Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[C:5]([CH3:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.Cl[CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1>>[CH3:13][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([S:1][CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)[NH:11][C:10]2=[O:12]
Reactant: ClCc1ccncc1
Reactant: Cc1cccc2c(=O)[nH]c(S)nc12
Agent: Cl
Product: Cc1cccc2c(=O)[nH]c(SCc3ccncc3)nc12
Yield: 44 %

Procedure:
The title compound was prepared in a yield of 44.0%, using 2-mercapto-8-methyl-4(3H)-quinazolinone in place of 2-mercapto-3-phenyl-4(3H)-quinazolinoe and 4-chloromethylpyridine hydrochloride in place of 2-chloromethyl-4methylpyridine hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](OS(C(F)(F)F)(=O)=O)=[C:7]([Cl:19])[CH:6]=1.C([O-])(O)=O.[Na+].[CH3:26][N:27](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:26]#[N:27])=[C:7]([Cl:19])[CH:6]=1
Reactant: CN(C)C=O
Reactant: COC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [C-]#N
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(C#N)c(Cl)c1
Temperature: 80 °C
Reaction time: 34 h

Procedure:
A solution of (3-chloro-4-trifluoromethanesulfonyloxy-phenyl)-acetic acid methyl ester 12 (24.5 g, 73.6 mmol) in dry DMF (45 mL) is combined with zinc cyanide (8.91 g, 75.9 mmol) and tetrakis(triphenylphosphine) palladium (8.50 g, 7.4 mmol). The mixture is stirred for 34 hours at 80° C., then cooled to room temperature, diluted with EtOAc (150 mL) and poured into a saturated NaHCO3 solution (150 mL). A white precipitate is removed by vacuum filtration. The organic layer of the filtrate is separated and washed with H2O. The organic layer is dried (MgSO4), filtered and concentrated. The remainder is purified by silica gel chromatography using 20% EtOAc/hexane to give (3-chloro-4-cyano-phenyl)acetic acid methyl ester 13 as a wax-like solid: 1H-NMR (400 MHz, CDCl3) δ=7.63 (d, J=8.0 Hz, 1H), 7.47 (d, J=1.2 Hz, 1H), 7.30 (dd, J=1.2 Hz, J=8.0 Hz, 1H), 3.72 (s, 3H), 3.69 (s, 2H). MS calculated for C10H9O2ClN (M+H+) 210.0, found 210.0.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][C@@H:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:27][CH:26]=2)O1>>[N:11]12[CH2:16][CH2:15][CH:14]([CH2:13][CH2:12]1)[C@@H:9]([O:8][C:5]1[N:4]=[CH:3][C:2]([C:25]3[CH:26]=[CH:27][C:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[CH:29][CH:30]=3)=[CH:7][N:6]=1)[CH2:10]2
Reactant: Brc1cnc(O[C@H]2CN3CCC2CC3)nc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cnc(O[C@H]3CN4CCC3CC4)nc2)cc1

Procedure:
The product of Example 19A (160 mg, 0.57 mmol) was coupled with t-butyl [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-carbamate (Frontier, 319 mg, 1 mmol) according to the procedure of Example 18B. The title product was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3H2O, 90:10:1, Rf. 0.20) as solid (150 mg, yield, 67%). 1H NMR (300 MHz, MeOH-d4) δ 1.48-1.63 (m, 10H), 1.65-1.91 (m, 2H), 2.02-2.16 (m, 1H), 2.22-2.30 (m, 1H), 2.75-3.05 (m, 5H), 3.36-3.48 (m, 1H), 5.13-5.21 (m, 1H), 7.54 (s, 4H), 8.78 (s, 2H) ppm. MS (DCl/NH3) m/z 397 (M+H)+.
Reaction SMILES: C[Si](C)(C)Br.[CH2:6]([O:8][C:9](=[O:28])[C@H:10]([NH:25]C=O)[CH:11]=[C:12]([CH3:24])[CH2:13][P:14]([O:20]C(C)C)([O:16]C(C)C)=[O:15])[CH3:7].C(O)C>ClCCl>[CH2:6]([O:8][C:9](=[O:28])[C@H:10]([NH2:25])[CH:11]=[C:12]([CH3:24])[CH2:13][P:14]([OH:16])([OH:20])=[O:15])[CH3:7]
Reactant: CCOC(=O)[C@@H](C=C(C)CP(=O)(OC(C)C)OC(C)C)NC=O
Agent: C[Si](C)(C)Br
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)[C@H](N)C=C(C)CP(=O)(O)O
Reaction time: 20 h
Yield: 88.2 %

