Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]([NH:37][C:38](=[O:48])[O:39][C@@H:40]1[C@H:47]2[C@H:43]([O:44][CH2:45][CH2:46]2)[O:42][CH2:41]1)[C@H:9]([OH:36])[CH2:10][N:11]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28]CC2C=CC=CC=2)=[CH:24][CH:23]=1)(=[O:21])=[O:20])[O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[CH2:1]([C@H:8]([NH:37][C:38](=[O:48])[O:39][C@@H:40]1[C@H:47]2[C@H:43]([O:44][CH2:45][CH2:46]2)[O:42][CH2:41]1)[C@H:9]([OH:36])[CH2:10][N:11]([O:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)[S:19]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CN(OC1CCCCC1)S(=O)(=O)c1ccc(OCc2ccccc2)cc1)O[C@H]1CO[C@H]2OCC[C@H]21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CN(OC1CCCCC1)S(=O)(=O)c1ccc(O)cc1)O[C@H]1CO[C@H]2OCC[C@H]21
Reaction time: 16 h
Yield: 87.1 %

Procedure:
A solution of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[{[4-(benzyloxy)phenyl]sulfonyl}(cyclohexyloxy)amino]-2-hydroxypropylcarbamate (140 mg, 0.206 mmol) in ethyl acetate (5 mL) was combined with Palladium on carbon (10 wt %, 28 mg) and reduced under an atmosphere of Hydrogen gas. After stirring for 16 hours, the reaction mixture was filtered and evaporated in vacuo to a residue. The residue was purified on a preparative TLC plate (20×20 cm, 500 μM) eluting with 3:2 ethyl acetate:hexane. The product band was removed, eluted with 4:1 methylene chloride:methanol, filtered, and evaporated in vacuo. The residue was triturated with water, filtered and dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-{(cyclohexyloxy)[(4-hydroxyphenyl)sulfonyl]amino}-2-hydroxypropylcarbamate (106 mg, 87%) as a white solid. H1-NMR (chloroform-D3): 1.27 (m, 6H), 1.67 (m, 5H), 2.05 (m, 2H), 2.93 (m, 4H), 3.11 (b, 1H), 3.68 (m, 2H), 3.90 (m, 4H), 4.19 (m, 1H), 4.81 (d, 1H), 4.99 (m, 1H), 5.65 (d, 1H), 6.24 (b, 1H), 6.92 (d, 2H), 7.22 (m, 5H), 7.67 (d, 2H). MS(ESI): 613(M+Na).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O.[CH:18]1([NH:21][C:22](=[O:50])[C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:25][C:24]=2[OH:49])[CH2:20][CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH:18]1([NH:21][C:22](=[O:50])[C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)=[CH:25][C:24]=2[O:49][CH2:4][C@@H:2]2[CH2:3][O:1]2)[CH2:19][CH2:20]1
Reactant: O=C(NC1CC1)c1ccc(OC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1O
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(OC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
A mixture of (2S)-oxiran-2-ylmethyl-3-nitrobenzenesulfonate (119 mg, 0.459 mmol), N-cyclopropyl-2-hydroxy-4-(trityloxy)benzamide (200 mg, 0.459 mmol) and cesium carbonate, Cs2CO3, (186.2 mg, 0.573 mmol) in dimethylformamide (3 mL) was kept on stirring at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulphate, Na2SO4, filtered, concentrated and the residue was purified by silica gel flash chromatography (0-40% ethyl acetate in petroleum ether) to give the subtitled compound (160 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:11][C:10]=2[C:21]2[CH:30]=[CH:29][C:24]([C:25]([NH:27][NH2:28])=[O:26])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.[CH:31](O)=[O:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:11][C:10]=2[C:21]2[CH:22]=[CH:23][C:24]([C:25]([NH:27][NH:28][CH:31]=[O:32])=[O:26])=[CH:29][CH:30]=2)=[CH:4][CH:3]=1
Reactant: Cn1c(-c2ccccn2)nc(-c2ccc(C(=O)NN)cc2)c1Sc1ccc(Cl)cc1
Reactant: O=CO
Product: Cn1c(-c2ccccn2)nc(-c2ccc(C(=O)NNC=O)cc2)c1Sc1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
4-{5-[(4-Chlorophenyl)thio]-1-methyl-2-pyridin-2-yl-1H-imidazol-4-yl}benzohydrazide (Step 1 of Example 48, 400 mg) was dissolved in 3 mL of formic acid. After stirring overnight, the volatiles were removed under reduced pressure to afford the title compound. 1H NMR (500 MHz, (CDCl3): 8.84 (broad d, 1H), 8.41 (d, 1H), 8.19 (d, 2H), 7.85 (t, 1H), 7.48 (broad d, 2H), 7.38 (t, 1H), 7.23 (d, 2H), 7.04 (d, 2H), 4.14 (s, 3H). LCMS: m/z 464, (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:25][C:22]2[CH:23]=[CH:24][C:19]([C:11]([CH3:13])([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:12])=[CH:20][CH:21]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)CC(C)(C)c1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 40 °C
Reaction time: 28 h
Yield: 95.3 %

