Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=3[F:26])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][C:28]1([CH3:40])[O:32][C@H:31]([CH2:33][N:34]2[CH:38]=[CH:37][C:36]([NH2:39])=[N:35]2)[CH2:30][O:29]1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=3[F:26])[CH:13]=[N:12]2)[C:8]([NH:39][C:36]2[CH:37]=[CH:38][N:34]([CH2:33][C@@H:31]3[CH2:30][O:29][C:28]([CH3:40])([CH3:27])[O:32]3)[N:35]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: Cc1ccc(F)c(Oc2cnn(C(CC3CCCC3)C(=O)O)c(=O)c2)c1
Product: Cc1ccc(F)c(Oc2cnn(C(CC3CCCC3)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)c(=O)c2)c1

Procedure:
Using the method described in Example 49, 3-cyclopentyl-2-[4-(2-fluoro-5-methyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 78) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 3-cyclopentyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-2-[4-(2-fluoro-5-methyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionamide as a light tan foam as a mixture of diastereomers (1.45 g, 97%).
Reaction SMILES: [OH-].[Na+].C(O)(=O)C.[NH:7]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:9][CH2:8]1.CC(=O)C.C(=O)=O.[C:25](Cl)(=[O:29])[O:26][CH2:27][CH3:28]>O1CCCC1.O>[CH2:27]([O:26][C:25]([N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:9][CH2:8]1)=[O:29])[CH3:28]
Reactant: O=C(O)CCC1CCNCC1
Reactant: CCOC(=O)Cl
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)N1CCC(CCC(=O)O)CC1
Reaction time: 3 h
Yield: 93 %

Procedure:
To a stirred solution of 152 parts of sodium hydroxide in 1000 parts of water was added a solution of 249.5 parts of 4-piperidinepropanoic acid acetate (1:1) in 900 parts of water. 270 Parts of tetrahydrofuran were added. After cooling in a 2-propanone/CO2 -bath, a solution of 119.4 parts of ethyl carbonochloridate in 270 parts of tetrahydrofuran was added dropwise. Upon completion, stirring was continued for 3 hours at a temperature between 0°-5° C. The whole was washed twice with 420 parts of 1,1-oxybisethane. The aqueous phase was acidified with concentrate hydrochloric acid. The product was extracted three times with 520 parts of dichloromethane. The whole was evaporated. The oily residue was suspended five times in 210 parts of petroleumether and the latter was decanted each time. The residue was evaporated to dry, yielding 200 parts (93%) of 1-(ethoxycarbonyl)-4-piperidinepropanoic acid as an oily residue (int. 44).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[OH:11].C(=O)([O-])[O-].[Na+].[Na+].[N:18]([C:21]1[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=1[CH3:29])=[C:19]=[S:20]>C(O)C>[OH:11][C:3]1[C:4]([N+:8]([O-:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:19]([NH:18][C:21]1[C:22]([CH3:29])=[CH:23][C:24]([CH3:28])=[CH:25][C:26]=1[CH3:27])=[S:20]
Reactant: Nc1cccc([N+](=O)[O-])c1O
Reactant: Cc1cc(C)c(N=C=S)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C)c(NC(=S)Nc2cccc([N+](=O)[O-])c2O)c(C)c1
Temperature: 25 °C
Yield: 78.9 %

