Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1.[N:34]1([CH2:40][CH2:41][CH2:42]Cl)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([O:15][CH2:42][CH2:41][CH2:40][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=1
Reactant: ClCCCN1CCCCC1
Reactant: COc1cc(-c2nc3ccc(O)cc3n2Cc2ccccc2C(F)(F)F)cc(OC)c1OC
Product: COc1cc(-c2nc3ccc(OCCCN4CCCCC4)cc3n2Cc2ccccc2C(F)(F)F)cc(OC)c1OC

Procedure:
The title compound was prepared by reacting the compound of Example 104 with 3-(piperidin-1-yl)propyl chloride essentially as previously described mp 138° C., IR, NMR, MS. 584
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]2=[N:14][CH:15]=[N:16][C:17]([O:18][C@@H:19]([CH2:30][O:31][C@H:32]([CH3:45])[CH2:33][O:34][Si:35]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])[C:20]([NH:22][C:23]3[CH:28]=[N:27][C:26]([CH3:29])=[CH:25][N:24]=3)=[O:21])=[C:12]2[CH:11]=[N:10]1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:88][N:89]1CCCC1=O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[C-]#N.[Zn+2].[C-]#N>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:88]#[N:89])[C:3]=1[N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([O:18][C@@H:19]([CH2:30][O:31][C@H:32]([CH3:45])[CH2:33][O:34][Si:35]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])[C:20]([NH:22][C:23]3[CH:28]=[N:27][C:26]([CH3:29])=[CH:25][N:24]=3)=[O:21])[C:12]=2[CH:11]=[N:10]1
Reactant: Cc1cnc(NC(=O)[C@H](CO[C@H](C)CO[Si](C(C)C)(C(C)C)C(C)C)Oc2ncnc3c2cnn3-c2c(Cl)cccc2Br)cn1
Reactant: CN1CCCC1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1cnc(NC(=O)[C@H](CO[C@H](C)CO[Si](C(C)C)(C(C)C)C(C)C)Oc2ncnc3c2cnn3-c2c(Cl)cccc2C#N)cn1
Temperature: 110 °C
Yield: 79 %

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) (0.261 g, 0.29 mmol) was added in one portion to a de-gassed mixture of (2S)-2-(1-(2-bromo-6-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyrazin-2-yl)-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanamide (Intermediate BO1) (4.1 g, 5.70 mmol), zinc cyanide (0.335 g, 2.85 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.330 g, 0.57 mmol) in N-methylpyrrolidone (41 mL) at 20° C. under nitrogen. The resulting suspension was degassed under vacuum with inlet of nitrogen four times and then heated to 110° C. (internal temperature) for 1 hour. The mixture was cooled, poured into water (100 mL) and extracted with ethyl acetate (2×50 mL). The organic layers were combined and washed with water (4×50 mL) and brine (50 mL), dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 30 to 100% EtOAc in isohexane to afford the product (3.0 g, 79%).
Reaction SMILES: Cl.[C:2]([O:6][C:7]([NH:9][C@H:10]([C:18]([OH:20])=O)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])([CH3:5])([CH3:4])[CH3:3].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1>CN(C)C=O.O>[C:2]([O:6][C:7]([NH:9][C@H:10]([C:18]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8])([CH3:3])([CH3:4])[CH3:5]
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1ccccc1
Reaction time: 6 h

Procedure:
To a solution of N-tert-butoxycarbonyl-L-phenylalanine hydrochloride (2.65 g) and aniline (1.02 g) in dimethylformamide (DMF, 50 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC.HCl) and hydroxybenzotriazole (HOBT, 1.5 g) at room temperature, and the mixture was stirred for 6 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a 10% aqueous citric acid solution, water, a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure to give N-tert-butoxycarbonyl-L-phenylalanylaminobenzene. To a solution of the obtained compound in dichloromethane (20 ml) was added trifluoroacetic acid (10 ml) at room temperature, and the mixture was stirred for 1 hour. Toluene (10 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. A 1M hydrogen chloride-ether solution (10 ml) was added to the residue, and crystallization gave the title compound (1.45 g, yield 52%).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[C:20](F)=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([N+:22]([O-:24])=[O:23])[CH:11]=1.CCN(CC)CC>C1COCC1>[CH2:1]([O:8][C:20]1[C:10]([F:9])=[CH:11][C:12]([N+:22]([O-:24])=[O:23])=[C:13]([CH:19]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(OCc2ccccc2)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.5 %

