Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:14][C:15](=[O:34])[NH:16][C@@H:17]([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH:35]1[C:47]2[CH:46]([CH2:48][O:49][C:50]([NH:52][C@@H:53]([CH2:57][CH2:58][CH2:59][CH2:60][NH:61][C:62](=[O:100])[CH2:63][N:64]3[CH2:75][CH2:74][N:73]([CH2:76][C:77](=[O:83])[O:78][C:79]([CH3:82])([CH3:81])[CH3:80])[CH2:72][CH2:71][N:70]([CH2:84][C:85](=[O:91])[O:86][C:87]([CH3:90])([CH3:89])[CH3:88])[CH2:69][CH2:68][N:67]([CH2:92][C:93]([O:95][C:96]([CH3:99])([CH3:98])[CH3:97])=[O:94])[CH2:66][CH2:65]3)[C:54](O)=[O:55])=[O:51])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39]=2[CH:38]=[CH:37][CH:36]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:35]1[C:47]2[CH:46]([CH2:48][O:49][C:50](=[O:51])[NH:52][C@@H:53]([CH2:57][CH2:58][CH2:59][CH2:60][NH:61][C:62](=[O:100])[CH2:63][N:64]3[CH2:65][CH2:66][N:67]([CH2:92][C:93](=[O:94])[O:95][C:96]([CH3:97])([CH3:98])[CH3:99])[CH2:68][CH2:69][N:70]([CH2:84][C:85](=[O:91])[O:86][C:87]([CH3:88])([CH3:89])[CH3:90])[CH2:71][CH2:72][N:73]([CH2:76][C:77]([O:78][C:79]([CH3:82])([CH3:81])[CH3:80])=[O:83])[CH2:74][CH2:75]3)[C:54](=[O:55])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[NH:14][C:15](=[O:34])[NH:16][C@H:17]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39]=2[CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCN)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CN1CCN(CC(=O)NCCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)[C@H](CCCCNC(=O)CN1CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 136 %

Procedure:
A solution of (S)-di-tert-butyl 2-(3-((S)-6-amino-1-(tert-butoxy)-1-oxohexan-2-yl)ureido)pentanedioate (0.048 g, 0.10 mmol), (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-6-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetamido)hexanoic acid (56 mg, 0.0607 mmol), EDCI (19 mg, 0.10 mmol), HOBt (13.5 mg, 0.10 mmol) and DIPEA (0.10 mL) in DCM (5.0 mL) was stirred at room temperature for 2 hrs. The solvent was evaporated to give a residue, which was purified by Biotage eluting with DCM to 10% MeOH in DCM to give (5S,12S,16S)-tri-tert-butyl 1-(9H-fluoren-9-yl)-3,6,14-trioxo-5-(4-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetamido)butyl)-2-oxa-4,7,13,15-tetraazaoctadecane-12,16,18-tricarboxylate (115 mg) containing some impurity. MS (ESI), 697.0 (M+H)+.
Reaction SMILES: [OH:1][C:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][C:5](=O)[CH3:6].[CH:10]([NH2:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:10]([NH:23][CH:5]([CH3:6])[CH2:4][CH2:3][C:2]([CH3:9])([OH:1])[CH3:8])([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)CCC(C)(C)O
Reactant: NC(c1ccccc1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(CCC(C)(C)O)NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
The obtained 5-hydroxy-5-methylhexan-2-one (14.23 g) was dissolved in methylene chloride (520 ml). Thereafter, benzhydrylamine (21.00 g) was added to the solution, and the obtained mixture was stirred at a room temperature overnight. Thereafter, sodium triacetoxy borohydride (46.30 g) was added to the reaction solution, and the obtained mixture was stirred at a room temperature for 4 hours. Thereafter, distilled water (173 ml) was added to the reaction solution, and the obtained solution was then adjusted to be pH 12 by addition of an aqueous 6 M sodium hydroxide solution. After extraction with chloroform, the organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under a reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluted with 67% ethyl acetate-hexane) to obtain 5-benzhydrylamino-2-methylhexan-2-ol (22.80 g).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][CH2:5][CH:6]([NH:15]C(=O)C1C=CC=CC=1)[CH:7]([OH:14])[C:8]([F:13])([F:12])[CH2:9][CH2:10][CH3:11].C(O)(=O)C1C=CC=CC=1>Cl>[ClH:1].[ClH:1].[NH2:2][CH2:3][CH2:4][CH2:5][CH:6]([NH2:15])[CH:7]([OH:14])[C:8]([F:13])([F:12])[CH2:9][CH2:10][CH3:11]
Reactant: CCCC(F)(F)C(O)C(CCCN)NC(=O)c1ccccc1
Agent: Cl
Agent: O=C(O)c1ccccc1
Product: CCCC(F)(F)C(O)C(N)CCCN
Temperature: 25 °C
Yield: 198.4 %

