Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:20])([CH3:19])[C:7]1=[O:21].[NH4+].[Cl-]>[Zn].O>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]2[O:9][C:8]([CH3:20])([CH3:19])[C:7](=[O:21])[N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:11]=2[CH:12]=1
Reactant: COCCCN1C(=O)C(C)(C)Oc2ccc([N+](=O)[O-])cc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Product: COCCCN1C(=O)C(C)(C)Oc2ccc(N)cc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 105.2 %

Procedure:
At room temperature, an ethanolic solution (80 ml) of 4-(3-methoxy-propyl)-2,2-dimethyl-6-nitro-4H-benzo[1,4]oxazin-3-one (9.76 g, 33.2 mmol) is treated with H2O (80 ml), NH4Cl (3.58 g, 66.9 mmol), and powdered Zn (10.97 g, 0.17 mol), heated to 80° C., stirred for 2 h under reflux, cooled to room temperature, and filtered via celite pad. After washing the cake with CH2Cl2 for several times, the both layers of the combined filtrate are separated. The aq. layer is treated with 5N NaOH (6.0 ml) to adjust its pH 9˜10, and extracted with CH2Cl2 (3×100 ml). The combined org. layer is washed with sat. aqueous solution of NaHCO3 (100 ml) and brine (50 ml), dried (Na2SO4), and evaporated. A SiO2 flash chromatography (250 g, CH2Cl2/acetone 3:1) gives 6-amino-4-(3-methoxy-propyl)-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one (9.23 g, 99%) as brown oil. Rf(CH2Cl2/EtOAc 2:1) 0.34. 1H-NMR (400 MHz, CDCl3) 1.39 (s), 1.80-1.91 (m, 2 H), 3.28 (s), 3.35 (t, J=8.0), 3.44 (br. s), 3.88 (t, J=9.0), 6.23 (dd, J=9.0, 0.4), 6.33 (d, J=0.4), 6.68 (d, J=9.0).
Reaction SMILES: Br([O-])(=O)=O.[Na+].[OH:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH:9]([C:13]([O:15][CH3:16])=[O:14])[CH2:8]1.C(O)(C)C>CCOCC.O.O.[Ru](=O)=O>[O:6]=[C:7]1[CH2:12][CH2:11][CH2:10][CH:9]([C:13]([O:15][CH3:16])=[O:14])[CH2:8]1
Reactant: COC(=O)C1CCCC(O)C1
Agent: O=[Ru]=O
Agent: [Na+]
Agent: [O-][Br+2]([O-])[O-]
Solvent: CC(C)O
Solvent: O
Solvent: CCOCC
Product: COC(=O)C1CCCC(=O)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
Ruthenium(IV) oxide hydrate (1.47 g, 11.1 mmol) and sodium bromate (100 g, 664 mmol) were combined in Et2O (600 mL) and water (300 mL). The resulting black mixture was stirred for 10 min and cooled in an ice bath. The methyl 3-hydroxycyclohexanecarboxylate (35 g, 221 mmol) was dissolved in Et2O (to bring total volume to 100 mL) and added dropwise to the ice cold reaction mixture. The temperature was not allowed to go above 30° C. The reaction mixture was stirred for 1 h with the reaction temperature at ˜15° C. Isopropanol was carefully added to the reaction mixture at a rate necessary to keep the reaction temperature at ˜27° C. The layers were separated and the organic layers were washed with Et2O. The combined organics were washed with saturated, aqueous NaHCO3 solution and brine. The organics were then dried over MgSO4, filtered, and concentrated to provide the crude title compound (34.5 g, 100% crude yield) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 3.68 (s, 3H), 2.79 (m, 1H), 2.52 (d, J=7.78 Hz, 2H), 2.23-2.42 (m, 2H), 1.98-2.15 (m, 2H), 1.82 (d, J=10.29 Hz, 1H), 1.61-1.77 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.Br[CH2:16][CH2:17][CH2:18][CH3:19]>>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:14][CH2:2][CH2:3][CH3:4])([CH2:16][CH2:17][CH2:18][CH3:19])[C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)Cc1ccccc1-2
Reactant: CCCCBr
Product: CCCCC1(CCCC)c2ccccc2-c2ccc(Br)cc21