Procedure:
8.25 g of Verkade base are added to a solution of 2.61 g of benzyl alcohol in 20 ml of THF. The mixture is stirred for 10 minutes at room temperature, and a solution of 5.3 g of ethyl 4,5-difluoro-2-nitrobenzoate and 2.55 g of Et3N in 150 ml of THF is added to this solution. The mixture is stirred for 1 hour at room temperature. The reaction medium is evaporated under reduced pressure. The residue is taken up in DCM and washed three times with aqueous 1N HCl solution, and then with water. The organic phase is dried over MgSO4 and filtered, and the filtrate is evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a PE/DCM mixture from (100/0, v/v) to (0/100, v/v) to give 4.5 g of the expected product.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:16]C([O-])(C)C.[K+].CI>C1COCC1>[C:1]([N:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:16])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CCOC(=O)CCNC(=O)OC(C)(C)C
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)CCN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 80.8 %

Procedure:
To a solution of ethyl 3-aminopropionate hydrochloride (19 g) in THF (600 mL) was added triethylamine (44 mL), dimethylaminopyridine (1.5 g) and di-tert-butyldicarbonate (30 g) at 0° C. and the mixture was stirred at 40° C. for four hours. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure to give ethyl N-Boc-3-aminopropionate (16.7 g) as a colorless oil. To a solution of ethyl N-Boc-3-aminopropionate (5.0 g) in THF (50 mL) was added t-BuOK (2.8 g) and methyl iodide (4.9 g) at 0° C. and the mixture was stirred at room temperature for an hour. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure to give ethyl 3-(N-Boc-N-methylamino)propionate (4.3 g) as a colorless oil. Subsequently, the title compound was prepared from ethyl 3-(N-Boc-N-methylamino)propionate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 1001.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]([CH3:25])([CH3:24])[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH:6]=[C:5]2[S:26]([N:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@@H:31]([CH2:42][OH:43])[CH2:30]1)(=[O:28])=[O:27].[CH:44]1([NH:47][C:48](=[O:66])[C:49]2[CH:54]=[C:53](B3OC(C)(C)C(C)(C)O3)[C:52]([CH3:64])=[C:51]([F:65])[CH:50]=2)[CH2:46][CH2:45]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Si:17]([O:16][CH2:15][C:14]([CH3:24])([CH3:25])[CH2:13][N:7]1[CH:6]=[C:5]([S:26]([N:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[C@@H:31]([CH2:42][OH:43])[CH2:30]2)(=[O:28])=[O:27])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:53]3[CH:54]=[C:49]([C:48](=[O:66])[NH:47][CH:44]4[CH2:45][CH2:46]4)[CH:50]=[C:51]([F:65])[C:52]=3[CH3:64])[CH:3]=2)[C:8]1=[O:12])([C:20]([CH3:22])([CH3:21])[CH3:23])([CH3:19])[CH3:18]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)Cn1cc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)[C@@H](CO)C2)c2cc(Br)ccc2c1=O
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc(S(=O)(=O)N3CCN(C(=O)OC(C)(C)C)[C@@H](CO)C3)c2c1
Temperature: 75 °C
Reaction time: 6 h
Yield: 80 %

