Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=2[NH:14][C:13]1=[O:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30]OC(OC)N(C)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=2[N:14]([CH3:30])[C:13]1=[O:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: O=C(NC1N=C(C2CCCCC2)c2ccccc2NC1=O)OCc1ccccc1
Solvent: Cc1ccccc1
Product: CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(C2CCCCC2)c2ccccc21

Procedure:
To a refluxing solution of 3(R,S)-[(benzyloxycarbonyl)amino]-5-cyclohexyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (5 g) in anhydrous toluene (400 ml) was added dimethylformamide dimethylacetal (7.3 ml) and the mixture was refluxed for 3.5 hours under nitrogen before additional dimethylformamide dimethyl acetal (1 ml) was added. After a further 50 minutes at reflux, solvents were removed under vacuum and the residue was triturated with diethyl ether (50 ml). The white solid was collected by filtration, washed with diethyl ether (2×20 ml) and dried to give the title compound (5 g); mp 205°-207° C.; dH (360 MHz, CDCl3) 7.55-7.25 (9H, m), 6.52 (1H, d, J=8.0 Hz), 5.10 (3H, m), 3.36 (3H, s), 2.76 (1H, m), 2.04-1.03 (10H, m).
Reaction SMILES: [CH3:1][C:2]([CH3:41])([CH3:40])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)[CH:15]=3)[N:12]=2)[N:7](COCC[Si](C)(C)C)[CH:6]=1)=[O:4]>C(Cl)Cl>[CH3:1][C:2]([CH3:41])([CH3:40])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)[CH:15]=3)[N:12]=2)[NH:7][CH:6]=1)=[O:4]
Reactant: CN1CCN(CCn2cc(-c3cnc4c(n3)c(C(=O)C(C)(C)C)cn4COCC[Si](C)(C)C)c3ccccc32)CC1
Solvent: ClCCl
Product: CN1CCN(CCn2cc(-c3cnc4[nH]cc(C(=O)C(C)(C)C)c4n3)c3ccccc32)CC1
Yield: 75 %

Procedure:
2,2-Dimethyl-1-(2-{1-[2-(4-methyl-piperazin-1-yl)-ethyl]-1H-indol-3-yl}-5H-pyrrolo[2,3-b]pyrazin-7-yl)-propan-1-one was prepared following a similar procedure but using 2,2-dimethyl-1-[2-{1-[2-(4-methyl-piperazin-1-yl)-ethyl]-1H-indol-3-yl}-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one as starting material. The product was isolated in 75% yield by SiO2 chromatography (DCM/[DCM/MeOH/NH4OH 60/10/1] 100-75% DCM).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[NH2:7][C:8]1[N:9]=[C:10]([CH3:22])[C:11]2[CH:17]=[C:16](Br)[C:15](=[O:19])[N:14]([CH2:20][CH3:21])[C:12]=2[N:13]=1.C([O-])(O)=O.[Na+]>C(N(CC)CC)C.[Cu]I.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>[NH2:7][C:8]1[N:9]=[C:10]([CH3:22])[C:11]2[CH:17]=[C:16]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[C:15](=[O:19])[N:14]([CH2:20][CH3:21])[C:12]=2[N:13]=1
Reactant: CCn1c(=O)c(Br)cc2c(C)nc(N)nc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Product: CCn1c(=O)c(C#C[Si](C)(C)C)cc2c(C)nc(N)nc21
Temperature: 50 °C
Yield: 64.9 %

