Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:22])([CH3:21])[O:6][C@@H:7]1[CH2:12][C@@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][NH:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>C1COCC1>[CH2:34]([O:33][C:31]([N:9]1[CH2:10][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:12][C@@H:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:22])[CH3:21])[CH2:8]1)=[O:32])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CNC[C@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
To a solution of 0.50 g (1.4 mmol) (3R,5R)-3,5-bis-(tert-butyl-dimethyl-silanyloxy)-piperidine and 0.15 g (1.5 mmol) triethylamine in 30 ml of THF was added dropwise a solution of 0.26 g (1.5 mmol) benzyl chloroformate in 2 ml of THF at 0° C. After completed addition, the mixture was allowed to warm to room temperature during 30 min. Quenching with a saturated aqueous solution of sodium hydrogencarbonate was followed by extraction with three portions of dichloromethane. The combined organic extracts were washed with brine and dried over sodium sulfate. Flash chromatography gave 0.62 g (90%) of the title compound as a colorless oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][CH2:10][CH2:11][NH2:12].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][CH2:10][CH2:11][NH:12][S:19]([CH3:18])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCC(CCCN)OC1CCCCO1
Solvent: c1ccncc1
Product: CCCCCC(CCCNS(C)(=O)=O)OC1CCCCO1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a stirred, ice cold solution of 4-(2-tetrahydropyranyloxy)nonylamine (7.29 g., 0.03 mole) in pyridine (40 ml.) is added methanesulfonylchloride (3.42 g., 0.03 mole) at such a rate as to maintain the reaction temperature at 5°-10° C. The reaction is then allowed to stand at room temperature for 6 hours, poured into ice water (200 ml.) and extracted with ether (2 × 100 ml.). The ether is washed with ice cold 5% hydrochloric acid (2 × 20 ml.), with brine (2 × 25 ml.), and then dried over sodium sulfate. Evaporation in vacuo affords N-[4-(2-tetrahydropyranyloxy)nonyl]methanesulfonamide as a pale yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:9](Cl)=[CH:10][C:11]([C:13]1[C:14]([Cl:24])=[N:15][C:16]([Cl:23])=[CH:17][C:18]=1[C:19]([F:22])([F:21])[F:20])=[O:12].Cl>O1CCOCC1>[NH:1]([C:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:10][C:11]([C:13]1[C:14]([Cl:24])=[N:15][C:16]([Cl:23])=[CH:17][C:18]=1[C:19]([F:22])([F:21])[F:20])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(C=C(Cl)Cl)c1c(C(F)(F)F)cc(Cl)nc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: O=C(C=C(Nc1ccccc1)Nc1ccccc1)c1c(C(F)(F)F)cc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
A solution of aniline (18.4 mL, 202 mmol) in TEA (28.2 mL, 202 mmol) was added slowly to a cooled (0° C.) and stirred solution of 3,3-dichloro-1-[2,6-dichloro-4-(trifluoromethyl)-3-pyridinyl]-2-propen-1-one (22.9 g, 67.4 mmol) in dioxane (220 mL). The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was treated with 10% HCl and extracted with Et2O (3×). The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo. Silica gel flash chromatography of the residue using 6:1 Hex:EtOAc gave 3,3-dianilino-1-[2,6-dichloro-4-(trifluoromethyl)-3-pyridinyl]-2-propen-1-one as an off-white solid (13.10 g, 43%): 1H-NMR (d6-DMSO, 300 MHz) δ 12.24 (brs, 1H), 9.20 (brs, 1H), 7.95 (s, 1H), 7.12-7.42 (m, 10H), 4.82 (s, 1H); Rf=0.60 (6:1 Hex:EtOAc).
