccc(OC)cc1
Agent: Cl
Product: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(CC(C)(C)CO)c(C(F)(F)F)c3)cc2F)c[nH]c1=O
Yield: 55.3 %

Procedure:
A solution of N-(4-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-3-(trifluoro methyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-3-fluorophenyl)acetamide (100 mg, 0.132 mmol) in HCl (MeOH, 5 mL, 20.00 mmol) was stirred at 20° C. After LCMS analysis showed the starting material had disappeared, the solvent was removed in vacuo. The crude product was purified by preparative HPLC to yield a white solid of 2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-3-fluorophenyl)-N-(4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide (37.98 mg, 0.073 mmol, 55.1% yield): 1H NMR (400 MHz, CD3OD) 7.94 (d, J=2.2 Hz, 1H), 7.70 (dd, J=2.0, 8.4 Hz, 1H), 7.51-7.45 (m, 1H), 7.45-7.37 (m, 3H), 7.28-7.21 (m, 2H), 4.15 (m, 2H), 3.75 (s, 2H), 3.29 (broad s, 2H), 2.77 (s, 2H), 1.46 (t, J=6.9 Hz, 3H), 0.82 (s, 6H); ES-LCMS m/z 521.2 (M+H).
Reaction SMILES: [CH3:1][C@@H:2]([OH:5])[CH2:3][CH3:4].CCN(CC)CC.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl>[CH3:13][S:14]([O:5][C@H:2]([CH3:1])[CH2:3][CH3:4])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: CC[C@@H](C)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H](C)OS(C)(=O)=O
Temperature: 0 °C

Procedure:
An ice cold solution of (R)-2-butanol (888 mg) in DCM (15 ml) was treated with Et3N (1.26 ml) and followed by dropwise addition of methanesulfonyl chloride (0.52 ml). After 1 h the solution was washed with saturated sodium hydrogen carbonate solution (5 ml), water (2×5 ml), brine (5 ml), dried (MgSO4) and evaporated to give the title compound (D33)(0.9 g). 1H NMR δ (CDCl3): 4.74 (1H, m), 3.00 (3H, s), 1.67 (2H, m), 1.41 (1H, d, J=6.5 Hz), 0.99 (3H, t, J=7.5 Hz).
Reaction SMILES: [H-].[Na+].[CH2:3]1COCC1.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]3[C:30](=[O:31])[C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[N:27]=[N:26]3)[CH2:19][CH2:18]2)=[CH:9]1.IC>O>[CH3:3][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]3[C:30](=[O:31])[C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[N:27]=[N:26]3)[CH2:19][CH2:18]2)=[CH:9]1
Reactant: C1CCOC1
Reactant: O=c1c2ccccc2nnn1CCN1CCC(c2c[nH]c3ccccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: Cn1cc(C2CCN(CCn3nnc4ccccc4c3=O)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41 %

Procedure:
A dried flask under nitrogen was loaded with sodium hydride (0.015 g, 0.37 mmol) and THF (10 mL). At 0° C. 3-{2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl}-1,2,3-benzotriazin-4(3H)-one (0.07 g, 0.19 mmol), was added and the mixture stirred for 15 minutes. Keeping the reaction temperature at 0° C., the iodomethane was added dropwise (0.01 mL, 0.19 mmol). This was allowed to warm to room temperature and stir overnight. Water was slowly added to the mixture to quench and the organics were extracted in chloroform, washed with water and dried over Na2SO4, filtered and concentrated. The residue was chromatograhed using silica and a 2% methanol:chloroform system. 0.03 g of 3-{2-[4-(1-methyl-1H-indol-3-yl)-1-piperidinyl]ethyl}-1,2,3-benzotriazin-4(3H)-one was isolated as an orange solid. Yield 41%; MS: 388.3 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 1.80 (q, 2H), 2.03 (d, 2H), 2.31 (t, 2H), 2.81 (m, 1H), 2.96 (t, 2H), 3.16 (d, 2H), 3.73 (s, 3H), 4.68 (t, J=5.19 Hz, 2H), 6.79 (s, 1H), 7.06 (t, 1H), 7.20 (t, 1H), 7.28 (m, 1H), 7.60 (d, 1H), 7.81 (t, 1H), 7.95 (t, 1H), 8.16 (d, 1H), 8.37 (d, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][OH:10])[C:5]([F:11])=[C:4]([F:12])[C:3]=1[CH2:13][OH:14].O.[OH-].[Na+].S(OC)(O[CH3:22])(=O)=O>C1(C)C=CC=CC=1>[CH3:22][O:14][CH2:13][C:3]1[C:2]([F:1])=[C:7]([F:8])[C:6]([CH2:9][OH:10])=[C:5]([F:11])[C:4]=1[F:12]
Reactant: OCc1c(F)c(F)c(CO)c(F)c1F
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: COCc1c(F)c(F)c(CO)c(F)c1F
Temperature: 65 °C
Yield: 100.8 %