Procedure:
Following procedure A, 2-Chloro-5-nitropyridine (303 mg, 1.91 mmol, 1.00 eq) and 4-tert-octylphenol (495 mg, 2.40 mmol, 1.25 eq) were dissolved in DMSO (5 mL). Anhydrous K2CO3 (426 mg, 3.08 mmol, 1.61 eq) was added and the reaction mixture was stirred at 40° C. for 28 h. After extraction with Et2O, the crude product was purified by flash column chromatography (SiO2; EtOAc/petrolether 1:50) to afford the title compound as colourless solid (598 mg, 1.82 mmol, 95% yield). Rf=0.65 (EtOAc/PE 1:10). HRMS (ESI) calcd. for C19H25N2O3+ [M+H]+ 329.1860. found: 329.1854. 1H NMR (400 MHz, CDCl3) δ 9.07 (d, J=2.8 Hz, 1H, aromatic H), 8.45 (dd, J=9.1, 2.8 Hz, 1H, aromatic H), 7.52-7.40 (m, 2H, aromatic H), 7.14-7.03 (m, 2H, aromatic H), 6.97 (d, J=9.1 Hz, 1H, aromatic H), 1.76 (s, 2H, Ar—C(CH3)2CH2C(CH3)3), 1.40 (s, 6H, Ar—C(CH3)2CH2C(CH3)3), 0.75 (s, 9H, Ar—C(CH3)2CH2C(CH3)3). 13C NMR (101 MHz, CDCl3) δ 167.24, 150.49, 148.12, 145.30, 140.29, 134.92, 127.78, 120.57, 111.15, 57.28, 38.63, 32.55, 31.93, 31.62.
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[Se:10][C:9]=1[C:17]([O:19]CC)=O)[CH3:5].O>C1COCC1>[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[Se:10][C:9]=1[C:17]([NH2:2])=[O:19])[CH3:5]
Reactant: [NH4+]
Reactant: CCOC(=O)c1[se]c(C(C)(C)C)cc1N=NN(C)C
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)N=Nc1cc(C(C)(C)C)[se]c1C(N)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To an ice cold (0-5° C.) solution of ammonium hydroxide (200 mL) was added a solution of ethyl 3-[(dimethylamino)diazenyl]-5-(tert-butyl)selenophene-2-carboxylate (1.2 g) in THF (30 mL) for 5 min and a catalytic amount of PEG-400 was added and stirred at rt for 48 h. The solution was poured into ice cooled water and extracted with chloroform (3×100 mL). The combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (94:6) as eluents to give the product as a pale brown color solid, which was recrystallized from chloroform-hexane (300 mg, 28%), mp 218-220° C. IR (Neat) νmax 3337, 3156, 2958, 1631, 1602, 1326, 1250, 1219, 1177, 1113, 1006 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.20 (1H, s, —CONH2), 7.41 (1H, s, H-4), 6.01 (1H, br s, —CONH2), 3.56 (3H, s, —NCH3), 3.16 (3H, s, —NCH3), 1.37 (9H, s, t-butyl); 13C NMR (100 MHz, DMSO-d6): δ 168.0, 166.1, 151.1, 129.0, 116.9, 36.8, 32.4; LC-MS (positive ion mode): m/z 323, 325 (M+Na)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:47])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([C:29]3[CH:33]=[C:32]([C:34]([NH:36]C(OC(C)(C)C)=O)=[NH:35])[S:31][C:30]=3[S:44][CH3:45])(=[O:28])=[O:27])[CH:21]=2)=[C:16]([CH3:46])[CH:15]=1)=[O:12])[CH3:2].[C:48]([OH:54])([C:50]([F:53])([F:52])[F:51])=[O:49].C(Cl)Cl>>[F:51][C:50]([F:53])([F:52])[C:48]([OH:54])=[O:49].[CH2:1]([O:3][C:4](=[O:47])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([C:29]3[CH:33]=[C:32]([C:34](=[NH:35])[NH2:36])[S:31][C:30]=3[S:44][CH3:45])(=[O:27])=[O:28])[CH:21]=2)=[C:16]([CH3:46])[CH:15]=1)=[O:12])[CH3:2]
Reactant: CCOC(=O)CCCCCNC(=O)Nc1ccc(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCCCCNC(=O)Nc1ccc(-c2cccc(S(=O)(=O)c3cc(C(=N)N)sc3SC)c2)c(C)c1