Procedure:
23 ml of trimethylbromosilane are added dropwise at room temperature within a period of 15 minutes to a solution of 10.3 g of 4 according to b) in 42 ml of dichloromethane. After 211/2 hours, 42 ml of ethanol are added while cooling with ice, and the mixture is stirred for 20 hours. The whole is then concentrated by evaporation and the residue is dissolved three times in 70 ml of toluene each time and in each case is concentrated by evaporation again. The residue is dissolved in 42 ml of ethanol, and 42 ml of propylene oxide are added. After 11/2 hours, the mixture is filtered. Drying the filtration residue in a vacuum desiccator over P2O5 /KOH (3 hours/80°) yields 6.17 g of 5; [α]D =-78° (c=0.6, H2O); m p. 194°-197° (decomp.), C8H16NO5P; calculated: C 40.51 %, H 6.80%, N 5.91%, P 13.06%; found: C 39.4%, H 7.09%, N 5.73%, P 12.98%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH2:12])[CH:7]=1.CCN(C(C)C)C(C)C.[CH3:29][O:30][CH2:31][C:32](Cl)=[O:33].N>C1COCC1.CO>[CH3:29][O:30][CH2:31][C:32]([NH:12][C:8]1[CH:7]=[C:6]([O:5][C:4]2[CH:13]=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:3]=2[O:2][CH3:1])[CH:11]=[CH:10][N:9]=1)=[O:33]
Reactant: COc1cc([N+](=O)[O-])ccc1Oc1ccnc(N)c1
Reactant: COCC(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2OC)ccn1
Temperature: 25 °C
Yield: 78.7 %

Procedure:
To a suspension of 4-(2-methoxy-4-nitrophenoxy)pyridin-2-amine (233 mg, 0.892 mmol) in THF (5.0 mL) and DIPEA (775 μL, 6.12 mmol) at 0° C. was added 2-methoxyacetyl chloride (325 μL, 3.57 mmol) in a single portion. The reaction mixture was warmed to RT for 1 hr and then a solution of NH3 in MeOH (7M, 2.0 mL) was added. After 30 min at RT the mixture was evaporated in vacuo and the residue was partitioned between DCM (50 mL) and brine (40 mL). The organic phase was separated and dried (MgSO4) and was evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 40 g, 2% MeOH in DCM, isocratic elution) to afford 2-methoxy-N-(4-(2-methoxy-4-nitrophenoxy)pyridin-2-yl)acetamide as an orange oil (234 mg, 78%); Rt 1.89 min (Method 2); m/z 334 (M+H)+ (ES+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)=[CH:11]/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N+:26]([C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)([O-:28])=[O:27].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:26]([C:29]1[CH:34]=[CH:33][C:32]([O:15][C:14](=[O:16])/[CH:13]=[CH:12]/[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:31][CH:30]=1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)/C=C/C=C(c1cccc([N+](=O)[O-])c1)c1cccc([N+](=O)[O-])c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(/C=C/C=C(c1cccc([N+](=O)[O-])c1)c1cccc([N+](=O)[O-])c1)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 95.5 %

