Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].CCN(C(C)C)C(C)C.[CH3:22][O:23][C:24]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:25]=1[CH2:26][NH2:27]>C1COCC1>[CH3:22][O:23][C:24]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:25]=1[CH2:26][NH:27][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: N#Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: COc1ccc(CN)c(OC)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2ccc(C#N)cc2[N+](=O)[O-])c(OC)c1
Reaction time: 24 h

Procedure:
A solution of 4-fluoro-3-nitrobenzonitrile (5.0 g) in THF (100 mL) was treated with DIEA (6.3 mL) and 2,4-dimethoxybenzylamine (5.0 mL), and then stirred for 24 h. The solvent was evaporated and the crude mixture was dissolved in EtOAc (100 mL). The solution was washed once with 1 M HCl and twice with saturated aqueous NaCl (100 mL each). The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo. Column chromatography (20% EtOAc/DCM) provided 9.25 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][CH:16]3[CH2:18][CH2:17]3)=[CH:12][N:11]=[C:10]([C:19]([OH:21])=O)[N:9]=2)=[CH:4][CH:3]=1.[CH:22]1([C:25]2[N:29]=[C:28]([CH2:30][NH2:31])[O:27][N:26]=2)[CH2:24][CH2:23]1>>[CH:22]1([C:25]2[N:29]=[C:28]([CH2:30][NH:31][C:19]([C:10]3[N:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[C:13]([O:14][CH2:15][CH:16]4[CH2:17][CH2:18]4)=[CH:12][N:11]=3)=[O:21])[O:27][N:26]=2)[CH2:24][CH2:23]1
Reactant: O=C(O)c1ncc(OCC2CC2)c(-c2ccc(Cl)cc2)n1
Reactant: NCc1nc(C2CC2)no1
Product: O=C(NCc1nc(C2CC2)no1)c1ncc(OCC2CC2)c(-c2ccc(Cl)cc2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyrimidine-2-carboxylic acid (example T) and (3-cyclopropyl-1,2,4-oxadiazol-5-yl)methane amine (CAS Registry No. 428507-31-7) as starting materials; LC-MS (UV peak area/ESI) 100%, 426.1324 (M+H)+.
Reaction SMILES: [N:1]1[N:2]([C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19](Br)[C:20](=[O:24])[O:21]3)=[CH:16][CH:15]=2)[N:3]=[C:4]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=12.[CH3:26][Si:27]([C:30]#[CH:31])([CH3:29])[CH3:28].C(N(CC)CC)C>C1COCC1.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.[Cu](I)I>[N:1]1[N:2]([C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19]([C:31]#[C:30][Si:27]([CH3:29])([CH3:28])[CH3:26])[C:20](=[O:24])[O:21]3)=[CH:16][CH:15]=2)[N:3]=[C:4]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=12
Reactant: O=c1oc2cc(-n3nc4ccc5ccccc5c4n3)ccc2cc1Br
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cc2ccc(-n3nc4ccc5ccccc5c4n3)cc2oc1=O

Procedure:
After charging 7.8 parts of 7-(naphtho[1,2]triazol-2-yl)-3-bromocoumarin synthesized by a known method, 2.4 parts of trimethylsilylacetylene, 0.46 parts of tetrakis(triphenylphosphine)palladium(0), 0.038 parts of copper iodide and 20 ml of triethylamine in 40 ml of THF, the mixture was refluxed for 9 hours. The reaction mixture was filtered and washed with THF, and the obtained filtrate was concentrated and then diluted with water and filtered. The obtained cake was recrystallized from methanol. Upon drying under reduced pressure there was obtained 4 parts of 7-(naphtho[1,2]triazol-2-yl)-3-trimethylsilylethynylcoumarin having a melting point of 250-252° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([N+:14]([O-])=O)[C:5]=1[NH:17][CH3:18])([O-])=O.C(O)(=O)C>[Fe].C(O)C>[CH3:18][NH:17][C:5]1[C:4]([NH2:1])=[CH:9][C:8]([C:10]([F:11])([F:13])[F:12])=[CH:7][C:6]=1[NH2:14]
Reactant: CNc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: CNc1c(N)cc(C(F)(F)F)cc1N
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 80.1 %

