Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.[CH3:6][C:7](=[N:9][OH:10])[CH3:8].[Br:11][C:12]1[CH:21]=[CH:20][C:15]([C:16](OC)=O)=[CH:14][CH:13]=1.O>C1COCC1>[Br:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]2[O:10][N:9]=[C:7]([CH3:8])[CH:6]=2)=[CH:14][CH:13]=1
Reactant: CC(C)=NO
Reactant: COC(=O)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(Br)cc2)on1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of n-BuLi (81 ml of a 1.6M solution in hexanes) was added to a solution of acetone oxime (4.85 g) in THF (100 ml) at 0° C. The reaction mixture was allowed to warm to rt over 1 h. A solution of methyl 4-bromobenzoate (9.4 g) in THF (30 ml) was then added to the reaction mixture and allowed to stir for 24 h. Water (50 ml) was added to the reaction, the organics were extracted and evaporated to give a brown oil, which was further evaporated from toluene (2×25 ml). The crude product was purified by column chromatography (silica gel, 10-25% gradient of EtOAc in hexane) to give the title compound (D39) as a pale yellow solid (5.4 g). LCMS electrospray (+ve) 239 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:34]=[CH:33][C:13]([O:14][C:15]2[CH:16]=[C:17]([CH:21]=[C:22]([O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=3)[CH:23]=2)[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([O:42][C:43](=[O:52])[NH:44][CH:45]1[CH2:50][CH2:49][CH:48](O)[CH2:47][CH2:46]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([O:42][C:43]([NH:44][CH:45]1[CH2:50][CH2:49][CH:48]([O:19][C:18](=[O:20])[C:17]2[CH:21]=[C:22]([O:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]#[N:32])=[CH:29][CH:30]=3)[CH:23]=[C:15]([O:14][C:13]3[CH:33]=[CH:34][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:11][CH:12]=3)[CH:16]=2)[CH2:47][CH2:46]1)=[O:52])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Reactant: O=C(NC1CCC(O)CC1)OCc1ccccc1
Product: CC(C)(C)OC(=O)NCc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)OC3CCC(NC(=O)OCc4ccccc4)CC3)c2)cc1
Yield: 39.1 %

Procedure:
Following the procedure of Example 9(e) 3-[4-(tert-butoxycarbonylamino-methyl)-phenoxy]-5-(4-cyano-phenoxy)-benzoic acid (0.85 g, 1.85 mmol) and (4-hydroxy-cyclohexyl)-carbamic acid benzyl ester (0.50 g, 2.03 mmol) were used to afford 0.5 g of the required product. Percentage purity (LCMS): 67.0%, (M+1) 691.2+1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=1.[CH3:15][N:16]1[CH:20]=[C:19]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=[N:17]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:21]([C:19]2[CH:18]=[N:17][N:16]([CH3:15])[CH:20]=2)(=[O:23])=[O:22])[CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=1
Reactant: O=Cc1c[nH]c(-c2ccccc2F)c1
Reactant: Cn1cc(S(=O)(=O)Cl)cn1
Product: Cn1cc(S(=O)(=O)n2cc(C=O)cc2-c2ccccc2F)cn1

Procedure:
By a similar operation as in Reference Example 65 and using 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (189 mg) and 1-methyl-1H-pyrazole-4-sulfonyl chloride (217 mg), the title compound was obtained as yellow crystals (yield 217 mg, 65%).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([CH2:7][CH2:8][CH3:9])=[N:4][C:3]=1[CH:10]=O.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[NH:13][NH2:14]>>[CH2:17]([O:16][C:12](=[O:15])[NH:13][N:14]=[CH:10][C:3]1[N:4]=[C:5]([CH2:7][CH2:8][CH3:9])[NH:6][C:2]=1[CH3:1])[CH3:18]
Reactant: CCOC(=O)NN
Reactant: CCCc1nc(C=O)c(C)[nH]1
Product: CCCc1nc(C=NNC(=O)OCC)c(C)[nH]1