Procedure:
As in Example 115, (E)-5,5-bis(3-nitrophenyl)-2,4-pentadienoic acid (0.78 g) and 4-nitrophenol (0.35 g) in dichloromethane (10 mL) was treated with 1,3-dicyclohexylcarbodiimide (0.47 g). The mixture was stirred at 0°-5° C. for 1 hour, then at room temperature for 1 hour. The usual work up furnished 1.01 g of crude (E)-5,5-bis(3-nitrophenyl)-2.4-pentadienoic acid 4-nitrophenyl ester. This intermediate was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:40])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[CH:11][C:12]3[C:21]4[C:16](=[CH:17][C:18]([C:22]5[NH:26][C:25]([C@@H:27]6[CH2:31][CH2:30][CH2:29][N:28]6[C:32](OC(C)(C)C)=[O:33])=[N:24][CH:23]=5)=[CH:19][CH:20]=4)[O:15][CH2:14][C:13]=3[CH:39]=2)[O:3]1.Cl.[CH3:42][O:43][C:44]([NH:46][CH:47]([CH:51]([CH3:53])[CH3:52])C(O)=O)=[O:45].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C.C(O)C>[CH3:52][CH:51]([CH3:53])[CH:47]([NH:46][C:44](=[O:45])[O:43][CH3:42])[C:32](=[O:33])[N:28]1[CH2:29][CH2:30][CH2:31][C@H:27]1[C:25]1[NH:26][C:22]([C:18]2[CH:17]=[C:16]3[C:21]([C:12]4[CH:13]=[CH:39][C:9]([B:4]5[O:3][C:2]([CH3:1])([CH3:40])[C:6]([CH3:7])([CH3:8])[O:5]5)=[CH:10][C:11]=4[CH2:14][O:15]3)=[CH:20][CH:19]=2)=[CH:23][N:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)OCc2cc(B4OC(C)(C)C(C)(C)O4)ccc2-3)[nH]1
Reactant: COC(=O)NC(C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COC(=O)NC(C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)OCc2cc(B4OC(C)(C)C(C)(C)O4)ccc2-3)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.8 %

Procedure:
A solution of (S)-tert-butyl 2-(5-(8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6H-benzo[c]chromen-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (670 mg, 1.23 mmol), ethanol (6 mL) and concentrated HCl (2 mL) was heated to 60° C. for 1.5 hours. The reaction was concentrated and the crude material dissolved in DCM (10 mL). This solution was concentrated and to this material was added a solution of 2-methoxycarbonylamino-3-methylbutyric acid (268 mg, 1.6 mmol) and HATU (537 mg, 1.41 mmol) in DMF (6 mL). To the resulting solution was added diisopropylethylamine (640 μL, 3.68 mmol). After stirring for 18 hours at room temperature, the reaction was diluted with ethyl acetate, washed with water and brine, dried (Na2SO4), concentrated. The crude residue was purified by flash chromatography to yield methyl 3-methyl-1-oxo-1-((S)-2-(5-(8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6H-benzo[c]chromen-3-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (205 mg, 28%). LCMS-ESI+: calculated for C33H41BN4O6: 600.53; observed [M+1]+: 601.39.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:20]=[C:19]3[C:15]([C:16]([CH:29]=[CH:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:17][N:18]3COCC[Si](C)(C)C)=[CH:14][CH:13]=2)=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.NC1C=C(C(C2C=C3C(C(C=CC4C=CC=CC=4)=NN3COCC[Si](C)(C)C)=CC=2)=O)C=CC=1>>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:20]=[C:19]3[C:15]([C:16]([CH:29]=[CH:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[N:17][NH:18]3)=[CH:14][CH:13]=2)=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(C(=O)c3cccc([N+](=O)[O-])c3)cc21
Agent: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(C(=O)c3cccc(N)c3)cc21
Product: Nc1cccc(C(=O)c2ccc3c(C=Cc4ccccc4)n[nH]c3c2)c1

Procedure:
(3-Nitro-phenyl)-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-methanone was converted to (3-amino-phenyl)-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-methanone as described in Example 11, step (iv) (102 mg, 84%). LCMS (ESI) [M+H]/z Calc'd 340, found 340.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH2:28][CH3:29])[NH:11]1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.CCO.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>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:35]4[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=4)=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH2:28][CH3:29])[NH:11]1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCc1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(Br)cc3)nc(=O)c1-2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCc1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(-c4ccc(OC)cc4)cc3)nc(=O)c1-2
Yield: 59.3 %

