Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C@H:3]([OH:6])[CH2:4][OH:5].[C:7]([Si:11]([CH3:14])([CH3:13])Cl)([CH3:10])([CH3:9])[CH3:8].N1C=CN=C1>CN(C)C=O>[Si:11]([O:5][CH2:4][C@@H:3]([OH:6])[CH2:2][Cl:1])([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:14])[CH3:13]
Reactant: OC[C@@H](O)CCl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H](O)CCl
Temperature: 0 °C
Yield: 93 %

Procedure:
To N,N-dimethylformamide (40 ml) solution of (R)-(−)-3-chloro-1,2-propanediol (7 g), under ice-cooling and stirring condition, were added tert-butyldimethylchlorosilane (10.6 g) and imidazole (5.2 g), then stirred at a room temperature overnight. Ice-water (120 ml) was added to the reaction mixture, and extracted with ethyl acetate (50 ml) 3 times, the extracts were combined together and washed with an aqueous solution being saturated with sodium chloride, then dried over anhydrous magnesium sulfate. After being filtrated under a reduced pressure, the filtrate was concentrated, there was obtained (R)-(−)-1-(tert-butyldimethylsilanyloxy)-3-chloropropan-2-ol (13.24 g, yield: 92.4%) as colorless liquid product.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([CH3:9])[N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:3]1=[O:20].[I:21]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C.O>[I:21][C:6]1[C:7](=[O:8])[N:2]([CH3:1])[C:3](=[O:20])[N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:5]=1[CH3:9]
Reactant: Cc1cc(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(I)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 71 %

Procedure:
To a solution of 3,6-dimethyl-1-(3-trifluoromethylphenyl)-pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 20) (800.0 mg) in acetic acid (13.0 ml) was added in water bath N-iodosuccinimide (784.5 mg) and the resulting mixture was stirred at room temperature for five hours. To the reaction mixture was added water (20 ml) and the resulting mixture was stirred for thirty minutes, and thereto was added sodium thiosulfate solution (20 ml) and the resulting mixture was stirred for thirty minutes. The precipitated solids were collected by filtration and washed with water to afford 5-iodo-3,6-dimethyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (819.3 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:33]([C:34]3[CH:39]=[CH:38][C:37]([C:40]4([NH:44]C(=O)OC(C)(C)C)[CH2:43][CH2:42][CH2:41]4)=[CH:36][CH:35]=3)[C:11]3=[N:12][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([N:22]5[CH2:27][CH2:26][CH:25]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH2:24][CH2:23]5)[CH:17]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.CO.[ClH:54]>C(OCC)(=O)C>[ClH:54].[NH2:44][C:40]1([C:37]2[CH:36]=[CH:35][C:34]([N:33]3[C:11]4=[N:12][C:13]([C:16]5[CH:17]=[C:18]([N:22]6[CH2:27][CH2:26][CH:25]([C:28]([N:29]([CH3:31])[CH3:30])=[O:32])[CH2:24][CH2:23]6)[CH:19]=[CH:20][CH:21]=5)=[CH:14][CH:15]=[C:10]4[N:9]=[C:8]3[C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=3)=[CH:39][CH:38]=2)[CH2:41][CH2:42][CH2:43]1
Reactant: CN(C)C(=O)C1CCN(c2cccc(-c3ccc4nc(-c5cccnc5N)n(-c5ccc(C6(NC(=O)OC(C)(C)C)CCC6)cc5)c4n3)c2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C)C(=O)C1CCN(c2cccc(-c3ccc4nc(-c5cccnc5N)n(-c5ccc(C6(N)CCC6)cc5)c4n3)c2)CC1
Yield: 100 %

