Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([CH2:10][C@H:11]([NH2:13])[CH3:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:22][C@@H:23]1[C@H:27]([O:28]C(=O)C2C=CC=CC=2)[C@@H:26]([CH2:37][O:38]C(=O)C2C=CC=CC=2)[O:25][C@H:24]1[N:47]1[CH:55]=[N:54][C:53]2[C:48]1=[N:49][C:50]([Cl:57])=[N:51][C:52]=2Cl)(=O)C1C=CC=CC=1.C(N(CC)CC)C>O1CCOCC1>[Cl:57][C:50]1[N:51]=[C:52]([NH:13][C@H:11]([CH3:12])[CH2:10][S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:8])=[O:9])[C:53]2[N:54]=[CH:55][N:47]([C:48]=2[N:49]=1)[C@@H:24]1[O:25][C@H:26]([CH2:37][OH:38])[C@@H:27]([OH:28])[C@H:23]1[OH:22]
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: C[C@@H](N)CS(=O)(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C[C@H](CS(=O)(=O)c1ccccc1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 41.3 %

Procedure:
(R)-1-Phenylsulphonyl-2-propylamine (0.4 g, 1.7 mmol) was reacted with 9-(2,3,5-tri- O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.7 g, 1.0 mmol) in dioxan (20 ml) in the presence of triethylamine (0.4 g, 4.3 mmol). The reaction mixture was stirred at room temperature for 48 h, heated at 60° C. for 4 h, cooled, filtered and evaporated. The product (after purification by flash chromatography) was debenzoylated with methanolic ammonia to provide the title 2-chloro- N-[(R)-1-phenylsulphonyl-2-propyl]adenosine (after column chromatography) as a foam (0.2 g, 24%), 1H NMR (DMSO-d6)δ 1.24 (3H, d, --CH3), 3.45 (1H, dd, --C--H), 3.53-3.61 (2H, m, H-5'a and --C--H), 3.64-3.71 (1H, m, H-5'b), 3.86 (1H, dd, --C--H), 3.97 (1H, q, H-4'), 4.14 (1H, m, H-3'), 4.53 (1H, m, H-2'), 5.09 (1H, t, 5'-OH), 5.23, 5.50 (2H, 2 d, 2' and 3'-OH), 5.83 (1H, d, H-1'), 7.45-7.82 (5H, m, Ar--H), 8.21 (1H, s, --N--H), 8.38 (1H, s, H-8).
Reaction SMILES: [I-].C1([C:8]([PH3+])([C:15]2[CH:20]=C[CH:18]=[CH:17][CH:16]=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(C)(C)C.[K+].[C:28]([N:35]1CCCC(=O)C1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>C1(C)C=CC=CC=1>[C:28]([N:35]1[CH2:18][CH2:17][CH2:16][C:15](=[CH2:20])[CH2:8]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=C1CCCN(C(=O)OC(C)(C)C)C1
Yield: 70.7 %

Procedure:
To a mixture of triphenylmethylphosphonium iodide (22.14 g) in toluene (135 ml) was added potassium tert-butanolate (5.32 g). The solution turned to orange. Then N-Boc-3-piperidone (6.0 g) in toluene (66 ml) was dropped into the solution under argon, at 30° C. The reaction was filtered and washed with water (200 ml, 2×) and then diluted by HCl (1M), dried with anhydrous sodium sulfate. The solution was purified by flash chromatography (silica gel, PE:EA=15:1) to obtain N-Boc-3-methylenepiperidine as an oil (4.2 g).
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[C:5](=[O:19])[CH2:6][O:7][CH2:8][CH:9]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][CH:17]=[CH2:18])[O:10]1)[CH2:2][CH3:3].ClC1C=C(C=CC=1)C(O)=[O:28]>C(Cl)Cl>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:19])[CH2:6][O:7][CH2:8][CH:9]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][CH:17]2[CH2:18][O:28]2)[O:10]1)[CH2:21][CH3:22]
Reactant: C=CCOCC1CCC(COCC(=O)N(CCC)CCC)O1
Reactant: O=C(O)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCN(CCC)C(=O)COCC1CCC(COCC2CO2)O1
Reaction time: 72 h
Yield: 92.2 %