Procedure:
Trimethylsilylethyne (1.44 mL, 10.2 mmol) was added to a pressure tube charged with 2-amino-6-bromo-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (1.58 g, 5.59 mmol) from above, CuI (0.053 g, 0.279 mmol), and PdCl2(PPh3)2 (0.211 g, 0.279 mmol) in triethylamine (20 mL). The pressure tube was sealed under nitrogen and heated to 50° C. 96 h. The reaction was cooled to room temperature and poured into a saturated solution of NaHCO3 (150 mL), then washed four times with ethyl acetate (50 mL). The organic layers were pooled and dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified on SiO2 (2:1, methylene chloride:ethyl acetate) to afford 2-amino-8-ethyl-4-methyl-6-((trimethylsilyl)ethynyl)pyrido[2,3-d]pyrimidin-7(8H)-one (1.09 g, 65% yield) as an off white solid.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][NH:18][C:19]2[N:28]=[C:27]([N:29]([CH3:31])[CH3:30])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.[Br:42][C:43]1[CH:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[C:45]([O:53][C:54]([F:57])([F:56])[F:55])[CH:44]=1>CO.C(Cl)Cl.[Pd]>[Br:42][C:43]1[CH:48]=[CH:47][C:46]([S:49]([NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([CH2:17][NH:18][C:19]3[N:28]=[C:27]([N:29]([CH3:31])[CH3:30])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)[CH2:13][CH2:12]2)(=[O:51])=[O:50])=[C:45]([O:53][C:54]([F:57])([F:56])[F:55])[CH:44]=1
Reactant: CN(C)c1nc(NC[C@H]2CC[C@H](NC(=O)OCc3ccccc3)CC2)nc2ccccc12
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Agent: [Pd]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CN(C)c1nc(NC[C@H]2CC[C@H](NS(=O)(=O)c3ccc(Br)cc3OC(F)(F)F)CC2)nc2ccccc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a suspension of trans-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-carbamic acid benzyl ester (500 mg, 1.15 mmol) in MeOH (5 mL) was added 5% Pd/C (50 mg). The mixture was stirred at ambient temperature under hydrogen atmosphere for 2 hr, at 50° C. for 8 hr, and at ambient temperature for 10.5 hr, filtered, and concentrated to give a colorless oil. To a solution of the above oil in CH2Cl2 (5 mL) was added diisopropylethylamine (420 μL, 2.41 mmol). The mixture was cooled to 4° C. and a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (431 mg, 1.27 mmol) in CH2Cl2 (2 mL) was added below 5° C. The reaction mixture was stirred at 4° C. for 1.5 hr. The reaction was quenched with saturated aqueous NaHCO3 The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 33% to 50% EtOAc in hexane) to give trans-4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-2-trifluoromethoxy-benzenesulfonamide (560 mg, 81%) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:21][CH2:20][C:15]3(OCC[O:16]3)[CH2:14][CH2:13]1)[CH2:7][CH2:6][CH2:5]2.Cl>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:21][CH2:20][C:15](=[O:16])[CH2:14][CH2:13]1)[CH2:7][CH2:6][CH2:5]2
Reactant: Brc1ccc2c(c1)CCCN2C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC(C)=O
Product: O=C1CCC(N2CCCc3cc(Br)ccc32)CC1
Reaction time: 16 h
Yield: 98 %

Procedure:
A solution of compound 4 (0.21 g, 0.596 mmol) in acetone (5 mL) was treated with 10% HCl solution (5 mL) and the resulting mixture was stirred for overnight (16 h). Acetone was evaporated, the crude was basified with 2 N NaOH solution and the product was extracted into CH2Cl2 (2×15 mL). The combined CH2Cl2 layer was washed with brine (10 mL) and dried (Na2SO4). The solvent was evaporated to obtain compound 5 (0.18 g, 98%) as a syrup. 1H NMR (CDCl3) δ 7.16 (dd, 1H, J=2.4, 4.3 Hz), 7.08 (s, 1H), 6.60 (d, 1H, J=9.0 Hz), 4.11-4.01 (m, 1H), 3.17 (t, 2H, J=5.7 Hz), 2.71 (t, 2H, J=6.3 Hz), 2.52-2.48 (m, 4H), 2.14-1.85 (m, 6H); ESI-MS (m/z, %): 308, 310 (MH+, 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:30])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]CC2C=CC=CC=2)=[O:19])=[CH:13][C:12]=1[O:28][CH3:29].[OH-].[Na+].Cl>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:30])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][C:12]=1[O:28][CH3:29]
Reactant: COc1cc(CC(=O)OCc2ccccc2)ccc1NC(=O)Nc1ccccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1F
Reaction time: 8 h
Yield: 65.3 %