Procedure:
A solution of tert-butyl (2R)-4-{[6-bromo-2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-1-oxo-1,2-dihydroisoquinolin-4-yl]sulfonyl}-2-(hydroxymethyl)piperazine-1-carboxylate (Example 49b, 0.58 g) in DMF (10 mL) was treated with N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.263 g), Pd-118 (0.016 g) and potassium carbonate (0.228 g). The resulting mixture was stirred at 75° C. for 6 h. The cooled reaction was concentrated under reduced pressure then purified (SiO2 chromatography, loaded in DCM, flushed with isohexane (100 mL), then DCM (200 mL), followed by a 10-100% gradient of ethyl acetate/isohexane) to afford the subtitle compound (0.537 g).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([Cl:11])[CH:5]=1)=[O:3].C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[F:32][C:33]([F:41])([F:40])[C:34]([C:36]([F:39])([F:38])[F:37])=[O:35].S(=O)(=O)(O)O>CCCCCC.O1CCCC1>[Cl:11][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH2:1][C:34]([OH:35])([C:36]([F:39])([F:38])[F:37])[C:33]([F:41])([F:40])[F:32])[CH:9]=[CH:8][C:7]=1[Cl:10]
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: O=S(=O)(O)O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: O=C(CC(O)(C(F)(F)F)C(F)(F)F)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 3,4-dichloroacetophenone (5.0 g.)in tetrahydrofuran (50 ml.) was added dropwise to a stirred solution of lithium diisopropylamide (prepared from n-butyl-lithium [19.8 ml. of a 1.6 molar solution in hexane] and diisopropylamine (4.3 ml.) in tetrahydrofuran (200 ml.) during 10 minutes at 0° C.) which was cooled to -78° C., and the mixture was stirred at -78° C. for 30 minutes and then at -50° C. for 45 minutes, and then recooled to -78° C. Anhydrous hexafluoroacetone (10 ml., generated by treating the sesquihydrate with concentrated sulphuric acid) was distilled into the mixture, which was then stirred for 1 hour at -78° C. Methanol (10 ml.) and saturated aqueous ammonium chloride solution (50 ml.) were added, the mixture was allowed to warm up to laboratory temperature and was poured into water (250 ml.) and the mixture was extracted with diethyl ether. The extract was washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated to dryness under reduced pressure, and there was thus obtained as an oil 1-(3,4-dichlorophenyl)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethylbutan-1-one which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[OH:10])[CH:5]=[O:6].[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1)([O-:14])=[O:13].C(=O)([O-])[O-].[Li+].[Li+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[O:10][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=1)[CH:5]=[O:6]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: O=Cc1cc(O)c(O)c(Br)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1cc(O)c(OCc2ccc([N+](=O)[O-])cc2)c(Br)c1

Procedure:
A mixture of 3-bromo-4,5-dihydroxy-benzaldehyde (2 g), 4-nitrobenzylbromide (2 g), lithium carbonate (680 mg) and a small amount of tetrabutylammonium iodide (ca 50 mg) in DMF (15 ml) was stirred at 60° C. for 4 h. The mixture was diluted with EtOAc and washed with water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Yield: 2.82 g. MS-ESI: [M+H]+=352.0/354.0
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)=[C:2]=[O:3].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23](=[S:33])[NH:24][C@H:25]([CH:30]([CH3:32])[CH3:31])[C:26]([O:28][CH3:29])=[O:27])[O:20][N:19]=2)=[CH:14][CH:13]=1>>[CH3:32][CH:30]([CH3:31])[C@@H:25]([NH:24][C:23]([C:21]1[O:20][N:19]=[C:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:2]([NH:1][C:4]3[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=3)=[O:3])=[CH:13][CH:14]=2)[CH:22]=1)=[S:33])[C:26]([O:28][CH3:29])=[O:27]
Reactant: Cc1ccc(N=C=O)cc1
Reactant: COC(=O)[C@H](NC(=S)c1cc(-c2ccc(N)cc2)no1)C(C)C
Product: COC(=O)[C@H](NC(=S)c1cc(-c2ccc(NC(=O)Nc3ccc(C)cc3)cc2)no1)C(C)C
Yield: 65 %

