Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6](=[O:7])[O:5][C:4]2[CH:8]=[CH:9][C:10]3[C:15]([C:3]1=2)=[CH:14][C:13]([CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)=[C:12]([C:22](Cl)=[O:23])[CH:11]=3.Cl.[CH3:27][NH:28][CH3:29].ClCCl.C(N(CC)CC)C>O>[CH3:1][C:2]1([CH3:25])[C:6](=[O:7])[O:5][C:4]2[CH:8]=[CH:9][C:10]3[C:15]([C:3]1=2)=[CH:14][C:13]([CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)=[C:12]([C:22]([N:28]([CH3:29])[CH3:27])=[O:23])[CH:11]=3
Reactant: CC1(C)C(=O)Oc2ccc3cc(C(=O)Cl)c(Cn4cncn4)cc3c21
Reactant: CNC
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)c1cc2ccc3c(c2cc1Cn1cncn1)C(C)(C)C(=O)O3
Reaction time: 0.5 h

Procedure:
A mixture of 1,2-dihydro-1,1-dimethyl-2-oxo-8-(1H-1,2,4-triazol-1-ylmethyl)naphtho[2,1-b]furan-7-carbonyl chloride, dimethylamine hydrochloride (0.25 g) and dichloromethane (2 ml) was stirred at 0° and treated with triethylamine (1 ml), and stirring was continued for 0.5 h. The mixture was treated with water (10 ml) and extracted twice with chloroform, and the combined extracts were dried and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography, using methanol:dichloromethane, 1:50 v/v, as eluant, to give 1,2-dihydro-1,1,N,N-tetramethyl-2-oxo-8-(1H-1,2,4-triazol-1-ylmethyl)naphtho[2,1-b]furan-7-carboxamide, m.p. 172°-173°.
Reaction SMILES: C(O[C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:9]=2[CH:10]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.CS([Cl:32])(=O)=O>O1CCCC1.C(Cl)Cl.N1C=CC=CC=1>[Cl:32][CH2:4][C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:9]=2[CH:10]=1
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2o1
Reactant: CS(=O)(=O)Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: ClCc1cc2cc(Cl)ccc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.2 %

Procedure:
To a suspension of ethyl-5-chloro-benzofuran carboxylate (1.05 g), prepared according to Helv. Chim. Acta., 818 (1935), in tetrahydrofuran (10 ml) was added lithium aluminum hydride (0.1 g). The mixture was stirred at room temperature for 1 hour. Ethyl acetate (50 ml) was slowly added to the reaction mixture, and the whole mixture was poured onto water (50 ml). The organic extract was separated, washed with water (2×25 ml), dried and evaporated to obtain 2-hydroxymethyl-5-cnlorobenzofuran as an oil [0.87 g; 'HNMR (CDCl3, 60 MHz): 4.6 (s, 2H), 6.6-7.4 (m, 4H)]. This material was added to a solution of methanesulfonyl chloride (1.15 g) in methylene chloride (20 ml) containing pyridine (1 ml). After stirring the reaction overnight it was poured onto ice-water (20 ml) and the organic extract was first washed with 10% HCl (5 ml) and then with water (2×10 ml). The washed extract was dried and evaporated to obtain 2-chloromethyl-5-chlorobenzofuran as a clear oil (yield: 0.5 g); HNMR (CDCl3, 60 MHz): 4.65 (s, 2H), 6.6 (s, 1H), 6.8-7.4 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[C:15](B4OC(C)(C)C(C)(C)O4)[CH:16]=[C:11]3[C:10]([CH3:26])=[N:9]2)=[CH:5][CH:4]=1.Br[C:30]1[CH:35]=[N:34][CH:33]=[C:32]([Cl:36])[N:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:36][C:32]1[N:31]=[C:30]([C:15]2[CH:16]=[C:11]3[C:10]([CH3:26])=[N:9][N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:28][CH:27]=4)[C:12]3=[N:13][CH:14]=2)[CH:35]=[N:34][CH:33]=1