Procedure:
To a mixture of (2,6-dinitro-4-trifluoromethyl-phenyl)-methyl-amine (5.0 g), acetic acid (11 mL), ethanol (100 mL), and ice (20 g), iron powder (6.4 g) was added under ice-cooling. The reaction mixture was stirred at 0° C. for 3.5 hours, and filtered through Celite®. The resulting filtrate was concentrated under reduced pressure, and diluted with 1N aqueous sodium hydroxide solution. The solution was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure to give 3.1 g of N′-methyl-5-trifluoromethyl-benzene-1,2,3-triamine. N′-methyl-5-trifluoromethyl-benzene-1,2,3-triamine
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10].[H-].[Na+].CCCCCC.[CH3:33][C:34]1[CH:35]=[N:36][NH:37][CH:38]=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([N:36]2[CH:35]=[C:34]([CH3:33])[CH:38]=[N:37]2)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10]
Reactant: O=C(c1ccc(F)cc1Cl)N1Cc2cccn2Cc2ccccc21
Reactant: Cc1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Cc1cnn(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)c(Cl)c2)c1
Yield: 62.6 %

Procedure:
In the manner of Example 9's Method 1, employing (2-chloro4-fluorophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.0 g), 60% sodium hydride in oil (0.3 g, degreased with hexane), 4-methylpyrazole (0.48 g) and dimethylformamide (25 ml), the title compound (0.74 g) was obtained as an amorphous solid, MS, m/z: 403.2 (M+H)+, 425.2 (M+Na)+, 805.3 (2M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([NH2:16])=[C:11]([Br:17])[C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][C:24](=O)[O:25]C(C)(C)C)([CH3:22])([CH3:21])[CH3:20]>C1COCC1.CN(C)C1C=CN=CC=1>[C:19]([O:23][C:24](=[O:25])[NH:16][C:12]1[CH:13]=[C:14]([F:15])[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([F:18])[C:11]=1[Br:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: Nc1cc(F)c(OCc2ccccc2)c(F)c1Br
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(F)c(OCc2ccccc2)c(F)c1Br
Temperature: 25 °C
Yield: 88.8 %

Procedure:
To a solution of 4-benzyloxy-2-bromo-3,5-difluorophenylamine (3.33 g) in THF (35 mL) were added di-tert-butylcarbonate (6.95 g) and 4-dimethylaminopyridine (130 mg), and the mixture was heated under reflux for 2 hours. The reaction mixture was allowed to stand for cooling to room temperature, and concentrated. The residue was diluted with ethyl acetate and washed with 0.5N hydrochloric acid and saturated aqueous brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=20:1) to give (4-benzyloxy-2-bromo-3,5-difluorophenyl)carbamic acid tert-butyl ester (3.9 g).
Reaction SMILES: O[N:2]1[C:23](=[O:24])[NH:22][C@H:21]2[C@@H:3]1[CH2:4][S:5][C@H:6]2[CH2:7][CH2:8][CH2:9][CH:10](N1C(=O)CCC1=O)[C:11](=[O:13])O.[NH2:25][CH2:26][CH2:27][N:28]1[C:40]2[C:39]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[N:33]=[C:32]([NH2:41])[C:31]=2[N:30]=[CH:29]1>>[NH2:41][C:32]1[C:31]2[N:30]=[CH:29][N:28]([CH2:27][CH2:26][NH:25][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]3[CH:21]4[CH:3]([NH:2][C:23](=[O:24])[NH:22]4)[CH2:4][S:5]3)[C:40]=2[C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[N:33]=1
Reactant: O=C(O)C(CCC[C@@H]1SC[C@H]2[C@@H]1NC(=O)N2O)N1C(=O)CCC1=O
Reactant: NCCn1cnc2c(N)nc3ccccc3c21
Product: Nc1nc2ccccc2c2c1ncn2CCNC(=O)CCCCC1SCC2NC(=O)NC21
Yield: 75.2 %

Procedure:
Using the general method of Example 24, N-hydroxysuccinimidobiotin (0.6 g, 1.76 mmol) was reacted with 1-(2-aminoethyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.4 g, 1.76 mmol) to provide 0.6 g of N1-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-5-(2-oxoperhydrothieno[3,4-d]imidazol-4-yl)pentanamide as a solid, m.p. 169° C.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O.[SH2]=N.[C:15]1([NH:21][C:22](C2C=CC=CC=2C(O)=O)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[C:15]1([NH:21][C:22]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccccc1C(=O)Nc1ccccc1
Reactant: NCc1ccccc1
Agent: N=[SH2]
Solvent: O
Solvent: CC(C)=O
Product: O=C(NCc1ccccc1)Nc1ccccc1
Temperature: 5 °C
Yield: 87.3 %

