Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=[N:4][S:5]([C:8]1[S:9][C:10]2[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[CH2:20])[CH:14]=[CH:13][C:11]=2[N:12]=1)(=[O:7])=[O:6].[OH-].[Na+].O.Cl>CO>[CH2:18]([O:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([S:5]([NH2:4])(=[O:7])=[O:6])[S:9][C:10]=2[CH:16]=1)[CH:19]=[CH2:20]
Reactant: C=CCOc1ccc2nc(S(=O)(=O)N=CN(C)C)sc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCOc1ccc2nc(S(N)(=O)=O)sc2c1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A solution of product from Step B (0.45 gm, 1.4 mmol) in methanol (1.5 mL) was added to 2N sodium hydroxide (2 mL) and stirred at 40° C. for 1 hour. The reaction was poured into water, acidified (HCl), and the product extracted into ethyl acetate. The extract was dried (Na2SO4) and evaporated to give crude product. Upon trituration of this residue with methylene chloride, the product precipitated and was collected (0.18 gm) and shown to be identical with the product of Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11](NCCC)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)(=[O:15])=[O:14])[CH:11]([CH2:9][CH2:10][CH2:11][NH:12][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCCNC1CCC(c2ccc(F)cc2)N1S(=O)(=O)c1ccc(C)cc1
Product: Cc1ccc(S(=O)(=O)N2C(CCCNS(C)(=O)=O)CCC2c2ccc(F)cc2)cc1

Procedure:
Reaction of (2RS,5RS)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propylamine with methanesulfonyl chloride according to the general method of example Id yielded the title compound as a white solid, m.p. =123° C. and MS: m/e=455.3 (M+H+).
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]2[NH:21][CH:20]([C:22]([OH:24])=[O:23])[C:19]([CH3:26])([CH3:25])[S:18]2)[CH:12]=1>C1COCC1>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]2[N:21]([CH:1]=[O:2])[CH:20]([C:22]([OH:24])=[O:23])[C:19]([CH3:26])([CH3:25])[S:18]2)[CH:12]=1
Reactant: CC1(C)SC(c2cccnc2)NC1C(=O)O
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC1(C)SC(c2cccnc2)N(C=O)C1C(=O)O
Reaction time: 17 h
Yield: 89.4 %

Procedure:
Formic acid (17 g, 378 mmol) and acetic anhydride (13 g, 126 mmol) where combined at 10° C. A slurry of 2-(3-pyridinyl)-5,5-dimethyl-4-thiazolidinecarboxylic acid (10 g, 42 mmol), Prepared as in step 1, in THF (250 mL) was added over five minutes. The resulting clear-yellow solution was wanted slowly to ambient temperature and stirred for 17 hours, during which time it became a white suspension. The THF was removed in vacuo, and the resulting slurry was filtered to yield a white solid. The solid was rinsed with ether to give 2-(3-pyridinyl)-3-formyl-5,5-dimethyl-4-thiazolidinecarboxylic acid (10 g) which was used without further purification.
Reaction SMILES: FC(F)(F)C1C=C(C=CC=1)C([O:8][CH:9]([CH2:14][N:15]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1)[C:16](=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)[C:10]([F:13])([F:12])[F:11])=O.N>CO>[F:34][C:30]1[CH:29]=[C:28]([N:15]([CH2:14][CH:9]([OH:8])[C:10]([F:11])([F:12])[F:13])[C:16](=[O:27])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: O=C(OC(CN(C(=O)c1cccc(C(F)(F)F)c1)c1cccc(F)c1)C(F)(F)F)c1cccc(C(F)(F)F)c1
Agent: N
Solvent: CO
Product: O=C(c1cccc(C(F)(F)F)c1)N(CC(O)C(F)(F)F)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 60.9 %

