Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=[O:45])[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH:21]=[C:20]([NH:22][C:23]([C:25]3[CH:26]=[N:27][N:28]4[CH:33]=[CH:32][CH:31]=[N:30][C:29]=34)=[O:24])[C:19]([C:34]3[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:35]=3[O:41][CH:42]([F:44])[F:43])=[N:18]2)[CH2:13][CH2:12]1)(C)(C)C.[C:46](O)(C(F)(F)F)=O.C(Cl)(=O)C>C(Cl)Cl.N1C=CC=CC=1>[ClH:40].[C:6]([NH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][CH:14]([N:17]2[CH:21]=[C:20]([NH:22][C:23]([C:25]3[CH:26]=[N:27][N:28]4[CH:33]=[CH:32][CH:31]=[N:30][C:29]=34)=[O:24])[C:19]([C:34]3[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:35]=3[O:41][CH:42]([F:43])[F:44])=[N:18]2)[CH2:15][CH2:16]1)(=[O:45])[CH3:46]
Reactant: CC(C)(C)OC(=O)NCCCN1CCC(n2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: CC(=O)NCCCN1CCC(n2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
[3-(4-{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}piperidin-1-yl)propyl]carbamic acid tert-butyl ester (129 mg, 0.20 mmol) was dissolved in DCM (2 mL) and TFA (2 mL) was added. The reaction was stirred at room temperature for 1 hour and then evaporated to dryness. The residue was dissolved in MeOH and loaded onto an SCX-2 cartridge which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH. Evaporation of the basic fractions gave a residue which was dissolved in pyridine (2 mL). Acetyl chloride (21 μL, 0.30 mmol) was added and the solution was allowed to stand at room temperature for 5 days. The volatiles were evaporated and azeotroped with toluene. The residue was dissolved in MeOH and loaded onto an SCX-2 cartridge which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH. Evaporation gave a glassy solid which was purified by HPLC (Method 3). The pure amine was dissolved in MeOH and 1.25M methanolic HCl was added. The volatiles were evaporated and the solid product was triturated with EtOAc/Et2O to give the title compound as a white solid (40 mg, 32%). LCMS (Method 5) [M+H]+=587.0, RT=2.91 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.89 (s, 1H), 9.76 (s, 1H), 9.35 (dd, 1H, J=1.5, 7.0 Hz), 8.69 (dd, 1H, J=1.6, 4.2 Hz), 8.67 (s, 1H), 8.39 (s, 1H), 8.04 (t, 1H, J=5.8 Hz), 7.67-7.61 (m, 2H), 7.46 (d, 2H, J=8.4 Hz), 7.31 (dd, 1H, J=4.2, 6.9 Hz), 7.26 (t, 1H, J=73.4 Hz), 4.64-4.54 (m, 1H), 3.64 (d, 2H, J=12.2 Hz), 3.21-3.01 (m, 6H), 2.40-2.29 (m, 4H), 1.84 (m, 5H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=2[Cl:22])[N:9]=[C:8]([CH:23]=[N:24][OH:25])[C:7]=1[S:26]([CH3:28])=[O:27].C(N(CC)CC)C>O1CCCC1>[C:1]([O:25][N:24]=[CH:23][C:8]1[C:7]([S:26]([CH3:28])=[O:27])=[C:6]([NH2:5])[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=2[Cl:22])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)c1c(C=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)ON=Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Reaction time: 1 h

Procedure:
Acetyl chloride (0.27 ml) was added to a solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde oxime (1.0 g) and triethylamine (0.56 ml) in tetrahydrofuran at 0° C. and the mixture stirred for 1 hour. The solvent was evaporated and the residue chromatographed on silica gel eluting with 3:1 dichloromethane/ethyl acetate to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde O-(acetyl)oxime (0.83 g)as an orange solid m.p. 130-134° C. Compound 10.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[CH:3]=1.Cl.[CH3:13]O>>[CH3:13][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[Cl:11]
Reactant: CO
Reactant: O=C(O)c1ccc(Br)cc1Cl
Agent: Cl
Product: COC(=O)c1ccc(Br)cc1Cl