Procedure:
To a mixture containing 0.10 g (0.65 mmol) of 2-amino-6-nitrophenol and 0.14 g (1.3 mmol) of sodium carbonate in ethanol was added 0.14 g (0.78 mmol) of 2-isothiocyanato-1,3,5-trimethylbenzene. The reaction was heated at reflux overnight. The reaction was cooled to room temperature, filtered and concentrated under reduced pressure. Purification of the residue via Biotage chromatography eluting with 20% ethyl acetate/dichloromethane gave 0.17 g (80%) of product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([OH:13])=O)=[CH:9][S:8][C:7]=2[CH:14]=1.Cl.[CH3:16][NH:17][O:18][CH3:19].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:19][O:18][N:17]([CH3:16])[C:11]([C:10]1[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][C:7]=2[S:8][CH:9]=1)=[O:13]
Reactant: COc1ccc2c(C(=O)O)csc2c1
Reactant: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: COc1ccc2c(C(=O)N(C)OC)csc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
6-Methoxy-benzo[b]thiophene-3-carboxylic acid (See Titus, R. L.; Titus, C. F. J. Heterocycl. Chem., 1973, 10, 679-681, incorporated herein by references), (1.2 g, 5.77 mmol) was stirred in dry CH2Cl2 (50 mL) with N,O-dimethyl-hydroxylamine hydrochloride (620 mg, 6.35 mmol). HOBT (1.54 g, 8.08 mmol), EDC (1.54 g, 8.08 mmol), and DIEA (2.16 mL, 12.11 mmol) were added, and the reaction stirred 3 h at r.t. The reaction was diluted with CHCl3 (50 mL) and washed with H2O, 1 N HCI, H2O, saturated NaHCO3, and brine (25 mL each). Organics were dried (Na2SO4) and concentrated in vacuo. Purification by silica gel chromatography (30% to 50% EtOAc/hexanes) gave 952 mg (66%) of 6-methoxy-benzo[b]thiophene-3-carboxylic acid methoxy-methyl amide as a clear oil. 1H NMR (300 MHz, CDCI3) δ8.11 (d, 1H, J=9.0 Hz), 7.89 (s, 1H), 7.31 (d, 1H, J=2.4Hz), 7.06 (dd, 1H, J=9.0, 2.4Hz), 3.88 (s, 3H), 3.61 (s, 3H). 3.40 (s, 3H). Anal. (C12H13NO3S) C, H, N. Calculated C=57.39, H=5.21, N=5.57; found C=57.39, H=5.11, N=5.57.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[O:7][C:8]([NH:10][CH2:11][C:12]1([CH2:18][C:19]([OH:21])=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:9].C1(N=C=NC2CCCCC2)CCCCC1.[CH2:37](O)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C1C=CN=CC=1)C.ClCCl>[OH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[O:7][C:8]([NH:10][CH2:11][C:12]1([CH2:18][C:19]([O:21][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:9]
Reactant: O=C(O)CC1(CNC(=O)O[C@@H]2CCC[C@H]2O)CCCCC1
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(CC1(CNC(=O)O[C@@H]2CCC[C@H]2O)CCCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.4 %

Procedure:
To a stirred solution of compound (49) (0.5 g, 1.67 mmol), 1,3-dicyclohexylcarbodiimide (1.0 g, 5.0 mmol) and DMAP (19 mg, 0.16 mmol) in dichloromethane (100 mL) at room temperature under nitrogen atmosphere was added benzyl alcohol (1.1 mL, 10 mmol). The reaction mixture was stirred at room temperature for 15 h (monitored by tlc and LC/MS), then filtered, and the white solid was washed with dichloromethane (2×15 mL). The combined filtrates were washed with water (2×25 mL), dried over Na2SO4 and concentrated in vacuo. The crude product was purified using flash chromatography on silica gel using hexane/ethyl acetate (2:1) as eluant to provide 0.51 g (78%) of compound (50) as a colorless liquid. 1H NMR (400 MHz, CDCl3): δ1.36–1.75 (14H, m); 1.99–2.10 (2H, m); 2.35 (2H, s); 3.17 (2H, d, J=6.8 Hz); 4.05 (1H, m); 4.65 (1H, m); 5.12 (2H, s); 5.34 (1H, t, J=6.8 Hz); 7.36 (5H, m). MS (ESI): m/z=390.22 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=4)[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(Cc3ccc(C#N)cc3)CC2)cc1
Yield: 89.6 %