Procedure:
tert-Butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-{3-[4-(dimethylcarbamoyl)piperidin-1-yl]phenyl}-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate (3.4 g, 4.9 mmol) was deprotected with methanol (15 mL) and 4M HCl in ethyl acetate (15 mL) for 18 h at rt. The mixture was solidified with ethyl acetate and collected with filtration to give the titled compound (2.9 g, 100%) as a white solid.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=1.C(I)C>O1CCCC1>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[C:19]=1[CH2:1][CH3:2]
Reactant: Fc1cncc(Br)c1
Reactant: [Li]CCCC
Solvent: CCI
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCc1c(F)cncc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
n-butyl lithium (92.3 mL, 0.147 mol, 1.6 M) was added to a solution of diisopropyl amine (20.1 mL, 0.147 mol) in tetrahydrofuran (120 mL) at −78° C. and allowed to stir for 30 min at 0° C. The reaction mixture was cooled to −78° C. and a solution of 3-bromo-5-fluoro-pyridine (20.0 g, 0.113 mol) in tetrahydrofuran (20 mL) was added and stirred for 30 min. Ethyl iodide (8.85 mL, 0.124 mol) was added to reaction mixture and allowed to stir at room temperature for 2 h. The reaction mixture was quenched with saturated ammonium chloride (100 mL) solution and extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with saturated sodium chloride, dried over sodium sulphate and concentrated to provide 3-bromo-5-fluoro-4-ethyl pyridine. 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1 H), 8.31 (s, 1 H), 2.87-2.82 (m, 2 H), 1.22-1.19 (t, J=4.0 Hz, 3 H). MS (M+1): 205.8.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:35]=[CH:34][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][CH2:25][C@@H:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23]3)=[C:18]([O:32][CH3:33])[CH:17]=2)=[O:14])=[C:11]([CH3:36])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:37](N1CCOCC1)=O>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:12](=[CH:34][CH:35]=1)[C:13](=[O:14])[N:15]([C:16]1[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][CH2:25][C@@H:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23]3)=[C:18]([O:32][CH3:33])[CH:17]=1)[CH:37]=[CH:36]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(NC(=O)c2ccc(OCc3ccccc3)cc2C)ccc1N1CC[C@@H](N2CCCC2)C1
Reactant: O=CN1CCOCC1
Product: COc1cc(-n2ccc3cc(OCc4ccccc4)ccc3c2=O)ccc1N1CC[C@@H](N2CCCC2)C1

Procedure:
According to Method Q, 4-benzyloxy-N—((R)-4-[1,3′]bipyrrolidinyl-1′-yl-3-methoxy-phenyl)-2-methyl-benzamide was reacted with N-formylmorpholine. In this way the product was obtained with molecular weight 495.63 (C31H33N3O3); MS (ESI): 496 (M+H+).
Reaction SMILES: Br[C:2]1[C:15]([CH3:16])=[C:14]([C:17]#[N:18])[C:5]2[N:6]=[C:7]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[O:8][C:4]=2[C:3]=1[F:19].[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[NH4+]>O1CCOCC1.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.C(OCC)(=O)C>[C:17]([C:14]1[C:5]2[N:6]=[C:7]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[O:8][C:4]=2[C:3]([F:19])=[C:2]([C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([F:20])[CH:26]=2)[C:15]=1[CH3:16])#[N:18]
Reactant: Cc1c(Br)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1c(-c2cccc(F)c2)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Temperature: 95 °C
Reaction time: 62 h
Yield: 36.5 %

Procedure:
6-Bromo-4-cyano-7-fluoro-N,N,5-trimethyl-1,3-benzoxazole-2-carboxamide (I-127) (200 mg, 0.61 mmol), 3-fluorophenylboronic acid (343 mg, 2.45 mmol) and tripotassium phosphate (261 mg, 1.23 mmol) were suspended in 1,4-dioxane (6 ml), and at room temperature, tetrakis(triphenylphosphine)palladium(0) (142 mg, 0.12 mmol) was added. The suspension was stirred under nitrogen atmosphere at 95° C. for 62 hours, followed by cooling to room temperature. The solution was fractionated with ethyl acetate and aqueous saturated ammonium chloride solution. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, hexane:ethyl acetate=5:2) to obtain the entitled compound (76 mg, 36%) as a white solid.
Reaction SMILES: [Br-].[CH2:2]([Zn+])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:10]1([C:16](Cl)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>O1CCCC1>[CH:10]1([C:16]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: [Zn+]Cc1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52 %

