Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH:11]([N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]3)[CH3:12])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:45]=[CH:44][CH:43]=[C:42]3[C:38]=2[CH:39]=[N:40][NH:41]3)O1>>[NH:41]1[C:42]2[C:38](=[C:37]([C:2]3[N:3]=[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:5]4[S:10][C:9]([CH:11]([N:13]5[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]5)[CH3:12])=[CH:8][C:6]=4[N:7]=3)[CH:45]=[CH:44][CH:43]=2)[CH:39]=[N:40]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: CC(c1cc2nc(Cl)nc(N3CCOCC3)c2s1)N1CCN(S(C)(=O)=O)CC1
Product: CC(c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1)N1CCN(S(C)(=O)=O)CC1

Procedure:
2-Chloro-6-[1-(4-methanesulfonyl-piperazin-1-yl)-ethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in general procedure A. Purification by column chromatography yielded 332. NMR: CDCl3: 1.56 (3 H, d, J 7.1, Me), 2.62-2.80 (4 H, m, CH2), 2.81 (3 H, s, Me), 3.26-3.31 (4 H, m, CH2), 3.95-3.99 (4 H, m, CH2), 4.02-4.11 (5 H, m), 7.45 (1 H, s, Ar), 7.50 (1 H, apparent triplet, J 8.2, Ar), 7.61 (1 H, d, J 8.2, Ar), 8.28 (1 H, d, J 7.5, Ar) and 9.03 (1 H, s, Ar). MS: (ESI+): MH+ 528.31
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:19](=[O:20])[N:18]([CH3:21])[C:11]3[N:12]=[C:13](SC)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[NH:22][C:23]([NH:25][C:26]1[C:27]([CH3:32])=[N:28][CH:29]=[N:30][CH:31]=1)=[O:24].[CH3:33][NH2:34].C1COCC1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:19](=[O:20])[N:18]([CH3:21])[C:11]3[N:12]=[C:13]([NH:34][CH3:33])[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[NH:22][C:23]([NH:25][C:26]1[C:27]([CH3:32])=[N:28][CH:29]=[N:30][CH:31]=1)=[O:24]
Reactant: CSc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cncnc4C)c3)c(=O)n(C)c2n1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cncnc4C)c3)c(=O)n(C)c2n1
Yield: 38 %

Procedure:
Using a procedure analogous to Example A1, 1-(2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(4-methylpyrimidin-5-yl)urea (300 mg, 0.664 mmol) and 2.0 N methylamine in THF (2.3 mL, 4.53 mmol) were combined to afford 1-(2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(4-methylpyrimidin-5-yl)urea (75 mg, 38% yield). 1H NMR (300 MHz, DMSO-d6), δ 2.45 (s, 3H), 2.88 (s, 3 H), 3.50-3.57 (m, 3 H), 7.23-7.29 (m, 2 H), 7.67-7.79 (m, 1 H), 7.82 (s, 1 H), 8.39-8.42 (m, 1 H), 8.60 (s, 3 H), 8.68 (s, 2 H), 9.13 (m, 1 H); MS (ESI) m/z: 435.2 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=3)[CH2:26][CH2:25]2)=[CH:22][CH:23]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=[N+]([O-])c1cccc(OCCCCCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cccc(OCCCCCN2CCN(c3ccc(F)cc3)CC2)c1
Yield: 94.7 %

Procedure:
To a stirred solution of 1-(5-bromo-pentyloxy)-3-nitro-benzene (432 mg, 1.5 mmol) and 1-(4-fluoro-phenyl)-piperazine (297 mg, 1.65 mmol) in acetonitrile (5 mL) was added potassium carbonate (414 mg, 3.0 mmol). After refluxed for 6 hours, the reaction mixture was quenched with water (10 mL) followed by extraction with ethyl acetate (10 mL×3). The combined organic layers were washed with brine and then concentrated under vacuum. The resulting residue was purified by silica gel column chromatography to give 1-(4-fluoro-phenyl)-4-[5-(3-nitro -phenoxy)-pentyl]-piperazine (549 mg, 1.42 mmol, 94%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([C:14]([OH:16])=[O:15])[CH2:11][C@@H:10]([C:17]([OH:19])=[O:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20](OC(=O)C)(=O)C>>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@H:10]([C:17]([O:19][CH3:20])=[O:18])[CH2:11][C@H:12]([C:14]([OH:16])=[O:15])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1C[C@H](C(=O)O)C[C@H](C(=O)O)C1
Product: COC(=O)[C@@H]1C[C@H](C(=O)O)CN(C(=O)OC(C)(C)C)C1
Temperature: -40 °C
Reaction time: 7 h