Procedure:
To a stirred solution of benzyl 4-[N′-(2-fluorophenyl)ureido]-3-methoxyphenylacetate (2.04 g, 5 mmol) in THF (40 mL) was added 0.25 N NaOH (40 mL). The resulting mixture was stirred overnight. The mixture was poured into 1 N HCl (10 mL), and the resulting precipitate was collected with suction. The residue was recrystallized from CHCl3-EtOH to give 1.04 g (66%) 4-[N′-(2-fluorophenyl)ureido]-3-methoxyphenylacetic acid as a white crystalline powder. mp 185 –188 (d); 1H-NMR (DMSO-d6) δ 3.50 (2H, s), 3.82 (3H, s), 6.78 (1H, dd, J=1.4 and 8.3 Hz), 6.92 (1H, d, J=1.4 Hz), 6.95–7.01 (1H, m), 7.10–7.14 (1H, m), 7.19–7.24 (1H, m), 8.01 (1H, d, J=8.3 Hz), 8.14–8.18 (1H, m), 8.72 (1H, s), 9.17 (1H, s); MS (FAB) m/z 319 (M++1); Anal. Calcd for C16H15N2O4F: C, 60.37; H, 4.75; N, 8.80. Found: C, 60.20; H, 4.82; N, 8.67.
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2C(OC(C)(C)C)=O)=[CH:8][CH:7]=[CH:6][N:5]=1)(=[O:3])[NH2:2].C(OC(C)C)(C)C.[ClH:31]>C(OCC)(=O)C>[ClH:31].[ClH:31].[NH:13]1[CH2:14][CH2:15][CH2:16][C@@H:12]1[CH2:11][O:10][C:9]1[C:4]([C:1]([NH2:2])=[O:3])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccnc1C(N)=O
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Product: NC(=O)c1ncccc1OC[C@H]1CCCN1
Yield: 92 %

Procedure:
A solution of (R)-tert-butyl 2-((2-carbamoylpyridin-3-yloxy)methyl)pyrrolidine-1-carboxylate (3.43 g, 10.7 mmol, EXAMPLE 1 Step 2) in 4.0 M hydrogen chloride in ethyl acetate (100 mL) was stirred at room temperature for 5 h. Diisopropyl ether (150 mL) was added to the mixture, and the formed white precipitate was collected by filtration. The precipitate was dried under reduced pressure to give 2.89 g (92%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:25])[N:5]([C:12]1([F:24])[CH2:17][CH:16]([O:18]C(=O)C)[C:15](=[O:22])[NH:14][C:13]1=[O:23])[C:6]2=[O:11].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:25])[N:5]([C:12]1([F:24])[CH2:17][CH:16]([OH:18])[C:15](=[O:22])[NH:14][C:13]1=[O:23])[C:6]2=[O:11]
Reactant: CC(=O)OC1CC(F)(N2C(=O)c3cccc(N)c3C2=O)C(=O)NC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: Nc1cccc2c1C(=O)N(C1(F)CC(O)C(=O)NC1=O)C2=O

Procedure:
A solution of 3-(4-amino-1,3-dioxoisoindolin-2-yl)-3-fluoro-2,6-dioxo-5-acetoxypiperidine (1 g, 2.9 mmol) and p-toluenesulfonic acid (0.28 g, 1.5 mmol) in methanol (10 mL) is heated at reflux for 5 h. The solvent is removed in vacuo to give 4-amino-2-(3-fluoro-5-hydroxy-2,6-dioxopiperid-3-yl)isoindoline-1,3-dione which is further purified by column chromatography.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH2:4][C:5]([NH:15][C:16](=[O:28])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH:24]=[C:25]([CH3:27])[CH3:26])([C:12]([OH:14])=[O:13])[CH2:6]2>CO.[Pd]>[F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH2:4][C:5]([NH:15][C:16](=[O:28])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH2:24][CH:25]([CH3:26])[CH3:27])([C:12]([OH:14])=[O:13])[CH2:6]2
Reactant: CC(C)=Cc1c(C)cccc1C(=O)NC1(C(=O)O)Cc2c(F)ccc(F)c2C1
Agent: [Pd]
Solvent: CO
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3c(F)ccc(F)c3C2)c1CC(C)C