Procedure:
2-bromo-9,9-dibutylfluorene was synthesized from 2-bromofluorene and 1-bromobutane following the general procedures outlined in Part A of Example 5.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:13]=[CH:12][N:11]=1.C(N(C(C)C)CC)(C)C.Cl.Cl.[CH2:33]([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:50]=[CH:49][C:45]([C:46](Cl)=[O:47])=[CH:44][C:43]=2[C:51]([F:54])([F:53])[F:52])[CH2:37][CH2:36]1)[CH3:34].O>C(#N)C.CN(C)C1C=CN=CC=1>[CH2:33]([N:35]1[CH2:36][CH2:37][N:38]([CH2:41][C:42]2[CH:50]=[CH:49][C:45]([C:46]([NH:6][C:5]3[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([NH:9][C:10]4[CH:15]=[C:14]([C:16]5[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=5)[CH:13]=[CH:12][N:11]=4)[CH:4]=3)=[O:47])=[CH:44][C:43]=2[C:51]([F:54])([F:52])[F:53])[CH2:39][CH2:40]1)[CH3:34]
Reactant: Cc1ccc(N)cc1Nc1cc(-c2cccnc2)ccn1
Reactant: CCN1CCN(Cc2ccc(C(=O)Cl)cc2C(F)(F)F)CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: CCN1CCN(Cc2ccc(C(=O)Nc3ccc(C)c(Nc4cc(-c5cccnc5)ccn4)c3)cc2C(F)(F)F)CC1
Yield: 22.4 %

Procedure:
200 mg of 4-methyl-3-[4-(3-pyridyl)pyridin-2-ylamino]aniline (Reference Example 23) was suspended in 4 ml of acetonitrile, and 78.8 mg of 4-(dimethylamino)pyridine and 484 μl of N,N-diisopropyl-N-ethylamine were added in turn. Under ice-cooling with stirring, 383 mg of 4-(4-ethylpiperazin-1-ylmethyl)-3-trifluoromethylbenzoyl chloride dihydrochloride (Reference Example 5) was added, followed by stirring at room temperature for 2 hours. To the reaction solution was added water and the mixture was subjected to extraction with ethyl acetate three times. The organic layers were washed with saturated saline and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 93 mg of the objective compound as pale yellow crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12](SC)=[N:11][C:10]=2[CH:16]=1)(=[O:5])=[O:4].[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]1>CC(N(C)C)=O>[CH2:28]([O:27][C:25]([N:22]1[CH2:21][CH2:20][CH:19]([NH:18][C:12]2[O:13][C:9]3[CH:8]=[CH:7][C:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:17])[CH3:1])=[CH:16][C:10]=3[N:11]=2)[CH2:24][CH2:23]1)=[O:26])[CH3:29]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: CSc1nc2cc(S(=O)(=O)N(C)C)ccc2o1
Solvent: CC(=O)N(C)C
Product: CCOC(=O)N1CCC(Nc2nc3cc(S(=O)(=O)N(C)C)ccc3o2)CC1
Temperature: 100 °C
Yield: 67.3 %

Procedure:
A mixture of 2-methylsulfanyl-benzooxazole-5-sulfonic acid dimethylamide (1.43 g, 5.25 mmol, 1.0 equiv) and ethyl 4-amino-1-piperidine carboxylate (1.36 g, 7.88 mmol, 1.5 equiv) in anhydrous DMAc (7.5 mL) was heated to 100° C. for 48 h. The solution was concentrated by evaporation under reduced pressure and the crude reaction product purified with column chromatography on silica eluting with ethyl acetate/hexane (2:1) to give 1.40 g (67%) of the title compound. 1H NMR (300 MHz, DMSO): δ 1.19 (t, J=7.1 Hz, 3H), 1.37-1.49 (m, 2H), 1.94-1.99 (m, 2H), 2.59 (s, 6H), 2.94-3.02 (m, 2H), 3.80-3.83 (m, 1H), 3.91-3.95 (m, 2H), 4.04 (q, J=7.1 Hz, 2H), 7.39 (dd, J=8.2 Hz, J=1.8 Hz, 1H), 7.53 (d, J=1.8 Hz, 1H), 7.59 (d, J=8.2 Hz, 1H), 8.39 (d, J=7.6 Hz, 1H). 13C NMR (75 MHz, DMSO): δ 14.56, 31.07, 37.62, 42.05, 49.70, 60.65, 108.88, 114.22, 120.40, 130.37, 143.98, 150.67, 154.59, 162.76. MS (ISP): 397.0 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C.[CH2:24]1[C:29]2([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:28][CH2:27][C:26](=O)[CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[CH3:2][O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][CH:32]2[CH2:33][CH2:34][C:29]3([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)[CH2:30][CH2:31]2)=[CH:7][CH:6]=1