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)piperidine-3,5-dicarboxylic acid (222 g) was suspended in acetic anhydride (2 L), and the suspension was heated under reflux for 3 hr. The reaction mixture was concentrated under reduced pressure. Toluene (200 ml) was added and the mixture was concentrated under reduced pressure. This operation was repeated twice. The obtained residue and quinidine (142 g) were dissolved in THF (900 ml), and the mixture was cooled to −40° C. A solution of methanol (161 ml) in THF (100 ml) was added dropwise over 30 min, and the mixture was stirred at the same temperature for 7 hr. THF (about 700 ml) was evaporated under reduced pressure, ethyl acetate was added, and the mixture was washed with 2 N hydrochloric acid. The aqueous layer was extracted with ethyl acetate, the organic layer was combined and the mixture was washed successively with 2 N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure and the obtained residue (106 g) was suspended in ethanol (410 ml). (R)-(+)-1-Phenylethylamine (45 g) was added, and the mixture was dissolved by heating to 75° C. The hot ethanol solution was rapidly filtered, and the filtrate was allowed to stand at room temperature for 12 hr. The resulting colorless crystals were collected by filtration, washed with ethyl acetate-hexane, and then with hexane and air-dried. The obtained solid was suspended in water (490 ml). Saturated aqueous potassium hydrogen sulfate solution (490 ml) was added and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to dryness to give the object compound (148 g) as a solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([OH:11])=O)[C:5]([F:12])=[C:4]([F:13])[C:3]=1[CH3:14].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]1[NH2:43]>C(Cl)Cl.CN(C=O)C>[F:12][C:5]1[C:4]([F:13])=[C:3]([CH3:14])[C:2]([F:1])=[C:7]([F:8])[C:6]=1[C:9]([NH:43][CH:38]1[CH2:39][CH2:40][CH2:41][CH2:42][CH:37]1[CH3:36])=[O:11]
Reactant: Cc1c(F)c(F)c(C(=O)O)c(F)c1F
Reactant: CC1CCCCC1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(F)c(F)c(C(=O)NC2CCCCC2C)c(F)c1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.7 %

Procedure:
2,3,5,6-tetrafluoro-p-toluic acid acid (4.00 g, 19.22 mmol), HOBt (5.19 g, 38.44 mmol) and EDCI (4.42 g 23.06 mmol) were mixed in 200 ml of anhydrous DCM and 30 ml of anhydrous DMF. The mixture was cooled to 0° C. and allowed to stir under Ar for 15 minutes. To the mixture was added 2-methylcyclohexanamine (3.05 mL, 23.06 mmol) and the reaction mixture was allowed to slowly warm to ambient temperature and stirred overnight. The reaction mixture was diluted with DCM, washed with 1N HCl, water, aqueous NaHCO3, water and brine, drying over MgSO4, filtration and removal of solvent in vacuo, afforded the crude product as a pale yellow solid Recrystallization (EtOH/H2O) and drying in vacuo gave 5.23 g of the title compound as a white solid (mixture of 2 diasteromers, 90%). 1H NMR (CDCl3) δ 0.95, 1.01 (d, J=7.0, 6.6 Hz, 3H) 1.1-2.1 (m, 9H), 2.29 (m, 3H), 3.70, 4.29 (m, 1H), 5.65, 5.92 (m, 1H). MS (304.1, M+H). m.p. 202-204° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]1.C(N(CC)CC)C.[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(CCCO)CC1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCCOC(=O)C(C)(C)C)CC1
Reaction time: 8 h

