Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](/[N+]([O-])=O)\[CH3:10])=[CH:4][C:3]=1[N+:14]([O-])=O.C(O)(=[O:19])C>[Fe]>[NH2:14][C:3]1[CH:4]=[C:5]([CH2:8][C:9](=[O:19])[CH3:10])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: CC(=O)O
Reactant: C/C(=C\c1ccc(Cl)c([N+](=O)[O-])c1)[N+](=O)[O-]
Agent: [Fe]
Product: CC(=O)Cc1ccc(Cl)c(N)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of 1-Chloro-2-nitro-4-((E)-2-nitro-propenyl)-benzene (13.6 g, 56 mmol) in glacial acetic acid (100 ml) is added slowly to a stirred slurry of Iron powder (34 g, 610 mmol) in glacial acetic acid (100 ml) at 60° C. The reaction mixture is stirred at 60° C. for 1 hour then allowed to cool to room temperature and stirred overnight. The reaction mixture is poured onto ice-water (300 ml) and filtered through Celite® (filter agent) washing with DCM (500 ml). The organic portion is separated and washed with water (2×300 ml) and brine (300 ml), dried over MgSO4, filtered and concentrated in vacuo to give a brown oil. The crude residue is absorbed onto silica and purification by flash chromatography on silica eluting with 20% EtOAc/Hexanes affords the title compound.
Reaction SMILES: [Li+].[OH-].[NH2:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([CH2:14][C@@H:15]([O:36][C:37]([N:39]2[CH2:44][CH2:43][CH:42]([N:45]3[CH2:51][CH2:50][C:49]4[CH:52]=[CH:53][CH:54]=[CH:55][C:48]=4[NH:47][C:46]3=[O:56])[CH2:41][CH2:40]2)=[O:38])[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[C@H:20]([C:31]([O:33]CC)=[O:32])[CH2:19]2)=[O:17])=[CH:6][C:5]=1[Cl:57]>C1COCC1>[NH2:3][C:4]1[C:9]([C:10]([F:11])([F:13])[F:12])=[CH:8][C:7]([CH2:14][C@@H:15]([O:36][C:37]([N:39]2[CH2:40][CH2:41][CH:42]([N:45]3[CH2:51][CH2:50][C:49]4[CH:52]=[CH:53][CH:54]=[CH:55][C:48]=4[NH:47][C:46]3=[O:56])[CH2:43][CH2:44]2)=[O:38])[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH:24]3[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]3)[C@H:20]([C:31]([OH:33])=[O:32])[CH2:19]2)=[O:17])=[CH:6][C:5]=1[Cl:57]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)[C@@H](Cc2cc(Cl)c(N)c(C(F)(F)F)c2)OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)CCN1C1CCN(C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CCC(N2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)C[C@H]2C(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.26 mL (0.13 mmol) 0.5 M LiOH solution were added to 50.0 mg (0.06 mmol) ethyl(S)-4-{(R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-1-(1-methyl-piperidin-4-yl)-piperazine-2-carboxylate in 0.8 mL THF and the reaction mixture was stirred overnight at RT. To complete the reaction another 50 μL (0.1 mmol) 0.5 M LiOH solution were added, it was stirred for another 4 h at RT and then the reaction mixture was purified by HPLC without working up; the fractions containing the product were combined and lyophilised.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C@@H:9]1[CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:26][O:25][CH2:24][CH2:23][CH2:22][CH2:21][C@H:9]1[CH2:10][NH:11][CH2:12][CH2:13][NH:8]1
Reactant: COCCCC[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCCC[C@H]1CNCCN1
Reaction time: 2 h

Procedure:
Into a stirred, room temperature solution of (S)-2-(4-methoxybutyl)-piperazine-1,4-dicarboxylic acid di-tert-butyl ester (0.198 g, 0.53 mmol) in CH2Cl2 (2.6 mL), add TFA (2.6 mL) and stir for 2 h. Concentrate the mixture under reduced pressure, dilute with H2O and load onto an SCX column (10 g). Wash the resin with H2O (3×100 mL), MeOH (3×100 mL) and elute the product with 2 M NH3 in MeOH (3×100 mL). Concentrate the purified fractions under reduced pressure and azeotrope the residue with CH2Cl2/hexanes (1:2). Place the residue under vacuum to give the title compound: orange crystals (0.093 g), mass spectrum (m/e):173.4 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[C:11]([C@@H:14]([NH:16][C:17]1[N:22]=[C:21](Cl)[N:20]=[C:19]([C:24]([NH2:26])=[O:25])[CH:18]=1)[CH3:15])(=[O:13])[NH2:12].C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[C:11]([C@@H:14]([NH:16][C:17]1[N:22]=[C:21]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[N:20]=[C:19]([C:24]([NH2:26])=[O:25])[CH:18]=1)[CH3:15])(=[O:13])[NH2:12]
Reactant: OB(O)c1ccc(O)cc1
Reactant: C[C@H](Nc1cc(C(N)=O)nc(Cl)n1)C(N)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H](Nc1cc(C(N)=O)nc(-c2ccc(O)cc2)n1)C(N)=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
A 100 mL round-bottom flask was charged with 4-hydroxyphenyl boronic acid (1 g, 7.25 mmol), 6-((S)-1-carbamoyl-ethylamino)-2-chloro-pyrimidine-4-carboxylic acid amide (7.25 mmol, 1.76 g), PdCl2(PPh3)2 (Aldrich, 0.5 mmol, 0.3562 g), Na2CO3 (7.25 mL, 2M aqueous solution), and dioxane (5 mL). The flask was purged with nitrogen and heated to 100° C. for 16 h at which time the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was suspended in 50% MeOH in DCM, filtered by vacuum, and the filter cake was discarded. The filtrate was concentrated under reduced pressure and was suspended in DCM, stirred for one hour, and filtered by vacuum filtration to provide the title compound as a light brown powder (2 g, 91%). 1H NMR (CD3OD) 8.25-8.09 (m, 2H), 7.09-6.92 (m, 1H), 6.82-6.70 (m, 2H), 4.62-4.40 (m, 1H), 1.49-1.31 (m, 3H). LC/MS: m/z 301[M+H]+.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][O:7]1)[CH:2]=[CH2:3].[CH2:11]([O:13][SiH:14]([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])[CH3:12]>>[CH2:5]([O:4][CH2:1][CH2:2][CH2:3][Si:14]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])[O:13][CH2:11][CH3:12])[CH:6]1[O:7][CH2:8][CH2:9][CH2:10]1
Reactant: CCO[SiH](OCC)OCC
Reactant: C=CCOCC1CCCO1
Product: CCO[Si](CCCOCC1CCCO1)(OCC)OCC
Temperature: 80 °C
Yield: 98.7 %

Procedure:
A 1 liter 3 neck flask equipped with a magnetic stirrer, pot thermometer, dry-ice condenser and an addition funnel was charged with 106.6 g of allyloxymethyltetrahydrofuran. The flask was heated to 80° C., and 8.7 g of triethoxysilane was added, followed by 0.5 g of Karstedt's catalyst with a Pt concentration of 2%. An exotherm was observed and an additional 120.6 g of triethoxysilane was added while maintaining the temperature between 80°-100° C. After the addition was complete, an additional 0.25 g of Karstedt's catalyst was added, and the mixture was heated to 90° C. for 1 hour. The mixture was distilled through a short Vigreux column. Tetrahydrofurfuryloxypropyltriethoxysilane (98.7% purity by GC) was obtained in 60% yield, having a boiling point of 130° C./3 mm and a density at 25° C. of 0.9899.