Reactant: Clc1cncc(Br)n1
Reactant: COc1ccc(Cn2nc(C)c3cc(B4OC(C)(C)C(C)(C)O4)cnc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: COc1ccc(Cn2nc(C)c3cc(-c4cncc(Cl)n4)cnc32)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of (1-(4-methoxybenzyl)-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine) 8 (105 mg, 0.276 mmol) and 2-bromo-6-chloropyrazine 40 (50 mg, 0.268 mmol, 1 equivalent) in DME (3 mL), ethanol (0.5 mL) and water (0.1 mL) was added sodium carbonate (2.0 M, 0.561 mmol, 2 equivalent) and degassed for min followed by charging Pd(PPh3)4 (9.5 mg, 0.0082 mmol, 0.03 equivalent). The resulting reaction mixture was purged with N2 and degassing was submitted for heating at 80° C. overnight under pressure in a sealed tube. After completion of the reaction the reaction was diluted with ethyl acetate and water. The organic layer was separated and aqueous phase was extracted with ethyl acetate. The combined organic layer was washed with brine and dried over sodium sulphate and evaporated. The crude product was flash chromatographed with 100-200 mesh silica gel eluting the pure compound at 40% ethyl acetate in hexane as off white coloured solid of compound 41 in 25 mg. The product 41 was confirmed by LCMS. MS: 365.9, (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:10](=[O:11])[N:9]([CH2:12][O:13][CH3:14])[CH:8]=[C:7]([S:15][CH2:16][CH2:17][C:18](OC)=O)[CH:6]=1.CC(C)([O-])C.[K+].Cl[CH2:29][C:30]1[CH:35]=[CH:34]C(CC)=[CH:32][CH:31]=1>C1COCC1>[CH2:35]([C:30]1[CH:29]=[CH:18][C:17]([CH2:16][S:15][C:7]2[CH:6]=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:10](=[O:11])[N:9]([CH2:12][O:13][CH3:14])[CH:8]=2)=[CH:32][CH:31]=1)[CH3:34]
Reactant: COCOc1cc(SCCC(=O)OC)cn(COC)c1=O
Reactant: CCc1ccc(CCl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCc1ccc(CSc2cc(OCOC)c(=O)n(COC)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.6 %

Procedure:
To a solution of methyl 3-{[5-(methoxymethoxy)-1-(methoxymethyl)-6-oxo-1,6-dihydropyridin-3-yl]sulfanyl}propanoate (Intermediate 16) (290 mg, 0.91 mmol) in THF (5 ml) at −45° C. was added potassium tert-butoxide (113 mg, 1.01 mmol) and the resulting mixture allowed to stir for 20 minutes. 1-(Chloromethyl)-4-ethylbenzene (170 mg, 1.10 mmol) was then added and the reaction mixture allowed to warm to room temperature and stirred for 4 hours before being quenched with water and extracted into dichlormethane. The combined organics were concentrated and subjected to column chromatography (SiO2; 0-10% methanol in dichloromethane) to yield 5-[(4-ethylbenzyl)sulfanyl]-3-(methoxymethoxy)-1-(methoxymethyl)pyridin-2(1H)-one (253 mg, 79%).