Procedure:
3.0 g of 4-bromo-2-chloro-benzoic acid (12.74 mmol) were dissolved in 60 ml methanol and treated with 0.6 ml of concentrated HCl. After 17 h at reflux the reaction mixture was concentrated in vacuo, diluted with DCM and washed with a saturated aqueous NaHCO3 solution and brine, dried with magnesium sulfate, filtered and concentrated in vacuo leading to 2.7 g (85%) of 4-bromo-2-chloro-benzoic acid methyl ester as a light yellow oil. MS (+cEI): 250.0 (M).
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:9](#N)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.Cl.C(OCC)(=[O:22])C>C1COCC1>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:9](=[O:22])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:11][CH:12]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc(C#N)cc1
Reactant: CCOC(=O)C[Zn]Br
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccc(OC)cc1
Yield: 94 %

Procedure:
Under nitrogen atmosphere, 30 mL of THF was added to 6.09 g (10 mmol, 1.0 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 1.33 g (10 mmol) of anisonitrile in 5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. for 92 hours. 15 mL of 10% hydrochloric acid was added dropwise at 20° C. or lower, and the mixture was stirred at 20˜25° C. for 1 hour and 35 minutes, followed by dilution with 50 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 15 mL of 1N hydrochloric acid, 20 mL of an aqueous saturated sodium chloride solution, 20 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 20 mL of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 2.08 g of the desired product (yield 94%).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][N:15]=2)[NH:10][C:9](=O)[CH:8]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:6])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>>[CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][N:15]=2)[NH:10][C:9](=[S:33])[CH:8]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)OC(=O)N1c2ncccc2NC(=O)C1c1ccccc1
Product: CC(C)OC(=O)N1c2ncccc2NC(=S)C1c1ccccc1
Yield: 62 %

Procedure:
200 mg (0.64 mmol) of 4-isopropoxycarbonyl-3-(R,S)-phenyl-3,4-dihydro-1,4,5-triazanaphthalen-2(1H)-one were reacted with 400 mg of Lawesson's reagent in analogy to Example 20 (reaction conditions: 10 hours at 80° C. The crude product was concentrated and chromatographed on silica gel (ethyl acetate/n-heptane=1:2). 130 mg (62%) of 4-isopropoxycarbonyl-3-(R,S)-phenyl-3,4-dihydro-1,4,5-triazanaphthalene-2(1H)-thione, of melting point 188°-189° C., were obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[CH3:12])=[C:8]([C:20]([NH2:22])=[O:21])[CH:7]=[N:6][N:5]2[CH:23]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N#N>O1CCOCC1>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C@H:11]([NH:10][C:9]1[C:4]2[N:5]([CH:23]=[C:2]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:3]=2)[N:6]=[CH:7][C:8]=1[C:20]([NH2:22])=[O:21])[CH3:12]
Reactant: OB(O)c1ccccc1
Reactant: C[C@@H](Nc1c(C(N)=O)cnn2cc(Br)cc12)c1ccccc1F
Agent: N#N
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(-c3ccccc3)cc12)c1ccccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(R)-6-bromo-4-(1-(2-fluorophenyl)ethylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide (Intermediate 7, 1 equiv), phenylboronic acid (1 equiv), PdCl2(dppf)-CH2Cl2 complex (0.05 equiv) and 2M K3PO4 (3.4 equiv) in dioxane (0.5 mL) was purged with N2 then at 140° C. for 0.5 h. Following cooling to rt, the product was isolated via reverse-phase preparative HPLC (condition F) of the crude reaction mixture to afford the title compound (3.8 mg) as a brown solid. HPLC (conditions B): retention time=4.28 min; LCMS: 375.14 (M+H)+; 1H NMR (CD3OD, 400 MHz) δ 8.17 (s, 1H), 7.88 (d, J=1.7 Hz, 1H), 7.52 (d, J=7.0 Hz, 2H), 7.14-7.44 (m, 7H), 7.03 (d, J=1.8 Hz, 1H), 5.80 (q, J=6.6 Hz, 1H), 1.70 (d, J=6.6 Hz, 3H).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][C@@H:25]([CH2:43][C:44]([OH:46])=[O:45])[C:24]1=[O:47])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[Si](C=[N+]=[N-])(C)(C)[CH3:51]>C(Cl)Cl>[Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][C@@H:25]([CH2:43][C:44]([O:46][CH3:51])=[O:45])[C:24]1=[O:47])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)[C@H](CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)[C@H](CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-((3S,5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic acid (741 mg, 1.076 mmol; Example 127, Step B) in 10 mL of a 10% solution of MeOH in DCM at room temperature was added TMS-diazomethane (2.0M in ether) (807 μL, 1.614 mmol). Evolution of gas was observed and the yellow mixture was stirred at room temperature for 45 min. More TMS-diazomethane (2.0M in ether) (807 μL, 1.614 mmol) was added and the reaction was stirred at room temperature for 45 min. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (24 g column; eluent: 0 to 30% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:15]=1.CO.C(OCC)(=O)C>CN(C=O)C>[ClH:11].[Cl:11][C:8]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2](=[NH:1])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:15]=2)[CH:9]=1
Reactant: CS(=O)(=O)c1cc(CBr)ccc1F
Reactant: NC(=O)c1cc(Cl)cnc1N
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1cc(Cn2cc(Cl)cc(C(N)=O)c2=N)ccc1F
Product: Cl
Temperature: 25 °C
Yield: 64.8 %