Procedure:
A solution of 2,2,2-trifluoro-1-[[(3-fluorophenyl)[3-(trifluoromethyl)benzoyl]amino]-methyl]ethyl 3-trifluoromethyl-benzoate (600 mg, 1.06 mmol) from EX-662 in methanol was treated with 28% ammonia solution (122 μL). The solution was stirred at room temperature for 10 h. The reaction was quenched with water and extracted with ether. The ether layer was washed with brine and water, then dried over anhydrous MgSO4. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1:8) to give 255 mg (61%) of the desired N-(3-fluorophenyl)-N-(3,3,3-trifluoro-2-hydroxypropyl)-3-(trifluoromethyl)benzamide product as a white powder, 97% pure by HPLC analysis. 1H NMR (CDCl3) δ7.56 (m, 3H), 7.32 (m 2H), 6.98 (m, 1H), 6.90 (m, 2H1), 4.49 (dd, 1H), 4.34 (d, 1H), 4.26 (m, 1H), 4.01 (dd, 1H). 19F NMR (CDCl3) δ−64.7 (s, 3F), −80.3 (s, 3F), −111.0 (m, 1F). HRMS calcd. for C17H12F7NO2: 396.0854 [M+H]+, found: 396.0821.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][CH2:8][C@@H:9]([C@@H:17]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:18]([NH:20][NH:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[O:19])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br.[N:31]1([C:36]([CH2:38][C:39](O)=[O:40])=[O:37])[CH:35]=[CH:34][N:33]=[CH:32]1.C(N1CCOCC1)C.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)C>[CH:1]1([CH2:6][CH2:7][CH2:8][C@@H:9]([C@@H:17]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:18]([NH:20][N:21]([CH2:22][CH:23]([CH3:24])[CH3:25])[C:39](=[O:40])[CH2:38][C:36]([N:31]2[CH:35]=[CH:34][N:33]=[CH:32]2)=[O:37])=[O:19])[C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)CC(=O)n1ccnc1
Reactant: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](CCCC1CCCC1)C(=O)OC(C)(C)C
Agent: Br
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CC(=O)n1ccnc1)[C@H](CCCC1CCCC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.6 %

Procedure:
A solution of 0.510 g of 2(R)-[4-cyclopentyl-1(S)-(tert-butoxycarbonyl)-butyl]-2′-isobutyl-4-methylvalerohydrazide in 10 ml of dimethylformamide was treated in sequence with 0.308 g of 2-(1-imidazoyl)acetic acid hydrogen bromide, 0.172 g of N-ethylmorpholine and 0.286 g of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride and then stirred overnight at room temperature. The mixture was diluted with diethyl ether and washed with water and saturated aqueous sodium chloride solution. Drying over anhydrous magnesium sulphate and evaporation gave a residue which was purified by column chromatography on silica gel, using ethyl acetate/hexane (1:3) and then dichloromethane/methanol (3:1) for the elution, to give 0.255 g of 2(R)-[4-cyclopentyl-1(S)-(tert-butoxycarbonyl)-butyl]-2′-isobutyl-2′-[2-(1-imidazoyl)acetyl]-4-methylvalerohydrazide in the form of a yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](Cl)=[O:5].Cl.[CH3:9][NH:10][O:11][CH3:12].C(N(CC)CC)C>ClCCl>[CH3:12][O:11][N:10]([CH3:9])[C:4](=[O:5])[CH:3]=[C:2]([CH3:7])[CH3:1]
Reactant: CNOC
Reactant: CC(C)=CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C=C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3,3-Dimethylacryloyl chloride (28.2 mL, 0.253 mol) was slowly added to a mixture of N,O-dimethylhydroxylamine hydrochloride (27.2 g, 0.278 mol) and triethylamine (75 mL, 0.519 mol) in dichloromethane (300 mL) at 0° to 30° C. and stirred 1 h at 0° C. The resultant mixture was washed with 1 N hydrochloric acid and then with 1 N sodium hydroxide and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue vacuum distilled (60° to 70° C. at 0.2 mm Hg) to give the product, 26.8 g (74%) as a colorless oil; IR(neat): 2938 and 1660 cm-1 : MS: m/z 144 (MH+); 1H NMR(CDCl3): δ 1.91 (d, J=1.2 Hz, 3H), 2.14 (d, J=0.9 Hz, 3H), 3.20 (s, 3H), 3.68 (s, 3H), and 6.12 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[O:12][C:13]2[CH:20]=[C:19](B3OC(C)(C)C(C)(C)O3)[CH:18]=[CH:17][C:14]=2[C:15]=1[CH3:16])=[O:10].Br[C:31]1[N:36]=[C:35]([C:37]([NH2:39])=[O:38])[CH:34]=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[O:12][C:13]2[CH:20]=[C:19]([C:31]3[N:36]=[C:35]([C:37]([NH2:39])=[O:38])[CH:34]=[CH:33][CH:32]=3)[CH:18]=[CH:17][C:14]=2[C:15]=1[CH3:16])=[O:10]
Reactant: NC(=O)c1cccc(Br)n1
Reactant: Cc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Product: Cc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(-c3cccc(C(N)=O)n3)ccc12