Procedure:
A solution of N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (180 mg, 0.510 mmol) and α-bromo-p-tolunitrile (104 mg, 0.530 mmol) in acetonitrile (5 mL) was treated with potassium carbonate and the resulting mixture was heated at reflux for 2 h. The mixture was poured into a mixture of ethyl acetate and water. The organic layer was concentrated in vacuo, the residue dissolved in 10% acetic acid/methanol, and the resulting solution loaded onto an ion exchange resin (SCX, Varian). Elution with methanol (4 column volumes) followed by 2 N ammonia in methanol (2 column volumes) and concentration of the appropriate fractions yielded 214 mg (90%) of the title compound.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:36])[C@@H:6]([NH2:35])[CH2:7][S:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:27]4[O:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[C:26]=4[CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.Cl>O1CCCC1.CO>[NH2:35][C@@H:6]([CH2:7][S:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:27]4[O:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[C:26]=4[CH:25]=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)[C:5]([OH:36])=[O:4]
Reactant: COC(=O)[C@@H](N)CSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: N[C@@H](CSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)C(=O)O
Reaction time: 1 h
Yield: 85.6 %

Procedure:
2N Sodium hydroxide (0.5 mL) was added to a stirred solution of the amino methyl ester, (2R)-Methyl-2-Amino-3-(4′-dibenzofuran-4-ylbipheny-4-ylmethylsulfanyl)-propionate (100 mg) in a mixture of tetrahydrofuran (5 mL) and methanol (1 mL). The solution was stirred for 1 hour and then acidified to pH 3 with 2N hydrochloric acid. The reaction mixture was extracted with ethyl acetate (3×10 mL). The combined extract was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 25% methanol in methylene chloride as eluent, afforded the title compound as a cream solid (83 mg, 86%); Rf: 0.10 (25% methanol in dichloromethane); 1H NMR (DMSO-d6, 300 MHz): δ 11.20 (3H, br s, NH, OH), 7.94 (1H, d, J=9 Hz, Ar—H), 7.91 (1H, d, J=8 Hz, Ar—H), 7.86 (2H, d, J=9 Hz, Ar—H), 7.67 (2H, d, J=9 Hz, Ar—H), 7.48-7.57 (4H, m, Ar—H), 7.21-7.39 (5H, m, Ar—H), 4.02 (1H, dd, J=8, 5 Hz, CHN), 3.74 (2H, s, PhCH2S), 2.94 (1H, dd, J=16, 5 Hz, CHHCHN), 2.86 (1H, dd, J=16, 8 Hz, CHHCHN); ESI-LCMS e/z calcd for C28H23NO3S 453.560, found 454 (M+H)+.
Reaction SMILES: C(N)C1C=CC=CC=1.[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1.[CH2:18]([NH:25][C:26]([C:28]1[S:32][C:31]([N:33]2[CH:37]=[C:36]([C:38](O)=[O:39])[N:35]=[N:34]2)=[N:30][C:29]=1[CH3:41])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:25][C:26]([C:28]1[S:32][C:31]([N:33]2[CH:37]=[C:36]([C:38](=[O:39])[NH:15][CH2:14][C:13]3[CH:16]=[CH:17][C:10]([F:9])=[CH:11][CH:12]=3)[N:35]=[N:34]2)=[N:30][C:29]=1[CH3:41])=[O:27])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1nc(-n2cc(C(=O)O)nn2)sc1C(=O)NCc1ccccc1
Reactant: NCc1ccc(F)cc1
Solvent: NCc1ccccc1
Product: Cc1nc(-n2cc(C(=O)NCc3ccc(F)cc3)nn2)sc1C(=O)NCc1ccccc1
Yield: 11 %