Reaction SMILES: [N:1]1([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[O:20][C:19]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[C:26](=NO)[CH2:25][CH2:24]5)=[C:18]([C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)[CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N1CC[O:41]CC1.C(N(CC)CC)C>ClCCl>[N:1]1([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[O:20][C:19]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[C:26](=[O:41])[CH2:25][CH2:24]5)=[C:18]([C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)[CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: C1COCCN1
Reactant: O=C(CN1CCOCC1)N1CCC(c2cc(-c3ccncc3)c(-c3ccc4c(c3)CCC4=NO)o2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCc2cc(-c3oc(C4CCN(C(=O)CN5CCOCC5)CC4)cc3-c3ccncc3)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.4 %

Procedure:
A solution of the product of Step 1 (0.15 g, 0.35 mmol) in dry dichloromethane (3 ml) was treated with morpholine (0.060 ml, 0.76 mmol) and triethylamine (0.11 ml, 0.76 mmol) and stirred at ambient temperature for 18 hours. The reaction mixture was diluted with dichloromethane, washed with water and saturated sodium chloride solution, dried MgSO4) and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of 0.880 ammonia/methanol/dichloromethane (0.5:4.5:95) to afford the title compound (0.05 g, 29%); MS(ES+) m/e 486 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([C@H:18]([CH2:23][NH:24]C(=O)C(F)(F)F)[CH2:19][C:20]([O-:22])=[O:21])[CH:14]=[CH:15][C:16]=1[Cl:17].C(N(C(C)C)CC)(C)C>ClCCl>[NH2:24][CH2:23][C@@H:18]([C:13]1[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([NH:10][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH:12]=1)[CH2:19][C:20]([OH:22])=[O:21]
Reactant: Nc1cc([C@H](CNC(=O)C(F)(F)F)CC(=O)[O-])ccc1Cl
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC[C@H](CC(=O)O)c1ccc(Cl)c(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
At 0° C., 0.65 mmol of benzoyl chloride was slowly added to (3R)-3-(3-amino-4-chlorophenyl)-4-(2,2,2-trifluoroacetylamino)butanoate (200 mg, 0.59 mmol) (65b), the diisopropylethylamine (1.13 mL, 0.65 mmol) of (3R)-3-(3-amino-4-chlorophenyl)-4-(2,2,2-trifluoroacetylamino)butanoate, and 113 mL (0.65 mmol) of diisopropylethyl amine in 15 mL of dichloromethane. The reaction solution was stirred for 3 h at room temperature. The reaction mixture was then washed with 1N HCl and saturated sodium bicarbonate solution. The solvent was removed under reduced pressure. The residue, methyl (3R)-3-[3-(acetylamino)-4-chlorophenyl]-4-(2,2,2-trifluoroacetylamino)butanoate, was dissolved in 2.5 mL of methanol and 0.2 mL 2N sodium hydroxide. The solution was stirred at room temperature for 16 h. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC to provide the title compound (65). 1H NMR (400 MHz, CD3OD): δ7.97 (d, J=8.0 Hz, 2H), 7.69 (s, 1H), 7.63-7.59 (m, 1H), 7.55-7.50 (m, 2H), 7.27 (d, J=8.0 Hz, 1H), 3.47-3.18 (m, 3H), 2.81 (dd, J=16.0, 8.0 Hz, 1H), 2.70 (dd, J=16.0, 8.0 Hz, 1H); MS (ESI) m/z 333.1 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][C@H:2]1[CH2:7][O:8][C:9]1[CH:23]=[C:13]2[C:14]3[C:19]([CH2:20][CH2:21][N:12]2[C:11](=[O:24])[N:10]=1)=[CH:18][C:17]([OH:22])=[CH:16][CH:15]=3.C[C:26]([CH3:32])([CH3:31])[CH2:27][CH2:28][CH2:29]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCOCC1>[CH:26]1([CH2:27][CH2:28][CH2:29][O:22][C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[C:13]2=[CH:23][C:9]([O:8][CH2:7][C@@H:2]4[CH2:3][O:4][CH2:5][CH2:6][O:1]4)=[N:10][C:11](=[O:24])[N:12]2[CH2:21][CH2:20]3)[CH2:31][CH2:32]1
Reactant: O=c1nc(OC[C@@H]2COCCO2)cc2n1CCc1cc(O)ccc1-2