Procedure:
To a stirred solution of 3-[4-(2-methoxyphenyl)-1-piperazinyl]propanol (4.76 g, 0.019 mol) and triethylamine (6 g, 0.06 mol) in 100 mL of methylene chloride was added pivaloyl chloride (2.28 g, 0.019 mol) and stirring was continued overnight at room temperature. The organic layer was washed with water, dried (anhydrous Na2SO4) and evaporated. The title compound was isolated by preparative HPLC and converted to the dihydrochloride salt; mp.=202°-204° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([F:9])[C:3]=1[F:10].[N+:11]([O-])([OH:13])=[O:12]>OS(O)(=O)=O>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:11]([O-:13])=[O:12])=[C:4]([F:9])[C:3]=1[F:10]
Reactant: Cc1cc(F)c(F)c(F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc(F)c(F)c(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
1,2,3-Trifluoro-5-methylbenzene (40 mmol) was added to conc. H2SO4 (50 ml) at 0-5° C. Then the reaction mixture was slowly treated with conc. HNO3 (3.39 ml, 48.44 mmol, 90%) while maintaining the internal temperature below 20° C. The reaction mixture was stirred at room temperature for 16 h and poured onto ice (300 g) and the oily layer was extracted with CH2Cl2 (2×125 ml). The organic layer was washed with water (2×200 ml), brine (200 ml) and dried (MgSO4) and evaporated to obtain the crude product which was purified over flash silica gel chromatography to obtain the title product (6.5 g, 85%). 1H-NMR (300 MHz, CDCl3): δ 6.96 (septet, 1H), 2.39 (s, 3H). 19FNMR (CDCl3): δ −128.18, −141.50, −159.05.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([O:28][C:29](=[O:32])[CH:30]=[CH2:31])([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:24]([O:28][C:29](=[O:32])/[CH:30]=[CH:31]/[C:13]1[CH:12]=[CH:11][C:10]([N:16]2[CH2:17][C:18](=[O:23])[NH:19][S:20]2(=[O:22])=[O:21])=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
To a mixture of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (2.0 g, 4.49 mmol), Pd(OAc)2 (100 mg) and acrylic acid t-butyl ester (0.78 mL, 5.8 mmol) in acetonitrile (15 mL) in a pressure vessel is added triethylamine (3.13, 22.5 mmol) and the mixture is stirred at 100° C. for 6 h. The solution is filtered through Celite, washed with acetonitrile and concentrated to give the title compound. This is used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29].Cl>N1C=CC=CC=1>[ClH:27].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:28](=[O:30])[CH3:29])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)C)C(=O)[C@@H]2OC(C)=O)cc1

Procedure:
A mixture of 6.35 g of (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 65 ml of acetic anhydride and 0.7 ml of pyridine is treated in the same manner as described in Example 2. The product is converted to its hydrochloride and recrystallized from acetone. 4.28 g of (-)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride are thereby obtained.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH3:19][C:20]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22]>>[CH3:19][C:20]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:21]=1[NH:22][C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: Cc1cccc(N)c1C
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: Cc1cccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c1C
Yield: 55.8 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 260 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 242 mg of 2,3-dimethylaniline in place of the 2,4-difluoroaniline. 190 mg of N-(2,3-dimethylphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:13]=[C:12]([C:14](=[O:20])[N:15]([CH3:19])[CH2:16][CH2:17][CH3:18])[CH:11]=[C:7]([C:8]([OH:10])=O)[CH:6]=1)[CH3:2].O[N:23]1[C:27]2C=CC=C[C:26]=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N)C>CN(C=O)C.ClCCl>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:13]=[C:12]([C:14](=[O:20])[N:15]([CH3:19])[CH2:16][CH2:17][CH3:18])[CH:11]=[C:7]([C:8](=[O:10])[NH:23][CH2:27][CH3:26])[CH:6]=1)[CH3:2]
Reactant: CCCN(C)C(=O)c1cc(C(=O)O)cc(C(=O)OCC)c1
Reactant: On1nnc2ccccc21
Agent: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(C(=O)NCC)cc(C(=O)OCC)c1
Yield: 98 %