Procedure:
The title compound was prepared according to the procedure as set, forth in example 151, except that 1-isocyanato-4-methylbenzene was used in place of 1-fluoro-3-isocyanatobenzene and (R)-methyl 2-(3-(4-aminophenyl)isoxazole-5-carbothioamido)-3-methylbutanoate was used in place of methyl 2-(3-(4-aminophenyl)isoxazole-5-carboxamido)-3-methylbutanoate to yield 65% of the title compound. MS (ESI): m/z 467(M+H); 1HNMR (DMSO-d6, 300 MHz): δ 10.924 (d, 1H), 8.902 (s, 1H), 8.630 (s, 1H), 7.865 (d, 2H), 7.607(d, 3H), 7.351(d, 2H), 7.094(d, 2H), 4.810 (s, 1H), 3.665(s, 3H), 2.489 (m, 1H), 2.367(s, 3H), 1.033(m, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:33])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]1([CH2:22][C:23]2[C:31]([CH3:32])=[CH:30][C:26]3[CH2:27][O:28][CH2:29][C:25]=3[CH:24]=2)SCCCS1)(=[O:10])=[O:9].CO.O.[O:37]1CCCC1>[Cl-].[Na+].O.[N+]([O-])([O-])=O.[Ag+]>[Cl:1][C:2]1[C:3]([CH3:33])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16](=[O:37])[CH2:22][C:23]1[C:31]([CH3:32])=[CH:30][C:26]2[CH2:27][O:28][CH2:29][C:25]=2[CH:24]=1)(=[O:10])=[O:9]
Reactant: C1CCOC1
Reactant: Cc1cc2c(cc1CC1(c3sccc3S(=O)(=O)Nc3onc(C)c3Cl)SCCCS1)COC2
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: Cc1cc2c(cc1CC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Cl)COC2
Temperature: 55 °C
Reaction time: 72 h
Yield: 18 %

Procedure:
A mixture of N-(4-chloro-3-methyl-1,2-oxazol-5-yl)-2-{2-[(6-methyl-1,3-dihydro-2-benzofuran-5-yl)methyl]-1,3-dithian-2-yl}thiophene-3-sulfonamide described in Production Example 1-7 (300 mg, 0.55 mmol), methanol (20 mL), water (2 mL) and silver nitrate (940 mg, 5.5 mmol) was stirred for 3 days at 55° C. The reaction mixture was allowed to cool to room temperature, tetrahydrofuran (40 mL) and brine (1 mL) were added at that temperature, and the mixture was filtered with Celite. The filtrate was extracted by addition of ethyl acetate (200 mL), water (100 mL) and saturated aqueous citric acid solution (1 mL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (methanol:ethyl acetate=1:9), and then further purified by silica gel thin-layer chromatography (methanol:ethyl acetate=1:32) to give the title compound (45 mg, 18% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.CCN(CC)CC.[OH:18][CH2:19][CH2:20][O:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([C:29]2[NH:38][C:37](=[O:39])[C:36]3[C:31](=[CH:32][C:33]([O:42][CH3:43])=[CH:34][C:35]=3[O:40][CH3:41])[N:30]=2)=[CH:24][C:23]=1[CH3:44]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[O:18][CH2:19][CH2:20][O:21][C:22]2[C:27]([CH3:28])=[CH:26][C:25]([C:29]3[NH:38][C:37](=[O:39])[C:36]4[C:31](=[CH:32][C:33]([O:42][CH3:43])=[CH:34][C:35]=4[O:40][CH3:41])[N:30]=3)=[CH:24][C:23]=2[CH3:44])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCO)c(C)c3)nc2c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCOC(=O)Nc4ccc(F)cc4)c(C)c3)nc2c1
Yield: 74 %

