Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:16][C:17]([F:21])([F:20])[CH2:18][OH:19]>CN(C=O)C.O>[CH3:9][S:8][C:4]1[N:3]=[C:2]([O:19][CH2:18][C:17]([F:21])([F:20])[F:16])[CH:7]=[CH:6][N:5]=1
Reactant: OCC(F)(F)F
Reactant: CSc1nccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nccc(OCC(F)(F)F)n1
Reaction time: 64 h
Yield: 103 %

Procedure:
To a solution of 4-chloro-2-methylthiopyrimidine (16.0 g) and potassium carbonate (27.6 g) in DMF (90 ml) at 0° C., was added with stirring a solution of 2,2,2-trifluoroethanol (10.0 g) in DMF (10 ml). Stirring was continued for 64 hours, then the reaction mixture was diluted with water and extracted with ether (3×150 ml). The combined extracts were washed with brine, dried and concentrated to give 2-methylthio-4-(2,2,2-trifluoroethoxy)pyrimidine (23.0 g, crude yield) as a clear pale orange oil, 1H NMR δ 2.57(3H,s); 4.79(2H,q); 6.54(1H,d); 8.33(1H,d) ppm.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.Cl[C:29]1[N:34]=[CH:33][N:32]=[C:31]([C:35]([N:37]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=[CH:38]2)=[O:36])[CH:30]=1>CN(C=O)C>[N:37]1([C:35]([C:31]2[N:32]=[CH:33][N:34]=[C:29]([N:3]3[CH2:4][CH2:5][CH:6]([N:9]4[C:17]5[C:12](=[N:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]4=[O:18])[CH2:7][CH2:8]3)[CH:30]=2)=[O:36])[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38]1
Reactant: O=C(c1cc(Cl)ncn1)n1ccc2ccccc21
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)n1ccc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
100 mg (0.34 mmol) 1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one dihydrochloride and 200 μL (1.162 mmol) DIPEA were added to 100 mg (0.39 mmol) (6-chloropyrimidin-4-yl)-indol-1-yl-methanone in 30 mL DMF. The reaction mixture was stirred for 3 h at RT. The reaction mixture was evaporated down i. vac. The residue was combined with 20 mL water and stirred for 10 min. The solid was suction filtered and purified by flash chromatography. The product fractions were combined and evaporated down i. vac. The residue was triturated with diisopropylether and suction filtered. The solid was dried at 40° C. in the CAD.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11]N3CC4(CCN(C)CC4)C3)=[CH:8][C:6]=2[N:7]=1.[N:28]1([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH:33]2[C:38]([NH2:40])=[O:39])[CH2:31][CH2:30][CH2:29]1>>[N:28]1([C@@H:32]2[CH2:37][CH2:36][N:35]([CH2:11][C:9]3[S:10][C:5]4[C:4]([N:22]5[CH2:27][CH2:26][O:25][CH2:24][CH2:23]5)=[N:3][C:2]([Cl:1])=[N:7][C:6]=4[CH:8]=3)[CH2:34][C@H:33]2[C:38]([NH2:40])=[O:39])[CH2:31][CH2:30][CH2:29]1
Reactant: CN1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2
Reactant: NC(=O)C1CNCCC1N1CCC1
Product: NC(=O)[C@@H]1CN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC[C@H]1N1CCC1

Procedure:
Prepared according to the method used in the preparation of 2-chloro-6-(7-methyl-2,7-diaza-spiro[3.5]non-2-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine using 4-azetidin-1-yl-piperidine-3-carboxylic acid amide in place of 7-methyl-2,7-diaza-spiro[3.5]nonane. The title compounds were separated by column chromatography.