Procedure:
Stir a solution of 5-(methyl-propylcarbamoyl)-isophthalic acid monoethyl ester (146 mg, 0.5 mmol), 1-hydroxybenzotriazole (74 mg, 0.55 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (110 mg, 0.55 mmol), ethylamine (2 N in THF, 0.275 mL, 0.55 mmol) in 0.75 mL DMF at room temperature overnight. Dilute with dichloromethane (15 mL) and wash with water (5 mL), 0.1 N aqueous citric acid (5 mL), saturated aqueous sodium bicarbonate (5 mL), and saturated aqueous sodium chloride (5 mL). Dry (magnesium sulfate) and concentrate to give the title compound (157 mg, 100%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]2[N:8]([CH2:28][C:29]3[C:30]([CH3:39])=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=3)[C:9](=[O:27])[C:10]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:6]2=[N:5][N:4]=1.[I-].[Na+].CC(C)=[O:44].O>[OH-].[Na+].CCOC(C)=O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[C:6]3[N:7]([C:3]([CH2:2][OH:44])=[N:4][N:5]=3)[N:8]([CH2:28][C:29]3[C:30]([CH3:39])=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=3)[C:9](=[O:27])[C:10]=2[C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)=[CH:13][CH:14]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1c(=O)c(-c2ccc(C#N)cc2)c(-c2ccc(Cl)cc2)c2nnc(CCl)n21
Reactant: CC(C)=O
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc(C(F)(F)F)ccc1Cn1c(=O)c(-c2ccc(C#N)cc2)c(-c2ccc(Cl)cc2)c2nnc(CO)n21
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
To a round bottom flask was added 4-(3-(chloromethyl)-8-(4-chlorophenyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)benzonitrile (30 mg, 0.053 mmol), sodium iodide (40 mg, 0.264 mmol) and acetone (2 ml). The reaction was stirred at room temperature for 8 hr. After this time, water (0.3 ml) was added followed by 1 drop of 1N NaOH. The reaction was stirred at room temperature for an additional 14 hrs. The solution was then diluted with EtOAc (25 ml) and washed with water (2×15 ml) and saturated NaCl (15 ml). The organic layer was dried (MgSO4), filtered and concentrated. The crude material was purified using an ISCO automated chromatography system (4 g silica gel, 20%-50% EtOAC/CH2Cl2) to give the product 4-(8-(4-chlorophenyl)-3-(hydroxymethyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)benzonitrile as a white solid (15 mg, 51% yield). HPLC retention time 2.990 min (Method A); LCMS (M+1)=551.0. 1HNMR (CDCl3, 500 Hz) 7.61(2H, d, J=8.25 Hz), 7.52(1H, d, J=7.7 Hz), 7.30-7.37(7H, m), 6.05(2H, s), 4.60(2H, s), 2.78(3H, s); 13CNMR (CDCl3, 500 Hz) 161.00, 158.90, 156.25, 146.20, 144.10, 137.10, 136.80, 132.80, 131.96, 131.74, 129.90, 129.09, 118.00, (m), 113.00, 100.00, 55.10, 49.10, 22.10.
Reaction SMILES: [C:1]([Si:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:6][CH2:7][CH2:8][C:9]([NH2:11])=[NH:10])([CH3:4])([CH3:3])[CH3:2].CN([CH:27]=[C:28]1[C:33](=[O:34])[CH2:32][CH2:31][CH2:30][C:29]1=O)C>CCO>[C:1]([Si:5]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:6][CH2:7][CH2:8][C:9]1[N:11]=[CH:27][C:28]2[C:33](=[O:34])[CH2:32][CH2:31][CH2:30][C:29]=2[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](OCCC(=N)N)(c1ccccc1)c1ccccc1
Reactant: CN(C)C=C1C(=O)CCCC1=O
Solvent: CCO
Product: CC(C)(C)[Si](OCCc1ncc2c(n1)CCCC2=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 3-(tert-butyl-diphenyl-silanyloxy)-propionamidine (25 g, 77 mmol) and 2-dimethylaminomethylene-cyclohexane-1,3-dione (12.8 g, 77 mmol) in 400 mL of dry EtOH was heated at 80° C. for 3 h. After cooling to RT, the solvent was evaporated. Flash chromatography (SiO2, EtOAc/hexane=1:1) gave the desired compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([N:29]3[CH2:34][CH2:33][CH:32]([O:35][C:36]4[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][C:37]=4[F:44])[CH2:31][CH2:30]3)=[C:20]([NH:25][CH:26]([CH3:28])[CH3:27])[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[F:44][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][C:36]=1[O:35][CH:32]1[CH2:31][CH2:30][N:29]([C:19]2[N:18]=[C:17]3[CH2:16][NH:15][CH2:24][CH2:23][C:22]3=[N:21][C:20]=2[NH:25][CH:26]([CH3:28])[CH3:27])[CH2:34][CH2:33]1)[C:40]#[N:41].[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(C#N)cc3F)CC1)CN(Cc1ccccc1)CC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(C#N)cc3F)CC1)CNCC2
Temperature: 23 °C
Reaction time: 4 h