Reactant: CC(C)(C)CCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=c1nc(OC[C@@H]2COCCO2)cc2n1CCc1cc(OCCCC3CC3)ccc1-2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Intermediate 6 (2.12 g, 2.42 mmol, 1 eq.), 4,4-dimethyl-pentan-1-ol (0.77 g, 7.71 mmol, 1.2 eq.) and PPh3 (2.02 g, 7.71 mmol, 1.2 eq.) were suspended in 1,4-dioxane (50 mL) and the mixture was degassed with N2. DIAD (1.56 mL, 7.71 mmol, 1.1 eq.) was added dropwise and the reaction was stirred at RT for 2 h. The reaction mixture was quenched with brine and extracted with EtOAc, the organic phase was dried over MgSO4 and evaporated to dryness. Compound 143 was obtained by purification by flash chromatography on silica gel, eluting from 60 to 100% EtOAc/H.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]4[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=4)[C:13](=O)[NH:12][N:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.P(Cl)(Cl)([Cl:25])=O>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]4[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=4)[C:13]([Cl:25])=[N:12][N:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccc2c(-c3ccc4c(c3)OCO4)n[nH]c(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(-c3ccc4c(c3)OCO4)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 4-(1,3-benzodioxol-5-yl)-7-methoxy-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[O:5]1[CH:9]=[CH:8][CH2:7][CH2:6]1>C(Cl)Cl>[C:1]([C:7]1[CH:8]=[CH:9][C:6]2[O:5][CH2:9][CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: C1=COCC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CCO2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 186.7 %

Procedure:
To a 0° C. solution of acetyl chloride (1.64 mL, 23.0 mmol, 1.3 equivalents) in methylene chloride (30 mL) was added stannic chloride (2.49 mL, 21.3 mmol, 1.2 equivalents), maintaining the temperature below 5° C. The solution was stirred 15 minutes at 0° C., and then a solution of 2,3-dihydrofuran (2.00 mL, 17.7 mmol) in methylene chloride (5 mL) was added dropwise while maintaining the temperature below 8° C. The dark red solution was stirred 1 hour at 2° C. and then poured into 50 mL of ice water. The reaction was stirred an additional 30 minutes, and the layers were separated. The organic layer was washed with water and aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on 150 9 silica gel, eluting with 18% ethyl acetate in hexanes. The solvents were removed under reduced pressure to yield the title compound (2.68 g, 93%) as a yellow solid.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].Cl.[F:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][N:25]([C:28]3[CH:29]=[CH:30][C:31]4[C:32]5[CH2:42][NH:41][CH2:40][CH2:39][CH2:38][C:33]=5[N:34]([CH3:37])[C:35]=4[CH:36]=3)[C:24](=[O:43])[CH:23]=2)=[N:18][CH:19]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:8]([N:41]1[CH2:40][CH2:39][CH2:38][C:33]2[N:34]([CH3:37])[C:35]3[CH:36]=[C:28]([N:25]4[CH:26]=[CH:27][C:22]([O:21][CH2:20][C:17]5[CH:16]=[CH:15][C:14]([F:13])=[CH:19][N:18]=5)=[CH:23][C:24]4=[O:43])[CH:29]=[CH:30][C:31]=3[C:32]=2[CH2:42]1)(=[O:10])[CH3:9]
Reactant: CC(=O)Cl
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(F)cn5)cc4=O)cc31)CNCCC2
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCCc2c(c3ccc(-n4ccc(OCc5ccc(F)cn5)cc4=O)cc3n2C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.3 %

Procedure:
Triethylamine (48 μL, 0.34 mmol), DMAP (4.0 mg, 0.034 mmol) and acetyl chloride (18 μL, 0.26 mmol) were added to a solution of 4-((5-fluoropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride (78 mg, 0.17 mmol) in CH2Cl2 (10 mL), and the resulting solution was stirred at ambient temperature for 3 h under N2. The resulting solution was concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 2 column volumes, increased to 50:50 over 20 column volumes and held for 1 column volume, then increased to 0:100 over 10 column volumes and held for 12 column volumes) gave the title compound (55 mg, 70%) as an off-white solid: mp 78-83° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.62 (d, J=3.0 Hz, 1H), 7.83 (ddd, J=8.5, 8.5, 3.0 Hz, 1H), 7.66-7.49 (m, 3H), 7.39 (dd, J=21.0, 2.0 Hz, 1H), 6.93 (ddd, J=22.5, 8.0, 1.5 Hz, 1H), 6.11 (dd, J=7.5, 2.5 Hz, 1H), 5.96 (dd, J=5.0, 3.0 Hz, 1H), 5.21 (s, 2H), 4.69-4.68 (m, 2H), 3.78-3.75 (m, 2H), 3.67-3.65 (m, 3H), 3.03-2.96 (m, 2H), 2.09-1.90 (m, 5H); ESI MS m/z 461 [M+H]+; HPLC (Method A) 98.7% (AUC), tR=16.0 min.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[CH2:23]([S:25]([N:28]1[CH2:31][C:30](=[CH:32][C:33]#[N:34])[CH2:29]1)(=[O:27])=[O:26])[CH3:24].C1CCN2C(=NCCC2)CC1>C(#N)C>[CH2:23]([S:25]([N:28]1[CH2:29][C:30]([CH2:32][C:33]#[N:34])([N:1]2[CH:5]=[C:4]([C:6]3[C:7]4[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=4[N:9]=[CH:10][N:11]=3)[CH:3]=[N:2]2)[CH2:31]1)(=[O:26])=[O:27])[CH3:24]