Procedure:
A mixture of 1.1 g benzylamine and 5 ml aceton was added dropwise to a suspension of 1.5 g phenylcarbamoyl-benzoic acid sulfimide with 20 ml aceton, under stirring. The reaction mixture was stirred for 35 minutes at room temperature, then diluted with 150 ml water and cooled to 5° C. The precipitated solid product was filtered, washed with water and dried. 1.02 g 1-phenyl-3-benzylurea was obtained with a melting point of from 170° to 172° C.
Reaction SMILES: [C:1]([OH:26])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O.C([N:29]([CH2:32][CH3:33])CC)C.COC(Cl)=O.[CH3:39][CH:40]([NH2:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1>[CH3:39][CH:40]([NH:47][C:22](=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13]#[C:12][C:11]#[C:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([NH:29][CH:32]([CH3:33])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:26])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CCN(CC)CC
Reactant: CC(N)c1ccccc1
Reactant: O=C(O)CCCCCCCCC#CC#CCCCCCCCCC(=O)O
Agent: COC(=O)Cl
Solvent: C1CCOC1
Product: CC(NC(=O)CCCCCCCCC#CC#CCCCCCCCCC(=O)NC(C)c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 725 mg (2.00 mmol) of 10,12- docosadiyndioic acid in 50 ml THF was added 405 mg (4.00 mmol) of triethylamine. The solution was cooled to 0° C. and 378 mg (4.00 mmol) of methylchloroformate was added dropwise over one minute. The resulting white mixture was stirred one hour at 0° C., the 485 mg (4.00 mmol) of d(+, -α-methylbenzylamine was added. The reaction mixture was heated at reflux for one hour (gas evolution began immediately upon amine addition and ceased after 20 minutes). The mixture was cooled to room temperature and filtered. The filtrate was washed with 25 ml portions of 1 M HCl, water, and saturated aqueous sodium bicarbonate solution and dried (MgSO4). Evaporation yielded 842 mg (74% crude yield) of a white solid, which polymerized rapidly upon exposure to UV light. Recrystallization from ether-petroleum ether gave 456 mg of white crystals, m.p. 87.5°-89° C. I.R. (film): 1530, 1635, 2850, 2920, and 3300 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1>>[ClH:1].[OH:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[NH:18][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: Nc1cccc(O)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Product: Cl
Product: Oc1cccc(Nc2cc(C(F)(F)F)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (89 mg, 0.344 mmol) and 3-aminophenol (30 mg, 0.275 mmol) similar to Example 58 and isolated as a yellow solid (61 mg, 67%). 1H NMR (DMSO-d6): 10.40 (s, 1H), 8.86 (dd, J=0.9, 5.1 Hz, 1H), 8.51 (d, J=7.8 Hz, 1H), 8.32-8.26 (m, 1H), 7.82-7.78 (m, 1H), 7.29 (s, 1H), 7.26 (s, 1H), 7.23 (s, 1H), 7.19 (d, J=7.5 Hz, 1H), 6.57 (dd, J=1.8, 9.0 Hz, 1H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[N:14]=[C:13](Cl)[C:12]([N+:16]([O-:18])=[O:17])=[C:11]([Cl:19])[N:10]=1.[CH:20]([NH2:23])([CH3:22])[CH3:21]>O>[CH3:8][C:9]1[N:10]=[C:11]([Cl:19])[C:12]([N+:16]([O-:18])=[O:17])=[C:13]([NH:23][CH:20]([CH3:22])[CH3:21])[N:14]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: CC(C)N
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NC(C)C)n1
Reaction time: 16 h
Yield: 73.4 %