Reaction SMILES: [OH:1][CH:2]([CH:4]1[CH:7]([C:8]#[C:9][Si](C)(C)C)[NH:6][C:5]1=[O:14])[CH3:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:8]([CH:7]1[NH:6][C:5](=[O:14])[CH:4]1[CH:2]([OH:1])[CH3:3])#[CH:9]
Reactant: CC(O)C1C(=O)NC1C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#CC1NC(=O)C1C(C)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of 578 mg (2.74 mmol) of 3-(1-hydroxyethyl)-4-(2-trimethylsilylethynyl)-2-azetidinone, which was prepared according to T. Chiba and T. Nakai [Chem. Lett., 651 (1985)], in 5 ml of THF, 4 ml (4 mmol) of a 1M solution of tetrabutylammonium fluoride in THF was added. After stirring at room temperature for 2 hours, 10 g of silica-gel was added, the solvent was distilled away and the resultant was eluted with diethyl ether. The eluent was concentrated and purified with 10 g of silica-gel column (diethyl ether) to give 347 mg of 4-ethynyl-3-(1-hydroxyethyl)-2-azetidinone (yield: 92%).
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[C:29]2[C:24](=[C:25]([NH:30][C:31](=[O:40])[C:32]3[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:39])[CH:26]=[CH:27][CH:28]=2)[N:23]=[CH:22][C:21]=1[CH2:41][O:42][CH3:43])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:39][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([Cl:38])[C:32]=1[C:31]([NH:30][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:24]=1[N:23]=[CH:22][C:21]([CH2:41][O:42][CH3:43])=[C:20]2[CH2:19][OH:18])=[O:40]
Reactant: COCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CO
Reaction time: 1 h
Yield: 83.4 %

Procedure:
To a solution of 4-(tert-butyldiphenylsilyloxymethyl)-8-(2,6-dichlorobenzoylamino)-3-(methoxymethyl)quinoline (359 mg) in tetrahydrofuran was added 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.684 ml) at ambient temperature, and the mixture was stirred for 1 hour at the same temperature. The mixture was partitioned between water and ethyl acetate, and the organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from isopropyl alcohol to give 8-(2,6-dichlorobenzoylamino)-4-hydroxymethyl-3-(methoxymethyl)quinoline (186 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[C:25]([NH:28][C:29]([C@@H:31]4[CH2:35][CH2:34][CH2:33][NH:32]4)=[O:30])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[C:41](O)(=[O:44])[CH:42]=[CH2:43].N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[C:25]([NH:28][C:29]([C@@H:31]4[CH2:35][CH2:34][CH2:33][N:32]4[C:41](=[O:44])[CH:42]=[CH2:43])=[O:30])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: COCCOc1cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2cc1NC(=O)[C@@H]1CCCN1
Reactant: C=CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=CC(=O)N1CCC[C@H]1C(=O)Nc1cc2c(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)ncnc2cc1OCCOC
Temperature: 0 °C
Yield: 17 %

Procedure:
288 mg of (2S)-pyrrolidine-2-carboxylic acid {4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-7-(2-methoxyethoxy)-quinazolin-6-yl}-amide as a starting material was dissolved in 10 ml of THF, and cooled to 0° C. The solution was reacted with 0.07 ml of acrylic acid, 0.17 ml of pyridine and 0.29 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride at 0° C. for 30 mins and at room temperature for 2 hours. The reacted solution was extracted with a mixture of chloroform and isopropanol after adding water, washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent-ethylacetate:methanol=30:1) to obtain the title compound (52 mg, 17%).