Procedure:
Following the procedure in Example 1: step d, 6-(3-{3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-2-methyl-biphenyl-4-yl}-ureido)-hexanoic acid ethyl ester ((Example 311: step a) 12 mg) was treated with 1:1 TFA/DCM. Purification by HPLC yielded the product (8.3 mg) as a white solid. 1H-NMR (CD3OD): δ 8.31 (s, 1H), 7.97 (m, 1H), 7.94 (m, 1H), 7.65 (m, 2H), 7.29 (m, 2H), 7.09 (m, 1H), 4.10 (q, 2H, 7.2 Hz), 3.20 (t, 2H, 7.0 Hz), 2.71 (s, 3H), 2.33 (t, 2H, J=7.3 Hz), 2.19 (s, 3H), 1.65 (m, 2H), 1.55 (m, 2H), 1.40 (m, 2H), 1.23 (t, 3H, J=7.2 Hz). ESI-MS (m/z): Calcd. for C28H34N4O5S3 (M+H): 603.2; found: 603.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[CH:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)=[O:33]>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([C:37]2[CH:38]=[CH:39][C:34]([CH:32]=[O:33])=[CH:35][CH:36]=2)[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=[O:31]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(Br)cc(C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Product: COC(=O)c1cc(-c2ccc(C=O)cc2)cc(C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 97.8 %

Procedure:
In the same manner as described in Example 241, 505.4 mg (1.0 mmol) of the product from Example 89 and 165 mg (1.1 mmol) of 4-formylbenzene boronic acid provided 519 mg (98%) of the desired product as a pale yellow solid. Electrospray Mass Spec 531 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:21]([F:22])=[C:20]([F:23])[C:8]2[N:9]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[NH:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].Cl>CO>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C:10]1[NH:11][C:7]2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:21]([F:22])=[C:20]([F:23])[C:8]=2[N:9]=1
Reactant: COC(=O)c1cc2[nH]c(-c3c(Cl)cccc3Cl)nc2c(F)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc2[nH]c(-c3c(Cl)cccc3Cl)nc2c(F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-(2,6-dichlorophenyl)-6,7-difluoro-3H-benzoimidazole-5-carboxylic acid methyl ester (700 mg, 1.97 mmol) in MeOH (15 mL) was added 1N NaOH (10 mL). The solution was stirred at ambient temperature overnight and carefully acidified to pH 3 with 1N HCl. The resulting suspension was filtered and washed with water. The pale yellow solid was dried under reduced pressure to give 2-(2,6-dichlorophenyl)-6,7-difluoro-3H-benzoimidazole-5-carboxylic acid.
Reaction SMILES: [CH:1]1([C:5]([OH:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.ClC(Cl)(Cl)C(=N)O[C:12]([CH3:15])([CH3:14])[CH3:13].C(=O)(O)[O-].[Na+]>C1COCC1>[CH:1]1([C:5]([O:7][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C1CCC1
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon, 99 μl (0.78 mmol) of boron trifluoride/diethyl ether complex were added to 5.2 g (52.3 mmol) of cyclobutanecarboxylic acid in 100 ml of THF. A little at a time, 13.7 g (62.75 mmol) of tert-butyl 2,2,2-trichloroethaneimidoate were then added, and the mixture was subsequently stirred at room temperature overnight. 5 g of sodium bicarbonate were then added, and the reaction mixture was stirred for 15 min. After filtration, the solution was concentrated to dryness under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 4:1). This gave 5.2 g (64% of theory) of the title compound as a yellow oil.
Reaction SMILES: [C:1]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])=[C:7]1[C:23](=[O:25])[CH3:24])([O:3][CH2:4][CH3:5])=[O:2].[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[C:1]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH:8]([CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])[CH:7]1[C:23](=[O:25])[CH3:24])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: [H][H]
Reactant: CCOC(=O)n1c(C(C)=O)c(CCNC(C)=O)c2cc(OC)ccc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)N1c2ccc(OC)cc2C(CCNC(C)=O)C1C(C)=O