Procedure:
5.0 g of N,N-dipropyl-2-[[tetrahydro-5-[(2-propenyloxy)methyl]-2-furanyl]methoxy]acetamide (0.016 mole) is dissolved in 300 ml of methylene chloride and 3.20 g of m-chlorobenzoic acid (1 equivalent @ 85% tech) is added at room temperature. The mixture is then stirred at 30° for 72 hours under nitrogen. The precipitated m-chlorobenzoic acid is removed via filtration. The methylene chloride mixture is then washed with 2×200 ml portions of saturated potassium carbonate solution and dried over anhydrous sodium sulfate. The methylene chloride is removed in vacuo yielding 4.86 g (92%) of the above compound as a pale yellow liquid.
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5].I[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1/[C:10](=[CH:18]/[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25])/[C:11](=[O:17])[NH:12]2>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:6][CH:3]([CH2:4][CH3:5])[C:2]#[C:1][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1/[C:10](=[CH:18]/[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25])/[C:11](=[O:17])[NH:12]2
Reactant: C#CC(O)CC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(O)C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, 1-pentyn-3-ol (40 mg, 0.48 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (146 mg, 0.4 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (20 mg) and CuI (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 15 h to yield rac-(Z)-1,3-dihydro-4-(3-hydroxy-1-pentynyl)-3-[(3methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 78 mg, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([NH:18][C:19]2[C:20]3[N:27]([CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33])[CH:26]=[CH:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([C:11](=[O:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1.[BH4-].[Na+].O>CO>[Cl:1][C:2]1[CH:17]=[C:16]([NH:18][C:19]2[C:20]3[N:27]([CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33])[CH:26]=[CH:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]([OH:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)c1cccc(Oc2ccc(Nc3ncnc4ccn(CCOCCO)c34)cc2Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(O)c1cccc(Oc2ccc(Nc3ncnc4ccn(CCOCCO)c34)cc2Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
To a solution of 1-{3-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-yl}amino)phenoxy]phenyl}ethanone (233 mg) in methanol (5 mL) was added sodium borohydride (38 mg), and the mixture was stirred at room temperature for 2 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was crystallized from ethyl acetate-diethyl ether to give the title compound (225 mg) as a white powder.
Reaction SMILES: N([O-])=O.[Na+].[Cl:5][C:6]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Cl:17])[C:7]=1[NH2:8].[N-:18]=[N+:19]=[N-].[Na+]>S(=O)(=O)(O)O.C(O)(=O)C>[N:8]([C:7]1[C:6]([Cl:5])=[CH:12][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:10][C:9]=1[Cl:17])=[N+:18]=[N-:19]
Reactant: Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: [N-]=[N+]=Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C

Procedure:
A solution of sodium nitrite (3.2 g) in concentrated sulphuric acid (22 ml) was added dropwise with cooling to a solution of 2,6-dichloro-4-trifluoromethylaniline (9.3 g) in glacial acetic acid (48 ml). The mixture was stirred at room temperature for half an hour and then cooled to 0°-5°. A solution of sodium azide (2.6 g) in the and the mixture stirred at 0°-5° for 1 hour and then at room temperature overnight. The mixture was poured into ice/water, extracted with dichloromethane and the extract worked up in conventional manner to give 1-azido-2,6-dichloro-4-trifluoromethylbenzene, as a red oil. A solution of this oil (25.6 g) and 2-propyn-1-ol (40 ml}in xylene (80 ml) were stirred under nitrogen and heated under reflux overnight. The mixture was cooled and the solvent was evaporated under reduced pressure. Trituration of the residue with light petroleum (bp 30°-40°) gave a crude material which was purified by filtration through silica to give [1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-1,2,3-triazol-4-yl]methanol, m.p.123°-125°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].CC[O:12][CH:13]=[C:14]([C:20](OCC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[CH2:18]([O:17][C:15]([C:14]1[C:13](=[O:12])[C:6]2[C:4](=[CH:3][C:2]([Cl:1])=[C:8]([F:9])[CH:7]=2)[NH:5][CH:20]=1)=[O:16])[CH3:19]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1c[nH]c2cc(Cl)c(F)cc2c1=O
Reaction time: 2 h
Yield: 118.8 %