Procedure:
6-[2-(2,4-Dichloro-benzoyl)-3-methyl-benzofuran-6-yl]-pyridine-2-carboxylic acid amide was prepared via a Suzuki coupling of ((2,4-dichlorophenyl)-[3-methyl-6-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-benzofuran-2-yl]-methanone and 6-Bromo-pyridine-2-carboxylic acid amide as described in method 6 step 2. 1H-NMR (CD3OD) δ 8.42 (s, 1H), 8.23-8.17 (m, 2H), 8.09-8.02 (m, 2H), 7.92 (d, J=8 Hz 1H), 7.64 (d, J=2 Hz, 1H), 7.58-7.51 (m, 2H), 2.64 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[CH3:14][O:15][C:16](=[O:23])[C@@H:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH2:18]>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([NH:18][C@H:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:16]([O:15][CH3:14])=[O:23])=[O:7]
Reactant: COc1cc(SC)ccc1C(=O)O
Reactant: COC(=O)[C@H](N)CC(C)C
Product: COC(=O)[C@@H](CC(C)C)NC(=O)c1ccc(SC)cc1OC

Procedure:
Prepared in a similar manner to example 4 using 2-methoxy-4-(methylthio)benzoic acid and D-leucine methyl ester. MS (M+H, 326).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]([N:15]([CH2:17][C@H:18]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:19][CH:20]=C)[CH3:16])=[O:14])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].FC1C=CC([C@H](CC=C)CN(C)C(=[O:54])C2C=C(C(F)(F)F)C=C(C(F)(F)F)C=2)=CC=1>>[C:1]([C:3]1[CH:4]=[C:5]([C:13]([N:15]([CH2:17][C@H:18]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:19][CH:20]=[O:54])[CH3:16])=[O:14])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2]
Reactant: C=CC[C@H](CN(C)C(=O)c1cc(C#N)cc2ccccc12)c1ccc(F)cc1
Reactant: C=CC[C@H](CN(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(F)cc1
Product: CN(C[C@@H](CC=O)c1ccc(F)cc1)C(=O)c1cc(C#N)cc2ccccc12

Procedure:
The compound was synthesized in an analogous way to that of Method 20b but using 3-cyano-N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-N-methyl-1-naphthamide rather than N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-N-methyl-3,5-bis(trifluoromethyl)benzamide (yield, 78%). 1H NMR (400 MHz, CDCl3): 2.4-2.6 (m, 1H), 2.7 (s, 3H), 2.8-4.4 (cm, 4H), 6.2 (s, <1H), 6.8-7.8 (cm, 9H), 8.2 (s, 1H), 9.8 (s, 1H).
Reaction SMILES: [CH:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([OH:12])[C:6]2=[N:5][C:4]=1[CH3:13])=[O:2].[C:14]([O:18][C:19]([NH:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:23]=1[CH2:24]Cl)=[O:20])([CH3:17])([CH3:16])[CH3:15].[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[C:14]([O:18][C:19]([NH:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:23]=1[CH2:24][O:12][C:11]1[C:6]2[N:7]([C:3]([CH:1]=[O:2])=[C:4]([CH3:13])[N:5]=2)[CH:8]=[CH:9][CH:10]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1cccc(NC(=O)OC(C)(C)C)c1CCl
Reactant: Cc1nc2c(O)cccn2c1C=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1cccc(NC(=O)OC(C)(C)C)c1COc1cccn2c(C=O)c(C)nc12

Procedure:
Starting from 3-formyl-8-hydroxy-2-methylimidazo[1,2-a]pyridine (2.4 g), 2-tert-butoxycarbonylamino-6-methylbenzyl chloride (4.2 g), sodium iodide (2.5 g) and sodium carbonate (3.7 g) in acetone (400 ml) analogously using the process of Example B1 gives, after recrystallization from diisopropyl ether/ethyl acetate, 4.4 g (80%) of the title compound of m.p. 189-191° C.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][C@H:24]4[CH2:29][CH2:28][C@@H:27]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH2:26][CH2:25]4)[CH:19]=3)[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Li+].O1CCCC1.O>>[C:30]1([C@@H:27]2[CH2:26][CH2:25][C@H:24]([O:23][C:18]3[CH:19]=[C:20]4[C:15](=[CH:16][CH:17]=3)[CH:14]=[C:13]([CH2:12][N:9]3[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]3)[CH:22]=[CH:21]4)[CH2:29][CH2:28]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)C1CCN(Cc2ccc3cc(O[C@H]4CC[C@@H](c5ccccc5)CC4)ccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CCN(Cc2ccc3cc(O[C@H]4CC[C@@H](c5ccccc5)CC4)ccc3c2)CC1