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[CH2:15]O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:19][CH2:15][C:11]1[N:10]([S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:17])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH:14]=[CH:13][N:12]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1ccc(S(=O)(=O)n2ccnc2CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccnc2CBr)cc1
Yield: 45.3 %

Procedure:
To a solution of the above alcohol (0.55 g, 2.17 mmol) and CBr4 (1.08 g, 3.26 mmol) in CH2Cl2 (25 mL) at 0° C. was added a solution of triphenylphosphine (0.68 g, 2.60 mmol) in CH2Cl2 (10 mL) as described in J. Med. Chem. (1997) 40, 14:2196. Purification by flash column chromatography using 25% EtOAc/hexanes afforded 2-bromomethyl-1-(toluene-4-sulfonyl)-1H-imidazole as a yellow oil (0.31 g, 45%). 1H NMR (CDCl3) δ 2.45 (s, 3H), 4.81 (s, 2H), 7.04 (s, 1H), 7.37 (d, 2H, J=9.0 Hz), 7.42 (s, 1H), 7.92 (d, 2H, J=9.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[NH:7][CH2:6][C@@H:5]([OH:13])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][O:23][CH3:24].[Cl-].[Na+]>CS(C)=O>[Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:11])(=[O:12])[N:7]([CH2:21][CH2:22][O:23][CH3:24])[CH2:6][C@@H:5]([OH:13])[C:4]=2[CH:3]=1
Reactant: O=S1(=O)NC[C@@H](O)c2cc(Cl)sc21
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: COCCN1C[C@@H](O)c2cc(Cl)sc2S1(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
A mixture of (S)-3,4-dihydro-6-chloro-4-hydroxy-2H-thieno[3,2-e]-1,2-thiazine-1,1-dioxide (5, 1.2 g) and potassium carbonate (2.1 g) in dimethylsulfoxide (7 mL) was treated with 1-bromo-2-methoxyethane (0.5 eq, 0.25 mL) and the mixture was stirred at ambient temperature for 3 hours. Another 0.25 mL of 1-bromo-2-methoxyethane was then added and the mixture was stirred at ambient temperature for 18 hours. TLC analysis after this period indicated incomplete reaction, so another 0.25 mL of 1-bromo-2-methoxyethane was added and the mixture was stirred at ambient temperature for another 3 hours. At this point, TLC indicated complete reaction. The mixture was poured into saturated aqueous sodium chloride (50 mL) and extracted with t-butyl methyl ether. The organic phase was washed sequentially with 10% aqueous sodium hydroxide, 1:1 5.25% sodium hypochlorite water, and saturated aqueous sodium chloride, dried over sodium sulfate, and stripped of solvent by rotary evaporation. Residual solvent was removed under vacuum to provide 1.1 grams (75%) of (S)-3,4-dihydro-6-chloro-4-hydroxy-2-(2-methoxyethyl)-2H-thieno[3,2-e]-1,2-thiazine-1,1-dioxide as a light yellow oil: IR (film) 3500-3400, 1430, 1340, 1170, 1120, 1080, 1040, 700 cm-1 ; 1H NMR (CDCl3) δ6.98 (s, 1H), 4.57 (br, 1H), 4.33 (dd, 1H, J=4 and 16 Hz), 4.16 (br, 1H), 3.91-3.38 (m, 5 H), 3.31 (s 3H); [α]25D +4.0° (c=1, CH3OH); Analysis for C9H12ClNO4S2 : Calcd: C, 36.30; H, 4.06; N, 4.70. Found: C, 36.23; H, 4.05; N, 4.66.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[CH2:19](Br)[CH:20]=[CH2:21]>>[CH2:21]([N:4]([CH2:3][C:2]([F:17])([F:18])[F:1])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:14])[F:15])[CH:6]=1)[CH:20]=[CH2:19]
Reactant: N#Cc1ccc(NCC(F)(F)F)cc1C(F)(F)F
Reactant: C=CCBr