Reaction SMILES: [C:1]1([C:7]([NH:15][C:16](=O)[CH:17]([O:20][CH3:21])[CH2:18][CH3:19])=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.O=C(Cl)OC(Cl)(Cl)[Cl:34]>C(Cl)Cl>[C:1]1([C:7]([N:15]=[C:16]([Cl:34])[CH:17]([O:20][CH3:21])[CH2:18][CH3:19])=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(OC)C(=O)NC(=Cc1ccccc1)c1ccccc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(OC)C(Cl)=NC(=Cc1ccccc1)c1ccccc1
Yield: 153.9 %

Procedure:
A solution of 21 g of the product of Step B, 300 ml of methylene chloride and 49.5 ml of triethylamine was cooled to -40° C. and at -40° C. a solution of 9.42 g of diphosgene in 90 ml of methylene chloride was added. The residue, after returning the temperature to 20° C. and concentrating the mixture under reduced pressure, was taken up in ether and filtered. The filtrate was concentrated under reduced pressure to obtain 23 g of the expected product.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:10])[CH3:9])[CH2:4][CH2:3]1.[Br:11][C:12]1[CH:13]=[C:14](O)[CH:15]=[N:16][CH:17]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:11][C:12]1[CH:13]=[C:14]([O:1][CH:2]2[CH2:7][CH2:6][N:5]([C:8](=[O:10])[CH3:9])[CH2:4][CH2:3]2)[CH:15]=[N:16][CH:17]=1
Reactant: Oc1cncc(Br)c1
Reactant: CC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)N1CCC(Oc2cncc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(4-Hydroxy-piperidin-1-yl)-ethanone (200 mg 1.40 mmol) and 5-bromo-pyridin-3-ol (248 mg; 1.425 mmol) are added dropwise to a solution of PPh3 (606 mg) in THF (30 ml). DIAD (462 mg) is added to the solution. The mixture is stirred at room temperature overnight. The mixture is washed with water, diluted with DCM and dried over Na2SO4, filtered and concentrated to give 1-[4-(5-bromo-pyridin-3-yloxy)-piperidin-1-yl]-ethanone.
Reaction SMILES: [CH:1]1([N:4]([CH2:28][C:29]2[CH:34]=[C:33]([NH:35][CH2:36][CH2:37][O:38][CH3:39])[CH:32]=[C:31]([Cl:40])[C:30]=2[Cl:41])[C:5]([C@H:7]2[C@H:12]([C:13]3[CH:18]=[CH:17][N:16]([CH3:19])[C:15](=[O:20])[CH:14]=3)[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.Cl>C(Cl)Cl>[CH:1]1([N:4]([CH2:28][C:29]2[CH:34]=[C:33]([NH:35][CH2:36][CH2:37][O:38][CH3:39])[CH:32]=[C:31]([Cl:40])[C:30]=2[Cl:41])[C:5]([C@H:7]2[C@H:12]([C:13]3[CH:18]=[CH:17][N:16]([CH3:19])[C:15](=[O:20])[CH:14]=3)[CH2:11][CH2:10][NH:9][CH2:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: COCCNc1cc(Cl)c(Cl)c(CN(C(=O)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@H]2c2ccn(C)c(=O)c2)C2CC2)c1
Agent: Cl
Solvent: ClCCl
Product: COCCNc1cc(Cl)c(Cl)c(CN(C(=O)[C@@H]2CNCC[C@H]2c2ccn(C)c(=O)c2)C2CC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a CH2Cl2 solution (0.09 M) of trans-1,1-dimethylethyl 3-({cyclopropyl[(2,3-dichloro-5-{[2-(methoxy)ethyl]amino}phenyl)methyl]amino}carbonyl)-4-(1-methyl-2-oxo-1,2-dihydro-4-pyridinyl)-1-piperidinecarboxylate (1 eq.) from the previous step was added HCl (4.0 M dioxane solution, 30 eq.). The resulting solution was stirred at RT for 4 h. Following the removal of the volatiles in vacuo, the resulting residue was directly loaded onto a SiO2 column packed with 95:5 (v/v) CH2Cl2:2.0 M NH3 in MeOH. Elution with the same solvent system furnished the desired compound but still contaminated with impurities. Further purification using preparatory HPLC-MS (C-18 reverse phase column, 15 mL/min, 95:5 (v/v) H2O:CH3CN→5:95 (v/v) H2O:CH3CN) afforded the title compound as a white solid. MS (ESI+, M+H): 508.