Procedure:
A solution of 4,7-difluoro-2-[3-methyl-2-(2-methyl-propenyl)-benzoylamino]-indan-2-carboxylic acid (392) (82 mg, 0.21 mmol) in MeOH (40 mL) is hydrogenated using 10% palladium/carbon catalyst at 40 bar and 30° C. using the Thales nanotechnology H-Cube for 5 h. The MeOH is concentrated to dryness in vacuo to give the product (393) as white solid powder.
Reaction SMILES: S([O-])(=O)(C1C=CC([NH2:9])=CC=1)=O.[Na+].N([O-])=O.[Na+].[OH:17][C:18]1[CH:19]=[C:20]([C:28]([OH:30])=[O:29])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2.C(=O)(O)[O-].[Na+].S([O-])(O)=O.[Na+]>O>[NH2:9][C:27]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([C:28]([OH:30])=[O:29])=[CH:19][C:18]=1[OH:17]
Reactant: Nc1ccc(S(=O)(=O)[O-])cc1
Reactant: O=C(O)c1cc(O)cc2ccccc12
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: O=S([O-])O
Solvent: O
Product: Nc1c(O)cc(C(=O)O)c2ccccc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
To a stirred solution of p-benzenediazonium sulfonate, which was prepared by the addition of sodium sulfanilate (0.525 g, 2.7 mmole) to sodium nitrite at 0°, and the compound from example 14 c) (0.413 g, 2.2 mmol) in water (20 mL), sodium bicarbonate (2.3 g, 27.0 mmol) was added slowly. The resulting solution was heated at 60° C. with stirring overnight. After the solution was cooled to 50° C., sodium hydrogen sulfite (1.05 g, 6.0 mmole) was added. The resulting solution was stirred for 30 min. at 50° C. After cooling down to room temperature, the solid was removed by filtration. The filtrate was evaporated to dryness and the residue was purified by flash chromatography (silica gel, 45% dichloromethane/45% ethyl acetate/10% methanol) to give the title compound (0.066 g, 15%) MS(ES) m/z 203.8 [M+H].
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:14][CH3:15])=[N:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]=[C:24]=[O:25].O>C1COCC1>[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24](=[O:25])[NH:1][C:2]1[C:3]([O:14][CH3:15])=[N:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccccc1Br
Reactant: CCOC(=O)Cc1ccc(N)c(OC)n1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)Cc1ccc(NC(=O)Nc2ccccc2Br)c(OC)n1
Reaction time: 8 h
Yield: 93.1 %

Procedure:
To a stirred solution of ethyl 3-amino-2-methoxy-6-pyridylacetate (1.61 g, 7.66 mmol) in THF (10 ml) were added 2-bromophenylisocyanate (948 ml, 7.66 mmol) and Et3 N (107 ml, 0.776 mmol). After stirring overnight, the mixture was poured into H2O (100 ml) and extracted with CHCl3-MeOH (4:1, 2×200 ml). The combined extracts were dried over MgSO4 and evaporated. The residue was recrystallized from CHCl3-MeOH-hexane to give ethyl 3-[N′-(2-bromophenyl)ureido]-2-methoxy-6-pyridylacetate (2.91 g, 93%) as a colorless crystalline powder. mp 160–163° C.; 1H-NMR (DMSO-d6) δ 1.19 (dt, J=7.1, 0.7 Hz, 3 H), 3.69 (s, 2 H), 3.95 (s, 3 H), 4.07–4.13 (m, 2 H), 6.90 (d, J=7.8 Hz, 1 H), 6.99 (t, J=7.8 Hz, 1 H), 7.33 (t, J=7.8 Hz, 1 H), 7.61 (d, J=7.8 Hz, 1 H), 7.96 (dd, J=7.8, 1.5 Hz, 1 H), 8.31 (d, J=7.8 Hz, 1 H), 8.82 (s, 1 H), 9.12 (s, 1 H); MS (FAB) m/z 408 (M+), 410 (M++2); Anal. Calcd for C17H18BrN3O4.0.25 H2O: C, 49.47; H, 4.52; 9.96. Found: C, 49.34; H, 4.48; N, 9.96.
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+:10].C([Li])CCC.[Na+].[C:17]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O-:31])=[O:30])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCCCCC.O1CCCC1>[OH:4][C:3]1[CH2:5][C:17]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:24][C:1](=[O:6])[CH:2]=1.[Na+:10].[C:17]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O-:31])=[O:30])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)CC(C)=O
Agent: O=C([O-])CCCCC(=O)c1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)CCCCC1(c2ccccc2)CC(O)=CC(=O)O1