Product: C=CCN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized according to Example 61A using 4-(2,2,2-trifluoro-ethylamino)-2-trifluoromethyl-benzonitrile and allyl bromide: 1H NMR (300 MHz, CDCl3) δ 7.65 (d, J=8.8 Hz, 1H), 7.07 (d, J=2.4 Hz, 1H), 6.93 (dd, J=8.8, 2.6 Hz, 1H), 5.80 (ddt, J=17.2, 10.4, 5.0 Hz, 1H), 5.31 (app. d, J=10.6 Hz, 1H), 5.14 (app. d, J=17.2 Hz, 1H), 4.19-4.11 (m, 2H), 3.98 (q, J=8.6 Hz, 2H); MS (APCI) m/z 309 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[N:16]=[C:17]=[O:18]>O1CCCC1>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[NH:16][C:17]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)=[O:18]
Reactant: Nc1ccncc1
Reactant: O=C=Nc1c(Cl)cccc1Cl
Solvent: C1CCOC1
Product: O=C(Nc1ccncc1)Nc1c(Cl)cccc1Cl

Procedure:
A solution of 4.7 g (0.05 mole) of 4-aminopyridine in 300 ml of anhydrous tetrahydrofuran was treated with 9.4 g (0.05 mole) of 2,6-dichlorophenylisocyanate. The solution was heated at reflux for 24 hours, cooled, and concentrated in vacuo to a solid. Recrystallization from aqueous ethanol afforded the crystalline product, mp 217°-219° C.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C:35]1[CH:40]=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=C[CH:36]=1.C(C1C=CC(C(Cl)=O)=CC=1)CC>>[CH3:32][CH:31]([CH3:33])[C@H:26]([N:21]1[CH2:20][C:19]2[C:23](=[CH:24][C:16]([C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:3]=[CH:4][C:5]([CH2:36][CH2:35][CH3:40])=[CH:6][CH:7]=4)=[CH:15][CH:14]=3)=[CH:17][CH:18]=2)[C:22]1=[O:25])[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Agent: CCCc1ccc(C(=O)Cl)cc1
Product: CCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)OC)C(C)C)C4)cc2)cc1
Yield: 91 %

Procedure:
The compound of example 169 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 4-(n-propyl)benzoyl chloride.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[N:5]=[C:4]([NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25]CC2C=CC=CC=2)[N:3]=1.[H][H]>CO.[Pd]>[NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[N:5]=[C:4]([NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[OH:25])[N:3]=1
Reactant: Nc1nc(NCCc2ccccc2OCc2ccccc2)nc2nc(-c3ccco3)nn12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1nc(NCCc2ccccc2O)nc2nc(-c3ccco3)nn12

Procedure:
A solution of the product of step (1) (0.9g) in methanol (150 ml) was hydrogenated at room-temperature and pressure using 10% palladium on carbon (0.9 g) catalyst. After the uptake of hydrogen was complete, the catalyst was filtered off and the solvent evaporated. The residue was crystallised from ethanol, and gave 7-amino-2-(2-furyl)-5-[2-(hydroxyphenyl)ethyl]amino-[1,2,4]triazolo[1,5-a][1,3,5]triazine, m.p. 260°-263° C. microanalysis, found: C, 57.2; H, 4.8; N, 28.6%; C16H15N7O2 (0.15) C2H5OH requires: C, 57.0; H, 4.7; N, 28.5%; NMR: 2.81 (t, 2H, phenyl-H), 3.49 (m, 2H, CH2N); 6.71 (d of d, 1H, furyl-4H), 7.03 (d, 1H, furyl-3H), 6.7-7.15 (complex, 4H, phenyl-H); 7.85 (m, 1H, NH); 7.84 (s, 1H, furyl-5H); 8.09 (br s, 2H, NH2) and 9.31 (s, 1H, OH); m/e 338 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:20])=[C:4]([CH2:14][CH2:15][C:16]([O:18]C)=[O:17])[CH:5]=[C:6]2[C:11]=1[O:10][C:9](=[O:12])[CH:8]=[C:7]2[CH3:13].Cl>[OH-].[Na+]>[Cl:1][C:2]1[C:3]([OH:20])=[C:4]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:5]=[C:6]2[C:11]=1[O:10][C:9](=[O:12])[CH:8]=[C:7]2[CH3:13]