Reaction SMILES: O1C=CC(=O)C=C1.[S].[O:9]=[C:10]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)CC#N.N1CCOCC1>C(O)C>[C:17]1([CH3:20])[CH:18]=[CH:19][C:14]([CH:10]=[O:9])=[CH:15][CH:16]=1
Reactant: Cc1ccc(C(=O)CC#N)cc1
Agent: O=c1ccocc1
Agent: [S]
Solvent: CCO
Solvent: C1COCCN1
Product: Cc1ccc(C=O)cc1
Temperature: 40 °C
Yield: 76.9 %

Procedure:
4-Pyranone (2.31 mL, 24.97 mmol) and sulphur (801 mg, 24.97 mmol) were added to a solution of 3-oxo-3-p-tolyl-propionitrile (3.79 g, 23.8 mmol) in ethanol (40 mL) followed by morpholine (2.18 mL, 24.97 mmol) and the reaction heated at 40° C. for 16 hours, The reaction mixture was concentrated in vacuo and the residue purified by flash chromatography on silica eluting with 0-20% ethylacetate/heptanes to afford 12-Amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-yl)-p-tolyl-methanone as a yellow solid (2.2 g, 36% yield). LCMS (2 min acidic) 1.07 min ES+/AP+ 274 (MH+). 1HNMR (400 MHz, CDCl3) δ ppm 2.00-2.03 (m, 2H), 2.42 (s, 3H), 3.80-3.84 (m, 2H), 4.80 (s, 2H), 6.60 (br s, 2H), 7.20 (d, 2H), 7.41 (d, 2H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29]([CH:31]3[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]3)=[O:30])[CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:37]1[CH2:39][C@@H:38]1[CH2:40][O:41][C:42]1[CH:51]=[CH:50][CH:49]=[C:48]2[C:43]=1[CH:44]=[CH:45][CH:46]=[N:47]2>C(O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29]([CH:31]3[CH2:36][CH2:35][CH2:34][N:33]([CH2:39][C@@H:38]([OH:37])[CH2:40][O:41][C:42]4[CH:51]=[CH:50][CH:49]=[C:48]5[C:43]=4[CH:44]=[CH:45][CH:46]=[N:47]5)[CH2:32]3)=[O:30])[CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCN(C(=O)C2CCCNC2)C1
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Solvent: CCO
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCN(C(=O)C2CCCN(C[C@@H](O)COc3cccc4ncccc34)C2)C1
Temperature: 25 °C
Yield: 67 %

Procedure:
1-(Piperidine-3-carbonyl)-piperidine-3-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (79) (243.4 mg; 0.497 mmol) is dissolved in ethanol (12 mL) at ambient temperature. (R)-5-Oxiranylmethoxy-quinoline (2) (100.0 mg; 0.497 mmol) is added, then the mixture is refluxed for 17 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (50%→100% acetone in hexanes, then 5%→20% ethanol in acetone) affording the desired product (230 mg) as a white solid. ESMS: MH+ 691.6
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([OH:10])[CH:7]([CH2:11][NH2:12])[CH2:6]1)=[O:4].C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl:49][C:50]1[S:54][C:53]([C:55](O)=[O:56])=[CH:52][CH:51]=1>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([OH:10])[CH:7]([CH2:11][NH:12][C:55]([C:53]2[S:54][C:50]([Cl:49])=[CH:51][CH:52]=2)=[O:56])[CH2:6]1)=[O:4]
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: COC(=O)C1CC(O)C(CN)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1CC(O)C(CNC(=O)c2ccc(Cl)s2)C1
Yield: 32 %

Procedure:
To a stirred suspension of the crude (1SR,3SR,4RS)-3-aminomethyl-4-hydroxy-cyclopentanecarboxylic acid methyl ester (189 mg) at r.t. in DMF (5 ml) under an argon atmosphere were added N-ethyldiisopropylamine (0.74 ml), BOP (531 mg) and 5-chloro-2-thiophenecarboxylic acid (195 mg). The reaction mixture was stirred over night, then diluted with EtOAc and washed with H2O. The aqueous phase was back extracted with EtOAc. The combined organics were washed with H2O and brine, dried (MgSO4), filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2/MeOH 93:7) to give (1SR,3SR,4RS)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-4-hydroxy-cyclopentanecarboxylic acid methyl ester (111 mg) as light brown gum. MS: 318.0 ([M+H]+).