Reactant: O=C1CCC2(CCCCC2)CC1
Reactant: COC(=O)c1ccc(CN)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CNC2CCC3(CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Aminomethylbenzoic acid methyl ester hydrochloride (1.45 g, 7.2 mmol) was suspended in 1,2-dichloroethane (50 mL) and added saturated aqueous potassium carbonate. The phases were separated and the aqueous layer was extracted with another portion of 1,2-dichloro-ethane (50 mL). The combined organic phases were added glacial acetic acid (435 μL, 7.6 mmol) followed by spiro[5.5]undecan-3-one (1.2 g, 7.2 mmol). The suspension was stirred for 30 min at 25° C. and sodium triacetoxyborohydride (2.27 g, 10.7 μmol) was added. After stirring for 2 days at 25° C., water (100 mL) and saturated aqueous potassium carbonate (15 mL) were added. The phases were separated and the aqueous layer was extracted with 1,2-di-chloroethane (2×100 mL). The combined organic phases were washed with water (100 mL) and brine (100 mL), dried over MgSO4 and evaporated to afford 4-(spiro[5.5]undec-3-ylaminomethyl)benzoic acid methyl ester which was used in the subsequent steps without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH:7]([NH:21][C:22]1[C:27]([NH2:28])=[CH:26][N:25]=[C:24]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[N:23]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:20])[N:17]([CH3:19])[CH3:18])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1.CN(C)CCCN>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:34])[CH:7]([NH:21][C:22]1[C:27]([NH:28][S:42]([C:39]2[CH:40]=[CH:41][C:36]([F:35])=[CH:37][CH:38]=2)(=[O:44])=[O:43])=[CH:26][N:25]=[C:24]([N:29]([CH2:30][CH3:31])[CH2:32][CH3:33])[N:23]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:20])[N:17]([CH3:18])[CH3:19])=[CH:11][CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CCN(CC)c1ncc(N)c(NC(Cc2ccc(OC(=O)N(C)C)cc2)C(=O)OC(C)(C)C)n1
Agent: CN(C)CCCN
Solvent: c1ccncc1
Product: CCN(CC)c1ncc(NS(=O)(=O)c2ccc(F)cc2)c(NC(Cc2ccc(OC(=O)N(C)C)cc2)C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
A pyridine (120 mL) solution of 2-(2-diethylamino-5-aminopyrimidin-4-ylamino)-3-(4-dimethylcarbamoyloxy-phenyl)propionic acid t-butyl ester(32.0 g, 0.067 mol) was cooled to −20° C. with a dry ice/CH3CN bath. The mixture stirred for 30 minutes, and then p-fluorobenzenesulfonyl chloride (13.18 g, 0.067 mol) was added slowly. The reaction was stirred at −20° C. for 4.5 hrs, and then 3-dimethylaminopropyl amine (8.52 mL, 0.067 mol) was added, and then the mixture was allowed to warm to room temperature overnight. The reaction was concentrated in vacuo. The residue was taken up in EtOAc (1 L), and the organic phase was washed with 0.5 M citric acid (3×900 mL), water (1×900 mL), sat. NaHCO3 (3×900 mL), brine (1×900 mL), dried (MgSO4), filtered, and concentrated in vacuo to yield a brown residue. The residue was purified by flash chromatography (50% EtOAc/hexanes on silica gel) to yield 33.04 g (77%) the title compound as a yellow foam. Rf=0.54 (3:2 EtOAc/hexanes on silica gel).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[N:8][NH:9][C:10]2=O)=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:4]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:10]1[C:11]2[C:6](=[C:5]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH:7]=[N:8][N:9]=1