Procedure:
Scheme B, step g (deprotection): Heat to reflux (110° C.) a solution of 9-Amino-6-benzamido-5-hydroxy-4,4-diflurononane, hydrochloride (26.85 g, 76.5 mmol) in conc aq HCl (250 mL) for 19 h. Benzoic acid crystals develop as the reaction mixture is cooled to room temperature. Remove the crystals by filtration. Extract the filtrate with diethyl ether (250 mL) and separate the layers. Treat the aqueous layer with activated carbon, heat (80° C.), filter through celite, concentrate and dry to provide 21.5 g, 75.9 mmol of title compound 1 as a tan solid in quantitative yield. MS (CI, CH4) m/z (% relative intensity) 211 (M+ +1, 43%); 19F NMR (CD3OD) δ (major diastereomer) -106.4 (dt) and -110.6 (m), (minor diastereomer) -107.6 (m) and -112.6 (m), 1H NMR (D2O) δ 4.0, 3.9 (2t, J=4 Hz, 1H, CHCF2), 3.5 (m, 1H, CHN), 2.9 (m, 2H, NCH2), 2.0-1.5 (m, 6H, 3 CH2), 1.3 (m, 2H, CH2), 0.8 (t, J=7 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)C=O.C(O[CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])C.Cl>C(O)C>[CH2:18]([O:17][CH:13]([O:14][CH2:15][CH3:16])[C:8]1[CH:7]=[CH:4][CH:3]=[C:2]([Br:1])[CH:9]=1)[CH3:19]
Reactant: O=Cc1cccc(Br)c1
Reactant: CCOC(OCC)OCC
Agent: Cl
Solvent: CCO
Product: CCOC(OCC)c1cccc(Br)c1
Temperature: 25 °C
Yield: 108.4 %

Procedure:
To a stirred solution of 3-bromobenzaldehyde (22.38 g, 121 mmol) in ethanol (150 mL) was added triethylorthoformate (27 g, 181 mmol) and concentrated HCl (0.5 mL). The mixture was heated to reflux for 3 hours and allowed to cool to ambient temperature. The reaction mixture was poured into ice/H2O and extracted thoroughly with hexanes. The combined organic extracts were washed with water and brine, dried (MgSO4) and concentrated in vacuo to give 34 g of 3-bromobenzaldehyde diethyl acetal as a colorless liquid.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]1[CH:13]=[C:14]([NH2:21])[C:15](=[CH:19][CH:20]=1)[C:16](O)=[O:17]>>[Cl:11][C:12]1[CH:13]=[C:14]2[C:15]([C:16](=[O:17])[N:6]3[C:5]4[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=4[NH:3][C:2]3=[N:21]2)=[CH:19][CH:20]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: Clc1nc2ccccc2[nH]1
Product: O=c1c2ccc(Cl)cc2nc2[nH]c3ccccc3n12