Procedure:
Following the procedure as described in Example 18, making variations as necessary to replace benzylamine with 4-fluorobenzylamine to react with 1-(5-(benzylcarbamoyl)-4-methylthiazol-2-yl)-1H-1,2,3-triazole-4-carboxylic acid, the title compound was obtained as a white solid in 11% yield: mp 198-201° C. (dichloromethane/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 9.34 (t, J=6.0 Hz, 1H), 9.23 (s, 1H), 9.02 (t, J=6.0 Hz, 1H), 7.40-7.12 (m, 9H), 4.47-4.45 (m, 4H), 2.63 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 169.4, 160.1, 158.4, 157.9, 154.3, 152.4, 152.4, 143.6, 138.9, 135.4, 129.4, 129.3, 128.3, 127.3, 126.9, 125.4, 123.6, 115.1, 114.8, 42.9, 41.4, 17.1; MS (ES+) m/z 451.4 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][S:26]([N:29]1[CH2:34][CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH2:31][CH2:30]1)(=[O:28])=[O:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH:31]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C2=CCN(S(C)(=O)=O)CC2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC([C@@]2(C)Cc3cc(Cl)ncc3O2)CC1
Product: CC(C)(C)OC(=O)N1CCC([C@@]2(C)Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O2)CC1

Procedure:
The title compound is prepared from (R)-4-(5-chloro-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine following a procedure analogous to that described for Intermediate 6. Mass spectrum (ESI+): m/z=478 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:6]([C:7](=O)[CH2:8][CH3:9])=[CH:5][S:4][CH:3]=1.CC(C)(C)C(C1SC=CC=1)=O>>[Br:1][C:2]1[C:6]([CH2:7][CH2:8][CH3:9])=[CH:5][S:4][CH:3]=1
Reactant: CCC(=O)c1cscc1Br
Agent: CC(C)(C)C(=O)c1cccs1
Product: CCCc1cscc1Br
Yield: 66 %

Procedure:
Following the procedure of Example 10a, substituting 3-bromo-4-(1-oxopropyl)thiophene, from step 52a above, for the 2,2-dimethyl-1-thiophenyl-1-propanone in step 10a, the title compound was prepared in 66% yield. NMR (CDCl3) δ:7.22 (d, J=3 Hz, 1H), 6.95 (d, J=3 Hz, 1H), 2.56 (t, 7.5 Hz, 2H), 1.65 (sextet, J=7.5 Hz, 2H), 0.98 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:24]1[CH:28]=[C:27]([C:29](O)=[O:30])[N:26]=[CH:25]1.CCN=C=NCCCN(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C.O.[Cl-].[Na+].O>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][N:13]([C:29]([C:27]3[N:26]=[CH:25][NH:24][CH:28]=3)=[O:30])[CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Reactant: O=C(O)c1c[nH]cn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C(=O)c2c[nH]cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.7 %

Procedure:
To a solution of COMPOUND 249 (93 mg, 0.30 mmol) in dry DMF (3 mL) was added imidazole-4-carboxylic acid (50 mg, 0.45 mmol) followed by EDCI (84 mg, 0.44 mmol), and DMAP (112 mg, 0.92 mmol). The mixture was stirred at room temperature overnight. The mixture was diluted with water (10 mL) and brine (10 mL) and extracted with CH2Cl2 (5×20 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (10:1:1 CH2Cl2-MeOH—NH4OH) provided 36 mg (30%) of COMPOUND 273 as a white solid. 1H NMR (CDCl3) δ 1.60-1.76 (m, 4H), 1.95-2.09 (m, 8H), 2.60-3.02 (m, 3H), 3.83 (br s, 3H), 4.73 (br s, 1H), 7.09 (dd, 2H, J=7.2, 4.8 Hz), 7.36-7.54 (m, 3H), 7.65 (br s, 1H), 8.34 (d, 2H, J=4.2 Hz); ES-MS m/z 405 (M+H).
Reaction SMILES: O1CCCC1.[CH3:6][S:7](Cl)(=[O:9])=[O:8].[F:11][C:12]([F:28])([F:27])[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:26])[CH2:21][C@@H:22]([OH:25])[CH2:23][CH3:24])=[CH:15][CH:14]=1.C(N(CC)CC)C>C(OCC)(=O)C.O>[F:11][C:12]([F:27])([F:28])[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:26])[CH2:21][C@@H:22]([O:25][S:7]([CH3:6])(=[O:9])=[O:8])[CH2:23][CH3:24])=[CH:15][CH:14]=1
Reactant: CC[C@H](O)CC(=O)Nc1ccc(C(F)(F)F)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: CC[C@@H](CC(=O)Nc1ccc(C(F)(F)F)cc1)OS(C)(=O)=O

