Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([O:7][CH:8]([CH3:10])[CH3:9])[C:3]=1[C:11]#[N:12].[CH3:13][N:14]=[C:15]=[O:16].C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC>O1CCCC1>[CH3:13][NH:14][C:15]([NH:1][C:2]1[S:6][N:5]=[C:4]([O:7][CH:8]([CH3:10])[CH3:9])[C:3]=1[C:11]#[N:12])=[O:16]
Reactant: CC(C)Oc1nsc(N)c1C#N
Reactant: CN=C=O
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: C1CCOC1
Product: CNC(=O)Nc1snc(OC(C)C)c1C#N
Yield: 74.9 %

Procedure:
In the manner of Example V D, a mixture of 11 g of 5-amino-4-cyano-3-isopropoxyisothiazole and 6.8 g of methyl isocyanate in 50 ml of dry tetrahydrofuran containing 2 ml of dibutyltin diacetate were allowed to react under reflux overnight. Volatile materials were removed under reduced pressure and the residue was recrystallized from ethyl acetate to yield 10.8 g of 1-methyl-3-(4-cyano-3-isopropoxy-5-isothiazolyl)urea, mp 238° (decomposes.) The ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [CH2:1]([P:12](=[O:21])([O:17][CH:18]([CH3:20])[CH3:19])[O:13][CH:14]([CH3:16])[CH3:15])[P:2](=[O:11])([O:7][CH:8]([CH3:10])[CH3:9])[O:3][CH:4]([CH3:6])[CH3:5].C=O.[CH3:24]NC>CO>[C:1]([P:2](=[O:11])([O:7][CH:8]([CH3:9])[CH3:10])[O:3][CH:4]([CH3:6])[CH3:5])([P:12](=[O:21])([O:13][CH:14]([CH3:16])[CH3:15])[O:17][CH:18]([CH3:20])[CH3:19])=[CH2:24]
Reactant: CC(C)OP(=O)(CP(=O)(OC(C)C)OC(C)C)OC(C)C
Reactant: CNC
Agent: C=O
Solvent: CO
Product: C=C(P(=O)(OC(C)C)OC(C)C)P(=O)(OC(C)C)OC(C)C
Yield: 24.3 %

Procedure:
11.95 g (34.7 mmol) of tetraisopropyl methylenebisphosphonate, 5.2 g (173.5 mmol) of paraformaldehyde and 2.54 g (34.7 mmol) of dimethylamine are combined with the same reactants and at the same conditions as described above in Example I. This mixture is then refluxed for 117 hours. After the methanol has been eliminated as described above in Example I, 3.0 g of tetraisopropyl ethenylidenebisphosphonate is produced as a clear liquid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][N:27]1[C:23](=[O:33])[C:24]2[C:25](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:26]1=[O:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 1,4-dibenzyl-2-(hydroxymethyl)piperazine (1.51 g), phthalimide (0.790 g) and triphenylphosphine (1.40 g) in tetrahydrofuran (20 ml) was added a 40% toluene solution (2.34 ml) of diethyl azodicarboxylate under ice cooling. The resulting mixture was stirred at room temperature for 6 hours. Furthermore, 1,4-dibenzyl-2-(hydroxymethyl)piperazine (0.87 g), phthalimide (0.486 g), triphenylphosphine (0.81 g) and tetrahydrofuran (5 ml) were added to the reaction mixture, followed by the addition of a 40% toluene solution (1.34 ml) of diethyl azodicarboxylate under ice cooling. The resulting mixture was stirred at room temperature for 18.5 hours. Phthalimide (0.405 g) and a 40% toluene solution (1.10 ml) of diethyl azodicarboxylate were added under ice cooling, followed by stirring at room temperature for 20 hours. The solvent was distilled off under reduced pressure. The residue was subjected to column chromatography twice (3% methanol—methylene chloride for the first time and ethyl acetate/hexane=1/3 for the second time) using as a carrier silica gel, whereby a crude product was obtained. The crude product was crystallized from hexane - methylene chloride, collected by filtration and washed with hexane, whereby the title compound (0.243 g) was obtained as colorless powder.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:8][N:7]([CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:6](=[O:18])[CH2:5][CH2:4][NH:3]1.I[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([F:29])([F:28])[F:27]>>[CH3:1][C@@H:2]1[CH2:8][N:7]([CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:6](=[O:18])[CH2:5][CH2:4][N:3]1[C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=1
Reactant: FC(F)(F)c1ccccc1I
Reactant: C[C@@H]1CN(CCCN2CCCCC2)C(=O)CCN1
Product: C[C@@H]1CN(CCCN2CCCCC2)C(=O)CCN1c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from (R)-2-methyl-4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one and iodobenzotrifluoride in analogy to example 33. MS: 398.3 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27]3[C:19]=2[C:20]2[CH:21]=[CH:22][C:23]([C:33](O)=[O:34])=[CH:24][C:25]=2[NH:26]3)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:50][N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1>C1COCC1.C(Cl)Cl.CN(C=O)C>[C:31]([C:28]1[C:27]2[NH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:33]([N:54]4[CH2:55][CH2:56][N:51]([CH3:50])[CH2:52][CH2:53]4)=[O:34])[CH:24]=3)[C:19]=2[C:18]([N:14]2[CH2:15][CH2:16][CH2:17][C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13]2)=[CH:30][CH:29]=1)#[N:32]
Reactant: N#Cc1ccc(N2CCC[C@@H](NC(=O)OCc3ccccc3)C2)c2c1[nH]c1cc(C(=O)O)ccc12
Reactant: CN1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: ClCCCl
Product: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C#N)ccc(N4CCC[C@@H](NC(=O)OCc5ccccc5)C4)c23)CC1
Yield: 39.3 %

