Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:9]([CH2:20][O:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:8][C@H:7]([O:30][C@H:31]2[C@@H:44]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C@H:43]([O:53][CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[C@@H:42]([CH2:61][O:62][CH2:63][C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[O:41][C@@H:32]2[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@H:6]1[O:70][C:71](=[O:78])[C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)C=C>CO.ClCCCl.Cl[Pd]Cl>[C:71]([O:70][C@H:6]1[C@@H:5]([OH:4])[C@H:10]([O:11][C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C@@H:9]([CH2:20][O:21][C:22](=[O:29])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:8][C@@H:7]1[O:30][C@H:31]1[C@@H:44]([O:45][CH2:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C@H:43]([O:53][CH2:54][C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[C@@H:42]([CH2:61][O:62][CH2:63][C:64]2[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=2)[O:41][C@@H:32]1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:78])[C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1
Reactant: C=CCO[C@@H]1[C@H](OC(=O)c2ccccc2)[C@@H](O[C@@H]2[C@@H](OCc3ccccc3)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: Cl[Pd]Cl
Solvent: ClCCCl
Solvent: CO
Product: O=C(OC[C@H]1O[C@H](O[C@@H]2[C@@H](OCc3ccccc3)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H](O)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Yield: 97.5 %

Procedure:
PdCl2 (40 mg) was added to a solution of the allyl ether (24) (1.09 g, 0.97 mmol) in MeOH (10 mL) and 1,2-DCE (10 mL) and the combined mixture was heated (70°, 40 min). After the time, the solvents were evaporated and the residue subjected to FC (20-30% EtOAc/hexanes) to yield the alcohol (25) as a colourless oil (0.96 g, 91%). 1H NMR (CDCl3) δ 3.68-3.81, 3.97-4.06, 4.32-4.71 (3 m, 18 H; H-2I,-3I,-4I,-5I,-6aI,-6bI,-3II,-5II,-6aII,-6bII, CH2Ph), 4.84 (d, 1 H, JA,B 12 Hz; A of AB quartet), 5.05 (d, 1 H, J1,2 1.9 Hz; H-1I), 5.26 (d, 1 H; J1,2 1.9 Ha; H-1II), 5.61 (dd, 1 H, J2,3 3.3 Hz; H-2II), 5.67 (dd, 1 H, J3,4 9.8, J4,5 9.9 Hz; H-4II), 7.13-7.40, 7.48-7.59, 7.98-8.06 (3 m, 35 H; Ar). 13C NMR (CDCl3) δ 60.61, 63.32 (2C; C-6I,-6II), 69.06, 69.12, 69.25, 69.44, 70.45, 72.14, 72.65, 72.77, 73.48, 74.79, 75.48, 75.47, 76.23 (13C; C-3I,-4I,-5I,-2II,-3II,-4II,-5II, OCH2, CH2Ph), 79.66(C-2I), 98.34, 99.40 (C-1I,-1II), 127.70-138.47 (42C; Ar), 165.97, 166.36, 166.97 (3C; C═O).
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:14][C@H:15]([OH:31])[C@@H:16]([NH:24]C(=O)C(F)(F)F)[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.C(Cl)Cl.O>CO>[S:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:14][C@H:15]([OH:31])[C@@H:16]([NH2:24])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)NN(Cc1ccc(-c2cncs2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NN(Cc1ccc(-c2cncs2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Temperature: 70 °C
Reaction time: 15 h