Reactant: COc1cc(-c2ccccc2)c2cn[nH]c(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc(-c2ccccc2)c2cnnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 7-methoxy-5-phenyl-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[C:11]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[CH3:12].Br[C:20]1[CH:25]=[C:24]([Br:26])[N:23]=[C:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[C:21]=1[CH2:34]Br>C1COCC1>[Br:26][C:24]1[N:23]=[C:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[C:21]([CH2:34][CH2:12][C:11]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:20][CH:25]=1
Reactant: CC(=O)OC(C)(C)C
Reactant: Clc1ccccc1-c1nc(Br)cc(Br)c1CBr
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCc1ccc(Br)nc1-c1ccccc1Cl
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To 25 mL of THF at −78° C. was added 26.6 mL of a 1.0M solution of lithium hexamethyldisilazane in THF. t-Butyl acetate (4.47 mL) was added dropwise to the cold solution, and the mixture was stirred for 10 min at −78° C. 4,6-Dibromo-3-(bromomethyl)-2-(2-chlorophenyl)pyridine (9.74 g) in 25 mL of THF was added dropwise over 15 min. The mixture was stirred 20 min at −78° C., then quenched by addition of 5 mL of saturated aqueous NaHCO3. The mixture was warmed to rt, diluted with 200 mL of saturated aqueous NaHCO3, and extracted with 3×100 mL of EtOAc. The combined organics were washed with 100 mL of brine, and dried over MgSO4. The residue was purified by flash chromatography on a Biotage 65M column, eluting with a gradient system of 95:5 to 90:10 hexanes-Et2O to yield the title compound as a white solid. Mass spectrum (ESI) 476 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[N:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[N:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)nn1
Product: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)nn1

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J1) (239 mg, 0.75 mmol) and 3-[3-(6-methyl-pyridazin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K6) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (254 mg).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:11])[CH2:6][CH2:7][C:8]([O-])=[O:9]>CN(C=O)C>[Cl:3][C:8](=[O:9])[CH2:7][CH2:6][C:5]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:11]
Reactant: CCCCOC(=O)CCC(=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCOC(=O)CCC(=O)Cl
Reaction time: 8 h

Procedure:
Excess thionyl chloride and a few drops of DMF are added to monobutyl succinate. The reaction starts with evolution of gas. The mixture is stirred overnight with the exclusion of moisture and the excess thionyl chloride is then removed by distillation at normal pressure. The crude product which remains is fractionally distilled at 0.05 mbar and the pure product is obtained at about 70° C. In the IR-spectroscopic characterization, the product has bands at 1,800 cm-1 (acid chloride) and 1,740 cm-1 (ester) of equal intensity.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]([CH3:26])[NH:21][CH2:20][CH2:19]2>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:20][CH2:19][C:18]4[C:23](=[CH:24][CH:25]=[C:16]([O:15][CH3:14])[CH:17]=4)[CH:22]3[CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: COc1ccc2c(c1)CCNC2C