Reactant: CCS(=O)(=O)N1CC(=CC#N)C1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCS(=O)(=O)N1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a suspension of 4-(1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (5, 440 g, 1.395 mol) and 2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile (11, 312.4 g, 1.68 mol, 1.2 equiv) in acetonitrile (4.4 L) was added DBU (249.8 mL, 1.67 mol, 1.2 equiv) drop wise to keep the reaction temperature between 15-25° C. After adding DBU, the reaction mixture became homogeneous, but a precipitate appeared in 30 min. The reaction mixture was stirred for 3 h at room temperature. When HPLC showed that the reaction was deemed complete, the reaction mixture was quenched with water (11 L). The resulting mixture was stirred at room temperature for additional 30 min and then filtered. The solid cake was washed with water (4 L), MTBE (2 L) and dried in vacuum oven at 35° C. for 24 h to afford crude 2-(1-(ethylsulfonyl)-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (12, 681 g, 699.8 g theoretical, 97.3% yield) as white solids, which was found to be sufficiently pure for the subsequent reaction without further purification. For 12: 1HNMR (CDCl3, 300 MHz), 6 8.86 (s, 1H), 8.45 (s, 1H), 8.35 (s, 1H), 7.43 (d, 1H), 6.80 (d, 1H), 5.68 (s, 2H), 4.65 (d, 2H), 4.27 (d, 2H), 3.55 (s, 2H), 3.4 (t, 2H), 3.07 (m, 2H), 1.42 (m, 3H), 0.92 (m, 2H), -0.05 (s, 9H) ppm; C22H31N7O3SSi (MW, 501.68), LCMS (EI) m/e 502 (M++H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH2:25]([O:27][C:28](=[O:33])[CH2:29][C:30]([OH:32])=O)[CH3:26].C(N(C(C)C)C(C)C)C.[C:43]([C:47]1[O:51][C:50]([C:52]2[C:53]([NH2:71])=[N:54][CH:55]=[C:56]([C:58]3[N:62]([CH2:63][CH3:64])[N:61]=[C:60]([CH:65]4[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]4)[N:59]=3)[N:57]=2)=[N:49][N:48]=1)([CH3:46])([CH3:45])[CH3:44]>CN(C=O)C>[NH2:71][C:53]1[N:54]=[CH:55][C:56]([C:58]2[N:62]([CH2:63][CH3:64])[N:61]=[C:60]([CH:65]3[CH2:66][CH2:67][N:68]([C:30](=[O:32])[CH2:29][C:28]([O:27][CH2:25][CH3:26])=[O:33])[CH2:69][CH2:70]3)[N:59]=2)=[N:57][C:52]=1[C:50]1[O:51][C:47]([C:43]([CH3:44])([CH3:45])[CH3:46])=[N:48][N:49]=1
Reactant: CCn1nc(C2CCNCC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Reactant: CCOC(=O)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)N1CCC(c2nc(-c3cnc(N)c(-c4nnc(C(C)(C)C)o4)n3)n(CC)n2)CC1
Temperature: 25 °C
Yield: 147 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (474 mg, 1.25 mmol) was added over 30 seconds in portions to a stirred solution of 3-ethoxy-3-oxopropanoic acid (150 mg, 1.13 mmol), N-ethyl-N-isopropylpropan-2-amine (0.394 mL, 2.26 mmol) and 3-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)-5-(1-ethyl-3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl)pyrazin-2-amine (450 mg, 1.13 mmol) dissolved in DMF (20 mL) at 50° C. The resulting solution was sampled after 1 min (complete reaction) and immediately allowed to cool to ambient temperature. The reaction mixture was concentrated and diluted with EtOAc (100 mL), and washed sequentially with water (20 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude ethyl 3-(4-(5-(5-amino-6-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-oxopropanoate (850 mg).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([Cl:15])=[N:10][C:11](I)=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[F:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([Cl:15])=[N:10][C:11]([C:32]2[CH:33]=[N:34][C:29]([F:28])=[CH:30][CH:31]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccc(F)nc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(I)nc1Cl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(-c2ccc(F)nc2)nc1Cl

Procedure:
By carrying out the operation analogously to example 1, starting from 2-chloro-6-iodo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation X, and 6-fluoro-3-pyridineboronic acid, the desired product is obtained in the form of a white powder (yield=43%).