Procedure:
100 ml of a 1N KDCO3 solution are added dropwise to a solution of 5.646 g (10.0 mmol) of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-(trifluoroacetyl)amino-6-phenyl-2-azahexane in 100 ml of methanol and the mixture is stirred at 70° C. for 15 hours. Methylene chloride and water are added; the aqueous phase is separated off and extracted 2× with methylene chloride. The organic phases are washed 2× with water, dried (Na2SO4) and concentrated by evaporation, yielding the title compound: Anal. (C25H32N4O3S (0.53 H2O)) calc. C 62.80, H 6.97, N 11.72, S 6.71, H2O 2.00: found C 63.2, H 7.01, N 11.57, S 6.49, H2O 1.98; HPLC20-100 : tRet =11.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:6]([C:7](O)=[O:8])=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1.S(Cl)(Cl)=O.[NH3:21]>>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:6]([C:7]([NH2:21])=[O:8])=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1
Reactant: N
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OC
Solvent: O=S(Cl)Cl
Product: COc1cc(C(N)=O)c([N+](=O)[O-])cc1OC

Procedure:
4,5-Dimethoxy-2-nitrobenzoic acid (3) was treated with thionyl chloride and then reacted with ammonia to give 4,5-dimethoxy-2-nitrobenzamide (4) as described by F. Nomoto et al. Chem. Pharm. Bull., 1990, 38, 1591-1595. The nitro group in compound (4) was reduced with sodium borohydride in the presence of copper sulfate (see C. L. Thomas, Catalytic Processes and Proven Catalysts, Academic Press, New York (1970)) to give 4,5-dimethoxy-2-aminobenzamide (5) which was cyclized by refluxing with formic acid to give 6,7-dimethoxyquinazoline-4(3H)-one (6). Compound (6) was refluxed with phosphorus oxytrichloride to provide the common synthetic precursor (7).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:30][CH2:31][CH2:32][O:33][C:34]4[N:39]=[CH:38][C:37]([Cl:40])=[CH:36][N:35]=4)=[N:12][N:13]([CH3:29])[C:14]=3[NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1.C[OH:42]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:30][CH2:31][CH2:32][O:33][C:34]4[N:39]=[CH:38][C:37]([Cl:40])=[CH:36][N:35]=4)=[N:12][N:13]([CH3:29])[C:14]=3[NH:15][S:16]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([CH3:28])([CH3:27])[CH2:26][OH:42])=[CH:23][CH:24]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CO
Reactant: Cn1nc(OCCOc2ncc(Cl)cn2)c(-c2ccc3c(c2)OCO3)c1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Product: Cn1nc(OCCOc2ncc(Cl)cn2)c(-c2ccc3c(c2)OCO3)c1NS(=O)(=O)c1ccc(C(C)(C)CO)cc1
Reaction time: 48 h

Procedure:
Amycolata autotrophica ATCC35203 maintained on a quarter strength ATCC172 agar slope was inoculated as a loopful of spores into a 300 ml Erlenmeyer flasks each containing 50 ml of MY inoculum medium. This was allowed to incubate for 2 days at 28° C., 200 rpm on an Infors Multitron™ Shaker with 1″ throw. Two mls of this inoculum was then transferred to each of nine 300 ml Erlenmeyer flask containing 50 ml of MY production medium and incubated under the same conditions for a further 24 hours. At this point 5 mg of N-(4-(1,3-benzodioxol-5-yl)-3-{2-[(5-chloro-2-pyrimidinyl)oxy]ethoxy}-1-methyl-1H-pyrazol-5-yl)4-(tert-butyl)benzenesulfonamide (GB Patent Application No 9917858.4) dissolved in 0.5 ml of methanol was added to each of the flasks and the fermentation allowed to continue under the same conditions for a further 96 hours. Each flask was then extracted with 200 mls of ethyl acetate and the combined ethyl acetate solubles concentrated to dryness to give a gum solid.
Reaction SMILES: [O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:10](=[O:51])[NH:11][C@@H:12]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][O:43][Si](C(C)(C)C)(C)C)=[CH:36][CH:35]=2)[C@H:13]([OH:32])[CH2:14][N:15]([S:20]([C:23]2[CH:31]=[CH:30][C:26]3[O:27][CH2:28][O:29][C:25]=3[CH:24]=2)(=[O:22])=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>O1CCCC1.C(OCC)(=O)C>[O:27]1[C:26]2[CH:30]=[CH:31][C:23]([S:20]([N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:14][C@@H:13]([OH:32])[C@@H:12]([NH:11][C:10](=[O:51])[O:9][C@@H:3]3[C@H:4]4[C@H:5]([O:6][CH2:7][CH2:8]4)[O:1][CH2:2]3)[CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][OH:43])=[CH:36][CH:35]=3)(=[O:22])=[O:21])=[CH:24][C:25]=2[O:29][CH2:28]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCO[Si](C)(C)C(C)(C)C)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCO)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 18 h
Yield: 101 %