Procedure:
A mixture of 3-chloro-4-fluoroaniline (1.46 g) and diethyl ethoxymethylene malonate (2.16 g) was heated at 120°-130° C. After 2 hours, the resulting ethanol was evaporated off. The residue was added to diphenyl ether (50 ml) and refluxed for 1 hour. After the solution cooled, the resulting precipitate was filtered, washed with benzene, and dried. The solid was recrystallized from N,N-dimethylformamide (DMF) to give 7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (3.2 g).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[C:31]([Cl:32])=[CH:30][C:13]([C:14]([NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH2:29])[CH2:20][CH2:19]2)=[O:15])=[C:12]([O:33][CH3:34])[CH:11]=1.[BH4-].[Na+].O>C(O)C>[NH2:9][C:10]1[C:31]([Cl:32])=[CH:30][C:13]([C:14]([NH:16][CH2:17][CH:18]2[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:22][CH2:23]2)=[O:15])=[C:12]([O:33][CH3:34])[CH:11]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN)CC1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2ccccc2)CC1
Yield: 72 %

Procedure:
Benzaldehyde (0.76 g) was added to a solution of 4-amino-N-(1-(5-aminopentyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (2.0 g) in ethanol (50 ml), and the mixture was stirred at refluxing temperature for 3 hr. Sodium borohydride (0.53 g) was added to the reaction mixture under ice-cooling, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol:ammonia=50:5:1) to give 1.78 g of 4-amino-N-((1-(5-benzylaminopentyl)piperidin-4-yl)methyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([N+:31]([O-])=O)[C:24]=3[N+:28]([O-])=O)[C:19]2=[O:34])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([NH2:31])[C:24]=3[NH2:28])[C:19]2=[O:34])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3ccc([N+](=O)[O-])c([N+](=O)[O-])c3C2=O)ccc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3ccc(N)c(N)c3C2=O)ccc1OC
Reaction time: 16 h
Yield: 73.1 %

Procedure:
A mixture of 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4,5-dinitroisoindoline-1,3-dione (4.35 g, 8.81 mmol) and Pd/C (800 mg) in ethyl acetate (200 mL) was shaken under hydrogen (50-60 psi) in a Parr bottle for 16 hours. The suspension was filtered through a pad of Celite filter material. The Celite filter material was washed with acetone (200 mL). The solvent was removed in vacuo to give a solid. The solid was stirred in ethyl acetate (10 mL) for 2 hours. The suspension was filtered to give 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4,5-diaminoisoindoline-1,3-dione as a yellow solid (2.79 g, 73% yield): mp, 205-207° C.; 1H NMR (DMSO-d6) δ 1.32 (t, J=6.9 Hz, 3H, CH3), 2.99 (s, 3H, CH3), 3.73 (s, 3H, CH3), 3.95-4.07 (m, 3H, CHH), 4.37 (dd, J=10.4, 14.0 Hz, 1H, CHH), 5.67 (dd, J=3.9, 10.2 Hz, 1H, NCH), 5.90-6.00 (m, 4H, 2NH2), 6.64 (d, J=7.7 Hz, 1H, Ar), 6.88-6.92 (m, 3H, Ar), 7.06 (s, 1H, Ar); 13C NMR (CDCl3) δ 14.64, 40.94, 46.65, 53.53, 55.46, 63.79, 109.36, 111.74, 112.29, 114.42, 117.04, 119.55, 130.68, 133.98, 134.06, 142.38, 147.74, 148.63, 167.16, 169.38; Anal Calcd for C20H23N3O6S: C, 55.42; H, 5.35; N, 9.69. Found: C, 55.71; H, 5.30; N, 9.29. MS: 434 (M++1), 456 (M++23 Na).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:7][O:6][C:5](=[O:8])[CH:4]=1.[CH2:9](O)[CH2:10]C>>[CH2:1]([O:2][C:3]1[CH2:7][O:6][C:5](=[O:8])[CH:4]=1)[CH2:9][CH3:10]
Reactant: COC1=CC(=O)OC1
Reactant: CCCO
Product: CCCOC1=CC(=O)OC1
Yield: 39 %