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][NH:13][CH2:12][C@@H:11]([C:15]([OH:17])=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH2:27]([O:34][C:35](ON1C(=O)CCC1=O)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[CH2:27]([O:34][C:35]([N:13]1[CH2:14][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10][C@H:11]([C:15]([OH:17])=[O:16])[CH2:12]1)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CNC[C@@H](C(=O)O)C1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of cis-(+/−)-5-(tert-butoxycarbonylamino)piperidine-3-carboxylic acid (1.0 eq.) in dichloromethane (0.2 M) was added DIEA(1.1 eq.), followed by N-(benzyloxycarbonyloxy)succinimide (1.0 eq.); the reaction was stirred at r.t. overnight. The solvent was removed under reduced pressure. To the crude was added EtOAc and 1N HCl. After extraction, the organic layer was washed with brine, dried and filtered, and concentrated to yield cis-(+/−)-1-(benzyloxycarbonyl)-5-(tert-butoxy-carbonylamino)piperidine-3-carboxylic acid (99% yield) LCMS (m/z): 379.2 (MH+); LC Rt=3.55 min.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11](Cl)=[C:10]([N+:15]([O-])=O)[CH:9]=2)=[CH:4][CH:3]=1.[C:20]1([CH:27]=[CH:26][C:24]([OH:25])=[CH:23][CH:22]=1)[OH:21]>>[NH2:15][C:10]1[CH:9]=[C:8]([O:7][CH2:6][C:5]2[CH:18]=[CH:19][C:2]([Br:1])=[CH:3][CH:4]=2)[CH:13]=[CH:12][C:11]=1[O:21][C:20]1[CH:27]=[CH:26][C:24]([OH:25])=[CH:23][CH:22]=1
Reactant: Oc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cc(OCc2ccc(Br)cc2)ccc1Cl
Product: Nc1cc(OCc2ccc(Br)cc2)ccc1Oc1ccc(O)cc1

Procedure:
4-(4-Bromo-benzyloxy)-1-chloro-2-nitro-benzene (from Example 16A) was reacted with hydroquinone according to the procedure from Example 39A and reduced according to the procedure from Example 39B to provide the title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][CH2:27][C@H:28]([F:40])[C@:29]([C:32]3[CH:37]=[C:36](Br)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[CH3:77][O:78][C:79]1[CH:85]=[CH:84][CH:83]=[CH:82][C:80]=1[NH2:81]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][CH2:27][C@H:28]([F:40])[C@:29]([C:32]3[CH:37]=[C:36]([NH:81][C:80]4[CH:82]=[CH:83][CH:84]=[CH:85][C:79]=4[O:78][CH3:77])[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)[C@@H](F)CO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: COc1ccccc1N
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(Nc4ccccc4OC)ccc3F)[C@@H](F)CO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 115 °C
Reaction time: 15 h
Yield: 31.8 %

Procedure:
In a dry tube under an atmosphere of argon to a solution of [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(4R,5R)-4-(5-bromo-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-amine (intermediate C4.3) (150 mg, 247 μmol) in dioxane (5 ml) was added consecutively sodium tert-butoxide (26.1 mg, 272 μmol), 2-di-tert-butylphosphino-2′4′,6′-triisopropylbiphenyl (10.5 mg, 24.7 μmol), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (7.9 mg, 7.41 μmol), and 2-methoxyaniline (60.8 mg, 55.7 μl, 494 μmol). The tube was sealed and heated 115° C. under stirring during 15 hours. For the workup, the reaction mixture was evaporated at reduced pressure, and the residue was purified by chromatography on a silica-NH2 phase using a gradient of heptane/ethyl acetate=100:0 to 60:30 as the eluent. The [bis-(4-methoxy-phenyl)-phenyl-methyl]-{(4R,5R)-5-fluoro-4-[2-fluoro-5-(2-methoxy-phenylamino)-phenyl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl}-amine (51 mg, 32% yield) was obtained as a pale yellow foam. MS (ISP): m/z=650.5 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[C@H:3]([NH:7][C:8]([N:10]1[C:18]2[CH2:17][CH2:16][N:15]([CH3:19])[CH2:14][C:13]=2[C:12]([C:20]2[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=2[F:28])=[N:11]1)=[O:9])[C:4]([OH:6])=O.CCN(C(C)C)C(C)C.C(OC(Cl)=O)C(C)C.[NH2:48][C@H:49]([C:54]([NH2:56])=[O:55])[CH2:50][CH:51]([CH3:53])[CH3:52]>C(Cl)Cl>[NH2:56][C:54](=[O:55])[C@@H:49]([NH:48][C:4](=[O:6])[C@@H:3]([NH:7][C:8]([N:10]1[C:18]2[CH2:17][CH2:16][N:15]([CH3:19])[CH2:14][C:13]=2[C:12]([C:20]2[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=2[F:28])=[N:11]1)=[O:9])[C:2]([CH3:30])([CH3:1])[CH3:29])[CH2:50][CH:51]([CH3:53])[CH3:52]