Procedure:
A tetrahydrofuran solution (2 mL) containing 703 mg (6.14 mmol) of methanesulfonyl chloride was added dropwise to a tetrahydrofuran solution (8 mL) containing 1.07 g (4.09 mmol) of (S)-N-[4-(trifluoromethyl)phenyl]-3-hydroxypentanoic acid amide produced in Example 2 and 621 mg (6.14 mmol) of triethylamine at 0° C. for 10 minutes. After stirring at the same temperature for lhour, water (25 mL) and ethyl acetate (30 mL) were added to carry out extraction. The organic layer was washed with saturated brine, and dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain (S)-N-[4-(trifluoromethyl)phenyl]-3-methanesulfonyloxypentanoic acid amide as a yellow solid (1.48 g, crude yield: 97%). 1H-NMR (CDCl3, 400 MHz/ppm): δ 1.04 (3H, t), 1.91 (2H, m), 2.73-2.87 (2H, m), 3.15 (3H, s), 5.01-5.09 (1H, m), 7.56 (2H, d), 7.66 (2H, d), 7.83 (1H, br)
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:52]([CH3:54])[CH3:53])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:20]=[C:21]3[C:33]4[C:34]5[C:24](=[CH:25][C:26]([C:35]6[NH:39][C:38]([C@@H:40]7[CH2:44][CH2:43][CH2:42][N:41]7C(OC(C)(C)C)=O)=[N:37][CH:36]=6)=[CH:27][C:28]=5[CH2:29][CH2:30][C:31]=4[CH:32]=2)[CH2:23][CH2:22]3)=[CH:17][N:18]=1)=[O:8])=[O:4].Cl.[CH3:56][O:57][C:58]([NH:60][C@@H:61]([CH:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1)[C:62]([OH:64])=O)=[O:59].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:52]([CH3:54])[CH3:53])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:32]=[C:31]3[C:33]4[C:34]5[C:28](=[CH:27][C:26]([C:35]6[NH:39][C:38]([C@@H:40]7[CH2:44][CH2:43][CH2:42][N:41]7[C:62](=[O:64])[C@@H:61]([NH:60][C:58](=[O:59])[O:57][CH3:56])[CH:65]7[CH2:70][CH2:69][O:68][CH2:67][CH2:66]7)=[N:37][CH:36]=6)=[CH:25][C:24]=5[CH2:23][CH2:22][C:21]=4[CH:20]=2)[CH2:29][CH2:30]3)=[CH:17][N:18]=1)=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2cc3c4c(c2)CCc2cc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)cc(c2-4)CC3)[nH]1)C(C)C
Reactant: COC(=O)N[C@H](C(=O)O)C1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2cc3c4c(c2)CCc2cc(-c5cnc([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C6CCOCC6)[nH]5)cc(c2-4)CC3)[nH]1)C(C)C
Reaction time: 1 h
Yield: 26.9 %