Procedure:
A 12 gm. portion of 5-methyl-2-n-propyl-4-imidazolecarboxaldehyde and 9.06 gm. of ethyl carbazate are reacted as described in Example 32 giving the desired product, m.p. 184°-188° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[CH2:5][CH:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:15]1([CH:23]=O)[C:16]([CH:21]=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=1>ClCCl>[CH3:2][O:3][C:4](=[O:14])[CH2:5][CH:6]([N:13]1[CH2:23][C:15]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:21]1=[O:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)CC(N)c1ccccc1
Reactant: O=Cc1ccccc1C=O
Agent: Cl
Solvent: ClCCl
Product: COC(=O)CC(c1ccccc1)N1Cc2ccccc2C1=O

Procedure:
3-Amino-3-phenyl-propionic acid methyl ester hydrochloride (1.3 mmol, 1 eq), benzene-1,2-dicarbaldehyde (0.8 eq) and glacial acid (15 eq) are dissolved in dichloromethane and refluxed for 2 h (J. Chem. Soc., Chem Commun 1985, 1183). The mixture is concentrated in vacuo and partitioned between dichloromethane and water. The organic phase is dried over Na2SO4, filtered and concentrated in vacuo. 3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-3-phenyl-propionic acid methyl ester is obtained as a brown solid (83% yield); ES-MS (MH+)=296.2; 1H-NMR (DMSO-d6, 400 MHz): δ [ppm] 7.73-7.30 (m, 9H), 5.82-5.78 (m, 1H), 4.54 (d, 1H, 17.4 Hz), 4.14 (d, 1H, 17.4 Hz), 3.57 (s, 3H), 3.31-3.28 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9]([NH2:11])=[O:10])[C:7]([NH2:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].O=[CH:15][C:16]([Cl:19])([Cl:18])[Cl:17]>>[N+:1]([C:4]1[CH:12]=[C:8]2[C:7](=[CH:6][CH:5]=1)[NH:13][CH:15]([C:16]([Cl:19])([Cl:18])[Cl:17])[NH:11][C:9]2=[O:10])([O-:3])=[O:2]
Reactant: NC(=O)c1cc([N+](=O)[O-])ccc1N
Reactant: O=CC(Cl)(Cl)Cl
Product: O=C1NC(C(Cl)(Cl)Cl)Nc2ccc([N+](=O)[O-])cc21

Procedure:
5-Nitroanthranilamide (6.5 g.) and anhydrous chloral (65 ml.) were stirred together at ambient temperature, until thin layer chromatography indicated that all the 5-nitroanthranilamide had disappeared (6 days). The excess of chloral was distilled off, and the resulting syrup was heated with concentrated sulphuric acid (125 ml.) on a steam bath for 10 minutes. The reaction mixture was cooled and poured into ice/water (1 kg.), and the solid product which was precipitated was filtered off, washed with water (3×200 ml.) and crystallised from ethanol (450 ml.) to give 1,2-dihydro-6-nitro-2-trichloromethylquinazolin-4-one, m.p. 278°-280° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:69]=[CH:68][C:67]([NH:70][CH2:71][C:72]([O:74][CH2:75][CH3:76])=[O:73])=[CH:66][CH:65]=1>>[CH2:75]([O:74][C:72](=[O:73])[CH2:71][NH:70][C:67]1[CH:68]=[CH:69][C:64]([NH:63][C:30]([C@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[CH:65][CH:66]=1)[CH3:76]
Reactant: CCOC(=O)CNc1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CNc1ccc(NC(=O)[C@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)cc1
Yield: 29.7 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (100 mg, 0.173 mmol), was reacted with diisopropylethylamine (89 mg, 0.690 mmol), diphenylphosphinic chloride (Alfa Aesar, 106 mg, 0.446 mmol), then reacted with ethyl 2-(4-aminophenylamino)acetate (35 mg, 0.181 mmol) to give rac-(4-{[(2′S,3′R,4′S,5′S)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-phenylamino)-acetic acid ethyl ester (33 mg, 29%). MS (ES+) m/z [(M+H)+]: 641
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.Cl[C:17]([O:19][CH3:20])=[O:18]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:17]([O:19][CH3:20])=[O:18])[S:10][C:3]=12
Reactant: COC(=O)Cl
Reactant: Clc1ccnc2ccsc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1cc2nccc(Cl)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.7 %