Procedure:
The title compound was prepared as described in General Method 1 using 25 nmol of methyl acetoacetate, 27.5 mmol of NaH 60% dispersion in oil, 26.25 mmol of 1.6M n-butyl lithium in hexane in 50 mL of tetrahydrofuran and 25 mmol of 5-benzoylpentanoic acid sodium salt in 100 mL of tetrahydrofuran. 5-Benzoylpentanoic acid sodium salt was prepared by reacting the acid (25 mmol) with hexane washed NaH (27.5 mmol) in tetrahydrofuran at 0° C. for 25 minutes. The crude solid was recrystallized from ethyl acetate (m.p. 136°-140° C.). 1H NMR (DMSO-d6) δ0.8-1.0 (m, 1H), 1.1-1.3 (m, 1H), 1.3-1.5 (m, 2H), 1.8-2.0 (m, 2H), 2.1 (t, 2H), 2.9 (ABq, 2H), 4.85 (s, 1H), 7.2-7.4 (m, 5H), 11.4 (bs, 1H), 12.0 (bs, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].[CH2:12]([O:14][C:15](=[O:18])[CH2:16]Br)[CH3:13].C(=O)([O-])[O-].[K+].[K+].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].C1(P(C2C3C(=CC=CC=3)C=CC=2)C2C3C(=CC=CC=3)C=CC=2)C2C(=CC=CC=2)C=CC=1.C1COCC1>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:16][C:15]([O:14][CH2:12][CH3:13])=[O:18])=[CH:5][CH:4]=1)=[O:2]
Reactant: CCOC(=O)CBr
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)Cc1ccc(C=O)cc1
Temperature: 65 °C
Yield: 85.1 %

Procedure:
A screw cap tube was loaded with (4-formylphenyl)boronic acid (450 mg, 3 mmol), ethylbromoacetate (0.22 mL, 2 mmol), potassium carbonate (830 mg, 6 mmol), Pd2(dba)3 (46 mg, 0.05 mmol), tri-1-naphtylphosphine (62 mg, 0.15 mmol), H2O (0.5 mL), and THF (4.5 mL). The mixture was degased with nitrogen for 5 minutes and then heated to 65° C. for 18 hours. The reaction was cooled to room temperature and diluted with ethyl acetate (50 mL) and washed with water (2×50 mL). The organic phase was filtered through a phase separator and the solvent was removed in vacuo. The residue was purified by silica gel chromatography, eluting with 0-20% EtOAc in isohexane, to yield ethyl 2-(4-formylphenyl)acetate as colourless oil (327 mg, 57%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Si:40](Cl)([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][CH2:9][C@H:10]([NH:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:11][O:12][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC[C@H](COCc1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H](COCc1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 88.9 %

Procedure:
A solution of (2R)-3-(benzyloxy)-2-(tritylamino)propan-1-ol (2.68 g, 6.34 mmol) dissolved in 100 mL of CH2Cl2 was treated with triethylamine (1.00 mL, 7.19 mmol), tert-butyldimethylsilyl chloride (1.08 g, 7.15 mmol) and DMAP (79 mg, 0.65 mmol) and the reaction mixture was stirred under N2 overnight. The reaction mixture was then concentrated and the resulting material was dissolved in 50 mL of CH2Cl2 and washed with H2O and brine. The organic portion was then dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 10% ethyl acetate/hexanes) gave 3.03 g of (2S)-1-(benzyloxy)-3-{[tert-butyl(dimethyl)silyl]oxy}-N-tritylpropan-2-amine as a colorless syrup.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15]([Cl:17])=[N:14][C:13](N)=[N:12][C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(OC(C)(C)C)=O.[Cl:26]CCCl>>[CH2:1]([N:8]1[C:16]2[C:15]([Cl:17])=[N:14][C:13]([Cl:26])=[N:12][C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nc(Cl)c2c(ccn2Cc2ccccc2)n1
Reactant: ClCCCl
Agent: CC(C)(C)ON=O
Product: Clc1nc(Cl)c2c(ccn2Cc2ccccc2)n1
Temperature: -10 °C
Reaction time: 5 h
Yield: 77 %