Procedure:
To a stirred solution of (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl-(1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-1-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)benzyl]-2-hydroxypropylcarbamate (160 mg, 0.21 mmol) in tetrahydrofuran (3 mL) at 5° C. was added a mixture of tetrabutylammonium fluoride (0.3 mL, 1M in tetrahydrofuran) and glacial acetic acid (0.3 mL) over 2 minutes. The reaction was allowed to warm to ambient temperature and stirred for 18 hours. The mixture was diluted with ethyl acetate (50 mL), washed with water (25 mL) followed by saturated sodium bicarbonate (20 mL) and then brine (20 mL), dried (magnesium sulfate) and concentrated in vacuo to afford the title compound (135 mg, quant.) as a white solid. 1H NMR (DMSO-d6): δ 0.78 (6H, dd), 1.17-1.42 (2H, m), 1.92 (1H, m), 2.33 (1H, t), 2.64-2.78 (3H, m), 2.89-3.02 (2H, m), 3.24-3.29 (1H, m), 3.52-3.73 (7H, m), 3.78-3.82 (1H, m), 3.86 (2H, t), 4.78-4.82 (2H, m), 4.99 (1H, d), 5.46 (1H, d), 6.12 (2H, s), 6.73 (2H, d), 7.02-7.28 (6H, m); MS: 637 (MH+)
Reaction SMILES: [NH:1]([C:5]1[CH:17]=[CH:16][C:8]([O:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)C(C)=O.C(O)(=O)C>[OH-].[K+]>[NH2:1][C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])=[CH:16][CH:17]=1
Reactant: CC(=O)Nc1ccc(OC(C)(C)C(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)(Oc1ccc(N)cc1)C(=O)O
Yield: 61.5 %

Procedure:
1.18 g (0.005 mol) of the 2-(4-acetaminophenoxy)-2-methyl propionic acid is boiled in 10% KOH (60 ml) for 1/2 hour. The solution is then cooled and acidified with acetic acid to yield 0.6 g (62% yield) of 2-(4-aminophenoxy)-2-methyl propionic acid as a yellowish white powder, mp 214°-16° C.
Reaction SMILES: [Cl:1][C:2]1[CH2:6][CH:5](C#N)[N:4]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[N:3]=1.N12CCCN=C1CCCCC2>CN(C)C=O>[Cl:1][C:2]1[CH:6]=[CH:5][N:4]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[N:3]=1
Reactant: N#CC1CC(Cl)=NN1c1cccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Clc1ccn(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.5 %