Procedure:
To a stirred mixture of 100 mg (0.2 mmol) of 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-bromobenzyl)pyrazolo[3,4-d]pyrimidin-4-one and 38 mg (0.25 mmol) of 4-methoxyphenylboronic acid in 10 mL of toluene, 0.5 mL of EtOH, and 2 mL of 2 M Na2CO3 was added to 5 mg of Pd(Ph3P)4. The mixture was heated to reflux overnight, poured into water, and extracted with CHCl3. The organic extract was dried (MgSO4), filtered through celite, chromatographed (elution with 5% MeOH/CH2Cl2), and recrystallized to afford 64 mg (59%) of 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-(4-methoxyphenyl)benzyl) pyrazolo[3,4-d]pyrimidin-4-one as a pale brown powder, mp 275-277° C., Mass spec.: 537 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[C:22]=3[CH3:28])=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:29]([CH3:31])[CH3:30])[NH:11]1.C(N(CC)CC)C.[Cl:39][CH2:40][C:41](Cl)=[O:42]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:41](=[O:42])[CH2:40][Cl:39])[C:22]=3[CH3:28])=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:29]([CH3:31])[CH3:30])[NH:11]1
Reactant: Cc1c(N)cccc1Cc1nc2n(-c3c(Cl)cc(Cl)cc3Cl)[nH]c(C(C)C)c-2c(=O)n1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(Cc2nc3n(-c4c(Cl)cc(Cl)cc4Cl)[nH]c(C(C)C)c-3c(=O)n2)cccc1NC(=O)CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
Part A: To a stirred, cooled (0° C.) solution of 110 mg (0.23 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-amino-2-methylbenzyl)pyrazolo[3,4-d]pyrimidin-4-one in 4 mL of THF was added 0.084 mL (0.6 mmol) of triethylamine followed by 0.024 mL (0.3 mmol) of chloroacetyl chloride. The solution was stirred 2 h, warming to ambient temperature. The reaction was quenched by dropwise addition of 5 mL of 0.5 N aq. HCl, and the resulting solid was collected by filtration. The product was washed with water then 1:1 ether-hexanes and air-dried to afford 96 mg (76%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-(chloroacetamido)-2-methylbenzyl)pyrazolo[3,4-d]pyrimidin-4-one, mp 237-238° C. 1H NMR (300 MHz, DMSO) δ 12.42(s, 1H); 9.69(s, 1H); 7.93(s, 2H); 7.15(d, 1H, J=7.3 Hz); 7.07(t, 1H, J=7.7 Hz); 6.95(d, 1H, J=8.7 Hz); 4.25(s, 2H); 3.90(s, 2H); 3.20-3.33(m, 1H); 2.07(s, 3H); 1.30(d, 6H, J=6.9 Hz).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].C(=O)([O-])[O-].[K+].[K+].[Br:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1>CS(C)=O>[Br:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25][C:5]([CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])([C:8]#[N:9])[C:6]#[N:7])=[CH:21][CH:20]=1
Reactant: BrCc1ccc(Br)nc1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(Br)nc1
Yield: 30.2 %

Procedure:
By using (3,3,3-trifluoropropyl)malononitrile (3.6 g), dimethylsulfoxide (20 ml), potassium carbonate (3.0 g) and 6-bromo-3-(bromomethyl)pyridine (5.5 g) according to the similar method described in Production Example 4 was obtained 2.2 g of 2-((6-bromo-3-pyridyl)methyl)-2-(3,3,3-trifluoropropyl)malononitrile represented by the following formula (hereinafter referred to as the present invention compound (10)).
Reaction SMILES: Br[CH:2]([C:6](=O)[CH3:7])[C:3](=[O:5])[CH3:4].[NH2:9][C:10]([NH2:12])=[O:11].C([O-])(O)=O.[Na+].[Na+].[Cl-]>CC(C)=O.O.CCOC(C)=O>[NH2:12][C:10]1[O:11][C:2]([C:3](=[O:5])[CH3:4])=[C:6]([CH3:7])[N:9]=1
Reactant: NC(N)=O
Reactant: CC(=O)C(Br)C(C)=O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(=O)c1oc(N)nc1C
Temperature: 100 °C
Yield: 57.9 %