Procedure:
To a solution of 11 ml of 0.5 M solution of benzyl zinc bromide in anhydrous tetrahydrofuran were added at 0° C. 5 mg of bis-triphenylphospinepalladium dichloride and 0.66 ml of cyclohexanecarbonyl chloride. The mixture was stirred at r.t. for 1.5 h, quenched with a saturated solution of ammonium chloride and extracted with ethyl acetate. The collected organic layers were washed with water, dried (Na2SO4) and the solvent was evaporated under vacuum. The crude was purified by flash chromatography eluting with petroleum ether-EtOAc 95:5 to give 0.78 g (52%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[NH:10]2)=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2].[H-].[Na+].Cl[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37]>C1COCC1>[C:15]([C:14]1[CH:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[S:29]([CH3:32])(=[O:31])=[O:30])[N:10]([C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:37])[C:11](=[O:28])[N:12]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[C:13]=1[CH3:17])#[N:16]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=C(C#N)C(c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)OCc2ccccc2)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.7 %

Procedure:
The reaction was carried out under argon. (4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (115 mg, 250 μmol) was initially charged in dry THF (3 ml), and sodium hydride (60% in mineral oil; 14 mg, 350 μmol; 1.4 eq.) was added at 0° C. The mixture was warmed to RT and stirred for 20 min. A solution of benzyl chloroformate (60 mg, 350 μmol; 1.4 eq.) in THF (1 ml) was then slowly added dropwise. After a reaction time of 1.5 h, the reaction mixture was concentrated and the crude product was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave the title compound as a colorless solid (68 mg, 46% of theory).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])=[N:9]1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[O:35].O>O1CCCC1>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:34]([O:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[O:35])[CH2:22][CH2:21]2)=[O:19])=[N:9]1
Reactant: O=C(Nc1noc2ccccc12)N1CCNCC1
Reactant: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)COC(=O)N1CCN(C(=O)Nc2noc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
To a solution of N-1,2-benzisoxazol-3-ylpiperazine-1-carboxamide trifluoroacetate (200 mg, 0.555 mmol) and triethylamine (0.309 ml, 2.22 mmol) in tetrahydrofuran (4 ml) was added isobutyl chloroformate (0.108 ml, 0.833 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured to water and extracted with ethyl acetate. The extract was washed with water, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 95.0 mg (49.5%) of the desired product as a solid.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:27]=[C:28]([S:32]([NH:35][CH2:36][CH2:37][O:38][CH3:39])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:27]=[C:28]([S:32]([NH:35][CH2:36][CH2:37][O:38][CH3:39])(=[O:33])=[O:34])[CH:29]=[CH:30][CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: COCCNS(=O)(=O)c1cccc(Br)c1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: COCCNS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 3-bromo-N-(2-methoxy-ethyl)-benzenesulfonamide (example B.33) (265 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (320 mg, 57%). MS (ISP) 551.3 [(M+H)+]; mp 147-148° C.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:16]C1C=CC(C(O)=O)=C(I)C=1.FC1C=CC(I)=C(C=1)C(O)=O>>[F:16][C:3]1[CH:2]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)[CH:4]=1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Reactant: O=C(O)c1ccc(F)cc1I
Agent: O=C(O)c1cc(F)ccc1I
Product: O=C(O)c1ccc(F)cc1-n1nccn1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 1, substituting for 4-fluoro-2-iodo-benzoic acid for 5-fluoro-2-iodo-benzoic acid in Step A. 1H NMR (400 MHz, CD3OD): 7.93 (s, 2H), 7.88 (dd, J=8.7, 5.9 Hz, 1H), 7.56 (dd, J=9.2, 2.5 Hz, 1H), 7.38-7.30 (m, 1H).
Reaction SMILES: C([SH-:5][C:6](=[S:24])[SH-:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[N+]([O-])=O)(C)(C)C.O>C(O)(=O)C>[N+:14]([C:13]1[C:8]2[S:7][C:6](=[S:24])[S:5][C:9]=2[CH:10]=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)([O-:16])=[O:15]
Reactant: CC(C)(C)[SH-]C(=S)[SH-]c1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc2sc(=S)sc12
Yield: 54.5 %