Reactant: CN1CCc2c(c(-c3cc(F)c(F)cc3F)nn2C(=O)N[C@H](C(=O)O)C(C)(C)C)C1
Reactant: CC(C)C[C@H](N)C(N)=O
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of compound 71 (40 mg) in DCM was added DIEA (45 uL) followed by isobutylchloroformate (26 uL). After stirring at room temperature for 30 min, leucine amide (18 mg) and DIEA (25 uL) was added and stirred for 1 h. The reaction mixture was evaporated and dissolved in MeOH, and purified with a preparative LC-MS to give compound 72. LCMS (+ESI) m/z=537.3 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]=[O:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[CH:18]([Mg]Br)=[CH2:19]>O1CCCC1>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]([OH:17])[CH:18]=[CH2:19])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: C=C[Mg]Br
Reactant: CCCCc1nc(=O)c2cc(C=O)ccc2[nH]1
Solvent: C1CCOC1
Product: C=CC(O)c1ccc2[nH]c(CCCC)nc(=O)c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 10.00 g of 2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxaldehyde in 350 ml of tetrahydrofuran, cooled to 0° C. is added 130.43 ml of 1.0M vinylmagnesium bromide in tetrahydrofuran over 15 minutes. The reaction mixture is stirred at 0° C. for 30 minutes. The reaction mixture is quenched at 0° C. with 50 ml of saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer is dried (Na2SO4) and concentrated in vacuo to afford a residue which is purified by column chromatography on silica gel using 1:1 ethyl acetate-hexane to give 4.81 g of the desired product, as a white solid, MP 141° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][CH:11]=[CH2:12])=[O:8])=[C:4]([Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1.[CH3:17][S:18](=S)(OC)=O.C(N(SC)C(C1SC=CC=1[Si](C)(C)C)=O)C>>[Cl:1][C:2]1[S:6][C:5]([C:7]([N:9]([S:18][CH3:17])[CH2:10][CH:11]=[CH2:12])=[O:8])=[C:4]([Si:13]([CH3:14])([CH3:16])[CH3:15])[CH:3]=1
Reactant: C=CCNC(=O)c1sc(Cl)cc1[Si](C)(C)C
Reactant: COS(C)(=O)=S
Agent: CCN(SC)C(=O)c1sccc1[Si](C)(C)C
Product: C=CCN(SC)C(=O)c1sc(Cl)cc1[Si](C)(C)C

Procedure:
The compound of Example 262 (1.1 g) was reacted with 0.52 g of methyl methanethiosulfonate using procedure described for the preparation of the compound of Example 272. The title compound (0.6 g) was purified by flash chromatography with 2% ethyl acetate-hexane and recovered as a colorless oil. nD25 1.5698.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=O)[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.[CH2:14]([NH2:18])[CH2:15][CH2:16][CH3:17].C(O)C>O>[OH:1][C:2]1[CH:3]=[C:4]2[C:11](=[O:13])[N:18]([CH2:14][CH2:15][CH2:16][CH3:17])[C:6](=[O:8])[C:5]2=[CH:9][CH:10]=1
Reactant: CCCCN
Reactant: O=C(O)c1ccc(O)cc1C(=O)O
Solvent: O
Solvent: CCO
Product: CCCCN1C(=O)c2ccc(O)cc2C1=O

Procedure:
In a 250-ml round bottom flask were placed 20.5 g (112.6 mmols) of 4-hydroxyphthalic acid, 8.2 g (112.6 mmols) of n-butylamine and 100 ml of absolute ethanol. After mixing, the resulting mixture generated heat gently. The mixture was sufficiently stirred until the solids were completely dissolved. The alcohol was distilled off under reduced pressure, after which the viscous liquid thus obtained was heated at 180° C. for about 3 hours with continuous extraction of water. After cooling, the residue was solidified. The solidified residue was dissolved in an ethyl acetatebenzene (1:1 by volume) mixed solvent, and the resulting solution was washed with water, an aqueous sodium carbonate solution and then water. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and then cooled to obtain powder crystals having a slightly yellowish white color. The crystals were collected by suction filtration and dried. Yield: 18.5 g (75%), m.p. 126°-127° C. The product was determined to be 4-hydroxy-N-n-butylphthalimide by investigation of its structure by NMR and infrared absorption spectrum.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](Cl)=[O:8].[NH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=O>>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[O:8][C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:11][N:10]=1
Reactant: O=C(Cl)c1sccc1Cl
Reactant: COc1ccc(C(=O)CN)cc1
Product: COc1ccc(-c2cnc(-c3sccc3Cl)o2)cc1

Procedure:
3-Choloro-thiophene-2-carboxylic acid-[2-(4-methoxy-phenyl)-2-oxo-ethyl]-amide: The title compound was prepared from 3-chloro-thiophene-2-carbonyl chloride and 2-amino-4′-methoxy acetophenone by a procedure similar to Example 93a as an orange solid. 1H NMR (DMSO-d6): 8.30 (s, NH), 8.02 (d, J=9.0 Hz, 1H), 7.89 (d, J=6.6 Hz, 2H), 7.20 (d, J=6.0 Hz, 2H), 7.10 (d, J=8.7 Hz, 1H), 4.80 (d, J=5.4 Hz, 2H), 3.86 (s, 3H).
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH:22]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([CH3:24])[CH3:23]>>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([N:28]4[CH2:29][CH2:30][N:25]([CH:22]([CH3:24])[CH3:23])[CH2:26][CH2:27]4)=[O:18])=[CH:13][CH:12]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: CC(C)N1CCNCC1
Product: CC(C)N1CCN(C(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)CC1
Yield: 93.9 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.23 g, 0.80 mmol) and 1-isopropylpiperazine (0.102 g, 0.80 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)phenoxy)-1-(4-isopropylpiperazin-1-yl)ethanone as a white solid (0.298 g, 93.7% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([N:18]4[CH2:23][CH2:22][CH:21]([C:24]5[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][CH:25]=5)[CH2:20][CH2:19]4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)[N:3]=1.[NH3:40]>O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([N:18]4[CH2:19][CH2:20][CH:21]([C:24]5[CH:32]=[CH:31][C:27]([C:28]([NH2:40])=[O:30])=[CH:26][CH:25]=5)[CH2:22][CH2:23]4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:33]2[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]2)[N:3]=1
Reactant: N
Reactant: CN1CCN(c2cc(N3CCc4ccc(N5CCC(c6ccc(C(=O)O)cc6)CC5)cc4C3)nc(N)n2)CC1
Solvent: O
Product: CN1CCN(c2cc(N3CCc4ccc(N5CCC(c6ccc(C(N)=O)cc6)CC5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 18 starting from 4-(1-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}piperidin-4-yl)benzoic acid and ammonia solution in water. LCMS (M+H)+: m/z=527.3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH3:14][N:15](C)C=O>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]#[N:15])=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: CN(C)C=O
Reactant: FC(F)(F)Oc1cc(Br)ccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Br)cc1OC(F)(F)F