Procedure:
A solution of 1-[6-(cis-4-phenyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid ethyl ester (0.9 g, 2 mmol) and lithium hydroxide (457 mg, 19.1 mmol) in tetrahydrofuran (7.74 mL, 95.4 mmol) and water (1.72 mL, 95.4 mmol) was stirred at room temperature overnight. LCMS showed a single desired product peak Rt=1.60 min, m/z=444.35, [M+1], 100%. The solvent was concentrated and neutralized with conc. HCl and concentrated and purified on HPLC to give product (245 mg, 30%).
Reaction SMILES: [Si](I)(C)(C)C.[CH3:6][O:7][C:8](=[O:46])[CH:9]([NH:38]C(OC(C)(C)C)=O)[CH2:10][S:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[C:30]4[O:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[C:29]=4[CH:28]=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.C(Cl)Cl.C(=O)(O)[O-].[Na+]>O>[CH3:6][O:7][C:8](=[O:46])[CH:9]([NH2:38])[CH2:10][S:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[CH:21][C:22]([C:25]3[C:30]4[O:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[C:29]=4[CH:28]=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)C(CSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)NC(=O)OC(C)(C)C
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(N)CSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
TMS-I (290 mg, 0.21 mL, 1.45 mmol) was added dropwise to a stirred solution of methyl-2-tert-butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethyl-sulfanyl)-propionate (748 mg, 1.32 mmol) in anhyd methylene chloride (20 mL). The reaction mixture was stirred at room temperature for 20-30 min (TLC control), and then diluted with water (20 mL). Sat'd aq sodium bicarbonate solution was added to adjust the solution to pH 8-9. The reaction mixture was extracted with diethyl ether (2×30 mL). The combined organic extracts were washed with water, sat'd aq NaCl, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography (5% methanol in methylene chloride) afforded the title compound has a pale yellow solid (596 mg).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH:30]=O>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:30][C:26]1[O:25][CH:29]=[CH:28][CH:27]=1
Reactant: O=Cc1ccco1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC(Br)=Cc1ccco1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Mix carbon tetrabromide (49.8 g, 150 mmol) and methylene chloride (75 mL) and cool to 0° C. Add, by dropwise addition, a solution of triphenylphosphine (78.6 g, 300 mmol) in methylene chloride (75 mL). Stir at 0° C. for 30 minutes. Add, by dropwise addition, a solution of 2-furan-carboxaldehyde (7.57 g, 78.8 mmol) in methylene chloride (75 mL). Remove the cooling bath and stir at room temperature until the reaction is complete. Pour onto ethyl ether and water, separate the organic layer and dry (MgSO4). Filter and evaporate the solvent in vacuo. Purify by silica gel chromatography to yield the title compound.
Reaction SMILES: C(Cl)CCl.[NH2:5][C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)=[CH:8][CH:7]=1.[CH3:17][N:18]1[C:22]([CH2:23][NH:24][CH3:25])=[CH:21][C:20]2[CH:26]=[CH:27][S:28][C:19]1=2.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C.O>[NH2:5][C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([N:24]([CH3:25])[CH2:23][C:22]2[N:18]([CH3:17])[C:19]3[S:28][CH:27]=[CH:26][C:20]=3[CH:21]=2)=[O:16])=[CH:8][CH:7]=1
Reactant: CNCc1cc2ccsc2n1C
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN(Cc1cc2ccsc2n1C)C(=O)/C=C/c1ccc(N)nc1
Yield: 34.4 %