Procedure:
(Step 2) A solution of 2-amino-5-chloronicotinamide (685 mg) and 4-(bromomethyl)-1-fluoro-2-(methylsulfonyl)benzene obtained in Step 1 (1.6 g) in DMF (10 ml) was stirred at 90° C. for 24 hr. The mixture was allowed to cool to room temperature, methanol and ethyl acetate were added, and the precipitated crystals were collected by filtration. The obtained crystals were dissolved in 1N sodium hydroxide solution, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=4:1). The obtained yellow solid was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (2 ml) was added, and the precipitated crystals were collected by filtration, and recrystallized to give the title compound (510 mg).
Reaction SMILES: C([O:14][C:15]1[C:16]2[C:35](=[O:36])[N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH2:33][C:17]=2[C:18]([C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)(C1C=CC=CC=1)C1C=CC=CC=1.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].C([SiH](CC)CC)C>ClCCl>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[C:18]1[C:17]2[CH2:33][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[C:35](=[O:36])[C:16]=2[C:15]([OH:14])=[C:24]2[C:19]=1[CH:20]=[CH:21][CH:22]=[N:23]2.[C:47]([OH:49])([C:46]([F:51])([F:50])[F:45])=[O:48]
Reactant: O=C1c2c(c(-c3c(F)cccc3F)c3cccnc3c2OC(c2ccccc2)c2ccccc2)CN1Cc1ccc(F)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1c2c(c(-c3c(F)cccc3F)c3cccnc3c2O)CN1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 283a (9 mg) dissolved in dichloromethane (1 mL) was added trifluoroacetic acid (100 μl) and triethylsilane (200 μl). The reaction mixture was stirred at room temperature for ½ hours under an inert atmosphere then concentrated in vacuo. The residue was triturated with diethyl ether/hexane (1/1) to afford 5-(2,6-difluoro-phenyl)-7-(4-fluoro-benzyl)-9-hydroxy-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one 284, TFA salt, (3.2 mg) as a yellow solid: 1H NMR (CDCl3) δ 9.0 (d, 1H), 8.0 (d, 1H), 7.6 (m, 1H), 7.5 (dd, 1H), 7.2 (m, 2H), 7.1 (m, 4H), 4.7 (s, 2H), 4.2(s, 2H); MS: 421 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([CH2:20][CH3:21])[CH2:18][OH:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](OCC)(=[O:32])[CH3:31]>N1C=CC=CC=1.C(OC(=O)C)(=O)C>[C:30]([O:19][CH2:18][C:17]([NH:22][C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])([CH2:20][CH3:21])[CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][CH:11]=1)(=[O:32])[CH3:31]
Reactant: CCC(CO)(CCc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCC(CCc1ccc(OCc2ccccc2)cc1)(COC(C)=O)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
A solution of 4-(4-benzyloxyphenyl)-2-tert-butoxycarbonylamino-2-ethylbutanol (24 g) in pyridine (200 ml) and acetic anhydride (32 ml) was allowed to stand at room temperature overnight. Ethyl acetate was added to the reaction mixture and the mixture was washed with water, a dilute hydrochloric acid, an aqueous sodium hydrogencarbonate solution and a saturated brine in order, and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure and the residue obtained was purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:1) to give the subject compound (13 g).
Reaction SMILES: ICl.[OH:3][CH2:4]C(CO)OCN1C=C(C=C)C(=O)NC1=O.[OH:20][CH2:21][CH2:22][O:23][CH2:24][N:25]1[CH:32]=[C:31]([CH:33]([N:36]=[N+:37]=[N-:38])[CH2:34][I:35])[C:29](=[O:30])[NH:28][C:26]1=[O:27]>C(Cl)(Cl)Cl.CO>[OH:20][CH2:21][CH:22]([CH2:4][OH:3])[O:23][CH2:24][N:25]1[CH:32]=[C:31]([CH:33]([N:36]=[N+:37]=[N-:38])[CH2:34][I:35])[C:29](=[O:30])[NH:28][C:26]1=[O:27]
Reactant: C=Cc1cn(COC(CO)CO)c(=O)[nH]c1=O
Reactant: [N-]=[N+]=NC(CI)c1cn(COCCO)c(=O)[nH]c1=O
Agent: ClI
Solvent: CO
Solvent: ClC(Cl)Cl
Product: [N-]=[N+]=NC(CI)c1cn(COC(CO)CO)c(=O)[nH]c1=O
Yield: 29.6 %