Procedure:
To a stirred solution of 2 (7.0 g, 41.3 mmol) in anhydrous THF (100 mL) at −78° C. under a nitrogen atmosphere was added n-BuLi (24.7 mL, 2.5 M in hexanes, 61.8 mmol). After 1 hour, methyl chloroformate (9.6 ml, 124 mmol) was added and the reaction mixture was stirred for an extra hour at the same temperature, quenched with excess methanol and allowed to warm to room temperature. The solvent was then evaporated and the residue was purified by flash chromatography using hexane—AcOEt (70:30) as an eluent. The product from the column was re-crystallized from ethyl acetate to afford title compound 37 (4.3 g, 46% yield) as a white solid 1H NMR (400 MHz, DMSO-d6) δ(ppm): 8.75 (dd, J=0.8 and 4.8 Hz, 1H), 8.26 (d, J=0.8 Hz, 1H), 7.74 (dd, J=0.8 and 5.2 Hz, 1H), 3.93 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[C:18]([C:24]4[CH:25]=[CH:26][C:27]([O:34][CH3:35])=[C:28]([CH:33]=4)[C:29]([O:31]C)=[O:30])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.O.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[C:18]([C:24]4[CH:25]=[CH:26][C:27]([O:34][CH3:35])=[C:28]([CH:33]=4)[C:29]([OH:31])=[O:30])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(-c3ccc(OC)c(C(=O)OC)c3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(-c3ccc(OC)c(C(=O)O)c3)cc12
Temperature: 50 °C

Procedure:
To a solution of methyl 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-nitrobenzofuran-5-yl)-2-methoxybenzoate (200 mg, 0.418 mmol) in THF (12 mL)/water (4.0 mL) at room temperature was added sodium hydroxide (1.045 mL, 2.090 mmol). The reaction mixture was heated to 50° C. and maintained at the same temperature for overnight. The reaction mixture was concentrated under vacuum to remove the solvent. The residue was diluted with water, acidified with 1.5 N HCl. The solid obtained was filtered and dried under suction. Yield: 175 mg (86%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.81 (br. s, 1H). 8.58 (q, J=4.52 Hz, 1H), 8.49 (s, 1H), 8.08-8.02 (m, 2H), 7.70 (s, 1H), 7.66 (d, J=2.51 Hz, 1H), 7.53 (dd, J=8.66, 2.38 Hz, 1H), 7.49-7.42 (m, 2H), 7.25 (s, 1H), 3.89 (s, 3H), 2.85 (d, J=4.77 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18]CC)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([OH:18])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reaction time: 2 h

Procedure:
15 g (43.4 mmol) of ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate and 1.85 g (46.3 mmol) of sodium hydroxide are treated with 60 ml of ethanol and 10 ml of water, then heated to boiling under reflux for 45 minutes, the ethanol is subsequently distilled off in vacuo, the residue is treated with 46.5 ml of 1 N hydrochloric acid and left to stand in an ice-bath for 2 hours. The precipitated material is filtered off under suction, washed with water and dried to constant weight. There is obtained (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylic acid which has a decomposition point of 265°.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][C:5]([NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])([CH3:7])[CH3:6].[OH-].[Na+]>CO>[CH2:12]([O:11][C:9]([NH:8][C:5]([CH3:7])([CH3:6])[CH2:4][C:3]([OH:19])=[O:2])=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)CC(C)(C)NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(CC(=O)O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.7 %