Procedure:
3-Chlorobenzimidazo[2,1-b]quinazolin-12(6H)one is prepared with 2-chlorobenzimidazole and 4-chloroanthranilic acid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[CH3:16][C:17]([S:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>C1COCC1>[C:17]([S:20]([N:22]=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1)=[O:21])([CH3:19])([CH3:18])[CH3:16]
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Reactant: CC(C)(C)S(N)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(=NS(=O)C(C)(C)C)CC1
Temperature: 55 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
A mixture of tert-butyl 4-oxocyclohexylcarbamate (1.0 g, 4.7 mmol), 2-methylpropane-2-sulfinamide (0.63 g, 5.17 mmol) and Ti(OEt)4 (2.1 g, 9.2 mmol) in 10 mL of THF was stirred at 50-60° C. overnight. The mixture was cooled to room temperature and the residue purified by column chromatography (silica gel, 200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate (4:1, v/v) to give tert-butyl 4-(tert-butylsulfinylimino)cyclohexylcarbamate (1.0 g, 67%) as an clear oil. MS: (M+H)+=317.3; 1H NMR (300 MHz, CDCl3): δ 4.88-4.86 (m, 1H), 3.83 (brs, 1H), 3.39-3.38 (m, 1H), 2.62-2.15 (m, 5H), 1.68-1.53 (m, 2H), 1.43 (s, 9H), 1.24 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][C:12]1[S:16][C:15]([C:17](Cl)=[O:18])=[CH:14][CH:13]=1>N1C=CC=CC=1>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:1][C:17]([C:15]1[S:16][C:12]([CH3:11])=[CH:13][CH:14]=1)=[O:18]
Reactant: Cc1ccc(C(=O)Cl)s1
Reactant: Nc1nc2ccccc2s1
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)Nc2nc3ccccc3s2)s1

Procedure:
Using 2-amino-benzothiazole and 5-methyl-thiophene-2-carboxylic acid chloride in pyridine the title compound was obtained as a yellow solid (87% yield), MS: m/e=275.1 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:54])[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[NH:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][C:29]([C:32]5[NH:33][C:34]([CH:37]6[CH2:41][CH2:40][CH2:39][N:38]6[C:42](=[O:52])[CH:43]([NH:47][C:48]([O:50][CH3:51])=[O:49])[CH:44]([CH3:46])[CH3:45])=[N:35][CH:36]=5)=[CH:28][CH:27]=4)=[CH:22][CH:21]=3)=[CH:18][N:19]=2)[C:9]1=[O:53])(C)(C)C.COC(=O)N[CH:59](C(N1CCCC1C1NC(C2C=CC(C3C=CC(C4NC(CN5CCCC(N)C5=O)=NC=4)=CC=3)=CC=2)=CN=1)=O)[CH:60](C)C>>[CH3:1][O:5][C:6](=[O:54])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]2[N:10]([CH:14]([C:15]3[NH:16][C:17]([C:20]4[CH:21]=[CH:22][C:23]([C:26]5[CH:31]=[CH:30][C:29]([C:32]6[NH:33][C:34]([CH:37]7[CH2:41][CH2:40][CH2:39][N:38]7[C:42](=[O:52])[CH:43]([NH:47][C:48]([O:50][CH3:51])=[O:49])[CH:44]([CH3:45])[CH3:46])=[N:35][CH:36]=6)=[CH:28][CH:27]=5)=[CH:24][CH:25]=4)=[CH:18][N:19]=3)[CH2:59][CH2:60]2)[C:9]1=[O:53]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(CN5CCCC(NC(=O)OC(C)(C)C)C5=O)[nH]4)cc3)cc2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(CN5CCCC(N)C5=O)[nH]4)cc3)cc2)[nH]1)C(C)C
Product: COC(=O)NC1CCC2CCC(c3ncc(-c4ccc(-c5ccc(-c6cnc(C7CCCN7C(=O)C(NC(=O)OC)C(C)C)[nH]6)cc5)cc4)[nH]3)N2C1=O

Procedure:
{3-[5-(4′-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-5-oxo-octahydro-indolizin-6-yl}-carbamic acid methyl ester was prepared following method 804 followed by method 805, substituting {3-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-5-oxo-octahydro-indolizin-6-yl}-carbamic acid tert-butyl ester for {1-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-ylmethyl]-2-oxo-piperidin-3-yl}-carbamic acid tert-butyl ester in method 804, and substituting {1-[2-(5-{4′-[2-(6-Amino-5-oxo-octahydro-indolizin-3-yl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester for {1-[2-(5-{4′-[2-(3-amino-2-oxo-piperidin-1-ylmethyl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester in method 805. C39H46N8O6 calculated 722.4 observed [M+1]+ 723.4; rt=1.62 min. 1H (DMSO-d6): δ=8.10 (m, 1H), 7.90 (m, 8H), 7.31 (m, 2H), 5.12 (m, 2H), 4.11 (m, 2H), 3.84 (m 21-1), 3.74 (m, 1H), 3.53 (s, 6H), 2.38 (m, 2H), 2.14 (m, 3H), 2.05 (m, 5H), 1.82 (m 3H), 0.81 (dd, J=8.8 Hz, J=17.6 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.[CH2:13]([S:15]([C:18]1[CH:23]=[CH:22][C:21](F)=[C:20]([Cl:25])[CH:19]=1)(=[O:17])=[O:16])[CH3:14]>>[Cl:25][C:20]1[CH:19]=[C:18]([S:15]([CH2:13][CH3:14])(=[O:17])=[O:16])[CH:23]=[CH:22][C:21]=1[O:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)Cc1cc(O)cc(F)c1
Reactant: CCS(=O)(=O)c1ccc(F)c(Cl)c1
Product: CCS(=O)(=O)c1ccc(Oc2cc(F)cc(CC(=O)O)c2)c(Cl)c1