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: COc1ccc2c(c1)CCN(C(=O)c1cc3ncc(Cl)cn3n1)C2C

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-Methoxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: Cl.O1CCOCC1.[O:8]=[C:9]1[NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[N:12]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:11][C@H:10]1[NH:26]C(OC(C)(C)C)=O>C(O)C>[O:8]=[C:9]1[NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[N:12]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:11][C@H:10]1[NH2:26]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C2CCCCC2)c2ccccc2NC1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: N[C@@H]1CN(C2CCCCC2)c2ccccc2NC1=O
Reaction time: 1 h
Yield: 57 %

Procedure:
4N HCl-dioxane (10 ml) was added to a solution of (R)-(−)-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (5.11 g) in ethanol (15 ml), and the mixture was stirred at 50: for one hour. After allowed to cool, the reaction mixture was concentrated under reduced pressure, the residue was neutralized with saturated aqueous sodium bicarbonate, and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, diisopropyl ether was added to crystals so precipitated, washed, and collected by filtration. This was recrystallized from a mixed solvent of ethanol and diisopropyl ether, to thereby obtain 2.1 g of the titled compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@H:9]([CH:14]2[CH2:17][N:16]([C@@H:18]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[C:19]3[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=3)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:15]2)[C:10]([F:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:37][N:38](C=O)C>O.[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C@H:18]([N:16]2[CH2:17][CH:14]([C@@H:9]([C:4]3[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([C:37]#[N:38])[CH:3]=3)[C:10]([F:13])([CH3:12])[CH3:11])[CH2:15]2)[C:19]2[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=2)[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:31][CH:32]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cccc([C@H](c2ccc(Cl)cc2)N2CC([C@@H](c3cc(F)cc(Br)c3)C(C)(C)F)C2)c1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CCOC(=O)c1cccc([C@H](c2ccc(Cl)cc2)N2CC([C@@H](c3cc(F)cc(C#N)c3)C(C)(C)F)C2)c1
Temperature: 125 °C
Reaction time: 12 h

Procedure:
A mixture of 5.64 g (9.77 mmol) of ethyl 3-[(S)-{3-[(1S)-1-(3-bromo-5-fluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}(4-chlorophenyl)methyl]benzoate, 700 mg (5.96 mmol) of zinc cyanide, 179 mg (0.195 mmol) of tris(dibenzylideneacetone)dipalladium, and 270 mg (0.489 mmol) of DPPF in 99 mL of DMF and 1 mL of water was degassed with N2 for 1 h at rt. Then it was stirred at 125° C. After 12 h, the reaction mixture was concentrated to remove solvents. The residue was poured into 200 mL of CH2Cl2 and 50 mL of aq NaHCO3 (pH=7-8). The aqueous layer was extracted with CH2Cl2and the combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate to afford the title compound as a white solid; 1H-NMR(CDCl3) δ 1.23 (d, 3H, J1=21.7 Hz), 1.28 (d, 3H, J1=21.7 Hz), 1.40(t, 3H, J=7.1 Hz), 2.29(t, 1H, J=7.5 Hz), 2.85-2.95(m, 2H), 3.05(m, 1H), 3.18(m, 1H), 3.64 (t, 1H, J=6.7 Hz), 4.29(s, 1H), 4.37 (q, 2H, J1=14.2 Hz, J2=7.1 Hz), 7.16 (d, 1H, J=9.3 Hz), 7.23 (d, 1H, J=7.8 Hz), 7.27-7.38(m, 6H), 7.55 (d, 1H, J=7.8 Hz), 7.86 (d, 1H, J=7.7 Hz), 8.0 (s, 1H); Mass Spectrum: m/e=523, (M+1, 35Cl), 525 (M+1, 37Cl).