Reaction SMILES: N([O-])=O.[Na+].[Cl:5][C:6]1[CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:7]=1N.[BrH:18]>S(=O)(=O)(O)O.C(O)(=O)C.O>[Cl:5][C:6]1[CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:7]=1[Br:18]
Reactant: Nc1ccc(OC(F)(F)F)cc1Cl
Reactant: Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)Oc1ccc(Br)c(Cl)c1
Reaction time: 0.5 h

Procedure:
A solution of sodium nitrite (16.31 g) in concentrated sulphuric acid was added dropwise to a solution of 2-chloro-4-trifluoromethoxyaniline (50 g) in acetic acid, while maintaining the temperature below 10° C. The mixture was stirred at 5°-10° C. for 0.5 hours then added slowly to a mixture of cuprous bromide (33.9 g) in aqueous hydrobromic acid (200 ml) and ice. The mixture was stirred at room temperature for 0.5 hours and left to stand overnight. The mixture was diluted with water and extracted with dichloromethane, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 2-chloro-4-trifluoromethoxybromobenzene (63.64 g) as a brown oil which was not further purified.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=O.Cl.[CH3:12][O:13][NH2:14]>C(O)C.N1C=CC=CC=1>[CH3:12][O:13][N:14]=[CH:5][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[C:8]([Cl:10])[CH:7]=1
Reactant: CON
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=Cc1cc(Cl)cc(Cl)c1
Yield: 93.6 %

Procedure:
A solution of 3,5-dichlorobenzaldehyde (0.0571 mol) and methoxyamine hydrochloride (0.0629 mol) in ethanol (50 ml) and pyridine (50 ml) was stirred 18 hours at room temperature. The reaction was concentrated and partitioned between methylene chloride and water. The organic phase was washed with 3N aqueous hydrogen chloride, dried over sodium sulfate and was concentrated to yield 10.9 g (94%) white solid, mp 53°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:19])[NH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:22]([O:28][CH2:29]Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:19])[N:14]([CH2:29][O:28][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]cnc2cc(OCc3ccccc3)ccc12
Reactant: CC(C)(C)C(=O)OCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCn1cnc2cc(OCc3ccccc3)ccc2c1=O
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
7-Benzyloxy-3,4-dihydroquinazolin-4-one (7.0 g, 27 mmol) was suspended in dry DMF (50 ml) and cooled to 5-10° C., then sodium hydride was added (1.22 g of a 60% suspension in mineral oil, 30 mmol). The reaction mixture was allowed to return to ambient temperature and chloromethyl pivalate (4.75 g, 31.5 mmol) was added over 10 minutes and the mixture stirred for 1 hour. The reaction mixture was quenched with water (250 ml), the aqueous phase adjusted to pH5 and extracted with ether (300 ml×3). The combined ether phases were washed with brine, dried (MgSO4) and the solvent removed by evaporation. The solid residue was triturated with isohexane, collected by filtration and dried under vacuum to give 7-benzyloxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (9.1 g, 90%).