Procedure:
Preparation analogous to Example 91 from 4-methoxy-2(5H)-furanone and propanol; b.p.10 143°-145° C. Yield: 39%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:34])[C:9]([CH2:30][CH2:31][CH:32]=O)([CH2:17][CH2:18][CH2:19][CH2:20][B:21]1[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]([CH3:34])[C:9]([CH2:30][CH2:31][CH2:32][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)([CH2:17][CH2:18][CH2:19][CH2:20][B:21]1[O:25][C:24]([CH3:26])([CH3:27])[C:23]([CH3:29])([CH3:28])[O:22]1)[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)C(CCC=O)(CCCCB1OC(C)(C)C(C)(C)O1)C(=O)OC(C)(C)C
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(C(=O)OC(C)(C)C)C(CCCCB1OC(C)(C)C(C)(C)O1)(CCCN1CCCC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
A solution of tert-butyl 2-(tert-butoxycarbonyl(methyl)amino)-2-(3-oxopropyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (193 mg, 0.40 mmol, 1.0 equiv) and pyrrolidine (43 mg, 0.60 mmol, 1.5 equiv) in 1,2-dichloroethane (2 mL) was treated with sodium triacetoxyborohydride (168 mg, 0.80 mmol) in one portion. After stirring at room temperature overnight, the reaction mixture was quenched with saturated aqueous NaHCO3 (1 mL) and stirred for an additional 5 min. The resulting mixture was added to a separatory funnel, diluted with saturated aqueous NaCl (5 mL) and extracted with dichloromethane (2×10 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. Purification by flash column chromatography eluting with gradient 1-10% methanol in chloroform gave tert-butyl 2-(tert-butoxycarbonyl(methyl)amino)-2-(3-(pyrrolidin-1-yl)propyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate as an oil (186 mg, 88%). Rf 0.35 (10% methanol in dichloromethane). ESI MS found for C29H55BN2O6 m/z [539.4 (M+1)].
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH2:17])=[O:16])[CH2:11][CH2:12][S:13][CH3:14])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl>C(O)(=O)C>[NH2:1][C@@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH2:17])=[O:16])[CH2:11][CH2:12][S:13][CH3:14])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CSCC[C@H](NC(=O)[C@@H](CC(C)C)NC(=O)OC(C)(C)C)C(N)=O
Agent: Cl
Solvent: CC(=O)O
Product: CSCC[C@H](NC(=O)[C@H](N)CC(C)C)C(N)=O
Yield: 78 %

Procedure:
Condensation of BocDLeuOH (2.49 g.) and HMetNH2 (1.85 g.) by the mixed anhydride method using isobutyl chloroformate gave BocDLeu-MetNH2 in 47% yield. De-t-butoxycarbonylation of BocDLeu-MetNH2 (1.70 g.) using hydrogen chloride in acetic acid gave HDLeu-MetNH2 in 78% yield. Condensation of BocGlyOSu (1.8 g.) and HDLeu-MetNH2 (1.0 g.) by the activated ester method gave BocGly-DLeu-MetNH2 in 95% yield. De-t-butoxycarbonylation of BocGly-DLeu-MetNH2 (1.35 g.) using hydrogen chloride in acetic acid gave HGly-DLeu-MetNH2 in 55% yield.
Reaction SMILES: [CH:1](=[N:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S([CH2:27][N+:28]#[C-:29])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].CO>O.C(COC)OC>[CH3:16][S:15][C:12]1[CH:13]=[CH:14][C:9]([N:8]2[C:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:29][N:28]=[CH:27]2)=[N:10][CH:11]=1
Reactant: CSc1ccc(N=Cc2ccccc2)nc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: COCCOC
Product: CSc1ccc(-n2cncc2-c2ccccc2)nc1
Temperature: 25 °C
Yield: 50.4 %