Reactant: COC(=O)CCc1cc2c(C)cc(=O)oc2c(Cl)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(=O)oc2c(Cl)c(O)c(CCC(=O)O)cc12
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
Ester 6a (0.75 g, 2.5 mmol) was dissolved in 10 ml of 1N NaOH. After being kept at room temperature for 30 min the solution was acidified with 1N HCl to pH of 3. The precipitated material was collected by filtration and washed with water. Drying under vacuum over P2O5 afforded 0.705 g of acid 7a as an off-white solid. 1H NMR (DMSO-d6): δ 12.2 (br s, 1H), 10.41 (br s, 1H), 7.50 (s, 1H), 6.23 (s, 1H), 2.89 (t, J=7.5 Hz, 2H), 2.53 (t, J=7.5 Hz, 2H), 2.38 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Li+].CC([N-]C(C)C)C.[Br:19][C:20]1[CH:32]=[CH:31][C:23]2[N:24]([CH2:29][CH3:30])[C:25]([CH2:27]Cl)=[N:26][C:22]=2[CH:21]=1>C1COCC1>[Br:19][C:20]1[CH:32]=[CH:31][C:23]2[N:24]([CH2:29][CH3:30])[C:25]([CH2:27][CH2:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[O:10])=[N:26][C:22]=2[CH:21]=1
Reactant: CC(=O)c1cccc(F)c1
Reactant: CCn1c(CCl)nc2cc(Br)ccc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCn1c(CCC(=O)c2cccc(F)c2)nc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-(3-fluoro-phenyl)-ethanone (0.55 g, 4.0 mmol) in THF (30 mL) at −78° C. under N2 is added LDA (2M in hexanes, 2.0 mL, 4.0 mmol). After 10 minutes, 5-bromo-2-chloromethyl-1-ethyl-1H-benzoimidazole (1 g, 3.65 mmol) in THF (5 mL) is added. The mixture is stirred at this temperature for an additional 1 hour and is gradually warmed to room temperature. The reaction is then quenched with saturated NH4Cl. The mixture is extracted with ethyl acetate (3×50 mL). Upon drying, the organic solvent is removed to give 3-(5-Bromo-1-ethyl-1H-benzoimidazol-2-yl)-1-(3-fluoro-phenyl)-propan-1-one as a yellow oil.
Reaction SMILES: Br.Br[CH2:3][C:4]1[N:5]=[C:6]2[C:11](=[N:12][CH:13]=1)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]2[NH2:15].Cl.[C:17]([O:21][C:22](=[O:37])[CH:23]([NH2:36])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][CH:26]=1)([CH3:20])([CH3:19])[CH3:18].C(N(C(C)C)C(C)C)C.C(=O)(O)[O-]>CN(C)C(=O)C>[C:17]([O:21][C:22](=[O:37])[CH:23]([NH:36][CH2:3][C:4]1[N:5]=[C:6]2[C:11](=[N:12][CH:13]=1)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]2[NH2:15])[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:29][CH:30]=1)([CH3:18])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)C(N)Cc1ccc(OC(C)(C)C)cc1
Reactant: Nc1nc(N)c2nc(CBr)cnc2n1
Agent: Br
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)C(Cc1ccc(OC(C)(C)C)cc1)NCc1cnc2nc(N)nc(N)c2n1
Temperature: 50 °C
Reaction time: 4 h
Yield: 37.8 %

Procedure:
To a solution of 6-bromomethyl-2,4-pteridinediamine hydrobromide (53.7 mg, 0.1598 mmol) in anhydrous N,N dimethylacetamide was added 2-amino-3-(4-tert-butoxy-phenyl)-propionic acid tert-butyl ester hydrochloride (51.58 mg, 0.1758 m mol). Under positive pressure of Argon, iPr2EtN (33.69 ul) was added. The reaction mixture was stirred at 50° C. for 4 hrs and then at room temperature overnight. The crude product was poured into saturated bicarbonate solution. The resulted precipitate was collected