Procedure:
15 g (0.037 mole) of III was dissolved in 125 ml of glacial acetic acid and heated to 90°-100° C. for 45 minutes. The mixture was poured into 500 ml of water, extracted with three 100 ml portions of methylene chloride. The organic extract was dried (Na2SO4) and solvent removed by distillation in vac. The residual solid was recrystallized from ethanol. There was obtained 6.0 g (55% theor.) of 4-nitro-6-trifluoromethyl-1,3-benzodithiole-2-thione, m.p. 163°-165° C. Analytical: Calcd. for C8H2F3NO2S3 : C, 32.32; H, 0.67; S, 32.32. Found: C, 32.18; H, 0.74; S, 32.21. Mass Spectrum mol. wt.=297. NMR(d6DMSO); 8.63δ(1H,m); 8.73(1H,m).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:30])=[C:4](I)[C:5]([O:26][CH2:27][CH3:28])=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH3:9])[CH:7]=1.CC1(C)C(C)(C)OB([C:39]2[CH:40]=[CH:41][C:42]([C:45]#[N:46])=[N:43][CH:44]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>C(#N)C.O.CCOC(C)=O>[Cl:1][C:2]1[C:3]([F:30])=[C:4]([C:39]2[CH:40]=[CH:41][C:42]([C:45]#[N:46])=[N:43][CH:44]=2)[C:5]([O:26][CH2:27][CH3:28])=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH3:9])[CH:7]=1
Reactant: CCOc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(F)c1I
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(F)c1-c1ccc(C#N)nc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
A solution of N-[1-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (170 mg, 0.31 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbonitrile (86 mg, 0.37 mmol, Frontier Scientific, Cat. No. C1628), sodium carbonate (66 mg, 0.62 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium-(H), complex with dichloromethane (1:1) (31 mg, 0.037 mmol) in acetonitrile (1.5 mL) and water (0.4 mL) was degassed with nitrogen for 10 min and stirred at 95° C. for 2 hours. The reaction mixture was diluted with EtOAc, washed with saturated sodium bicarbonate, water, and brine, dried over sodium sulfate, filtered and concentrated to a crude residue which was purified by flash column chromatography using EtOAc in hexanes (25%-100%) to give the desired product (81 mg, 50%). LCMS for C26H26ClFN7O2 (M+H)+: m/z=522.2. Found: 522.2.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]([C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:24])=O.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O.C(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:23][C:22]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=1[N:7]1[C:6](=[O:24])[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([CH2:1][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:4]=2)[N:9]=[CH:8]1
Reactant: COC(=O)c1ccc(C)c(-n2cnc3ccc(C=O)cc3c2=O)c1
Reactant: C1COCCN1
Agent: [Ti+4]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)[O-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(C)c(-n2cnc3ccc(CN4CCOCC4)cc3c2=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-(6-formyl-4-oxoquinazolin-3(4H)-yl)-4-methylbenzoate (0.60 g) and titanium isopropoxide (1.10 ml) in methylene chloride (15 ml) was added morpholine (0.33 ml). The reaction was stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (0.80 g) was added and stirred for a further 16 hours. The reaction mixture was diluted with water/methylene chloride (1:1) and filtered through diatomaceous earth (Celite®). The layers were separated, the aqueous layer extracted with methylene chloride. The combined organics were dried (magnesium sulphate) and concentrated to give a solid. The solid was purified by column chromatography on a silica column using initially methylene chloride and then a 19:1 mixture of methylene chloride and methanol as eluent to give methyl 4-methyl-3-[6-(morpholin-4-ylmethyl)-4-oxoquinazolin-3(4H)-yl]benzoate as a solid (0.62 g). NMR Spectrum: (DMSOd6) 2.18 (s, 3H), 2.40 (m, 4H), 3.59 (m, 4H), 3.63 (s, 2H), 3.87 (s, 3H), 7.62 (d, 1H), 7.75 (d, 1H), 7.85 (m, 1H), 8.03 (m, 2H), 8.12 (d, 1H), 8.28 (s, 1H); Mass Spectrum: M+H+ 394.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH2:8][CH2:7]1.C([N:18](CC)CC)C.O>C(Cl)(Cl)Cl>[Cl:1][CH2:2][C:3]([NH2:6])=[O:4].[Cl:1][CH2:2][C:3]([NH2:18])=[O:4].[NH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH2:8][CH2:7]1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)CCl
Agent: c1ccc2c(c1)NCCN2
Solvent: O
Solvent: ClC(Cl)Cl
Product: NC(=O)CCl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 1 L three-necked round bottomed flask equipped with a magnetic stir bar, reflux condenser and addition funnel, was added chloroacetyl chloride (9.6 mL, 0.120 mol) and CHCl3 (100 mL). The addition funnel was charged with a solution of tetrahydroquinoxaline (8.0 g, 0.0596 mol) and triethylamine (20.8 mL) in CHCl3 (100 mL). The flask was chilled to 0° C., and the amine was slowly added to the acid chloride. After the addition was complete, the mixture was allowed to warm to ambient temperature and stir for 1 hour. The flask was then cooled to 0° C. and H2O (50 mL) was slowly added. The mixture was diluted with CHCl3 (250 mL) and the layers were separated. The organic layer was washed with H2O (50 mL), 0.05 N NaOH (2×50 mL), H2O (50 mL), 1 N HCl (3×50 mL) and H2O (2×50 mL), and was dried over anhydrous Na2SO4. The solution was filtered and concentrated to a brown solid. The solid was collected by filtration, washed with 2-propanol (2×30 mL) and diethylether (2×40 mL) and dried to yield the title product (4.41 g, 51.5%). 1H NMR (DMSO-d6): δ3.89 (s, 4 H), 4.01 (s, 4 H), 7.25 (s, 2 H), 7.65 (br s, 2 H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13](C(C)=C)[C:12]2=[O:23])=[N:2]1>C(O)C.O.Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12]2=[O:23])=[N:2]1
Reactant: C=C(C)n1c(=O)n(Cc2noc3ccccc23)c2ccccc21
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=c1[nH]c2ccccc2n1Cc1noc2ccccc12
Temperature: 60 °C
Yield: 88.7 %