Procedure:
N-benzal-5-(methylthio)pyridine-2-amine (200 g), tosylmethyl isocyanide (255 g), potassium carbonate (255 g), methanol (3 L) and dimethoxyethane (2 L) were refluxed overnight. The reactant was cooled to room temperature, 10 L water was added and extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, and dried with anhydrous sodium sulfate. The solvent was removed by filtration and reducing pressure. The crude product was purified by column chromatography to obtain the brown solid target compound (118 g, 50% yield). 1H-NMR (300 MHz, CDCl3): δ 2.52 (3H, s), 6.74-6.77 (1H, dd), 7.18-7.22 (3H, m), 7.30-7.33 (3H, m), 7.45-7.48 (1H, dd), 8.05-8.05 (1H, d), 8.38-8.39 (1H, d). LC-MS m/z: 268 [M++1].
Reaction SMILES: [O:1]1[CH:8]2[CH:2]1[CH2:3][O:4][CH2:5][O:6][CH2:7]2.[C:9]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1)(=[O:11])[CH3:10]>>[C:9]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([NH:22][C@@H:2]2[CH2:3][O:4][CH2:5][O:6][CH2:7][C@H:8]2[OH:1])(=[O:20])=[O:21])=[CH:17][CH:18]=1)(=[O:11])[CH3:10]
Reactant: C1OCC2OC2CO1
Reactant: CC(=O)Nc1ccc(S(N)(=O)=O)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)N[C@@H]2COCOC[C@H]2O)cc1
Temperature: 25 °C

Procedure:
A mixture of 5,6-epoxy-1,3-dioxepane (0.5 g) and of 4-acetylaminobenzenesulfonamide (0.92 g) was heated in a sealed ampule at the temperature of 150° C. for 15 minutes. The mixture was cooled to room temperature, chromatographed on a silica gel column by elution with a mixture of ethyl acetate-methanol (9.5:0.5) and trans-6-(4-acetylaminobenzenesulfonamido)-1,3-dioxepane-5-ol was obtained. M.p. 208°-210° C./ethyl acetate-methanol (6:1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[N:14]([CH3:15])[CH:13]=[CH:12][C:7]=2[C:8](Cl)=[N:9][CH:10]=1)=[O:4].[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].CS(O)(=O)=O>O1CCOCC1.CO>[CH3:1][O:2][C:3]([C:5]1[C:6]2[N:14]([CH3:15])[CH:13]=[CH:12][C:7]=2[C:8]([NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:17]([Cl:16])[CH:18]=2)=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc(Cl)c2ccn(C)c12
Reactant: Nc1cccc(Cl)c1
Agent: CS(=O)(=O)O
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1cnc(Nc2cccc(Cl)c2)c2ccn(C)c12

Procedure:
4-Chloro-1-methyl-1H-pyrrolo[3,2-c]pyridine-7-carboxylic acid methyl ester (1.04 g), 3-chloroaniline (0.97 ml) and methanesulfonic acid (0.60 ml) in 1,4-dioxan (10 ml) were irradiated at 180° C. for 30 minutes with microwaves. The solid mass obtained was dissolved in methanol and the solvent evaporated. The residue was dissolved in ethyl acetate and washed with water followed by saturated brine solution then dried (MgSO4)), filtered and evaporated to yield a brown oil (1.6 g). The brown oil was purified by column chromatography on a Biotage® 40M column eluting in 20% ethyl acetate/iso-hexane, to give the title compound as an off-white solid (0.62 g).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5](Cl)=[N:6][CH:7]=1.[C:11]1([CH2:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(O)=O.[Na+]>CCCCO.CCOC(C)=O>[CH2:17]([NH:18][C:5]1[N:4]([CH3:9])[C:3](=[O:10])[C:2]([Br:1])=[CH:7][N:6]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cn1c(Cl)ncc(Br)c1=O
Reactant: NCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: Cn1c(NCc2ccccc2)ncc(Br)c1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 98.7 %