Procedure:
Into a reaction vessel that was charged nitrogen, 5.00 g (23.1 mmol) of 2,3,5,6-tetrafluoro-1,4-benzenedimethanol, 15.00 g of water and 6.85 g (46.3 mmol) of 27% aqueous sodium hydroxide solution were charged subsequently, and heated to 65° C. with stirring. The starting compound was completely dissolved to be clear solution. Then, the reaction mixture was allowed to cool to room temperature with stirring. At this time, some precipitate was observed. To the reaction mixture, 20.0 g of toluene was added and then 4.33 g (32.6 mmol) of dimethyl sulfate was added dropwise over 7.5 hours at room temperature. After the addition, the pH of the aqueous layer became 13.5. The layers of the reaction mixture were separated, and the pH of the aqueous layer was adjusted to about 3 by adding 10% sulfric acid. The aqueous layer was extracted with 30 ml of ethyl acetate, and the combined organic layers were washed- with 30 ml of water, concentrated, and dried under a reduced pressure to give 5.22 g of crude 4-methoxymethyl-2,3,5,6-tetrafluorobenzenemethanol. The crude 4-methoxymethyl-2,3,5,6-tetrafluorobenzenemethanol was subjected to content analysis by GC internal standard method (Analytical method 1 given later). GC area percentage of the crude product: 85% of the objective compound, 1% of the starting compound and 13% of the by-product compound Content analysis by GC internal standard method: 85% of the objective compound and 86% of the yield of pure compound
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl.[CH3:29][O:30][C:31](=[O:38])[C@H:32]([C@H:34]([CH2:36][CH3:37])[CH3:35])[NH2:33]>C(Cl)Cl>[CH3:29][O:30][C:31](=[O:38])[CH:32]([NH:33][C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:9])[CH:34]([CH3:35])[CH2:36][CH3:37]
Reactant: O=C(O)c1cccnc1
Reactant: CC[C@H](C)[C@H](N)C(=O)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(C)C(NC(=O)c1cccnc1)C(=O)OC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 70.2 %

Procedure:
To a solution of nicotinic acid (2.0 g, 16.5 mmol) in DCM (20 mL), was added N-methylmorpholine (6.9 mL, 49.5 mmol), EDCI.HCl (6.3 g, 33.0 mmol) and isoleucine methyl ester (3.0 g, 16.5 mmol). The mixture was allowed to stir at room temperature (25° C.) over 2.5 h under nitrogen atmosphere. The resulting mixture was diluted with DCM (200 mL), washed with water (3×100 mL) and dried over sodium sulphate. The crude product obtained upon evaporation of the solvent was further purified by silica gel column chromatography to obtain product as yellow solid (2.9 g, 72%).
Reaction SMILES: [CH3:1][C:2]1([SH:15])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Li+].[CH3:17][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[CH3:1][C:2]1([S:15][CH3:17])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CC1(S)CCN(C(=O)OC(C)(C)C)CC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CSC1(C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Yield: 96.8 %

Procedure:
To a solution of tert-butyl 4-methyl-4-sulfanyl-piperidine-1-carboxylate (380 mg, 1.642 mmol) in THF (5 mL) cooled to −78° C. was added LiHMDS (1.724 mL of 1 M, 1.724 mmol) and the solution stirred for 10 mins before MeI (256.3 mg, 0.1124 mL, 1.806 mmol) was added and the solution allowed to warm to 0° C. over approximately 1 h. The reaction was then quenched carefully by the addition of saturated ammonium chloride and extracted into EtOAc. The aqueous was further extracted with EtOAc and the combined organics were washed with brine, dried (MgSO4) and concentrated to give a yellow oil (390 mg, 96%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)[C:3]1=[O:19].[CH3:20][O:21][C:22]1[CH:31]=[C:30]2[C:25]([CH:26]=[CH:27][C:28]([S:32](Cl)(=[O:34])=[O:33])=[CH:29]2)=[CH:24][CH:23]=1>C(Cl)Cl>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][S:32]([C:28]3[CH:27]=[CH:26][C:25]4[C:30](=[CH:31][C:22]([O:21][CH3:20])=[CH:23][CH:24]=4)[CH:29]=3)(=[O:34])=[O:33])[C:3]2=[O:19])=[CH:10][C:11]=1[N+:16]([O-:18])=[O:17]
Reactant: Nc1ccc(CCN2CC[C@H](N)C2=O)cc1[N+](=O)[O-]
Reactant: COc1ccc2ccc(S(=O)(=O)Cl)cc2c1
Solvent: ClCCl
Product: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(CCc4ccc(N)c([N+](=O)[O-])c4)C3=O)cc2c1