Procedure:
3-Chloro-1-(pyridine-3-yl)-4,5-dihydro-1H-pyrazole-5-carbonitrile (0.500 g, 2.42 mmol) was stirred in N,N-dimethylformamide (6.05 mL). 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.543 mL, 3.63 mmol) was added and the dark mixture was stirred at room temperature overnight. LC/MS analysis indicated that the reaction was complete. The mixture was concentrated and the dark oil was dissolved in ethyl acetate and washed with 15% aqueous lithium chloride (LiCl) and brine. The organic portion was dried over sodium sulfate (Na2SO4) and concentrated. The residue was purified by flash column chromatography using ethyl acetate. The pure fractions were concentrated and the residue was vacuum dried at 45° C. to yield the desired product as a white solid (450 mg, 93%): mp: 66-68° C.; 1H NMR (400 MHz, CDCl3) δ 8.93 (d, J=27 Hz, 1H), 8.57 (dd, J=4.8, 1.4 Hz, 1H), 8.02 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.91 (d, J=2.6 Hz, 1H), 7.47-7.34 (m, 1H), 6.45 (d, J=2.6 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 148.01, 142.72, 140.12, 135.99, 128.64, 126.41, 124.01, 108.0.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:11][C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]2[O:12][CH:3]12.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[NH:25][N:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:25]([CH:4]3[C:5]4[CH:6]=[N:7][CH:8]=[CH:9][C:10]=4[O:11][C:2]([CH3:13])([CH3:1])[CH:3]3[OH:12])[N:24]=[CH:23][CH:22]=2)=[CH:19][CH:20]=1
Reactant: CC1(C)Oc2ccncc2C2OC21
Reactant: Clc1ccc(-c2ccn[nH]2)cc1
Product: CC1(C)Oc2ccncc2C(n2nccc2-c2ccc(Cl)cc2)C1O

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-6-aza-cyclopropa[a]naphthalene and 5-(4-chloro-phenyl)-1H-pyrazole as starting materials, the title compound was prepared as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[C:24]([F:31])[C:23]=1[F:32].[Si:33](Cl)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].N1C=CN=C1>ClCCl>[Si:33]([O:18][CH2:17][C@H:10]1[O:9][C@:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[C:24]([F:31])[C:23]=3[F:32])[CH:4]=2)([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@@H:11]1[OH:16])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)c(F)c1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 107.5 %

Procedure:
To a solution of (2S,3R,4S,5S,6R)-2-[4-chloro-3-[ (4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 23g (9.02 g, 18.95 mmol) in dichloromethane (150 mL) were added tert-butyldimethylsilyl chloride (4.29 g, 28.43 mmol), imidazole (2.58 g, 37.9 mmol) and N,N-dimethylaminopyridine (0.23 g, 1.9 mmol) in turn at 0° C. The mixture was stirred at room temperature for 3 hours, and then washed with water (100 mL×3) and saturated aqueous sodium chloride (100 mL) in turn. The resulting mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 23h as a yellow solid (12.0 g, 100%). This material was not further purified.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH3:8][C:9]([CH3:53])([CH2:51][CH3:52])[CH2:10][C:11]1[N:12]=[C:13]([CH2:35][CH:36]([C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][N:45]=3)=[CH:40][CH:39]=2)[NH2:37])[N:14]([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=1>ClCCl>[CH3:8][C:9]([CH3:53])([CH2:51][CH3:52])[CH2:10][C:11]1[N:12]=[C:13]([CH2:35][CH:36]([NH:37][C:5](=[O:7])[CH3:6])[C:38]2[CH:39]=[CH:40][C:41]([C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][N:45]=3)=[CH:42][CH:43]=2)[N:14]([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:15]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(N)c2ccc(-c3ccc(F)cn3)cc2)n1
Solvent: ClCCl
Product: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(NC(C)=O)c2ccc(-c3ccc(F)cn3)cc2)n1
Reaction time: 2 h

Procedure:
Acetic anhydride (16 μL, 0.17 mmol) was added to a solution of 2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]ethanamine (51 mg, 0.08 mmol) in dichloromethane (4 mL) at ambient temperature. After stirring for 2 hr, the reaction mixture concentrated in vacuo to afford N-{2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]ethyl}acetamide which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:17][CH2:16][CH2:15][C@@H:14]3[N:9]2[C:10](=[O:19])[CH:11](I)[CH2:12][CH2:13]3)[CH:5]=[CH:6][CH:7]=1.[P:20]([O:27]CC)([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23]>>[F:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[CH2:17][CH2:16][CH2:15][C@H:14]3[N:9]2[C:10](=[O:19])[CH:11]([P:20](=[O:27])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])[CH2:12][CH2:13]3)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C(I)CC[C@@H]2CCC[C@H](c3cccc(F)c3)N12
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(OCC)C1CC[C@H]2CCC[C@@H](c3cccc(F)c3)N2C1=O
Temperature: 120 °C
Reaction time: 5 h