Procedure:
EDC (132 mg, 0.69 mmole) was added to a solution (E)-3-(6-aminopyridin-3-yl)acrylic acid (95 mg, 038 mmole), 6-methyl-5-(methylaminomethyl)-6H-thieno[2,3-b]pyrrole (142 mg, 0.69 mmole). HOBt.H2O (93 mg, 0.69 mmole), and Et3N (0.16 mL, 1.16 mmole) in dry DMF (3 mL) at RT. After 18 hr the mixture was diluted with H2O and extracted with EtOAc (3×). The combined organic layers were dried (MgSO4) and concentrated. The residue was taken up in MeOH and collected by filtration to give the title compound (65 mg, 34%) as a yellow solid: 1H NMR (400 MHz, d6-DMSO) δ 8.15 (s, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.43 (d, J=15.2 Hz, 1H), 6.96 (m, 2H), 6.43 (m, 3H), 4.70 (s, 2H), 3.61 (s, 3H), 3.00 (s, 3H); for minor rotomer δ 4.87 (s, 2H), 2.90 (s, 3H); MS (ES) m/e 327 (M+H)+.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][C:10]([C:12]2[CH:25]=[CH:24][C:23]3[O:22][C:21]4[C:16](=[CH:17][C:18]([C:26](=[O:36])[CH2:27][CH2:28][CH2:29][N:30]5[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]5)=[CH:19][CH:20]=4)[CH2:15][C:14]=3[CH:13]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].CO.[OH-].[Na+]>O1CCCC1.O>[N:1]1([CH2:7][CH2:8][CH2:9][CH:10]([C:12]2[CH:25]=[CH:24][C:23]3[O:22][C:21]4[C:16](=[CH:17][C:18]([CH:26]([CH2:27][CH2:28][CH2:29][N:30]5[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]5)[OH:36])=[CH:19][CH:20]=4)[CH2:15][C:14]=3[CH:13]=2)[OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CCCN1CCCCC1)c1ccc2c(c1)Cc1cc(C(=O)CCCN3CCCCC3)ccc1O2
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: OC(CCCN1CCCCC1)c1ccc2c(c1)Cc1cc(C(O)CCCN3CCCCC3)ccc1O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled, stirred solution of 25.6 g (0.053 moles) of 2,7-bis(4-piperidinobutyryl)xanthene dissolved in 200 ml of tetrahydrofuran is added a solution of 4.2 g (0.11 moles) of sodium borohydride contained in a solution of 50 ml of methanol and 5 ml of a 10% sodium hydroxide solution. The resulting mixture is allowed to warm gradually to room temperature and stirring continued overnight. The reaction mixture is diluted with water and the solid which forms is filtered, washed with water and air dried. The solid product is dissolved in a 10% hydrochloric acid solution, filtered and the filtrate made alkaline with a 10% sodium hydroxide solution. The alkaline filtrate is extracted with methylene chloride. The organic extract is then washed with water, followed by a wash of saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness in vacuo. The residue containing the desired α,α'-bis(3-piperidinopropyl)xanthene-2,7-dimethanol is recrystallized twice from benzene to yield a product having a m.p. of 145°-6° C.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH:28]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[C@H:29]([C:45]([NH:47][C@H:48]([C:53](O)=[O:54])[CH2:49][CH:50]([CH3:52])[CH3:51])=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:33][CH:32]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[NH:28]([C:56]([O:58][C:59]([CH3:61])([CH3:60])[CH3:62])=[O:57])[C@H:29]([C:45]([NH:47][C@H:48]([C:53]([NH:1][C@H:2]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)=[O:54])[CH2:49][CH:50]([CH3:52])[CH3:51])=[O:46])[CH2:30][C:31]1[CH:32]=[CH:33][C:34]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:35][CH:36]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)OC(=O)NCCCCNC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCCCCNC(=O)OC(C)(C)C
Yield: 33.1 %