Procedure:
The product N-[2-(1-carbethoxy-2-acetyl-5-methoxyindol-3-yl)ethyl]acetamide (100 mg) is dissolved in ethanol (10 ml) in a round-bottomed flask (25 ml), 100 mg of Pd(OH)2 are added and the mixture is stirred for 12 h at a normal pressure of hydrogen. After filtration, N-[2-(1-carbethoxy-2-acetyl-5-methoxyindolin-3-yl)ethyl]acetamide is obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](/[CH:6]=[CH:7]/[C:8]([OH:10])=O)=[CH:2]1.CO[CH2:13][N:14]([CH2:20][C:21]1C=CC=C[CH:22]=1)[CH2:15][Si](C)(C)C>>[CH2:20]([N:14]1[CH2:15][C@H:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[C@@H:7]([CH2:8][OH:10])[CH2:13]1)[CH:21]=[CH2:22]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C(O)/C=C/c1ccsc1
Product: C=CCN1C[C@H](CO)[C@@H](c2ccsc2)C1

Procedure:
The title compound was prepared from trans-3-(3-thienyl)acrylic acid using procedures analogous to those described in EXAMPLE 1, Steps A-C, substituting N-methoxymethyl-N-trimethylsilylmethyl(prop-2-enyl)amine for N-methoxymethyl-N-trimethylsilylmethylbenzyl amine in Step B. For the title compound: 1H NMR (500 MHz) δ 2.30-2.34 (m, 1H), 2.44 (t, J=8.5, 1H), 2.67 (t, J=9.0, 1H), 2.77 (dd, J=5.0, 9.0, 1H), 3.02-3.15 (4H), 3.53 (dd, J=7.5, 10.0, 1H), 3.64 (dd, J=5.0, 10.0, 1H), 5.07 (d, J=10.0, 1H), 5.17 (d, J=17.5, 1H), 5.83-5.91 (m, 1H), 6.97-6.99 (2H), 7.20-7.22 (m, 1H); ESI-MS 224 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][CH2:15][N:14]([CH3:17])[C:13](=[N:18][C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:28][N:29]=[C:30]=[O:31].O>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([C:30](=[O:31])[NH:29][CH3:28])[CH2:15][N:14]([CH3:17])[C:13](=[N:18][C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=CC(=Nc3c(C)cc(C)cc3C)N(C)CN2)cc1OC
Reactant: CN=C=O
Solvent: O
Solvent: c1ccncc1
Product: CNC(=O)N1CN(C)C(=Nc2c(C)cc(C)cc2C)C=C1c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 6-(3,4-dimethoxyphenyl)-3-methyl-1,2,3,4-tetrahydro-4-(2,4,6-trimethylphenylimino)pyrimidine (1.0 g) in pyridine (10 ml) was added methyl isocyanate (0.18 ml), and the mixture was stirred at ambient temperature for 3 hours. Then the mixture was poured into water (150 ml), and the resultant precipitates were collected. The precipitates were washed with water, and dried to give 6-(3,4-dimethoxyphenyl)-3-methyl-1-(N-methylcarbamoyl)-1,2,3,4-tetrahydro-4-(2,4,6-trimethylphenylimino)pyrimidine (0.99 g).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].C([NH+]([CH2:21][CH3:22])CC)C>C(Cl)(Cl)Cl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH:22]2[CH2:21][CH2:4][CH2:3][CH:2]2[OH:1])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: CC[NH+](CC)CC
Agent: [I-]
Solvent: ClC(Cl)Cl
Product: OC1CCCC1Oc1ccc(Oc2ccccc2)cc1
Temperature: 150 °C
Reaction time: 7 h