Procedure:
A mixture of 4-fluorophenylisocyanate (0.138 mL, 1.14 mmol), Et3N (0.185 mL, 1.32 mmol) and 4 (0.0700 g, 0.189 mmol) in THF (1.00 mL) was heated at reflux for 8 hours. The mixture was cooled, diluted with EtOAc (200 mL), washed with saturated aqueous NH4Cl (3×75 mL), brine (75 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified on silica gel (12 g, CH2Cl2/MeOH) and the product was freeze-dried from MeCN/H2O to provide 2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl 4-fluoro-phenylcarbamate (5) (0.0710 g, 74%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 11.83 (s, 1H), 9.78 (s, 1H), 7.91 (s, 2H), 7.54-7.44 (m, 2H), 7.18-7.08 (m, 2H), 6.73 (d, J=2.31 Hz, 1H), 6.51 (d, J=2.31 Hz, 1H), 4.47-4.38 (m, 2H), 4.12-4.03 (m, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 2.31 (s, 6H); MS (APCI) m/z 508 [C27H26FN3O6+H]+.
Reaction SMILES: [OH:1][C:2]([C:22]1[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=1)([C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1)[CH2:3][NH:4]C(=O)OCC1C=CC=CC=1>C(O)C.[Pd]>[NH2:4][CH2:3][C:2]([C:22]1[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=1)([C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1)[OH:1]
Reactant: Cc1cccc(C(O)(CNC(=O)OCc2ccccc2)c2cccc(C)c2)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1cccc(C(O)(CN)c2cccc(C)c2)c1
Reaction time: 8 h
Yield: 59.9 %

Procedure:
Benzyl 2-hydroxy-2,2-dim-tolylethylcarbamate (0.309 g, 0.823 mmol) was dissolved in ethanol (6 mL) and treated with 5% Pd/C (˜20 mgs). The reaction was stirred overnight under a hydrogen atmosphere (balloon). The reaction was filtered and the residue was purified on Biotage chromatography (10% to 60% methanol/dichloromethane) to give the title material (0.119 g, 60%) as an oil. 1H NMR (400 MHz, DMSO-d6) δ: 2.24 (6H, s), 3.16 (2H, ddd, J=3.16, 1.77 and 1.64 Hz), 4.27 (2H, s), 6.96 (2H, d, J=7.07 Hz), 7.15 (4H, m), 7.23 (2H, br s). LC/MS (M+H)+: 242. HPLC ret. time (Condition B): 1.328 min.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([F:22])=[C:18]([C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[N:17]=[C:16]2Cl)=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].N1C=CC=CC=1.[CH2:37]([OH:40])[C:38]#[CH:39]>>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([F:22])=[C:18]([C:23]([F:29])([F:28])[C:24]([F:26])([F:27])[F:25])[N:17]=[C:16]2[O:40][CH2:37][C:38]#[CH:39])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:8])[CH3:9])=[O:5]
Reactant: CC(C)OC(=O)c1cc(-n2c(Cl)nc(C(F)(F)C(F)(F)F)c(F)c2=O)c(F)cc1Cl
Reactant: C#CCO
Solvent: c1ccncc1
Product: C#CCOc1nc(C(F)(F)C(F)(F)F)c(F)c(=O)n1-c1cc(C(=O)OC(C)C)c(Cl)cc1F

Procedure:
using isopropyl 2-chloro-5-[2-chloro-5-fluoro-6 -oxo-4-pentafluoroethyl-1(6H)-pyrimidinyl]-4-fluorobenzoate and pyridine in propargyl alcohol there is obtained isopropyl 2-chloro-5-[5-fluoro-6-oxo-4 -pentafluoroethyl-2-(2-propynyloxy)-1(6H)-pyrimidinyl]-4-fluorobenzoate, 1H-NMR (CDCl3, 400 MHz): 7.86 ppm (d,1H), 7.43 ppm (d,1H), 5.27 ppm (m,1H), 4.97 ppm (d,2H), 2.53 ppm (t,1H), 1.39 ppm (d,3H), 1.38 ppm (d,3H);
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:21]2[CH:26]=[C:25]([N+:27]([O-])=O)[C:24]([O:30][CH3:31])=[C:23]([O:32][CH3:33])[CH:22]=2)[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[C:21]2[CH:22]=[C:23]([O:32][CH3:33])[C:24]([O:30][CH3:31])=[C:25]([NH2:27])[CH:26]=2)[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COc1ccc(C(NC(C)c2cc(F)cc(F)c2)c2cc(OC)c(OC)c([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(NC(C)c2cc(F)cc(F)c2)c2cc(N)c(OC)c(OC)c2)cc1