Procedure:
The title compound was prepared by the method of example 2 step (iii) using the product of step (iv) and the product of example 3 step (i).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:15][CH:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]4[N:26]([CH3:34])[C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=3)[C:4]=2[C:5]([N:8]=CN(C)C)=[N:6][CH:7]=1.[Cl:37][CH2:38][CH2:39][CH2:40][N:41]=[C:42]=[O:43]>>[NH2:8][C:5]1[C:4]2[C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]4[N:26]([CH3:34])[C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=3)=[CH:14][S:15][C:3]=2[C:2]([NH:1][C:42]([NH:41][CH2:40][CH2:39][CH2:38][Cl:37])=[O:43])=[CH:7][N:6]=1
Reactant: O=C=NCCCCl
Reactant: COc1cc(-c2csc3c(N)cnc(N=CN(C)C)c23)ccc1NC(=O)c1cc2ccccc2n1C
Product: COc1cc(-c2csc3c(NC(=O)NCCCCl)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
The title compound was prepared using N-[4-(7-amino-4-{[(dimethylamino)methylene]amino}thieno[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-indole-2-carboxamide and 3-chloropropyl isocyanate using General Procedure N followed by General Procedure M. 1H NMR (DMSO-d6, 400 MHz) δ 9.50 (s, 1H), 8.69 (s, 1H), 8.19 (br, 1H), 8.13 (d, 1H), 7.94 (s, 1H), 7.71 (d, 1H), 7.60 (d, 1H), 7.35 (m, 1H), 7.29 (s, 1H), 7.16 (m, 2H), 6.08 (m, 2H), 4.04 (s, 3H), 3.93 (s, 3H), 3.71 (t, 2H), 3.25 (m, 2H), 1.93 (m, 2H); MS: (MH)+ 563.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=O)=O.[F-:19].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:19][CH2:6][C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COS(C)(=O)=O
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CF

Procedure:
The product from Example 164A (7 g) in 100 mL of THF and tetrabutylammonium fluoride (42 mL of a 1M solution in THF) was heated at reflux for 17 hours, cooled, concentrated to dryness, diluted with 125 mL of ethyl acetate, washed with 5% aqueous NaHCO3, brine, dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure to provide an oil. The oil was distilled in vacuo (50° C., 1.2 torr) to give 4.9 g of the title compound as a colorless oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:22][CH2:21][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.C(OCC)(=O)C>[O:1]=[C:2]1[CH2:3][CH2:4][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:12])[CH2:7][CH2:6]2)[CH2:21][CH2:22]1
Reactant: O=C(OCc1ccccc1)N1CCC2(CCC(O)CC2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1CCC2(CC1)CCN(C(=O)OCc1ccccc1)CC2
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 391C (23.66 g) in dichloromethane (350 mL) was added Dess-Martin Periodinane (33.1 g). The mixture was stirred overnight. The mixture was diluted with ethyl acetate (600 mL) and washed with 2N aqueous NaOH, water, and brine. After drying over Na2SO4, the mixture was filtered and concentrated to provide the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[NH2:13][C:14]1[CH:15]=[N:16][C:17]([Cl:20])=[CH:18][CH:19]=1>>[Cl:20][C:17]1[N:16]=[CH:15][C:14]([NH:13][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Nc1ccc(Cl)nc1
Product: O=C(Nc1ccc(Cl)nc1)c1ccccc1[N+](=O)[O-]