Procedure:
A mixture of 4-((1-(6-benzyl-2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)-3-fluorobenzonitrile 2,2,2-trifluoroacetate (579 mg, 0.942 mmol) and Pd(OH)2 (20 wt % Pd (dry basis) on carbon, wet, Degussa Type E101 NEW, 198 mg, 0.283 mmol) in THF (10 mL) was stirred under H2 (1.899 mg, 0.942 mmol) at 23° C. for 4 h. The mixture was filtered, rinsed with THF, concentrated via rotary evaporation, and dried in vacuo to give the title compound as a TFA salt (494 mg, 100%) as a brown oil. ESI-MS m/z [M+H]+ 411.4.
Reaction SMILES: [ClH:1].C([CH:6]([NH:12][C:13](=[O:34])[C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]([CH3:33])[CH2:25][CH2:24][N:23]=2)=[CH:16][CH:15]=1)[CH2:7][NH:8]C(=O)[O-])(C)(C)C>C(OCC)C>[ClH:1].[NH2:8][CH2:7][CH2:6][NH:12][C:13](=[O:34])[C:14]1[CH:15]=[CH:16][C:17]([CH:20]=[CH:21][C:22]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]([CH3:33])[CH2:25][CH2:24][N:23]=2)=[CH:18][CH:19]=1
Reactant: CN1CCN=C(/C=C/c2ccc(C(=O)NC(CNC(=O)[O-])C(C)(C)C)cc2)c2ccccc21
Agent: Cl
Solvent: CCOCC
Product: CN1CCN=C(C=Cc2ccc(C(=O)NCCN)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A few drops of a saturated solution of hydrogen chloride in diethyl ether were added to a solution of 15 mg (0.033 mmol) (tert-butyl (E)-[2-[4-[2-(2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-5-yl)-vinyl]-benzamido]ethyl)]carbamate. The mixture was stirred at room temperature for 16 hours and the resultant solid filtered off, dissolved in methanol and evaporated. There was obtained 8 mg of N-(2-aminoethyl)-4-[2-(2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-5-yl)vinyl]benzamide hydrochloride as a dark red gum MS: m/e 349.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2(O)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(Cl)Cl.CCN(S(F)(F)[F:24])CC>CO>[Cl:1][C:2]1[C:7]([C:8]2([F:24])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: OC1(c2cccnc2Cl)CCOCC1
Reactant: CCN(CC)S(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: FC1(c2cccnc2Cl)CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(2-chloropyridin-3-yl)tetrahydro-2H-pyran-4-ol (0.11 g, 0.515 mmol) in DCM (1 mL, 15.54 mmol) was added dropwise DAST (0.102 mL, 0.772 mmol) at room temperature, followed by one drop of MeOH. The resulting mixture was stirred at room temperature for 3 hr. Reaction was quenched with water and extracted with DCM. The recovered residue was advanced to the next step.
Reaction SMILES: ClC(OCC(C)C)=O.[NH:9]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:10]([C:26]([OH:28])=O)[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].CN1CCOCC1.[NH2:43][C@H:44]([C:49]([NH:51][C@H:52]([C:57]([O:59][CH3:60])=[O:58])[CH2:53][CH:54]([CH3:56])[CH3:55])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47].Cl>C(OCC)(=O)C>[NH:9]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:10]([C:26]([NH:43][C@H:44]([C:49]([NH:51][C@H:52]([C:57]([O:59][CH3:60])=[O:58])[CH2:53][CH:54]([CH3:55])[CH3:56])=[O:50])[CH2:45][CH:46]([CH3:47])[CH3:48])=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
Isobutyl chloroformate (13.66 g, 100 mmol) was added dropwise over 15 min at −15 to −10° C. to a solution of Boc-Lys(Z)—OH (38.04 g, 100 mmol) in ethyl acetate (200 g). Another portion of ethyl acetate was added (10 g) and the mixture was stirred for 15 min. 4-Methylmorpholine (10.12 g, 100 mmol) was added dropwise over 15 min at −15 to −10° C., followed by an additional portion of ethyl acetate (10.0 g) and the resulting mixture was stirred for 2 h. In a separate reaction vessel 4-methylmorpholine (10.12 g, 100 mmol) was added dropwise over 15 min, to a solution of H-Leu-Leu-OMe.HCl (29.48 g, 100 mmol) in ethyl acetate (200.0 g) at −23 to −10° C. An additional portion of ethyl acetate (10.0 g) was added followed by the addition of the formed anhydride over 30 to 45 min at a temperature of −8 to −10° C. Another portion of ethyl acetate (30.0 g) was added and the resulting mixture was stirred for 1.5 h. Ethyl acetate (50.00 g) was added, the solution was filtered and the resulting organic filtrate was concentrated in vacuo. The resulting solid was recrystallized from petroleum ether (bp 100 to 125) to give Boc-Lys(Z)-Leu-Leu-OMe (55.9 g, 90.2%).