Procedure:
A mixture of (6R*,9aS*)-6-(3-fluorophenyl)-3-iodooctahydroquinolizin-4-one (597 mg) with triethyl phosphite (6 mL) was stirred at 120° C. for five hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure to obtain 670 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15]3)(=[O:13])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:23][NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=1.[ClH:33].C(=O)([O-])[O-].[NH4+:38].[NH4+]>C(O)C>[ClH:33].[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15]3)(=[O:12])=[O:13])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:23][NH:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](=[NH:38])[NH2:32])=[CH:29][CH:30]=1
Reactant: [NH4+]
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(S(=O)(=O)N3CCc4ccccc43)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(S(=O)(=O)N3CCc4ccccc43)ccc21
Yield: 15 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-5-(2.3-dihydroindol-1-yl-sulphonyl)-benzimidazole and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 15% of theory, Rf value: 0.36 (silica gel; dichloromethane/methanol=4:1) C24H24N6O2S (460.6) EKA mass spectrum: (M+H)+ =461
Reaction SMILES: CO.[H-].[Na+].[C:5]1([SH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:12][C:13]([CH3:31])=[CH:14][CH2:15][C@H:16]1[O:18][C@@:17]1([C@@H:20]1[C@:25]2([O:27][CH2:26]2)[CH2:24][CH2:23][C@@H:22]([OH:28])[C@H:21]1[O:29][CH3:30])[CH3:19]>O>[O:18]1[CH:16]([CH2:15][CH:14]=[C:13]([CH3:31])[CH3:12])[C:17]1([CH:20]1[CH:21]([O:29][CH3:30])[CH:22]([OH:28])[CH2:23][CH2:24][C:25]1([CH2:26][S:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:27])[CH3:19]
Reactant: CO[C@@H]1[C@H](O)CC[C@]2(CO2)[C@H]1[C@@]1(C)O[C@@H]1CC=C(C)C
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1C(O)CCC(O)(CSc2ccccc2)C1C1(C)OC1CC=C(C)C
Reaction time: 15 h
Yield: 95 %

Procedure:
To methanol (5 ml) was added, under ice-cooling, 60% sodium hydride (213 mg), and the mixture was stirred for 5 minutes at room temperatures, to which was then added thiophenol (0.55 ml), followed by stirring for 15 hours. To the resultant mixture was added fumagillol (500 mg), which was stirred for 30 minutes, followed by adding water to suspend the reaction. The product was extracted with ethyl acetate, and the extract solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 25 g, developing solvent: ethyl acetate-hexane=1:2), followed by crystallization from isopropylether to afford 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)- 3-methoxy-1-phenylthiomethyl-1,4-cyclohexanediol (660 mg: yield 95%) as colorless crystals, m.p. 94° to 96° C.
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:32])=[C:6]([NH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]3[O:20][CH:19]([CH2:21][CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:18][C:17]=3[C:30]=2[Cl:31])=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[C:33](OCC)(=O)[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[Cl:31][C:30]1[C:17]2[CH2:18][CH:19]([CH2:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:20][C:16]=2[CH:15]=[CH:14][C:13]=1[C:11]([NH:10][C:6]1[C:5]2[O:32][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:2][C:1](=[O:3])[C:4]=2[CH:9]=[CH:8][CH:7]=1)=[O:12]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1cccc(NC(=O)c2ccc3c(c2Cl)CC(CCCc2ccccc2)O3)c1O
Product: CCOC(=O)c1cc(=O)c2cccc(NC(=O)c3ccc4c(c3Cl)CC(CCCc3ccccc3)O4)c2o1
Yield: 61 %