Procedure:
Using methods substantially equivalent to those described in example 1-A, N-(6-chloropyridin-3-yl)-2-nitrob nzamide (1.24 g, 73%) was prepared from 2-nitro-benzoyl chloride and 3-amino-6-chloropyridine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]1[CH2:23][O:22][CH:19]([CH2:20]Br)[CH:18]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[O:17]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH2:16]1[CH2:23][O:22][CH:19]([CH2:20][N:13]2[CH2:12][CH2:11][CH:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:15][CH2:14]2)[CH:18]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[O:17]1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: COc1ccc(C2OCCOC2CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(C2OCCOC2CN2CCC(CNC(=O)OC(C)(C)C)CC2)cc1
Temperature: 80 °C
Reaction time: 16.5 h
Yield: 77.2 %

Procedure:
To a solution of 4-(tert-butoxycarbonylaminomethyl)piperidine (9.70 g) in toluene (160 ml) were added 3-ethylenedioxy-3-(4-methoxyphenyl)propyl bromide (13.0 g) and potassium carbonate (18.8 g), and the resulting mixture was stirred at 80° C. for 16.5 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol=20:1) to give 14.7 g of 1-(3-ethylenedioxy-3-(4-methoxyphenyl)propyl)-4-(tert-butoxycarbonylaminomethyl)piperidine.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]2[N:5]=[CH:6][N:7]([C:17]=2[N:18]=[CH:19][N:20]=1)[C@@H:8]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[C@H:9]1[OH:10].ClC1C=CC=C(C(OO)=[O:29])C=1.O>C(O)(=O)C>[CH3:1][NH:2][C:3]1[N+:20]([O-:29])=[CH:19][N:18]=[C:17]2[C:4]=1[N:5]=[CH:6][N:7]2[C@@H:8]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[C@H:9]1[OH:10]
Reactant: CNc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(=O)O
Solvent: O
Product: CNc1c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2nc[n+]1[O-]
Yield: 45 %

Procedure:
A solution of N6 -methyladenosine (2 g, 6.7 mmol) and m-chloroperbenzoic acid (2.3 g, 13.4 mmol) in acetic acid (20 ml) was stirred at room temperature for two days. Water (20 ml) was added to the reaction mixture, and a resulting thick precipitate was removed by filtration and discarded. The filtrate was co-evaporated repeatedly with water under high vacuum, and the foamy residue was chromatographed on a silica gel column (CHCl3 : MeOH 2:1). The product was obtained as a white solid (mp 145° C., crystallization from EtOH) in 45% yield (0.9 g). 1H NMR (DMSO)d: 8.62 (s, H-2), 8.55 (s, H-8), 5.88 (d, J=5.4 Hz, 1H, H-1), 4.51 (`t`, J=5.1 Hz, 1H, H-2'), 4.15 (`t`, J=4.5 Hz, 1H, H-3'), 3.94 (ABq, 1H, H-4'), 3.61 (ABdq, J=12, 4 Hz, 2H, H-5'), 3.46 (s, 3H, Me) ppm. MS (CI) m/e: 298 (MH+).
Reaction SMILES: [O-]CC.[Na+].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][OH:14])=[CH:8][CH:7]=1.[CH2:15](Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22]>C(O)C.O1CCCC1>[CH2:22]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][OH:14])=[CH:8][CH:7]=1)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15]
Reactant: OCCc1ccc(O)cc1
Reactant: C=CCCCCCCBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: C=CCCCCCCOc1ccc(CCO)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
Sodium ethoxide (4.98 g) was added to a solution (240 ml) of 2-(4-hydroxyphenyl)ethyl alcohol (8.68 g) in absolute ethanol and the mixture was stirred at 50° C. for 30 minutes. A solution of 7-octenyl bromide (10 g) in anhydrous tetrahydrofuran was dropwise added thereto and the mixture was stirred at 50° C. for 6 hours. The reaction mixture was concentrated, poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled away and the residue was purified by silica gel chromatography (eluent; ethyl acetate:hexane=1:5) to give the subject compound (10.76 g) as an oily substance.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[CH3:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([CH2:12][O:13][NH2:14])=[CH:10][CH:9]=1>N1C=CC=CC=1>[S:1]([NH:14][O:13][CH2:12][C:11]1[CH:15]=[CH:16][C:8]([O:7][CH3:6])=[CH:9][CH:10]=1)([CH3:4])(=[O:3])=[O:2]
Reactant: COc1ccc(CON)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1ccc(CONS(C)(=O)=O)cc1
Yield: 64.9 %