Procedure:
Step 4 A solution of (R)-5-(3-(benzyloxycarbonylamino)piperidin-1-yl)-8-cyano-9H-carbazole-2-carboxylic acid (130 mg, 0.277 mmol), EDC (74.5 mg, 0.388 mmol), HOBT (59.5 mg, 0.388 mmol), and 1-methylpiperazine (0.092 mL, 0.832 mmol) in THF-DCM-DMF (4:1:1, 6 mL) was stirred at rt over a weekend. The mixture was concentrated and partitioned between EtOAc and NaHCO3 (aq). The organic phase was washed with brine, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 100:0 to 92.5:7.5 DCM-2 M methanolic ammonia) to provide (R)-benzyl 1-(1-cyano-7-(4-methylpiperazine-1-carbonyl)-9H-carbazol-4-yl)piperidin-3-ylcarbamate as a yellow solid (60 mg). 1H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H) 8.09 (d, J=8.13 Hz, 1H) 7.82 (d, J=8.35 Hz, 1H) 7.64 (s, 1H) 7.49 (d, J=7.69 Hz, 1H) 7.24-7.40 (m, 6 H) 6.93 (d, J=8.35 Hz, 1H) 4.87-5.11 (m, 2H) 3.00-3.96 (m, 12H) 2.83 (s, 3H) 2.55-2.70 (m, 1H) 1.73-2.08 (m, 3H) 1.34-1.57 (m, 1H).). Mass spectrum m/z 551.2 (M+H)+.
Reaction SMILES: Cl.O1CCOCC1.C(OC([N:15]1[C@H:19]([C:20]2[NH:21][CH:22]=[C:23]([C:25]3[CH:26]=[C:27]4[C:32](=[CH:33][CH:34]=3)[CH:31]=[C:30]([C:35]3[CH:40]=[CH:39][C:38]([C:41]5[N:42]=[C:43]([C@H:46]6[N:50](C(OC(C)(C)C)=O)[C@H:49]7[CH2:58][CH2:59][CH2:60][C@H:48]7[CH2:47]6)[NH:44][CH:45]=5)=[CH:37][CH:36]=3)[CH:29]=[CH:28]4)[N:24]=2)[CH2:18][C@@H:17]2[CH2:61][CH2:62][CH2:63][C@H:16]12)=O)(C)(C)C.C(Cl)Cl>C1(C)C=CC=CC=1>[NH:15]1[C@H:19]([C:20]2[NH:21][CH:22]=[C:23]([C:25]3[CH:26]=[C:27]4[C:32](=[CH:33][CH:34]=3)[CH:31]=[C:30]([C:35]3[CH:40]=[CH:39][C:38]([C:41]5[N:42]=[C:43]([C@H:46]6[NH:50][C@H:49]7[CH2:58][CH2:59][CH2:60][C@H:48]7[CH2:47]6)[NH:44][CH:45]=5)=[CH:37][CH:36]=3)[CH:29]=[CH:28]4)[N:24]=2)[CH2:18][C@@H:17]2[CH2:61][CH2:62][CH2:63][C@H:16]12
Reactant: CC(C)(C)OC(=O)N1[C@H](c2nc(-c3ccc(-c4ccc5cc(-c6c[nH]c([C@@H]7C[C@@H]8CCC[C@@H]8N7C(=O)OC(C)(C)C)n6)ccc5c4)cc3)c[nH]2)C[C@@H]2CCC[C@@H]21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: c1cc(-c2c[nH]c([C@@H]3C[C@@H]4CCC[C@@H]4N3)n2)ccc1-c1ccc2cc(-c3c[nH]c([C@@H]4C[C@@H]5CCC[C@@H]5N4)n3)ccc2c1