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-2-(trifluoromethoxy)iodobenzene (25 g, 68 mmol) and zinc(II) cyanide (4.0 g, 34 mmol) in 150 mL of degassed dimethylformamide was added tetrakis(triphenylphosphine)palladium (3.1 g, 4 mole %). The solution was stirred at 80 ° C. for one hour, then cooled to room temperature. Additional portions of zinc(II) cyanide (800 mg) and tetrakis(triphenylphosphine)palladium (700 mg) were added, and the solution was heated at 80° C. for 3 hours. The mixture was diluted with EtOAc and extracted with saturated NaHCO3 solution and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel column chromatography (0-5% ether/hexane) gave the titled product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:18])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][O:15][CH3:16])[CH2:9][CH2:8][C:7]=2[CH:17]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][C:28]=2[O:39][CH3:40])[C:23]([Cl:41])=[CH:22][N:21]=1.Cl.C(O)(C)C>O1CCOCC1>[Cl:41][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:29][C:28]=2[O:39][CH3:40])=[N:25][C:20]([NH:18][C:4]2[C:3]([O:2][CH3:1])=[CH:17][C:7]3[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][O:15][CH3:16])[CH2:11][CH2:12][C:6]=3[CH:5]=2)=[N:21][CH:22]=1
Reactant: COCCN1CCc2cc(N)c(OC)cc2CC1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: COCCN1CCc2cc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4OC)n3)c(OC)cc2CC1
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
Combined 8-Methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (55 mg, 0.00022 mol), (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine (86 mg, 0.00024 mol), 4 M of Hydrogen chloride in 1,4-Dioxane (70 uL) and Isopropyl alcohol (2.2 mL, 0.029 mol) in microwave vessel. Heat at 130° C. for 10 minutes. Heat for another 10 minutes. Cool to room temp. Solid precipitated out of solution. Filtered off solid. The filtrate was treated with MP-carbonate 250 mgs and stirred for 30 min. The mixture was concentrated and purified by ISCO chromatography (40 g SiO2 column, gradient 100% DCM to 10% MeOH/DCM. Isolated 5-Chloro-N*2*-[8-methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl]-N*4*-(2-methoxy-4-morpholin-4-yl-phenyl)-pyrimidine-2,4-diamine as an off-white solid (49 mgs, 39%) Melting point: 138-140° C. δ 8.30 (d, J=8.8 Hz, 1H), 8.12 (s, 1H), 8.03 (d, J=1.8 Hz, 1H), 7.57 (s, 1H), 7.45 (s, 1H), 6.65 (s, 1H), 6.57-6.52 (m, 2H), 3.94-3.88 (m, 10H), 3.36 (br s, 2H), 3.39 (d, J=1.7 Hz, 3H), 3.18-3.17 (m, 4H), 2.90-2.74 (m, 10H); LC/MS: 568.87 (M+H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:26]=[C:27]=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][CH2:37][C:38]([N:40]1[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]1)=[O:39]>C(Cl)Cl>[CH2:8]([NH:26][C:27](=[O:28])[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][CH2:37][C:38]([N:40]1[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]1)=[O:39])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CN1CCN(C(=O)CCc2ccccc2O)CC1
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCNC(=O)Oc1ccccc1CCC(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Triethylamine (0.62 mld) and octadecyl isocyanate (1.40 ml) were added to a solution containing 3-(2-hydroxyphenyl)-1-(4-methylpiperazino)-1-propanone (1.00 g) in methylene chloride (10 ml) and stirred for 4 hours at room temperature. The insoluble matters were filtrated out and washed with chloroform. The filtrate and washings were combined and the i mixture was washed with saturated sodium hydrogencarbonate aqueous solution and brine successively, dried over sodium sulfate anhydride, and concentrated. The residue was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=50:1), thereby yielding the entitled compound (2.05 g) as white solid.