Procedure:
63.0 g (0.55 mole) of mesyl chloride was added dropwise to a solution of 76.5 g (0.5 mole) of O-(p-methoxybenzyl)-hydroxylamine in 400 ml of pyridine while ice-cooling and stirring. After completion of the addition, the resulting mixture was stirred at room temperature (about 20°-30° C) for 5 hours and then the solvent was removed by distillation. 600 ml of ethyl acetate was added to the resulting residue, and the mixture was washed successively with 1N hydrochloric acid and water. The mixture was then dried and the solvent was distilled off to obtain 75 g (64.8% yield) of N-mesyl-O-(p-methoxybenzyl)hydroxylamine (IV) having a melting point of 114°-116° C.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Br[C:6]1[N:10]([C@@H:11]2[CH2:16][CH2:15][C@H:14]([OH:17])[C@H:13]([OH:18])[CH2:12]2)[C:9]2[CH:19]=[C:20]([Cl:24])[C:21]([Cl:23])=[CH:22][C:8]=2[N:7]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH:1]([NH:4][C:6]1[N:10]([C@@H:11]2[CH2:16][CH2:15][C@H:14]([OH:17])[C@H:13]([OH:18])[CH2:12]2)[C:9]2[CH:19]=[C:20]([Cl:24])[C:21]([Cl:23])=[CH:22][C:8]=2[N:7]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: O[C@@H]1C[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)CC[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)Nc1nc2cc(Cl)c(Cl)cc2n1[C@@H]1CC[C@H](O)[C@H](O)C1
Temperature: 100 °C
Yield: 7.5 %

Procedure:
Isopropylamine (227.8 mg, 3.85 mmol) was added to (±)-(1S*,2R*,4R*)-4-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)cyclohexane-1,2-diol (Example 51, part b, 146.5 mg, 385.4 mmol) in ethanol (3.9 ml) and the reaction was heated at 100° C. in a sealed tube for 68 hr. The reaction was cooled, saturated sodium carbonate added, extracted with ethyl acetate, dried with magnesium sulfate, and concentrated. The residue was purified by column chromatography eluting with methanol:ethyl acetate (1:19) to give the title compound (104.1 mg, 75%). Rf=0.20 (1:19 methanol:ethyl acetate); 1H-NMR (CD3OD, 300 MHz) δ7.53 (s, 1H), 7.36 (s, 1H), 4.31 (tt, 1H, J=13, 4), 4.06 (h, 1H, J=7), 3.97 (s, 1H), 3.75-3.68 (m, 1H), 2.50 (q, 1H, J=12), 2.39 (dq, 1H, J=13, 4), 2.02-1.96 (m, 1H), 1.78-1.49 (m, 3H), 1.29 (d, 3H, J=7), 1.28 (d, 3H, J=7); MS (ES) M+H=358.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:6][CH:7]=1.C([O-])(=[O:16])C.[Na+].CN(C)C=O>O>[C:8]1([C:5]2[S:6][CH:7]=[C:3]([CH2:2][OH:16])[N:4]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCc1csc(-c2ccccc2)n1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OCc1csc(-c2ccccc2)n1
Temperature: 80 °C
Reaction time: 6 h
Yield: 89.9 %

Procedure:
A mixture of 4-chloromethyl-2-phenylthiazole (8.60 g), sodium acetate (10.1 g) and N,N-dimethylformamide (80 ml) was stirred at 80° C. for 6 hours. After cooling, the reaction solution was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. A mixture of the residue, 4N aqueous sodium hydroxide solution (25 ml), tetrahydrofuran (50 ml) and methanol (50 ml) was stirred at room temperature for 5 minutes, and poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain 2-phenyl-4-thiazolylmethanol (7.05 g, yield 90%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). This was recrystallized from hexane. Melting point: 71–72° C.