Procedure:
4N HCl in dioxane (20 equiv) was added to a solution of (2S,3aS,6aS)-tert-butyl 2-(4-(4-(6-(2-((2S,3aS,6aS)-1-(tert-butoxycarbonyl)-octahydrocyclopenta[b]pyrrol-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)hexahydrocyclopenta[b]pyrrole-1(2H)-carboxylate in an. DCM and the mixture was stirred at rt for 2-3 h Anhydrous toluene was added to the resultant yellow suspension and then evaporated to dryness to an HCl salt of (2S,3aS,6aS)-2-(4-(4-(6-(2-((2S,3aS,6aS)-octahydrocyclopenta[b]pyrrol-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)octahydrocyclopenta[b]pyrrole as a beige solid: LC-MS retention time: 2.343 min; m/z 555 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[NH2:19])[O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([NH:11][CH3:12])=[O:10].[Cl:20][C:21]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=S)=[CH:31][C:22]=1[CH2:23][N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1.C(Cl)CCl>CC#N>[Cl:20][C:21]1[CH:34]=[CH:33][C:32]([NH:35][C:36]2[NH:19][C:18]3[CH:17]=[CH:16][C:4]([O:5][C:6]4[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=4)[C:9]([NH:11][CH3:12])=[O:10])=[CH:3][C:2]=3[N:1]=2)=[CH:31][C:22]=1[CH2:23][N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1
Reactant: CN1CCN(Cc2cc(N=C=S)ccc2Cl)CC1
Reactant: CNC(=O)c1cccc(Oc2ccc(N)c(N)c2)c1
Solvent: ClCCCl
Solvent: CC#N
Product: CNC(=O)c1cccc(Oc2ccc3[nH]c(Nc4ccc(Cl)c(CN5CCN(C)CC5)c4)nc3c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(3,4-Diamino-phenoxy)-N-methyl-benzamide (Step C, 400 mg, 1.5 mmol, 1.0 eq.) was dissolved in anh. CH3CN (10 mL) and a solution of 1-(2-chloro-5-isothiocyanato-benzyl)-4-methyl-piperazine (330 mg, 1.2 mmol, 0.8 eq.) in CH3CN (10 mL) was added dropwise. The reaction was stirred at RT for 2 h. EDC (240 mg, 1.3 mmol, 0.9 eq.) was added, the mixture was heated to 80° C. and stirred for 2 h. The CH3CN was evaporated and the crude compound was dissolved in CH2Cl2, washed with water and sat. NaHCO3 (aq.). The organic layer was dried (MgSO4), filtered and concentrated. Further purification by column chromatography (0-10% EtOH/CH2Cl2, two runs were required) gave pure 3-{2-[4-chloro-3-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-1H-benzimidazol-5-yloxy}-N-methyl-benzamide. MS m/z=505.2 (M+H)+; MW Calc'd for C27H29N6O2: 504.20.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([OH:22])=O)[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[NH:19])[NH:15][N+:16]([O-:18])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:38]([O:40][C:41]([CH2:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)=[O:42])[CH3:39]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([N:47]1[CH2:48][CH2:49][CH:44]([CH2:43][C:41]([O:40][CH2:38][CH3:39])=[O:42])[CH2:45][CH2:46]1)=[O:22])[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[NH:19])[NH:15][N+:16]([O-:18])=[O:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)O
Reactant: CCOC(=O)CC1CCNCC1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1CCN(C(=O)[C@H](CCCNC(=N)N[N+](=O)[O-])NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred and cooled suspersion of (S)-Nα -t-butoxycarbonyl-Nω -nitroarginine (3.1 g) in anhydrous tetrahydrofuran (THF) (50 ml) is added triethylamine (0.8 g) dropwise over 5 minutes at -20° C. and stirring is continued for a further 10 minutes. To the stirred mixture is then added isobutyl chloroformate (1.1 g) dropwise over 10 minutes at -20° C. and the mixture is stirred for a further 10 minutes. To the stirred mixture is then added 4-(ethoxycarbonylmethyl)piperidine (1.4 g) in THF (20 ml) dropwise over 10 minutes at -20° C. and then after stirring for a further 10 minutes at -20° the mixture is allowed to warm to room temperature with stirring for 1 hour. The reaction mixture is concentrated by evaporation and the residue is diluted with ethyl acetate (100 ml) and the mixture is washed with portions of water (3×15 ml), aqueous 5% NaHCO3 (2×15 ml), aqueous 10% citric acid (2×15 ml), then water (2×15 ml) and dried (MgSO4). Solvent is evaporated to give an oil which is chromatographed on silica gel using ethyl acetate as eluant to yield 1-((S)-Nα -t-butoxycarbonyl-Nω -nitroarginyl)-4-(ethoxycarbonylmethyl)piperidine as a pale yellow oil, Rf (ethanol)=0.16.
Reaction SMILES: [CH3:1][C@@H:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:9])([CH3:8])[C@H:3]1[C:10](=[O:12])[CH3:11].[H+].[B-](F)(F)(F)F.O(CC)CC>>[CH3:1][CH:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:8])([CH3:9])[CH:3]1[C:10](=[O:12])[CH3:11]
Reactant: CC(=O)[C@H]1[C@H](C)C=CCC1(C)C
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCOCC
Product: CC(=O)C1C(C)C=CCC1(C)C
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
To trans 1-(2,6,6-trimethyl-3-cyclohexen-1-yl)-1-ethanone (4.52 mol; trans/cis=94/5 to 99/1, purity≧99%) stirred under nitrogen at 20° C. was added HBF4.OEt2 (4.54 mmol of HBF4) and [Ru(COD)(methallyl)2] (4.54 mmol) was added consecutively. The resulting solution was heated to 130° C. and stirred over 30 minutes at 130° C. under nitrogen. Afterwards, the resulting mixture was cooled to 20° C. and there was obtained a mixture comprising (% by weight of the final mixture, obtained by GC analysis):
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])[NH:15][C:12]2=[CH:13][N:14]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO.C(O)C>[NH2:8][C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([CH:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[OH:19])[NH:15][C:12]2=[CH:13][N:14]=1
Reactant: O=C(c1ccccc1)c1cc2cc(N(Cc3ccccc3)Cc3ccccc3)ncc2[nH]1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCO
Product: Nc1cc2cc(C(O)c3ccccc3)[nH]c2cn1