Procedure:
A mixture of 18.6 g of 4-phenoxyphenol, 12.8 g of 1,2-carbonyldioxycyclopentane and 4.6 g of triethylammonium iodide is stirred for 7 hours at 150° C. After cooling, the reaction mixture is taken up in chloroform. The solution is washed with water and once with saturated sodium chloride solution, dried over sodium sulphate and concentrated by rotary evaporation. Fractional distillation of the residue yields (2-(4-phenoxyphenoxy)-cyclopentan-1-ol as a colourless oil with a melting point of 181°-185° C./0.001 torr.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]O)=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:20]>C(OCC)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][Br:20])=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(CO)ccc1OCc1ccccc1
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: COc1cc(CBr)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 192.6 %

Procedure:
To a solution of 4-(benzyloxy)-3-methoxybenzyl alcohol (9.0 g, 36.84 mmol) in anhydrous diethyl ether (150 mL) was slowly added PBr3 (4.99 g, 18.42 mmol) via syringe, and the resulting mixture was stirred at room temperature for 3 hours. The mixture was diluted with diethyl ether (100 mL) and washed with saturated aqueous NaHCO3 (2×75 mL) and brine (2×75 mL). The organic layer was dried over anhydrous MgSO4, and the solvent was removed under reduced pressure to afford 4-(benzyloxy)-3-methoxybenzyl bromide (10.9 g, 96%) as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH2:3][C@H:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C(N(C(C)C)CC)(C)C.[Br:29][C@H:30]([CH3:34])[C:31](Cl)=[O:32]>ClCCl>[Br:29][C@H:30]([CH3:34])[C:31]([N:1]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH2:3][C@H:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:32]
Reactant: O=C(OCc1ccccc1)[C@@H]1CC2=C(CCCC2)N1
Reactant: C[C@@H](Br)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](Br)C(=O)N1C2=C(CCCC2)C[C@H]1C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
Introduce 200 g of benzyl (2S)-2,3,4,5,6,7-hexahydro-1H-indole-2-carboxylate and 1.5 litres of dichloromethane into a reactor, then bring the temperature of the reaction mixture to 0° C. and add 201 ml of diisopropylethylamine followed by 132 g of (2R)-2-bromopropionyl chloride. Subsequently, bring the mixture to ambient temperature. After stirring for 1 hour at that temperature, wash the mixture with water and then with a dilute acetic acid solution. The benzyl (2S)-1-[(2R)-2-bromopropionyl]-2,3,4,5,6,7-hexahydro-1H-indole-2-carboxylate solution so obtained is used as it is in the following Step.
Reaction SMILES: C1C=CC(O[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:9][C:10]#[N:11])=CC=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>ClCCl>[O:12]([C:8](=[N:9][C:10]#[N:11])[N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C1CCNCC1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: ClCCl
Product: N#CN=C(Oc1ccccc1)N1CCCCC1
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
a)To a stirred solution of 6 g of diphenyl cyanocarbonimidate in 50 ml of dichloromethane at room temperature were added portionwise 2.1 g of piperidine. Stirring was continued for 30 minutes at room temperature. The reaction mixture was evaporated and the residue was crystallized from 2,2'- oxybispropane. The crystals were filtered off and dried, yielding 4.6 g (80.7%)of [phenoxy(1-piperidinyl)methylene]cyanamide; mp. 85.7° C. (interm. 32).
Reaction SMILES: [CH3:1][C:2]1([C:26]2[S:27][CH:28]=[CH:29][N:30]=2)[C:8]2[CH:9]=[C:10]([C:13]3[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:15]=[CH:16][CH:17]=3)[CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[O:25])[CH2:4][O:3]1.ClS([N:35]=[C:36]=O)(=O)=O>>[C:36]([C:15]1[N:14]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[C:13]([C:10]2[CH:11]=[CH:12][C:7]3[NH:6][C:5](=[O:25])[CH2:4][O:3][C:2]([CH3:1])([C:26]4[S:27][CH:28]=[CH:29][N:30]=4)[C:8]=3[CH:9]=2)=[CH:17][CH:16]=1)#[N:35]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1cccc1-c1ccc2c(c1)C(C)(c1nccs1)OCC(=O)N2
Product: CC(C)(C)OC(=O)n1c(C#N)ccc1-c1ccc2c(c1)C(C)(c1nccs1)OCC(=O)N2