Procedure:
3-Bromo-2,4-pentandione (P8) (26.66 g, 148.93 mmol) obtained in Step I as described above, is dissolved in acetone (87 mL). This mixture is added to a solution of urea (22.36 g, 372 mmol, 2.5 eq) in water (20 mL). The resulting mixture is heated in order to obtain a clear solution and is distributed into 38 microwave tubes (3 ml each). The vials are heated to 100° C. for 1200 s each in the microwave oven. All vials are combined, NaHCO3 sat (100 ml) and EtOAc (100 ml) are added, the aqueous phase is saturated with NaCl and the phases are separated. The aqueous phase is extracted with EtOAc (4 times 100 ml). Combined organic layers are dried over MgSO4, filtrated and evaporated under reduced pressure to give 1-(2-amino-4-methyl-1,3-oxazol-5-yl)ethanone (P5) as an orange solid (12.09 g). It is further recrystallized in MeOH, affording a brownish solid (5.56 g, 27%). 1H NMR (DMSO-d) δ: 2.22 (s, 3H), 2.25 (s, 3H), 7.51 (s, 2H).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].Cl.[NH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(C(C)C)CC)(C)C>CN(C)C=O>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:12])=[CH:13][CH:14]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(O)c1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(O)c1ccc(C(=O)NCCC(=O)OCC)cc1
Reaction time: 16 h
Yield: 92.5 %

Procedure:
N,N-dimethylformamide (8.60 mL) was added to a vial containing 4-(1-hydroxybutyl)benzoic acid (250 mg, 1.29 mmol), ethyl 3-aminopropanoate hydrochloride (395 mg, 2.57 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (979 mg, 2.57 mmol). Diisopropylethylamine (1.12 mL, 6.44 mmol) was then added. The reaction was stirred for 16 h, and was then concentrated. Purification by column chromatography (0-50% ethyl acetate in heptane) afforded ethyl 3-(4-(1-hydroxybutyl)benzamido)propanoate (350 mg, 93% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J=8.2 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H), 6.84 (br.s., 1H), 4.74 (t, J=6.5 Hz, 1H), 4.23-4.07 (m, 2H), 3.72 (q, J=5.9 Hz, 2H), 2.64 (t, J=5.9 Hz, 2H), 1.85-1.72 (m, 1H), 1.72-1.58 (m, 1H), 1.52-1.37 (m, 1H), 1.37-1.30 (m, 1H), 1.28 (t, J=7.2 Hz, 3H), 0.93 (t, J=7.3 Hz, 3H). MS (M+1) 294.3.
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][CH:18]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[C@@H:2]([C:11](O)=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].C(N(CC)C(C)C)(C)C.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.C(OCC)(=O)C.CO>[CH:20]1[C:19]2[CH:18]([CH2:17][O:16][C:14]([NH:1][C@@H:2]([CH2:11][OH:12])[CH2:3][C:4]([O:5][C:6]([CH3:7])([CH3:9])[CH3:8])=[O:10])=[O:15])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)C[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C

Procedure:
A solution of Fmoc-D-Asp(OtBu)-OH (9.0 g, 21.8 mmol) and N,N-diisopropylethylamine (4.6 mL) in THF (100 mL) at −40° C. was treated with isobutyl chloroformate (3.1 mL, 24.1 mmol), warmed to 0° C. over 30 minutes, cooled to −20° C., and treated slowly with sodium borohydride (1.64 g, 43.6 mmol) and methanol (10 mL). The reaction was gradually warmed to room temperature over 2 hours, diluted with ethyl acetate (200 mL), washed with water (100 mL) and brine (50 mL), dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI(+)) m/e 398 (M+H)+.
Reaction SMILES: [F:1][CH2:2][CH:3]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:4][C:5](=C)[CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[O:24]=[O+][O-].CSC>CO.C(Cl)Cl>[F:1][CH2:2][CH:3]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:4][C:5](=[O:24])[CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: C=C(CNC(=O)OC(C)(C)C)CC(CF)NC(=O)OC(C)(C)C
Reactant: O=[O+][O-]
Solvent: CSC
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)CC(CF)NC(=O)OC(C)(C)C
Temperature: -78 °C