Procedure:
A mixture of 5-bromo-2-chloro-3-methylpyrimidin-4(3H)-one (Example 143, Step B, 0.100 g, 0.448 mmol), phenylmethanamine (0.064 ml, 0.582 mmol) and NaHCO3 (0.150 g, 1.79 mmol) in n-BuOH (3 mL) was stirred at 60° C. for 4 hours. The reaction mixture was cooled to room temperature and then diluted with EtOAc. The EtOAc layer was washed with H2O and saturated aqueous NaCl. The aqueous phase was re-extracted with EtOAc (1×). The combined EtOAc layers were dried (Na2SO4), filtered and concentrated to yield the desired product (0.130 g, 99%) as a pale yellow solid that was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.96 (t, 1H), 7.90 (s, 1H), 7.32 (s, 2H), 7.31 (m, 2H), 7.23 (m, 1H), 4.57 (d, 2H), 3.39 (s, 3H). LRMS (ESI pos) m/e 294, 296 (M+, Br pattern).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(N(CC)CC)C.[CH2:18]([S:20](Cl)(=[O:22])=[O:21])[CH3:19]>C(Cl)Cl>[CH2:18]([S:20]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)(=[O:22])=[O:21])[CH3:19]
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)Nc1ccc2[nH]ccc2c1
Temperature: 23 °C
Yield: 99.1 %

Procedure:
To a solution of 5-amino-1H-indole (10.0 g, 76 mmol) and triethylamine (15.8 mL, 114 mmol) in 100 mL CH2Cl2 at 0° C. was added dropwise a solution of ethanesulfonyl chloride (7.9 mL, 83 mmol) in 25 mL of CH2Cl2. The solution was allowed to slowly warm to 23° C. over 20 h. The reaction mixture was concentrated in vacuo and the residue dissolved in 400 mL of ethyl acetate. The organic layer was washed with 100 mL of water, 50 mL of 0.1M HCl, 50 mL of saturated NaHCO3 solution, and 50 mL of saturated NaCl solution. The organic layer was dried over anhydrous K2CO3, filtered, and concentrated in vacuo to obtain 5-ethanesulfonylamino-1H-indole (16.9 g, >99%) which was used without further purification.
Reaction SMILES: Br[C:2](=[CH:5]OC(C)C)[CH:3]=[O:4].[NH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][N:12]=1.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[N:10]1[C:2]([CH:3]=[O:4])=[CH:5][N:12]2[CH2:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]=12
Reactant: CC(C)OC=C(Br)C=O
Reactant: NC1=NCc2ccccc21
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1cn2c(n1)-c1ccccc1C2
Temperature: 25 °C
Reaction time: 3.25 h
Yield: 21.9 %

Procedure:
The solution of 2-bromo-3-isopropoxy-propenal (4.97 g) in dry acetonitrile (3 mL) was added to the mixture of 3-amino-1H-isoindole (3.4 g) in dry acetonitrile (100 mL). The reaction mixture was stirred for 3.25 h at room temperature. Then triethylamine (3.6 mL) was added to the mixture and heated to reflux for 2 h. The mixture was cooled to room temperature, diluted with ethyl acetate, and washed with 20% potassium hydrogen carbonate. After filtration through a pad of Celite, the organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was applied to silica gel column chromatography, then eluted with ethyl acetate-hexane (3/1˜4/1). The crude compound was crystallized from ethyl acetate and n-hexane to give the title compound (1.04 g, 22%). 1H NMR (400 MHz, CDCl3) δ 5.01 (s, 2H), 7.28-7.52 (m, 3H), 7.90 (s, 1H), 7.91-7.93 (m, 1H), 9.92 (s, 1H).
Reaction SMILES: C(OC(=O)[CH:5]([C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)[C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.C(O)(=O)C.[Cl-].[Li+].C([O-])(O)=O.[Na+]>CN1CCCC1=O>[O:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[CH2:5][C:6]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:13]
Reactant: CCOC(=O)C(C(=O)c1ccccc1)c1ccco1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: O=C(Cc1ccco1)c1ccccc1

Procedure:
2-Furan-2-yl-3-oxo-3-phenyl-propionic acid ethyl ester, prepared as described by Dorsch J. B. and McElvain S. M., J Am. Chem. Soc 1932, 54, 2960-2963; (10.0 g, 39 mmol) was dissolved in N-methylpyrrolidin-2-one (13 mL) and acetic acid (3.9 mL) and lithium chloride (4.7 g, 110 mmol) was added. The reaction mixture was heated at reflux for 7 h, then saturated aqueous NaHCO3 was added and the mixture was extracted with diethyl ether. The organic extracts were dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash column chromatography using 1% ethyl acetate in hexane as eluent. Yield: 6.2 g, 85%.