and purified by preparative HPLC. 27.6 mg product was obtained. Yield: 41%; 1H NMR (500 MHz, DMSO-d6): δ 1.22491(s, 9H), 1.26835 (s, 9H), 2.921–2.971 (m, 2H), 4.130 (b, 1H), 4.427(s, 2H), 6.91485–6.93165(d, J=8.4 Hz, 2H), 7.16037–7.17723(d, J=8.43 Hz, 2H), 8.89353 (s, 1H); 9.13119 (s, 2H), 9.30829 (s, 2H); ESI-MS: m/z 468 (M++1)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:42][N:43]=[C:44]=[O:45]>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:44]([NH:43][CH3:42])=[O:45])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CN=C=O
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Solvent: ClCCl
Product: CNC(=O)Oc1ccc(C[C@H](NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)[C@H](O)CN(CC(C)C)S(=O)(=O)c2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S, 2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propylcarbamate (80 mg), methyl isocyanate (0.5 mL), dichloromethane (3 mL) and disopropylamine (0.05 mL) was stirred at ambient temperature for 1 h. Solvent was evaporated and the residue was purified by chromatography (silica gel, hexanes/ethyl acetate, 3:1) to provide the title compound as a solid foam (57 mg). 1H NMR (DMSO-d6): δ 0.78 (3H, d), 0.82 (3H, d), 1.17 (1H, dd), 1.30-1.45 (1H, m), 1.9-2.0 (1H, m), 2.42 (1H, t), 2.6 (3H, d), 2.62-2.80 (3H, m), 2.99 (2H, dd), 3.15-3.20 (1H, m), 3.50-3.63 (4H, m), 3.7 (1H, t), 3.8 (1H, dd), 4.8 (1H, dd), 5.04 (1H, d), 5.5 (1H, d), 6.18 (2H, s), 6.95 (2H, d), 7.05 (1H, d), 7.15 (2H, d), 7.2 (1H, s), 7.25 (1H, d), 7.5 (1H, quartet), 8.08 (1H, d); MS: 650 (MH+).
Reaction SMILES: O=[C:2]1[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][O:13][C:7]3=[CH:6][C:5]=2[C:4](=[O:14])[N:3]1[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.O1CCC[CH2:31]1.C[Mg]I.C(OCC)C.Cl>O.C(OCC)(=O)C>[CH2:31]=[C:2]1[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][O:13][C:7]3=[CH:6][C:5]=2[C:4](=[O:14])[N:3]1[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN2C(=O)c3cc4c(cc3C2=O)OCO4)CC1
Reactant: C1CCOC1
Agent: C[Mg]I
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C=C1c2cc3c(cc2C(=O)N1CCC1CCN(C(=O)OC(C)(C)C)CC1)OCO3
Temperature: 5 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
To a reaction vessel, 75 g (0.19 mol) compound XI and 500 ml tetrahydrofuran were added while stirring under nitrogen, The mixture was cooled to 0-10° C., 400 ml 1.2N methylmagnesium iodide/ethyl ether solution was slowly added into the reaction vessel, the reaction was kept for 1 h, a minor amount of water was added until there was no bubble formed, concentrated hydrochloric acid was added to adjust the pH to acidic, the reaction was kept for 15 min, 500 ml ethyl acetate and 300 ml water were added, extracted, washed, the organic layer was collected, dried over sodium sulfate, filtered, the filtrate was concentrated to a minor amount, petroleum ether was added, solid was precipitated out, filtered, dried, and 47.6 g compound IX-1 was obtained, with yield of 63.8%. H NMR (DMSO-d6): δ 0.95-1.05 (m, 2H), 1.38 (s, 10H), 1.48 (q, 2H, J=7.0 Hz), 1.71 (d, 2H, J=12.2 Hz), 2.65 (br s, 2H), 3.70 (t, 2H, J=7.2 Hz), 3.90 (d, 2H, J=11.6 Hz), 4.95 (s, 1H), 5.34 (s, 1H), 6.17 (s, 2H), 7.15 (s, 1H), 7.53 (s, 1H); MS (ESI): m/z 423 [M+Na]+.