Procedure:
30 ml of triethylamine are added to 32.5 g (0.156 mol) of 2-methyl- 4,6-dichloro-5-nitro-pyrimidine. At -18°C, 3.5 g of isopropylamine (0.16 mol) are added dropwise and the mixture is then stirred for 1 1/4 hours at this temperature. The mixture is subsequently poured on 4 liters of water, the precipitate is filtered off with suction, and washed 3 times with water. The crude product is dried at 50°C and 11 Torr for 16 hours, to yield 26.4 g of 2-methyl-4-chloro-5-nitro-isopropylamino-pyrimidine with a melting point of 69°-72°C. The pure substance (recrystallised from hexane) melts at 77°-79°C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:17][C:16]3[C:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C:23]=4[CH:24]=[CH:25][C:15]=3[CH2:14]2)(=O)=O)=CC=1.[N-:26]=[N+:27]=[N-:28].[Na+]>>[N:26]([CH2:12][CH:13]1[O:17][C:16]2[C:18]3[CH2:19][CH2:20][CH2:21][CH2:22][C:23]=3[CH:24]=[CH:25][C:15]=2[CH2:14]1)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3ccc4c(c3O2)CCCC4)cc1
Agent: [Na+]
Product: [N-]=[N+]=NCC1Cc2ccc3c(c2O1)CCCC3

Procedure:
Treatment of (±)-2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan-2-ylmethyl 4-methylbenzenesulfonate (2.05 g, 5.72 mmol) with sodium azide (0.929 g, 14.30 mmol) generally according to the procedure described for Intermediate 24 gave (±)-2-(azidomethyl)-2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan. Treatment of the azide with palladium on carbon (10 wt. %, 0.094 g) generally according to the procedure described for Example 2 afforded 0.917 g (67%) of (±)-1-(2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan-2-yl)methanamine as a white solid, hydrochloride salt. mp>220° C. (dec.); Anal. calcd. for C13H17NOHCl.0.1H2O: C, 64.15; H, 7.50; N, 5.75. Found: C, 64.41; H, 7.64; N, 5.67.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].Cl[C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:12][CH:13]=2)[N:8]=[C:7]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[S:26][CH2:27][CH3:28])[N:6]=1>C1COCC1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:7]2[N:6]=[C:5]([NH:3][CH2:1][CH3:2])[C:14]3[C:9](=[CH:10][C:11]([C:15]([F:17])([F:16])[F:18])=[CH:12][CH:13]=3)[N:8]=2)=[C:20]([S:26][CH2:27][CH3:28])[CH:21]=1
Reactant: CCSc1cc(Cl)ccc1-c1nc(Cl)c2ccc(C(F)(F)F)cc2n1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNc1nc(-c2ccc(Cl)cc2SCC)nc2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1.5 ml of ethylamine (a 70% aqueous solution) was added to a mixture of 600 mg of 4-chloro-2-(4-chloro-2-ethylsulfanylphenyl)-7-trifluoromethylquinazoline and 10 ml of THF, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous sodium bicarbonate solution was added to the residue, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure to obtain 606 mg of 2-(4-chloro-2-ethylsulfanylphenyl)-4-ethylamino-7-trifluoro methylquinazoline (Compound of Present Invention 15).
Reaction SMILES: [CH3:1][C:2]([CH3:35])([CH3:34])[CH2:3][N:4]([CH3:33])[C:5]1[N:10]=[C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:15]([NH:17][O:18][CH2:19][CH3:20])=[O:16])[CH:8]=[C:7]([N:25]2[CH2:31][CH2:30][CH2:29][N:28]([CH3:32])[CH2:27][CH2:26]2)[N:6]=1.[C-:36]#[N:37].[Na+].BrBr>C(=O)(O)[O-].[Na+].C(Cl)Cl.O>[C:36]([C:8]1[C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:15]([NH:17][O:18][CH2:19][CH3:20])=[O:16])=[N:10][C:5]([N:4]([CH2:3][C:2]([CH3:34])([CH3:1])[CH3:35])[CH3:33])=[N:6][C:7]=1[N:25]1[CH2:31][CH2:30][CH2:29][N:28]([CH3:32])[CH2:27][CH2:26]1)#[N:37]
Reactant: CCONC(=O)c1ccc(C)c(Nc2cc(N3CCCN(C)CC3)nc(N(C)CC(C)(C)C)n2)c1
Reactant: [C-]#N
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCONC(=O)c1ccc(C)c(Nc2nc(N(C)CC(C)(C)C)nc(N3CCCN(C)CC3)c2C#N)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred mixture of 3-[2-[(2,2-dimethyl-propyl)-methyl-amino]-6-(4-methyl-[1,4]diazepan-1-yl)-pyrimidin-4-ylamino]-N-ethoxy-4-methyl-benzamide (50 mg, 0.1 mmol) and sodium cyanide (0.044 g, 0.89 mmol) in sat. aq. sodium bicarbonate (1 mL) and methylene chloride (3 mL) was added at room temp bromine (0.045 mL, 0.87 mmol). The resulting mixture was continued stirring for 16 h at room temp. The reaction mixture was diluted with water and extracted with methylene chloride (2×15 mL). The combined organic layer was dried (sodium sulfate), filtered and concentrated under reduced pressure, and the product was purified by HPLC. C27H40N8O2 MS m/e=509 (M+H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[S:17][C:18]([C:22]([O:24]CC)=[O:23])=[C:19]([CH3:21])[N:20]=3)[CH:14]=2)[C:9](=[O:27])[N:8]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:7]=1[CH2:32][NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>O1CCCC1.C(O)C>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[S:17][C:18]([C:22]([OH:24])=[O:23])=[C:19]([CH3:21])[N:20]=3)[CH:14]=2)[C:9](=[O:27])[N:8]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:7]=1[CH2:32][NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3nc(C)c(C(=O)OCC)s3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3nc(C)c(C(=O)O)s3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a solution of ethyl 2-(4-butoxy-3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-4-methyl-1,3-thiazole-5-carboxylate (0.91 g, 1.6 mmol) in tetrahydrofuran (5 ml) and ethanol (5 ml) was added 1N sodium hydroxide solution (3 ml). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crystals were recrystallized from ethyl acetate-diisopropyl ether to give 2-(4-butoxy-3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-4-methyl-1,3-thiazole-5-carboxylic acid (0.78 g, 89.7%) as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C:7]([CH3:11])([CH3:10])[CH:8]=[O:9])=[CH:4][CH:3]=1.[CH3:14][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C:7]([CH3:10])([CH3:11])[CH:8]([OH:9])[CH3:14])=[CH:4][CH:3]=1
Reactant: CC(C)(C=O)Oc1ccc(Br)cc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)C(C)(C)Oc1ccc(Br)cc1
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of 2-(4-bromophenoxy)-2-methylpropanal (5.3 g) in tetrahydrofuran (100 mL) was added methylmagnesium bromide (9.5 mL, 3 M diethyl ether solution) at −20° C., and the mixture was stirred for 1 hr. A saturated ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (4.0 g, 70%).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)=[O:2].[CH2:12]([N:14](CC)[CH2:15][CH3:16])[CH3:13].C(OC(Cl)=O)C(C)C.C(NCC)C>C1COCC1>[CH2:12]([N:14]([CH2:15][CH3:16])[C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:11][CH:10]=1)[CH3:13]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Solvent: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(C=O)cc1
Yield: 48.3 %