Procedure:
compound SP296P. Same procedure as above with Trp-NH(CH2)4NHBoc (264.7 mg, 0.706 mmol), N-Boc-Tyr(Bn)-Leu-OH (342.6 mg, 0.707 mmol), EDC (150.3 mg, 0.784 mmol), HOBt (105.3 mg, 0.78 mmol) and NEt3 (0.39 mL, 2.8 mmol) in CH2Cl2/DMF (3 mL, 1/1). The crude residue was triturated with Et2O/pentane to give a white solid (196.7 mg, 33%). 1H NMR (300 MHz, DMSO-d6) δ 0.82 (d, J=6.2 Hz, 3H, CH3 Leu), 0.86 (d, S=6.2 Hz, 3H, CH3 Leu), 1.25-1.41 (m, 4H, 2 CH2 putrescine), 1.29 (s, 9H, (CH3)3), 1.36 (s, 9H, (CH3)3), 2.59-3.1 (m, 8H, CH2 Tyr, CH2 Trp, 2 CH2 putrescine), 4.09 (m, 1H, CHα), 4.32 (m, 1H, CHα), 4.44 (m, 1H, CHα), 5.02 (s, 2H, CH2 (Bn)), 6.71 (m, 1H), 6.87-7.4 (m, 14 aromatic H), 7.54 (d, J=7.7 Hz, 1H), 7.79 (m, 1H), 7.94 (m, 2H), 10.8 (s, 1NH). 13C NMR (75 MHz, DMSO-d6) δ 20.3, 21.8, 22.7 (2 CH3, CH Leu), 24.9, 25.5 (2 CH2 putrescine), 26.7 (CH2 Trp), 26.9, 27 (2 (CH3)3), 34.9 (CH2 Tyr), 37, 39.2, 39.7 (2 CH2 putrescine, CH2 Leu), 49.8, 52.2, 54.6 (CHα Ala, Tyr, Trp), 67.8 (CH2 (Bn)), 76, 76.8 (2 C(CH3)3), 108.6, 109.9, 113, 116.9, 117.1, 119.5, 122.1, 126.1, 126.3, 126.5, 127.1, 128.9, 129.1, 134.7, 136 (19 aromatic C), 154, 154.3, 155.6 (Car-O, 2 CO carbamate), 169.5, 170.3, 170.4 (3 CO amide). Anal. Calcd. for C47H64N6O8, 0.5H2O: C, 66.40; H, 7.70; N, 9.88. Found: C, 66.34; H, 7.67; N, 10.07.
Reaction SMILES: [CH2:1]([N:3]1[CH2:12][CH2:11][C@:10]2([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=3)[C@H:5]([CH2:6][C:7]3[C:23]([CH3:24])=[C:22]([C:25]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[O:26])[NH:21][C:8]=3[CH2:9]2)[CH2:4]1)[CH3:2].B(Br)(Br)Br>>[CH2:1]([N:3]1[CH2:12][CH2:11][C@:10]2([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)[C@H:5]([CH2:6][C:7]3[C:23]([CH3:24])=[C:22]([C:25]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[O:26])[NH:21][C:8]=3[CH2:9]2)[CH2:4]1)[CH3:2]
Reactant: CCN1CC[C@@]2(c3cccc(OC)c3)Cc3[nH]c(C(=O)N4CCCC4)c(C)c3C[C@@H]2C1
Agent: BrB(Br)Br
Product: CCN1CC[C@@]2(c3cccc(O)c3)Cc3[nH]c(C(=O)N4CCCC4)c(C)c3C[C@@H]2C1
Yield: 23.3 %

Procedure:
0.63 g (1.37 mmol) of (±)-trans-6-ethyl-8a-(3-methoxyphenyl)-3-methyl-2-pyrrolidinocarbonyl-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-g]isoquinoline were treated with 0.77 ml (8.22 mmol) of boron tribromide as described in example 2. The residue was purified by flash chromatography (EtOAc/MeOH/conc. NH4OH 80:20:0.5). The resulting solid was triturated with Et2O, yielding 0.13 g of the title compound. M.p.=224°-226° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[C:13]([N+:16]([O-])=O)[CH:14]=2)[N:9]=[CH:8][C:7]=1[C:26]#[N:27].C(O)(=O)C>CO.[Fe]>[NH2:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[N:19]1[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]1)[N:9]=[CH:8][C:7]([C:26]#[N:27])=[C:6]2[NH:5][C:4]1[CH:28]=[CH:29][C:30]([F:31])=[C:2]([Cl:1])[CH:3]=1
Reactant: CN1CCN(c2cc3ncc(C#N)c(Nc4ccc(F)c(Cl)c4)c3cc2[N+](=O)[O-])CC1
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCN(c2cc3ncc(C#N)c(Nc4ccc(F)c(Cl)c4)c3cc2N)CC1

Procedure:
In the manner of Example 23 4-(3-chloro-4-fluoroanilino)-7-(4-methyl-1-piperazinyl)-6-nitro-3-quinolinecarbonitrile was reduced with iron powder and acetic acid in MeOH to give the title compound as an amorphous solid; ms 411.2 (M+H)+, 206.2 (M+2H)+2.