Procedure:
A solution of 18.27 g (68.9 mmol) of 3-benzyloxycarbonylamino-3-methylbutanoic acid methyl ester in 20 mL of methanol at room temperature was treated dropwise with 51 mL of 2N NaOH (102 mmol). The mixture was stirred at room temperature for 16 hours then transferred to a separatory funnel and washed with hexane (3×). The aqueous layer was removed, cooled to 0° C. and slowly acidified to pH 2 (paper) by dropwise addition of 6N HCl. This mixture was extracted with ether (6×); combined extracts were washed with 1N HCl and brine, then dried over magnesium sulfate, filtered and solvent removed under vacuum to afford 17.26 g (68.7 mmol, 99%) of the product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:8]2[C:13](Cl)=[N:12][C:11](=[O:15])[N:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[NH:22][C:23]=1[CH3:24])=[O:5])[CH3:2].[C:31]([NH:41][NH2:42])(=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=1.C(N(CC)CC)C>CCO>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:8]2[C:13]([N:41]([C:31](=[O:40])[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)[NH2:42])=[N:12][C:11](=[O:15])[N:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[NH:22][C:23]=1[CH3:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(C)Nc2c(c(Cl)nc(=O)n2-c2ccccc2)C1c1ccccc1
Reactant: COc1cccc(C(=O)NN)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(C)Nc2c(c(N(N)C(=O)c3cccc(OC)c3)nc(=O)n2-c2ccccc2)C1c1ccccc1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
The compound of step 6 (100 mg, 0.237 mmol) was taken in 2 ml EtOH and treated successively with m-anisic hydrazide (99.6 mg, 0.6 mmol) and TEA (Triethylamine) (35 microl, 0.25 mmol) at room temperature and stirred at 60° C. for 72 h.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].O=[C:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][C@H:15]2[CH2:16][CH2:17][C@H:18]([NH:21][C:22]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:28])[CH2:19][CH2:20]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)cc(N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (5 g, 20.57 mmol) and tert-butyl (4-oxocyclohexyl)carbamate (5.6 g, 26.7 mmol) in methanol (50 mL), acetic acid (1.2 g, 20.57 mmol) was added and reaction stirred at room temperature for 8 h. Then sodium cyanoborohydride (1.6 g, 26.74 mmol) was added at 0° C. and reaction stirred overnight. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography twice eluting with ethyl acetate:hexane to afford (4 g, 44%) of less polar cis isomer and (3 g, 33%) of the pure more polar trans isomer.
Reaction SMILES: [P:1]([O:19][CH2:20][CH2:21][C:22]([CH3:26])([CH3:25])[CH2:23][OH:24])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:28].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH2:4]([O:3][P:1]([O:19][CH2:20][CH2:21][C:22]([CH3:26])([CH3:25])[C:23]([OH:28])=[O:24])([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)(CO)CCOP(=O)(OCc1ccccc1)OCc1ccccc1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: CC(C)(CCOP(=O)(OCc1ccccc1)OCc1ccccc1)C(=O)O
Reaction time: 16 h
Yield: 89.1 %

Procedure:
To a solution of the product from Example 11A (0.922 g, 2.4 mmol) in DMF (20 mL) at room temperature was added pyridinium dichromate (5.5 g), and the mixture was stirred for 16 hours. 10% citric acid was added and the reaction was extracted twice with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with a gradient starting with chloroform and ending with 5% methanol in chloroform, to give the title compound (0.839 g, 88%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2.C([Sn](CCCC)(CCCC)[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)CCC.[Li+].[Cl-]>C1(C)C=CC=CC=1>[N:27]1[CH:28]=[CH:29][C:24]([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]3)=[CH:25][CH:26]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCc2c(Br)cccc2C1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2c(cccc2-c2ccncc2)C1
Temperature: 110 °C
Reaction time: 72 h
Yield: 64 %

Procedure:
(Tet. Lett, 1995, 36, 5247) To tert-butyl 5-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.989 g, 3.17 mmol), 4-(tributylstannyl)pyridine (1.75 g, 4.75 mmol), LiCl (1.343 g, 31.7 mmol) in toluene (15 mL) was added dichlorobis(triphenylphosphine) palladium (II) (0.222 g, 0.317 mmol) and the reaction was heated to 110° C. After 72 h, the reaction was partitioned with 10% aq KF (20 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (15 mL) and dried (MgSO4). Purification by silica gel chromatography afforded 0.63 g of Intermediate 17A as clear oil (64%). 1H NMR (400 MHz, CDCl3) δ 8.66 (2 H, d, J=6.06 Hz), 7.23-7.33 (3 H, m), 7.17-7.21 (1 H, m), 7.13 (1 H, d, J=7.58 Hz), 4.65 (2 H, s), 3.55 (2 H, br. s), 2.72 (2 H, t, J=5.68 Hz), 1.50 (9 H, s) ppm.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([O:34][C:35]([N:37]([CH2:43][CH2:44][OH:45])[CH2:38][CH2:39][C:40](O)=[O:41])=[O:36])([CH3:33])([CH3:32])[CH3:31].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2N=CC=CC=2N=N1>ClCCl>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH:24]3[CH2:29][CH2:28][N:27]([C:40](=[O:41])[CH2:39][CH2:38][N:37]([CH2:43][CH2:44][OH:45])[C:35](=[O:36])[O:34][C:30]([CH3:31])([CH3:32])[CH3:33])[CH2:26][CH2:25]3)[N:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)[C:22]=12
Reactant: CC(C)(C)OC(=O)N(CCO)CCC(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCO)CCC(=O)N1CCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.8 %