Procedure:
To (S)-tert-butyl 2-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-4,5,9,10-tetrahydropyren-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (55 mg, 0.08 mmol) in DCM (3 mL) was added HCl (4M in dioxane, 0.25 mL). The solution stirred for 1 h, and the solvent was removed. The intermediate was dissolved in DMF (2 mL). (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (16 mg, 0.08 mmol), HATU (29 mg, 0.08 mmol), and DIPEA (0.06 mL, 0.37 mmol) were added sequentially. The solution was stirred o/n and the mixture was purified by HPLC to yield product (17.9 mg). LCMS-ESI+: calc'd for C46H56N8O7: 832.99 (M+); Found: 833.25 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:3]=1[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@:7]1([CH3:15])[C:11]([O:13]C)=[O:12])=[O:5]>[OH-].[K+]>[NH2:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:3]=1[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@:7]1([CH3:15])[C:11]([OH:13])=[O:12])=[O:5]
Reactant: COC(=O)[C@@]1(C)CCCN1C(=O)c1c(N)cccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Product: C[C@]1(C(=O)O)CCCN1C(=O)c1c(N)cccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
930 mg (3.02 mmol) methyl(R)-1-(2-amino-6-nitro-benzoyl)-2-methyl-pyrrolidine-2-carboxylate are dissolved in 3 mL 20% ethanolic KOH and stirred for 1.5 h at 50° C. Then the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier material used is silica gel and the eluant used is dichloromethane, to which 15% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution has been added.
Reaction SMILES: Cl[Sn](Cl)(Cl)Cl.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([SH:14])[CH:11]=[CH:12][CH:13]=1.[CH2:15]([O:17][C:18](=[O:30])[CH:19]([C:25](OCC)=[O:26])[C:20](OCC)=[O:21])[CH3:16]>CCOC(C)=O.C(Cl)Cl>[CH2:15]([O:17][C:18]([C:19]1[C:20](=[O:21])[S:14][C:10]2[C:11]([C:25]=1[OH:26])=[CH:12][CH:13]=[C:8]([O:7][CH3:6])[CH:9]=2)=[O:30])[CH3:16]
Reactant: COc1cccc(S)c1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(O)c2ccc(OC)cc2sc1=O
Temperature: 210 °C
Yield: 5.5 %

Procedure:
SnCl4 was added to a neat mixture of 3-methoxy-benzenethiol (0.91 g, 6.5 mmol) and 2-ethoxycarbonyl-malonic acid diethyl ester (2.27 g, 9.77 mmol) in a 20-mL open vial. The reaction mixture was heated in a 210° C. oil bath for 2.5 h. After cooling, the reaction mixture was subjected to silica gel chromatography (3%-50% EtOAc/CH2Cl2) to provide 4-hydroxy-7-methoxy-2-oxo-2H-thiochromene-3-carboxylic acid ethyl ester (100 mg). MS ESI(+) m/e: 281.10 (M+1).
Reaction SMILES: [Cl: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]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4](Cl)[N:3]=1.CCN(C(C)C)C(C)C.[C:33]1([CH:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:40][NH2:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[Cl: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]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4]([NH:41][CH2:40][CH:39]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:3]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: NCC(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
N-[(1S,2R,3S,4R)-4-(2,6-dichloro-purin-9-yl)-2,3-dihydroxy-cyclopentyl]-propionamide (160 mg, 0.44 mmol) is dissolved in THF (5 mL) under an atmosphere of argon. DIPEA (69 mg, 0.53 mmol) is added followed by 2,2-diphenylethylamine (96 mg, 0.49 mmol) and the reaction mixture is stirred at 50° C. The reaction is shown to be complete by LCMS after 2 hours. The solvent is removed in vacuo and the title compound is obtained after purification by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water-0.1% TFA).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]=[O:11])=[C:7]([CH3:12])[C:6]=2[CH:13]=1.[CH:14]1([Mg]Br)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[OH:11])=[C:7]([CH3:12])[C:6]=2[CH:13]=1
Reactant: Br[Mg]C1CCCCC1
Reactant: Cc1c(C=O)oc2ccc(Cl)cc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1c(C(O)C2CCCCC2)oc2ccc(Cl)cc12
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution (10 mL) of 5-chloro-3-methyl-1-benzofuran-2-carbaldehyde (600 mg) synthesized above in tetrahydrofuran was added a 1.0M solution (4.62 mL) of cyclohexylmagnesium bromide in tetrahydrofuran at 0° C., and the mixture was stirred for 1 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15% ethyl acetate/hexane) to give the title object compound (518 mg, 60%) as a pale-yellow oil.