Procedure:
Following a similar procedure to that described in Example (1b), 870 mg of N-[1-(3,5-difluorophenyl)ethyl-N-[(3,4-dimethoxy-5-nitrophenyl)-(4-methoxyphenyl)methyl]amine [prepared as described in step (a) above], 1.04 g of nickel chloride hexahydrate and 302 mg of sodium borohydride were reacted, to obtain 550 mg of the title compound as a colorless oil.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[O:8][CH2:7][CH2:6][O:5]1.CN(C)CCN(C)C.[Li]CCCC.CN([CH:30]=[O:31])C>C1COCC1.CCCCCC>[CH3:3][C:4]1([C:9]2[S:10][C:11]([CH:30]=[O:31])=[CH:12][CH:13]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: CN(C)C=O
Reactant: CC1(c2cccs2)OCCO1
Agent: CN(C)CCN(C)C
Agent: N#N
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(c2ccc(C=O)s2)OCCO1
Temperature: -78 °C
Reaction time: 16 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of commercially available 2-methyl-2-thiophen-2-yl-[1,3]dioxolane (5.00 g, 28.49 mmol) in THF (145.0 mL) at −78° C. was added dropwise N,N,N′,N′-tetramethyl-ethylendiamine (4.41 mL, 29.06 mmol) followed by n-BuLi (18.14 mL of a 1.6M solution in hexane, 29.06 mmol), maintaining the temperature at −78° C. The reaction mixture was then stirred for 2 h at −78° C. before DMF (6.74 mL, 87.22 mmol) was added dropwise. The cooling bath was removed and the reaction mixture was stirred for 16 h. The reaction mixture was poured in sat. aq. NaH4Cl (200 mL) and extracted with EA (2×200 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give crude 5-(2-methyl-[1,3]dioxolan-2-yl)-thiophene-2-carbaldehyde as an yellow oil. LC-MS-conditions 02: tR=0.87 min; [M+AcCN+H]+=240.32. The crude material was dissolved, under inert atmosphere (N2) in MeOH (51.2 mL) and treated at 0° C., portionwise, over 20 min, with NaBH4 (1.35 g, 34.19 mmol in five equal portions). The reaction mixture was stirred at rt for 45 min. The reaction mixture was poured in water (90 mL) and the aq. layer was extracted with EA (2×225 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound. TLC: rf (50:50 hept-EA)=0.40. LC-MS-conditions 02: tR=0.72 min; [M+H]+=201.46.
Reaction SMILES: O[CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:38]1(=[O:48])[NH:42][C:41](=[O:43])[C:40]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]12.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[O:43]=[C:41]1[C:40]2[C:39](=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:38](=[O:48])[N:42]1[CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)NCC(O)Cc1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Reaction time: 1 h
Yield: 83.2 %

Procedure:
To a solution of 1,1-dimethylethyl (2-hydroxy-3-phenylpropyl)carbamate (10.0 g, 39.8 mmol), PPh3 (12.5 g, 47.8 mmol) and phthalimide (6.44 g, 43.8 mmol) in THF (125 mL) at RT was added DEAD (9.4 mL, 59.7 mmol) over 5 min. After 1 h at RT, the reaction solution was concentrated and purified on silica (hexanes/EtOAc, 2:1) to give the title compound as a white solid (12.6 g, 83%): LCMS (ES) m/z 381 (M+H)+.