Procedure:
A mixture of [5-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridin-2-yl](phenyl)methanone (Example 55) (674 mg, 1.61 mmol), ammonium formate (2.04 g, 32.3 mmol) and 10% palladium on carbon (350 mg, 50% by wt.) in methanol (40.2 mL) and ethanol (40.2 mL) was heated under reflux for 1 h. The reaction mixture was filtered through diatomaceous earth to remove the catalyst. After concentration to dryness, the residue was treated with a small amount of methanol (ca. 3 mL) and a precipitate formed. The solid was filtered, rinsed with a small amount of methanol, and collected. Additional material was obtained from Biotage chromatography of the filtrate. This provided (5-amino-1H-pyrrolo[2,3-c]pyridin-2-yl)(phenyl)methanol (119 mg, 32%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ5.81 (1H, s), 5.94 (1H, s), 6.44 (1H, s), 7.27-7.53 (5H, m), 8.06 (1H, s), 8.20 (1H, s), 10.9 (1H, br s); ESI MS m/z 240 [C14H13N3O+H]+; HPLC (Method A) 89.0% (AUC), tR=14.0 min.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:20][S:21][CH2:22][C@H:23]([O:39][C:40](=[O:52])[NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:24][O:25][C:26](=[O:38])[NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=O)C1C=CC=CC=1.C([O-])=O.[NH4+].CO.O>CO.[Pd]>[NH2:11][C@@H:12]([CH2:20][S:21][CH2:22][C@H:23]([O:39][C:40](=[O:52])[NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:24][O:25][C:26](=[O:38])[NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14]
Reactant: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C)OC(=O)NCCCCCCCCCC
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](N)C(=O)OC(C)(C)C)OC(=O)NCCCCCCCCCC
Temperature: 40 °C