Procedure:
The 1-1,2-benzisoxazol-3-ylmethyl-3-isopropenyl-1,3-dihydro-benzimidazol-2-one (0.26 g, 0.85 mmol) was diluted with ethanol (2 ml), water (2 ml) and 37% HCl (1 ml). The resulting mixture was warmed to 60° C. for 1 h and cooled to ambient temperature. The reaction was diluted with water and the product was extracted into dichloromethane. The layers were separated and the organic phase was dried (MgSO4). Filtration and concentration gave 0.20 g (89%) of the desired product which was used without further purification.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([C:26](=C)C(OCC)=O)[CH:23]=[CH:24][CH:25]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:33]([O:36][CH2:37][CH3:38])(=[O:35])[CH3:34]>[Pd]>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH2:26][CH2:34][C:33]([O:36][CH2:37][CH3:38])=[O:35])[CH:23]=[CH:24][CH:25]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(C(=O)OCC)c1cccc(CCc2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reactant: CCOC(C)=O
Agent: [Pd]
Product: CCOC(=O)CCc1cccc(CCc2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 27 h
Yield: 90 %

Procedure:
A solution of ethyl 3-[2-(4,5-diphenyl-2oxazolyl)-ethyl]phenyl-2-propenoate (1.02 g, 2.4 mmol) in ethyl acetate (50 mL) was hydrogenated over 10% palladium on charcoal (0.06 g) at 35 psi. After 27 hours, the mixture was filtered, concentrated and the residue subjected to chromatography on a column of silica gel using a mixture of ethyl acetate and hexanes (9:1) as eluent. Elution gave ethyl 3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]benzene propanoate (0.92 g, 90%) as an oil.