Reaction SMILES: ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]4[CH2:36][CH2:35][O:34][CH2:33]4)[CH:30]=3)[C:25](O)=[O:26])=[CH:17][CH:16]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.[NH2:37][C:38]1[CH:43]=[N:42][C:41]([CH3:44])=[CH:40][N:39]=1.N1C=CC=CC=1>C(Cl)Cl>[N:9]1([C:13]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]4[CH2:36][CH2:35][O:34][CH2:33]4)[CH:30]=3)[C:25]([NH:37][C:38]3[CH:43]=[N:42][C:41]([CH3:44])=[CH:40][N:39]=3)=[O:26])=[CH:17][CH:16]=2)=[O:14])[CH2:10][CH2:11][CH2:12]1
Reactant: Cc1cnc(N)cn1
Reactant: O=C(O)c1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(O[C@H]2CCOC2)c1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(O[C@H]3CCOC3)c2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
1-Chloro-N,N,2-trimethyl-1-propenylamine (0.133 mL, 1.0 mmol) was added to a suspension of 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoic acid (350 mg, 0.94 mmol) in DCM (10 mL) and stirred at RT for 30 min. 2-Amino-5-methylpyrazine (196 mg, 1.82 mmol) and pyridine (0.148 mL, 1.82 mmol) were added and the reaction stirred at RT for 2 hours. The solvent was removed in vacuo and water (30 mL) added. The mixture was extracted with ethyl acetate (3×20 mL), washed with 2N hydrochloric acid (20 mL), water (10 mL), saturated aqueous sodium bicarbonate solution (20 mL), water (10 mL) and brine (20 mL). The combined organic extracts were dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by chromatography, eluting with 0-10% methanol in DCM, to give the desired product as a colourless oil (150 mg). 1H NMR δ (CDCl3): 2.12-2.18 (1H, m), 2.22-2.29 (1H, m), 2.31-2.40 (2H, m), 2.56 (3H, s), 3.89-4.03 (4H, m), 4.25 (2H, t), 4.71 (2H, t), 4.97-5.00 (1H, m), 6.76 (1H, t), 7.15 (1H, t), 7.25 (1H, d), 7.38-7.40 (1H, m), 8.12 (1H, s), 8.14 (1H, d), 8.32 (1H, s), 8.34 (1H, d), 9.52 (1H, d); m/z 476 (M+H)+, 474 (M−H)−
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][N:20]([CH2:28][CH2:29][CH3:30])[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][N:22]=1>>[CH3:19][N:20]([CH2:28][CH2:29][CH3:30])[C:21]1[N:22]=[CH:23][C:24]([NH:27][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:25][CH:26]=1
Reactant: CCCN(C)c1ccc(N)cn1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: CCCN(C)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(methyl-propyl-amino)-pyridin-3-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N2-methyl-N2-propyl-pyridine-2,5-diamine. LCMS calcd for C20H19F3N4O2 (m/e) 404, obsd 405 (M+H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([NH:30][C@@H:31]([CH2:34][CH3:35])[CH2:32][OH:33])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([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.C(N(CC)CC)C>ClCCl>[C:11]([NH:30][C@@H:31]([CH2:34][CH3:35])[CH:32]=[O:33])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred solution of dry dimethylsulfoxide (2.4 ml, 2.8 eq, 33.82 mmol) in dry dichloromethane (30 ml) under an argon atmosphere at −78° C., was added oxalyl chloride (2M solution in DCM, 8.45 ml, 1.40 eq, 16.9 mmol), dropwise. The reaction mixture was stirred at −78° C. for 1 h, after which time a solution of (S)-2-(trityl-amino)-butan-1-ol (4 g, 1 eq, 12.07 mmol) in DCM (30 ml) was added dropwise with stirring. The reaction mixture was stirred at this temperature for 2 h after which was added a solution of triethylamine (TEA, 8.4 ml, 5 eq, 60.27 mmol) in DCM (30 ml), and the solution allowed to warm to room temperature over 1 h. The reaction mixture was diluted with more DCM (100 ml) and washed with water (250 ml). The aqueous phase was extracted with DCM (3×50 ml), and the combined organic phase washed with brine (50 ml), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash silica chromatography (ethyl acetate:Hexane 1:4) to afford (S)-2-(trityl-amino)-butyraldehyde as a light yellow oil; Yield: 3.64 g (91%). 1H-NMR (CDCl3, 250 MHz): δ 0.95 (3 H, t, J=7.5 Hz, —NHCH(CH2CH3)CHO), 1.72-1.52 [2 H, m, NHCH(CH2CH3)CHO], 2.76 (1 H, s, br, —NH), 3.41-3.36 [1 H, m, NHCH(CH2CH3)CHO], 7.35-7.17 (12 H, m, ArH), 7.67-7.51 (3 H, m, ArH), 9.05 (1 H, s, NHCH(CH2CH3)CHO). δC (250 MHz, CDCl3) 202.95 (CO), 146.23 (C), 129.23 (6×CH), 127.96 (6×CH), 126.85 (3×CH), 71.13 (C), 62.62 (CH), 24.78 (CH2), 10.48 (CH3)