Procedure:
A solution of (R)-tert-butyl 2-(benzyloxycarbonylamino)-3-((R)-2,3-bis(decylcarbamoyloxy)propylthio)propanoate (14) in MeOH (0.1 M) was stirred under nitrogen at room temperature. A small scoop (catalytic) of Pd/C was then added and stirred. A solution of ammonium formate (8 eq) in 9:1 MeOH/water was then added, the reaction vessel purged with nitrogen and heated to 40° C. for 4 hours. The reaction was then cooled to room temperature and diluted with EtOAc. The reaction mixture was filtered through celite then Na2SO4 and concentrated. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-60% EtOAc/Hex to afford the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([NH:6][C:7]([C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[F:16][C:17]1([F:33])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:18]1=[O:32]>>[CH2:1]([NH:6][C:7]([C:9]1[N:10]=[N:11][C:12]([N:29]2[CH2:30][CH2:31][CH:26]([N:19]3[C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:17]([F:16])([F:33])[C:18]3=[O:32])[CH2:27][CH2:28]2)=[CH:13][CH:14]=1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCNC(=O)c1ccc(Cl)nn1
Reactant: O=C1N(C2CCNCC2)c2ccccc2C1(F)F
Product: CCCCCNC(=O)c1ccc(N2CCC(N3C(=O)C(F)(F)c4ccccc43)CC2)nn1
Yield: 65 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 6-chloropyridazine-3-carboxylic acid pentylamide in place of 6-chloropyridazine-3-carboxylic acid (3-cyclopropylpropyl)amide to react with 3,3-difluoro-1-piperidin-4-yl-1,3-dihydroindol-2-one, the title compound was obtained as a white powder in 65% yield (0.063 g). m.p. 100-102° C. 1H NMR (300 MHz, CDCl3) δ 8.03 (d, J=9.6 Hz, 2H), 7.92 (br, 1H), 7.54 (m, 1H), 7.41 (t, J=8.1 Hz, 1H), 7.14 (t, J=7.5 Hz, 1H), 7.04 (d, J=9.3 Hz), 6.95 (d, J=7.8 Hz, 1H), 4.70 (m, 2H), 4.41 (m, 1H), 3.50 (m, 2H), 3.12 (t, J=12.3 Hz, 2H), 2.45 (m, 2H), 1.94 (m, 2H), 1.60 (m, 2H), 1.34 (m, 4H), 0.88 (t, J=6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 165.2, 164.8, 163.1, 159.8, 145.0, 142.5 142.4, 133.5, 127.1, 125.2, 123.8, 120.7, 120.4, 120.1, 113.6, 112.4, 110.8, 110.3, 107.0, 50.9, 44.7, 39.4, 29.3, 29.1, 27.8, 22.4, 14.0. MS (ES+) m/z 444.1 (M+1).
Reaction SMILES: [Cl-:1].[Al+3].[Cl-:3].[Cl-].[C:5]1([CH3:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[Cl:1][C:6]1[CH:7]=[C:8]([C:5]([CH3:11])([CH3:10])[CH3:6])[C:9]([Cl:3])=[CH:10][C:5]=1[CH3:11]
Reactant: [Cl-]
Reactant: Cc1ccccc1
Agent: [Al+3]
Product: Cc1cc(Cl)c(C(C)(C)C)cc1Cl
Yield: 270.8 %

Procedure:
After adding a large excess of 2000 g of toluene and 64 g (0.48 mol) of anhydrous aluminum chloride, as a catalyst, to 284 g (1.3 mol) of 2,5-dichloro-4-t-butyltoluene obtained as stated above, the mixture was brought into reaction for 5 hours at room temperature under a vigorous agitation thereof.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>CN(C=O)C>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[CH:5]=1)[CH3:17]
Reactant: CCOC(=O)CBr
Reactant: Oc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 64.1 %