Procedure:
The title compound is prepared in CH2Cl2 instead of CH3CN as described in EXAMPLE 1, Part K using 3-(S)-amino-1-[2-(4-amino-3-nitrophenyl)-ethyl]-pyrrolidin-2-one in place of 7-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-1-chloro-isoquinoline hydrochloride and 7-methoxynaphthalene-2-sulfonyl chloride as prepared in EXAMPLE 1, Part J. After similar workup, the organic phase is concentrated in vacuo to afford the title compound as a pale yellow solid which is used as is in the subsequent step.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:24]([O:27][C:28]1[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=1[CH:30]=[CH:31][C:32](O)=[O:33])(=[O:26])[CH3:25].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:24]([O:27][C:28]1[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=1[CH:30]=[CH:31][C:32]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=1)=[O:33])(=[O:26])[CH3:25]
Reactant: CC(=O)Oc1ccccc1C=CC(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1ccccc1OC(C)=O
Yield: 68 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (8.0 g), triethylamine (5.4 mL), 2-acetoxycinnamic acid (8.1 g), WSC.HCl (7.5 g), and methylene chloride (200 mL), to give the captioned compound (8.8 g, 68%) as crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([N:12]([CH2:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=3)=[O:14])[CH2:9]2)=[CH:4][CH:3]=1.[C:34](Cl)(=[O:38])[CH:35]([CH3:37])[CH3:36].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:23][C:18]1[CH:17]=[C:16]([NH:15][C:13](=[O:14])[N:12]([CH:8]2[CH2:9][C:10]3[CH:11]=[C:2]([NH:1][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:3]=[CH:4][C:5]=3[CH2:6][CH2:7]2)[CH2:24][CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: CC(C)C(=O)Cl
Reactant: CN1CCN(CCCN(C(=O)Nc2ccc(F)c(Cl)c2)C2CCc3ccc(N)cc3C2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)Nc1ccc2c(c1)CC(N(CCCN1CCN(C)CC1)C(=O)Nc1ccc(F)c(Cl)c1)CC2
Reaction time: 16 h
Yield: 87.5 %

Procedure:
To a solution of 1-(7-amino-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-(3-chloro-4-fluoro-phenyl)-1-[3-(4-methyl-piperazin-1-yl)-propyl]-urea (Preparative Example 27, 0.020 g, 0.042 mmol) in CH2Cl2 (0.2 mL) at 0° C. were added isobutyryl chloride (0.0054 mL, 0.052 mmol) and DIEA (0.026 mL, 0.15 mmol). After stirring from 0° C. to room temperature for 16 hours, the mixture was concentrated in vacuo and the residue was purified by preparative HPLC to give 0.020 g (88%) of N-(7-{3-(3-chloro-4-fluoro-phenyl)-1-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-5,6,7,8-tetrahydro-naphthalen-2-yl)-isobuty ramide as a light yellow gum. 1H NMR (300 MHz, CD3OD): δ 7.60 (dd, 1H, J=6.9, 2.4 Hz), 7.40 (d, 1H, J=2.1 Hz), 7.30 (ddd, 1H, J=9.0, 4.2, 2.4 Hz), 7.20 (dd, 1H, J=8.4, 2.1 Hz), 7.15 (t, 1H, J=9.0 Hz), 7.05 (d, 1H, J=8.4 Hz), 4.31 (m, 1H), 3.62 (m, 8H), 3.49 (m, 2H), 3.27 (t, 2H, J=6.9 Hz), 2.98 (m, 7H), 2.10 (m, 4H), 1.38 (dd, 1H, J=6.6, 2.7 Hz), 1.19 (d, 6H, J=6.6 Hz). MS-ESI: 544.1 (M+H+).
Reaction SMILES: [CH:1]1([C:6](=[NH:8])[NH2:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][O-:10].[Na+]>C(O)C>[CH:1]1([C:6]2[NH:7][C:9](=[O:10])[CH:5]=[C:1]([CH2:2][CH3:3])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N=C(N)C1CCCC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCc1cc(=O)[nH]c(C2CCCC2)n1
Temperature: 85 °C
Yield: 122.1 %

Procedure:
A solution of cyclopentanecarboximidamide (8.5 g, 75.8 mmol) in ethanol (150 mL) was treated with ethyl propionaylacetate (13.7 g, 94.7 mmol), followed by the addition of sodium methoxide (4.9 g, 90.9 mmol). The mixture was then heated to 85° C. overnight. After this time, the mixture was cooled and concentrated to a volume of approximately 50 mL. Then, 2M HCl in EtOH (68 mL) was added slowly. The resulting precipitate was filtered, washed with water and ether, and the residue was dried on a high vacuum overnight to afford the title compound (8.9 g, crude) as a pink solid. MW=192.26. 1H NMR (DMSO-d6, 500 MHz) δ 12.00 (s, 1H), 6.14 (s, 1H), 3.01 (quin, J=8.0 Hz, 1H), 2.55 (q, J=7.5 Hz, 2H), 2.13-2.01 (m, 2H), 1.94-1.77 (m, 4H), 1.74-1.63 (m, 2H), 1.22 (t, J=7.5 Hz, 3H); APCI MS m/z 193 [M+H]+.