Procedure:
1-Fluoro-2,5-di-t-butoxycarbonylamino-4-methylenepentane (800 mg, 2.4 mmoles) prepared as in Example 1, Step F, dissolved in a 1/1 mixture (30 mL) of methanol and methylene chloride is cooled to -78° C. and treated with ozone (flow rate 0.3 L/min) for 6 min and 15 sec. An excess of dimethylsulfide is added (about 2 mL) and then the reaction mixture is allowed to warm up to room temperature. After concentration, the residue is extracted twice with methylene chloride/water and work-up of the organic layer affords 800 mg of an oil which is crystallized from ether/petroleum ether (410 mg, 51%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4](Cl)[N:3]=1.[O:19]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[O:22][CH2:21][CH:20]1[C:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30].C(N(CC)CC)C.CN(C)C=O>C(O)CCC.O1C2C=CC=CC=2OCC1C(N1CCNCC1)=O.CCOCC>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:34]2[CH2:35][CH2:36][N:31]([C:29]([CH:20]3[O:19][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[O:22][CH2:21]3)=[O:30])[CH2:32][CH2:33]2)[N:3]=1
Reactant: COc1cc2c(N)nc(Cl)nc2c(OC)c1OC
Reactant: O=C(C1COc2ccccc2O1)N1CCNCC1
Solvent: CCCCO
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1cc2c(N)nc(N3CCN(C(=O)C4COc5ccccc5O4)CC3)nc2c(OC)c1OC
Reaction time: 8 h
Yield: 32.5 %

Procedure:
4-amino-2-chloro-6,7,8-trimethoxyquinazoline (1 g.) and N-(1,4-benzodioxan-2-carbonyl)piperazine (1.168 g.) were heated under reflux in n-butanol (67 ml.) with triethylamine (1.87 g.) for 24 hours. Further N-(1,4-benzodioxan-2-carbonyl)piperazine (0.026 g.) was then added and the mixture heated under reflux for an additional 30 hours. Butanol was then removed in vacuo and the residue partitioned between aqueous sodium carbonate solution and chloroform. The combined chloroform extracts were washed with water, dried (Na2SO4) and evaporated in vacuo to leave a solid (3.4 g.) which was taken up in the minimum quantity of dimethylformamide then set aside at 0° C. overnight. Ether was then added and the cloudy solution further cooled to yield 4-amino-2-[4-(1,4-benzodioxan-2-carbonyl)piperazin-1-yl]-6,7,8-trimethoxyquinazoline (0.58 g.), m.p. 269°-271° C.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][N:19]=[CH:18]4)=[O:13])[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].O>CN(C=O)C>[CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:19]=[CH:18]4)=[O:13])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)CBr
Reactant: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc3[nH]ncc3c2)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc3c(cnn3CC(=O)OCC)c2)ncn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 6-((cyclopropylmethyl)(propyl)amino)-N-(1H-indazol-5-yl)pyrimidine-4-carboxamide (Example 45, 350 mg; 1 mmol) in DMF (4 ml) was treated with potassium carbonate (140 mg; 1 mmol), and ethyl 2-bromoacetate (184 mg; 1.1 mmol). After stirring at RT for 18 hours the mixture was poured into water (20 ml) and stirred at RT for 30 minutes. The solid was removed by filtration and purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as an off-white solid, together with ethyl {5-[({6-[(cyclopropylmethyl)(propyl)amino]pyrimidin-4-yl}carbonyl)amino]-2H-indazol-2-yl}acetate (Example 120 below).