Procedure:
Following the process described in example 1 (point A), starting from N-(3-acetyl-2-hydroxyphenyl)-4-chloro-2-(3-phenylpropyl)-2,3-dihydrobenzofuran-5-carboxamide and diethyl oxalate, the title compound was prepared, which was purified by chromatography through a silica gel column, eluting with petroleum ether:chloroform, 4:6 (61% yield).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[F:10][C:11]([F:21])([F:20])[C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Br.C([O-])([O-])=O.[Na+].[Na+]>>[OH:1][CH:2]1[CH2:6][N:5]([CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[C:12]([C:11]([F:21])([F:20])[F:10])[CH:13]=2)[CH:4]([C:7]([O:9][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[C:12]([C:11]([F:10])([F:20])[F:21])[CH:13]=2)=[O:8])[CH2:3]1
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(OCc1cccc(C(F)(F)F)c1)C1CC(O)CN1Cc1cccc(C(F)(F)F)c1

Procedure:
The title compound (D81) (1.02 g) was prepared according to the general procedure for substituted benzyl amines preparation starting from cis-4-Hydroxy-D-proline (4.0 g; available from Aldrich#H5877) and 3-(Trifluoromethyl)benzyl bromide (9.37 ml). (Na2CO3: 2.5 eq; Reaction time: 24 hrs; 60° C.).
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([I:23])[CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.Cl.[NH2:25][C@H:26]([CH3:36])[C@H:27]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[OH:28]>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([I:23])[CH:20]=[CH:19][C:15]=3[C:16]([NH:25][C@H:26]([CH3:36])[C@H:27]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[OH:28])=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: C[C@@H](N)[C@@H](O)c1ccc(Cl)cc1
Agent: Cl
Product: C[C@@H](NC(=O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12)[C@@H](O)c1ccc(Cl)cc1
Yield: 67 %

Procedure:
The title compound (42 mg, 67%) was obtained from 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodobenzoic acid (EXAMPLE 101, Part D) and (1S,2R)-2-amino-1-(4-chloro-phenyl)-propan-1-ol hydrochloride salt as in Example 1, Part C. HPLC: RT=10.13 min. MS (ESI−): mass calcd. for C22H18ClIN4O4S2, 628.89; m/z found, 627/629 [M−H]−. 1H NMR (500 MHz, CDCl3): 11.49 (s, 1H), 8.37 (dd, J=7.0, 0.8, 1H), 8.23 (dd, J=8.8, 0.8, 1H), 8.07 (d, J=1.5, 1H), 7.73 (dd, J=8.8, 7.1, 1H), 7.37-7.27 (m, 5H), 6.98 (d, J=8.3, 1H), 6.20 (d, J=8.1, 1H), 4.95 (d, J=2.7, 1H), 4.42-4.38 (m, 1H), 2.65 (s, 1H), 1.03 (d, J=6.9, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([S:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.N.CS(C)=[O:34]>>[NH2:1][C:2]1[N:10]=[C:9]([S:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:34])[N:6]2[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1nc(Sc2ccc3ccccc3c2)nc2c1nc(Br)n2Cc1ccccc1
Reactant: CS(C)=O
Agent: Cl
Agent: N
Product: Nc1nc(Sc2ccc3ccccc3c2)nc2c1nc(O)n2Cc1ccccc1
Yield: 35 %

Procedure:
6-Amino-9-benzyl-8-bromo-2-(2-naphthylthio)purine (33 mg, 0.043 mmol) in a mixture of concentrated hydrochloric acid (20 ml) and dimethyl sulfoxide (7 ml) was refluxed for 6 hours under heating. The reaction mixture was made basic with 28% aqueous ammonia, and the resulting crystals were filtered, washed with water and the crude product was purified by thin-layer chromatography to give the subject compound (6 mg, yield 35%).