Procedure:
A 50 ml three-necked round-bottomed flask equipped with temperature probe and nitrogen bubbler was charged with Sodium Hydride (785 mg, 19.6 mmol) and DMF (10.0 ml) and cooled to 0° C. A solution of 3-Fluorophenol (2.00 g, 17.8 mmol) in DMF (2.0 ml) was added dropwise maintaining reaction temperature below 10° C. The mixture was stirred for an additional 15 minutes then Ethyl bromoacetate (2.48 ml, 22.3 mmol) was added dropwise maintaining the reaction temperature below 10° C. The reaction was stirred at room temperature for 4 hours. The reaction was then concentrated under reduced pressure and the crude product was taken up in Ethyl acetate, washed with water, dried (Na2SO4), filtered, concentrated and further purified via flash chromatography using 4:1/heptane:Ethyl acetate as eluant. Fractions containing product were combined and concentrated to afford (3-Fluoro-phenoxy)-acetic acid ethyl ester (2.26 g, 69%) as a clear oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][Si](C)(C)C)[CH2:9]OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.[CH2:24]([O:26][C:27](=[O:34])/[CH:28]=[CH:29]/[CH2:30][CH:31]([CH3:33])[CH3:32])[CH3:25]>C(Cl)Cl>[CH2:24]([O:26][C:27]([C@H:28]1[C@H:29]([CH2:30][CH:31]([CH3:32])[CH3:33])[CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12]1)=[O:34])[CH3:25]
Reactant: CCOC(=O)/C=C/CC(C)C
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1CC(C)C
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 44.2 %

Procedure:
N-Benzyl-N-(methoxymethyl)trimethylsilylmethylamine (2.84 g, 12 mmol), followed by TFA (1.0 M solution in CH2Cl2, 1.0 mL, 1 mmol) were added to a solution of (E)-5-methyl-hex-2-enoic acid ethyl ester (1.56 g, 10.0 mmol) in methylene chloride (30 mL) maintained at −5° C. under nitrogen atmosphere. After 15 minutes, the bath was removed and stirring was continued overnight. Saturated sodium bicarbonate was added, and the organic portion was separated, washed with brine, and dried. The product was purified by chromatography on silica gel, and compound was eluted with 20% ethyl acetate in hexane to give (trans)-1-Benzyl-4-isobutyl-pyrrolidine-3-carboxylic acid ethyl ester 3 as an oil (1.28 g, 44%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:9])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:10](Cl)(=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[C:10]([O:9][C:3]1[C:2]([Cl:1])=[CH:7][NH:6][C:5](=[O:8])[CH:4]=1)(=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCC(=O)Cl
Reactant: O=c1cc(O)c(Cl)c[nH]1
Product: CCCCCC(=O)Oc1cc(=O)[nH]cc1Cl
Yield: 39.7 %

Procedure:
The general procedure of Example 3 was followed using 2.00 g of 5-chloro-4-hydroxy-2-pyridone and 2.75 g of hexanoyl chloride, thereby producing 1.33 g of the title compound in a yield of 40%.
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19]([OH:21])=O)[NH:3][C:4](=[O:17])[NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[NH2:22][C@@H:23]([CH3:47])[C:24]([N:26]([C@@H:38]([CH3:46])[CH:39]([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:37]=1[N:36]=[CH:35][CH:34]=[CH:33]2)=[O:25]>>[CH2:41]([O:40][CH:39]([O:43][CH2:44][CH3:45])[C@@H:38]([N:26]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:37]=1[N:36]=[CH:35][CH:34]=[CH:33]2)[C:24](=[O:25])[C@@H:23]([NH:22][C:19](=[O:21])[CH2:18][N:2]([CH3:1])[NH:3][C:4]([NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)=[O:17])[CH3:47])[CH3:46])[CH3:42]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](C)N
Reactant: CN(CC(=O)O)NC(=O)NCc1cccc2ccccc12
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](C)NC(=O)CN(C)NC(=O)NCc1cccc2ccccc12

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(naphthalen-1-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-8) 120 mg (0.42 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-11) 100 mg (0.28 mmol) to obtain the title compound.