Procedure:
Reaction of iodine monochloride (72.0 mg, 0.44 mmol) with 9a (95 mg, 0.39 mmol), using the procedure described for the preparation of 2c, and purification of the product by silica gel column chromatography using chloroform-methanol (90:10, v/v) as eluent afforded 10c as a syrup (48 mg, 29.6%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]1[C:21]([OH:23])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:48][CH:49]([CH3:52])[CH2:50][NH2:51].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:48][CH:49]([CH3:52])[CH2:50][NH:51][C:21]([C@H:9]1[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:23]
Reactant: CC(C)CN
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)O)C1
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: CC(C)CNC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 118.4 %

Procedure:
A 20 mL vial was charged with ((2R)-1,4-bis(tert-butoxycarbonyl)-2-piperazinecarboxylic acid (1.52 g, 4.60 mmol, ASW MedChem Inc., New Brunswick, N.J.), HATU (2.10 g, 5.52 mmol, ChemImpex International Inc., Wood Dale, Ill.), 2-methylpropan-1-amine (0.457 mL, 4.60 mmol, Sigma-Aldrich, St. Louis, Mo.), DIPEA (1.60 mL, 9.19 mmol) and DMF (8 mL). The mixture was stirred at room temperature for 2.5 h. and then partitioned between water (80 mL) and EtOAc (50 mL). The aqueous phase was extracted with EtOAc (50 mL). The combined organic extracts were washed with saturated aqueous NaHCO3 (100 mL), water (100 mL) then brine (100 mL). The organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford di-tert-butyl (2R)-2-((2-methylpropyl)carbamoyl)-1,4-piperazinedicarboxylate (2.10 g) as a light brown foam.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH3:8])[NH:5][C:6]=1[Br:7].[H-].[Na+].[CH3:11][Si:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][O:15][CH2:16]Cl>CN(C)C=O>[Br:1][C:2]1[N:3]=[C:4]([CH3:8])[N:5]([CH2:16][O:15][CH2:14][CH2:13][Si:12]([CH3:19])([CH3:18])[CH3:11])[C:6]=1[Br:7]
Reactant: Cc1nc(Br)c(Br)[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(Br)c(Br)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
4,5-Dibromo-2-methylimidazole (4.91 g) was dissolved in N,N-dimethylformamide (50 ml), and 60% sodium hydride (901 mg) was added gradually under ice-cooling. After stirring at room temperature for 1 hour, 2-(trimethylsilyl)ethoxymethyl chloride (3.75 g) was gradually added dropwise under ice-cooling, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure and ethyl acetate was added to the residue. The reaction mixture was washed with saturated aqueous sodium hydrogencarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to give 4,5-dibromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)imidazole (7.6 g) as a colorless oil.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][C:16]3=[O:21])=[CH:11][CH:12]=2)[N:7]=[CH:6][N:5]=1.Br[CH2:23][C:24]1[S:28][C:27]2[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:26]=2[CH:25]=1.C([O-])([O-])=O.[K+].[K+].FC(F)(F)C(O)=O>CN(C=O)C.O>[NH2:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][N:15]3[CH2:20][CH2:19][N:18]([CH2:23][C:24]4[S:28][C:27]5[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:26]=5[CH:25]=4)[CH2:17][C:16]3=[O:21])=[CH:11][CH:12]=2)[N:7]=[CH:6][N:5]=1
Reactant: Nc1ncnc2cc(CN3CCNCC3=O)ccc12
Reactant: Clc1ccc2cc(CBr)sc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2cc(CN3CCN(Cc4cc5ccc(Cl)cc5s4)CC3=O)ccc12
Reaction time: 16 h