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[N:3]=1.Cl.[CH3:12][NH:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Cl>C(O)C>[CH3:12][NH:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][S:1][C:2]1[NH:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[N:3]=1
Reactant: Sc1nc2c([nH]1)CCCC2
Reactant: CNc1ccccc1CCl
Agent: Cl
Solvent: CCO
Product: CNc1ccccc1CSc1nc2c([nH]1)CCCC2
Yield: 53.3 %

Procedure:
To a suspension of 1.3 g (9 mmol) of 2-mercapto-4,5,6,7-tetrahydro-1H-benzimidazole in 20 ml of ethanol was added 1.35 g (7 mmol) of 2-methylaminobenzyl chloride hydrochloride for a period of 15 min. The solvent was distilled off, and the residue was shaken sufficiently with a combination of 1N aqueous sodium hydroxide and chloroform for performing extraction. The organic portion was taken out and then dried over anhydrous sodium sulfate. Chloroform was distilled off, and the residue was crystallized from ether/hexane to give 1.02 g of the desired compound as a pale brown crystalline product, yield 53%.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.[CH:19]1([NH2:23])[CH2:22][CH2:21][CH2:20]1.[OH-].[Na+]>CO>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4]([NH:23][CH:19]2[CH2:22][CH2:21][CH2:20]2)[N:3]=1
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Reactant: NC1CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1nc(NC2CCC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Temperature: 25 °C

Procedure:
A solution of (±)-cis-4-(2-Amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol from Example 4 (0.53 g 2 mmol) and cyclobutylamine (1.387 g, 19.5 mmol) in methanol (15 mL) was heated at 70°-75° C. (oil bath) for 29 hours. After cooling to room temperature, 2 mL of 1.0N NaOH was added. The solution was concentrated and the residue chromatographed on silica gel. Title compound was eluted with 5% methanol-chloroform as colourless foam which solidified to white powder in acetonitrile (454 mg, 75.7%), m.p. 181°-183° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH2:6].C([Li])CCC.CCCCCC.Cl[Si](C)(C)C.[CH3:23][C:24](=[O:26])[CH3:25]>O1CCCC1>[NH2:6][C:2]1[S:1][C:5]([C:24]([OH:26])([CH3:25])[CH3:23])=[CH:4][N:3]=1
Reactant: CC(C)=O
Reactant: Nc1nccs1
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(O)c1cnc(N)s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a −78° C. solution of thiazol-2-amine (7.0 g, 69.9 mmol) in tetrahydrofuran (200 mL) was added a 10.0 M solution of butyllithium in hexane (14 mL, 140 mmol). The mixture was stirred at −78° C. for 1 hour and chlorotrimethylsilane (15.2 g, 140 mmol) was added dropwise. The mixture was allowed to warm up to −40° C., cooled to −78° C. and a 10.0 M solution of butyllithium in hexane (7.0, 70 mmol) was added. After 10 minutes, propan-2-one (8.12 g, 140 mmol) was added and the mixture was stirred for 12 hours. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with ether. The organic extract was dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-100% ethyl acetate in hexanes) to afford the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 1.61 (s, 6H) 5.04-5.19 (brs, 2H) 6.89 (s, 1H); MS (ESI) m/z 159 (M+H)+.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C@H:9]1[CH2:15][CH2:14][C:11]2([CH2:13][CH2:12]2)[O:10]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CO>[OH:7][CH2:8][C@H:9]1[CH2:15][CH2:14][C:11]2([CH2:13][CH2:12]2)[O:10]1
Reactant: C1CCC(OC[C@H]2CCC3(CC3)O2)OC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: OC[C@H]1CCC2(CC2)O1
Temperature: 40 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