Procedure:
tert-Butyl 2-cyano-5-[5-methyl-2-oxo-5-(1,3-thiazol-2-yl)-1,2,3,5-tetrahydro-4,1-benzoxazepin-7-yl]-1H-pyrrole-1-carboxylate was prepared from tert-butyl 2-[5-methyl-2-oxo-5-(1,3-thiazol-2-yl)-1,2,3,5-tetrahydro-4,1-benzoxazepin-7-yl]-1H-pyrrole-1-carboxylate and chlorosulfonyl isocyanate generally according to the procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.22 (s, 1H), 7.73 (d, J=3.2 Hz, 1H), 7.71 (d, J=3.1 Hz, 1H), 7.39(d, J=2.3 Hz, 1H), 7.32 (dd, J=8.1, 2.3 Hz, 1H), 7.19 (d, J=4.1 Hz, 1H), 7.14, (d, J=8.3 Hz, 1H), 6.42 (d, J=4.2 Hz, 1H), 4.42 (d, J=15.0 Hz, 1H), 4.25 (d, J=14.9 Hz, 1H), 2.02 (s, 3H), 1.3 (s, 9H). MS (ES) m/z 449 ([M−H]−, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.C(O[CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C.O>CN(C)C=O>[CH2:20]([O:19][C:17](=[O:18])[C:16](=[CH:15][NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:21]
Reactant: Nc1ncnc2ccccc12
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(=CNc1ncnc2ccccc12)C(=O)OCC
Temperature: 160 °C
Reaction time: 0.33 h
Yield: 90.1 %

Procedure:
A mixture of 4-aminoquinazoline (11.6 g) and diethyl ethoxymethylenepropanedioate (19.0 g) in N,N-dimethylformamide (40 ml) was stirred for 1 hour and 20 minutes at 160° C. and then cooled to 0° C. to precipirate crystals. To the mixture was added small volume of water with stirring. The crystals were separated by filtration, washed with water, dried overnight under reduced pressure and dissolved in ethyl acetate. The resultant solution was dried over anhydrous magnesium sulfate and recrystallized from a mixture of ethyl acetate and hexane to give crystalline diethyl[(4-quinazolinylamino)methylene]propanedioate (22.7 g).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[OH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH2:23]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][OH:17])[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: NCCCCCO
Solvent: CCN(CC)CC
Product: OCCCCCNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-[5-(hydroxy)pentylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 5-hydroxypentylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: O=[C:2]([NH:8][CH2:9][C:10](=[O:12])[CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:11][C:10]1[O:12][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:8][CH:9]=1
Reactant: CCOC(=O)C(=O)NCC(C)=O
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1ncc(C)o1
Yield: 44.7 %

Procedure:
To a solution of ethyl 2-oxo-2-(2-oxopropylamino)acetate (1.7 g, 9.8 mmol) in toluene (10 mL) was added phosphorus oxychloride (2 mL). The mixture was heated to reflux for 3 h. The reaction was concentrated to dryness and the residue was taken up in ethyl acetate (20 mL). This organic phase was washed with saturated aqueous sodium bicarbonate solution and brine, dried and concentrated to give a crude product which was purified via silica gel chromatography eluting with petroleum ether/ethyl acetate (4:1) to give ethyl 5-methyloxazole-2-carboxylate (0.68 g, 44.1% yield) as yellow syrup. 1H-NMR (CDCl3) δ 6.97 (s, 1H), 4.44-4.49 (q, 2H), 2.43 (s, 3H), 1.42-1.46 (t, 2H). LCMS retention time 0.643 min; LCMS MH+ 156.