Procedure:
To a solution of 1-(4-aminoquinazoline-7-ylmethyl)piperazine-2-one bishydrochloride (1.84 g, 5.73 mmol), EXAMPLE 72, in DMF (20 mL) is added 2-bromomethyl-6-chloro-benzo[b]thiophene, EXAMPLE 5, (1.5 g, 5.73 mmol) and K2CO3 (4.0 g, 28.7 mmol). The solution is stirred for 16 hours. After this time, the solution is diluted with water. The solution is acidified with trifluoroacetic acid. The product is purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 50% CH3CN/H2O (0.1% TFA). The appropriate collected fractions are lyopholized to afford the title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ9.78 (bs, 3H), 8.82 (s, 1H), 8.34 (d, 1H), 8.07 (s, 1H), 7.81 (d, 1H), 7.63 (d, 1H), 7.51 (s, 1H), 7.32 (m, 2H), 4.71 (s, 2H), 3.95 (s, 2H), 3.28 (m, 4H), 2.80 (m, 2H).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:21][CH2:22][OH:23])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C@H](C(O)=O)CC(O)=O.CCN(C(C)C)C(C)C.CS(C)=O>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Si:1]([O:18][CH2:19][C@@H:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:21][CH:22]=[O:23])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: N[C@@H](CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (S)-tert-butyl (1-((tert-butyldiphenylsilyl)oxy)-4-hydroxybutan-2-yl)carbamate (prepared according to the procedure described in WO2013124826 A1 using L-aspartic acid) (15.0 g, 33.8 mmol) and DIPEA (29.5 mL, 169 mmol) in DCM (50 mL) at 0° C. was added a slurry of DMSO (7.20 mL, 101 mmol) and sulfurtrioxide pyridine complex (16.14 g, 101 mmol) in DCM (50 mL). After stirring at rt for 1.5 h, the mixture was diluted with saturated NaHCO3 (aq) and the layers were separated. The aqueous layer was extracted with DCM and the combined organic portions were dried over Na2SO4 and concentrated in vacuo to afford the title compound (16.9 g, assumed quantitative) as a ight brown oil. It was used as such without further purification. LCMS: Rt=1.20 min, m/z=442.2 (M+1) Method 2m_acidic.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:12][CH3:13])[CH:7]([Cl:8])[CH:6](OC)[NH:5][C:4]1=[O:11].[C:14]([O:17][C@@H:18]1[C@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@@H:21]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[O:20][C@H:19]1[N:32]1[C:41]2[N:40]=[CH:39][N:38]=[C:36]([NH2:37])[C:35]=2[N:34]=[CH:33]1)(=[O:16])[CH3:15]>CCCCCC.CC(C)=O>[C:14]([O:17][C@@H:18]1[C@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@@H:21]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[O:20][C@H:19]1[N:32]1[C:41]2[N:40]=[CH:39][N:38]=[C:36]([NH:37][CH:6]3[NH:5][C:4](=[O:11])[C:3]([O:2][CH3:1])([O:12][CH3:13])[CH:7]3[Cl:8])[C:35]=2[N:34]=[CH:33]1)(=[O:16])[CH3:15]
Reactant: COC1NC(=O)C(OC)(OC)C1Cl
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CCCCCC
Solvent: CC(C)=O
Product: COC1(OC)C(=O)NC(Nc2ncnc3c2ncn3[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]2OC(C)=O)C1Cl
Yield: 63.2 %

Procedure:
3,3,5-Trimethoxy-4-chloro-2-pyrrolidinone (500 mg) was evenly admixed with adenosine 2',3',5'-triacetate (940 mg) and the mixture was melted and reacted at 170° C. for 1 hour. The reaction mixture was subjected to silica gel column chromatography using hexane-acetone (1:1) as the eluent to obtain N6 -(2-oxo-3,3-dimethoxy-4-chloro-5-pyrrolidinyl)adenosine 2',3',5'-triacetate (860 mg). This product was dissolved in ammonia-saturated methanol (40 ml) and allowed to stand at 5° C. for 15 hours, at the end of which time the solvent was distilled off. The residue was washed with chloroform and the insolubles were subjected to silica gel column chromatography using chloroform-methanol (10:1) as the eluent. The active fractions were pooled and concentrated under reduced pressure to give N6 -(2-oxo-3,3-dimethoxy-4-chloro-5-pyrrolidinyl)adenosine (590 mg).