To a mixture of (5R)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)-4-oxaspiro[2.4]heptane (101 mg, 0.48 mmol) in 5 mL of MeOH was added PPTS (12.1 mg, 0.048 mol, Aldrich) at room temperature. The reaction mixture was stirred at 40° C. overnight and then concentrated in vacuo. The residue was purified by a silica gel column chromatography (CH2Cl2) to give the title compound as colorless oil (55 mg, 89%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:25])[NH:21][CH2:22][CH2:23][CH3:24])=[CH:16][CH:15]=1)=[O:12])[CH2:5]2.N1C=CC=CC=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>CN(C)C=O>[CH3:32][S:33]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:25])[NH:21][CH2:22][CH2:23][CH3:24])=[CH:16][CH:15]=1)=[O:12])[CH2:5]2)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(NS(C)(=O)=O)cc3C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide (0.035 g, 0.103 mmol), pyridine (0.017 mL, 0.207 mmol) and catalytic N,N-dimethylaminopyridine in dimethylformamide (0.7 mL) was cooled to 0° C. Methanesulfonyl chloride (0.014 g, 0.126 mmol) was added and the reaction solution was allowed to stir at room temperature for 2 hours. The reaction mixture was concentrated and purified by reverse-phase HPLC to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.74 (s, 1H), 8.54 (s, 1H), 8.26 (t, J=5.6 Hz, 1H), 7.74-7.78 (m, 2H), 7.63-7.66 (m, 2H), 7.32 (d, J=8.1 Hz, 1H), 7.14-7.20 (m, 2H), 4.73-4.76 (m, 4H), 3.15-3.25 (m, 2H), 2.98 (s, 3H), 1.45-1.62 (m, 2H), 0.89 (t, J=7.4 Hz, 3H); MS (ESI(+)) m/e 417 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=1[Cl:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:15])[S:10][C:11]=1[Cl:12]
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1ncc(Br)c1-c1cc(C(=O)O)sc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(Br)c1-c1cc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxylic acid (204 mg, 0.60 mmol), 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (215 mg, 0.64 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (5.03 g, 17.7 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (380 mg, 0.81 mmol) in chloroform (6 mL). DIEA (570 μL, 3.26 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (247 mg, 45%): LC-MS (ES) m/z=603 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][C:8]1[CH:9]=[C:10]([CH:30]=O)[CH:11]=[C:12]2[C:16]=1[C:15](=[O:17])[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1)[CH2:13]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:7][C:8]1[CH:9]=[C:10]([CH2:30][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH:11]=[C:12]2[C:16]=1[C:15](=[O:17])[N:14]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][C:26]([F:29])([F:27])[F:28])=[CH:23][CH:24]=1)[CH2:13]2
Reactant: Cc1cc(C=O)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(CN2CCOCC2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Yield: 37.2 %

Procedure:
Morpholine (8.2 mg, 0.094 mmol) was dissolved in dichloromethane (2.0 mL) and 7-Methyl-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-carbaldehyde (30.0 mg, 0.085 mmol) was added. The mixture was stirred for ten minutes and sodium triacetoxy borohydride (29.7 mg, 0.14 mmol) was added and the reaction was allowed to stir overnight. The reaction was then diluted with dichloromethane, washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated. Column chromatography (20% MeOH/EtOAc) provided the title compound as a colourless oil (13.3 mg, 37%). 1H NMR (300 MHz, CDCl3): δ 7.35 (d, 2H), 7.19 (d, 4H), 4.78 (s, 2H), 4.23 (s, 2H), 3.72 (t, 4H), 3.53 (s, 2H), 2.76 (s, 3H), 2.45 (t, 4H).