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[CH:5][C:4]([O:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])=[CH:3]1.[H-].[Na+].[CH3:19][O:20][C:21](=[O:30])[CH:22](Br)[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1>[CH3:19][O:20][C:21](=[O:30])[CH:22]([N:7]1[C:2](=[O:1])[CH:3]=[C:4]([O:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH:5]=[N:6]1)[CH2:23][CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: N#Cc1ccccc1Oc1cn[nH]c(=O)c1
Reactant: COC(=O)C(Br)CC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1)n1ncc(Oc2ccccc2C#N)cc1=O
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
A solution of 2-(6-oxo-1,6-dihydro-pyridazin-4-yloxy)-benzonitrile (13.4 g, 62.9 mmol) in tetrahydrofuran (300 mL) cooled to −10° C. under nitrogen was treated with a 60% suspension of sodium hydride in mineral oil (3.5 g, 88.1 mmol). The reaction was stirred at −10° C. for 10 min and then warmed to 25° C. where it stirred for an additional 40 min. After this time, the reaction was treated with 2-bromo-3-cyclopentylpropionic acid methyl ester (Intermediate 10, 17.7 g, 75.5 mmol). The reaction was warmed to 50° C. for 18 h. After this time, the reaction was partitioned between water and methylene chloride. The aqueous layer was back extracted with methylene chloride. The combined organics were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, rinsed and concentrated in vacuo. Silica gel column chromatography afforded 2-[4-(2-cyano-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-propionic acid methyl ester (14.7 g, 63%) as a pale yellow solid; ESI-MS 368 [M+H+]; HPLC: >92% (purity). 1H-NMR (300 MHz, CDCl3) δ 7.91 (s, 1H), 7.69-7.79 (m, 2H), 7.41-7.46 (m, 1H), 7.28-7.31 (m, 1H), 5.97 (s, 1H), 5.52-5.57 (m, 1H), 3.73 (s, 3H), 2.28-2.37 (m, 1H), 2.04-2.15 (m, 1H), 1.48-1.81 (m, 7H), 1.11-1.28 (m, 2H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C@@H:14]1[C@H:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:17][C:16](=[O:25])[N:15]1[C:26](=[O:35])[CH2:27][CH2:28][C@H:29]([CH3:34])[CH2:30][CH2:31][CH2:32][CH3:33].Br[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>C1COCC1>[C:41]([O:40][C:38](=[O:39])[CH2:37][C@@H:27]([C:26]([N:15]1[C@H:14]([CH3:13])[C@H:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:17][C:16]1=[O:25])=[O:35])[CH2:28][C@H:29]([CH3:34])[CH2:30][CH2:31][CH2:32][CH3:33])([CH3:44])([CH3:43])[CH3:42]
Reactant: CCCC[C@@H](C)CCC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCC[C@@H](C)C[C@@H](CC(=O)OC(C)(C)C)C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
To a solution of diisopropylamine (1.8 mL, 12.6 mmol) in 30 mL THF at −78° C. was added n-butyllithium (1.6 M soln in hexanes, 7.6 mL, 12.1 mmol), and the mixture stirred 10 minutes at which time oxazolidinone 137 (3.2 g, 10.1 mmol) in 10 mL THF was added dropwise. The solution was stirred for 30 minutes, t-butyl bromoacetate (1.8 mL, 12.1 mmol) was added quickly dropwise at −50° C., and the mixture was allowed to warm slowly to 10° C. over 3 hours. The mixture was partitioned between Et2O and sat. NH4Cl (aq), the phases were separated, and the organic phase dried (MgSO4), and concentrated. The residue was purified by flash chromatography (16:1 to 8:1 hexanes:EtOAc) to provide 2.65 g (61%) of ester 138 as a colorless crystalline solid, mp=84–86° C. [α]D23+17.1 (c=1.00, CHCl3); 1H NMR (CDCl3): δ 7.34 (m, 5H), 5.62 (d, J=7.3 Hz, 1H), 4.73 (quint, J=6.8 Hz, 1H), 4.29 (m, 1H), 2.67 (dd, J=9.8, 16.4 Hz, 1H), 2.40 (dd, J=5.1, 16.4 Hz, 1H), 1.69 (m, 1H), 1.38 (s, 9H), 1.28 (m, 7H), 1.08 (m, 1H), 0.88 (m, 9H); 13C NMR (CDCl3) δ 176.45, 171.22, 152.71, 133.64, 128.86, 125.86, 80.83, 78.87, 55.33, 40.02, 38.21, 37.59, 36.31, 30.86, 29.29, 28.22, 23.14, 20.41, 14.36, 14.26. Anal. Calcd for C25H37NO5: C, 69.58; H, 8.64; N, 3.25. Found: C, 69.37; H, 8.68; N, 3.05.