Procedure:
To a suspension of 5-benzyl-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine (641 mg, 2.5 mmol) in 1,2-dichloroethane (35 mL) was cooled to −10° C. SbCl3 (850 mg, 3.7 mmol) was added. The reaction mixture was stirred for 5 min. t-butyl nitrite (2.1 mL, 17.4 mmol) was added dropwise and the stirred mixture was from −10° C. to room temperature for 5 h. Upon completion of the reaction, the reaction mixture was poured into ice water and washed with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with Hexanes:Ethyl acetate (9:1-1:1), and gave the product as an off-white solid (528 mg, 77%).
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[SH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1>C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:1](=[O:10])[S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:3][CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Sc1ccccn1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Sc2ccccn2)cc1

Procedure:
Following the general procedure described above, reaction of p-anisoyl chloride (4.70 g, 30.0 mmol) with 2-mercaptopyridine (3.33 g, 30.0 mmol) in THF (30 mL) for 30 min at room temperature afforded pale yellow solid after precipitation (6.70 g, 91%): mp 73° C.; 1H NMR δ 3.88 (s, 3H), 6.93-7.00 (m, 2H), 7.30-7.34 (m, 1H), 7.70-7.74 (m, 2H), 7.75-7.80 (m, 1H), 7.97-8.02 (m, 1H), 8.64-8.69 (m, 1H); Anal. Calcd for C13H11NO2S: C, 63.65; H, 4.52; N, 5.71. Found: C, 63.78; H, 4.59; N, 5.66.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].I[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.C(N(CC)CC)C.Cl>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.O.C(#N)C>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:3]#[C:2][CH2:1][OH:4])[CH:7]=1
Reactant: C#CCO
Reactant: Ic1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: OCC#Cc1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
2-Propynyl alcohol (2.1 g) was added dropwise to a stirred mixture of 3-iodopyridine (2.2 g), bis(triphenylphosphine)palladium chloride (0.1 g), triethylamine (1.4 ml), cuprous iodide (0.1 g) and acetonitrile (10 ml) and the mixture was stirred at ambient temperature for 30 minutes and the heated to 60° C. for 2 hours. The mixture was cooled to ambient temperature, poured into water (100 ml) and neutralised by adding dilute aqueous hydrochloric acid. The mixture was extracted with diethyl ether (2×100 ml) and the combined extracts were washed with water (100 ml), dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with methylene chloride to give 3-(3-pyridyl)prop-2-yn-1-yl alcohol (0.8 g), m.p. 99°-100° C.
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=4[F:50])[CH:34]=3)[O:32][C@@:10]1([C:51]([OH:54])([CH3:53])[CH3:52])[CH2:11][O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([C:51]([OH:54])([CH3:53])[CH3:52])([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=1[F:50]
Reactant: COc1ccc(Cc2cc([C@]34OC[C@](C(C)(C)O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)c(F)c1F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: Clc1ccccc1Cl
Solvent: CO
Product: COc1ccc(Cc2cc([C@]34OC[C@](C(C)(C)O)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)c(F)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
To a solution of 2-[(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]propan-2-ol 22c (86 mg, 0.11 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 10 mL) were added o-dichlorobenzene (0.064 mL, 0.57 mmol) and 10% Pd/C (13 mg, 0.01 mmol) at room temperature. The mixture was stirred at room temperature under H2 for 4 hours and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=1/3 to give the title compound 22 as white oil (43.9 mg, 79.8%, HPLC: 92.7%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 531.0 [M+HCOO]−; and 1H NMR (400 MHz, DMSO-d6) δ(ppm): 7.42 (m, 1H), 7.37 (m, 2H), 6.96 (m, 1H), 6.93-6.85 (m, 1H), 5.51 (d, 1H), 5.05 (d, 1H), 5.00 (d, 1H), 4.24 (s, 1H), 4.05 (m, 3H), 3.85 (s, 3H), 3.79 (d, 1H), 3.75-3.65 (m, 1H), 3.50-3.36 (m, 2H), 1.20 (s, 3H), 1.15 (s, 3H).