Procedure:
A mixture of 3-(4-phenoxyphenyl)-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.05 g, 0.00013 mol), 3-[(tert-butoxycarbonyl)(2-hydroxyethyl)amino]propanoic acid (0.038 g, 0.000163 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.031 g, 0.000163 mol), N,N-diisopropylethylamine (0.031 g, 0.00024 mol) and 1-hydroxy-7-azabenzotriazole (0.018 g, 0.00013 mol) in anhydrous dichloromethane (5 mL) was stirred for 18 hours at room temperature. The solvent was removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield tert-butyl N-(3-{4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidino}-3-oxopropyl)-N-(2-hydroxyethyl)carbamate (0.050 g, 0.000083 mol). RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min) Rt 10.4 min. MS: MH+ 602.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]1[S:12][CH:13]([CH2:16][C:17]([OH:19])=O)[CH2:14][N:15]=1)=[CH:7]2.[NH2:31][CH2:32][C@H:33]([OH:35])[CH3:34].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[OH:35][C@H:33]([CH3:34])[CH2:32][NH:31][C:17](=[O:19])[CH2:16][CH:13]1[S:12][C:11]([C:8]2[NH:9][C:10]3[C:6]([CH:7]=2)=[CH:5][C:4]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:3][C:2]=3[CH3:1])=[N:15][CH2:14]1
Reactant: C[C@@H](O)CN
Reactant: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)NC[C@@H](C)O)S3)[nH]c12
Reaction time: 15 h
Yield: 78 %

Procedure:
To a solution of [2-(7-methyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (300 mg) and (R)-(−)-1-amino-2-propanol (78 mg) in N,N-dimethylformamide (20 mL) were added 1-hydroxybenzotriazole (137 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (194 mg) under ice-cooling, and the mixture was stirred under ice-cooling and then at room temperature for 15 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained pale-yellow crystals were washed with ethyl acetate-hexane and recrystallized from tetrahydrofuran-ethyl acetate to give the title compound (264 mg, yield 78%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH2:18][C:19]([OH:21])=[O:20])=[CH:5]2.[CH3:22][CH2:23]O>S(=O)(=O)(O)O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5]2
Reactant: Cc1ccc2nc(-c3ccccc3)c(CC(=O)O)cc2c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc2cc(C)ccc2nc1-c1ccccc1

Procedure:
0.50 g (1.80 mmol) of 13 was dissolved in 10 ml of EtOH, one drop of conc. sulfuric acid was added, and the mixture was heated under reflux for 2 h. The solvent was removed, the residue was taken up in ethyl acetate and washed 2× with water. The organic phase was dried and evaporated. The colourless oily residue is compound 16.
Reaction SMILES: Cl[S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([Cl:15])=[N:12][O:13][CH3:14])(=[O:4])=[O:3].[NH3:16]>O1CCCC1>[NH2:16][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([Cl:15])=[N:12][O:13][CH3:14])(=[O:4])=[O:3]
Reactant: CON=C(Cl)c1ccccc1S(=O)(=O)Cl
Reactant: N
Solvent: C1CCOC1
Product: CON=C(Cl)c1ccccc1S(N)(=O)=O
Temperature: -30 °C
Reaction time: 0.25 h

Procedure:
To a solution of the oil prepared in Example 3 in 100 ml of tetrahydrofuran, cooled at -30° C. with external cooling, was added dropwise 1.7 ml of ammonia. After stirring at -30° C. for about 15 minutes, the suspension was purged with N2 to remove excess ammonia, then evaporated at less than 30° C. under vacuum. After adding ice-water to the residue, the suspension was extracted with methylene chloride, dried (MgSO4) and evaporated under vacuum. The residue was triturated with hexane to yield 2.5 g of the subject compound as a crude solid, m.p. 155° to 158° C., NMR(CDCl3 +DMSO):