Procedure:
4-Formylbenzoic acid (11.2 g, 74.6 mmol) and triethylamine (10.4 mL, 75 mmol) was dissolved in THF (100 mL) and cooled to −10° C. i-Butylchloroformate (10.3 mL, 78 mmol) was added and stirring was continued for 10 minutes at −10° C. before diethylamine (9.7 mL, 94 mmol) was added and solution was allowed to reach 25° C. After concentration, aqueous workup and chromatography on silica (0-100% EtOAc in heptane), a total of 7.4 g (50%) compound I was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH:25]=O)[CH:8]=2)[N:3]=1.Cl.[CH3:32][O:33][C:34]([CH:36]1[CH2:40][CH2:39][CH2:38][NH:37]1)=[O:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl.O1CCCC1>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH2:25][N:37]3[CH2:38][CH2:39][CH2:40][CH:36]3[C:34]([O:33][CH3:32])=[O:35])[CH:8]=2)[N:3]=1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3C=O)ccc2n1
Reactant: COC(=O)C1CCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCCl
Product: COC(=O)C1CCCN1Cc1ccccc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
500 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]benzaldehyde are dissolved in 5 ml of 1,2-dichloroethane and 5 ml of tetrahydrofuran. 314 mg of methylpyrrolidine-2-carboxylate hydrochloride are added, and the mixture is stirred at 60° C. for 6 h. After cooling to 25° C., 566 mg of sodium triacetoxyborohydride are added and stirred at 25° C. for a further 12 h. The mixture is poured into water, extracted three times with dichloromethane, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC).