Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([NH2:11])[C:5]=2[N:4]=[CH:3][CH:2]=1.CO.[NH4+].[OH-].[CH3:16][CH2:17][O:18]C(C)=O>>[N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C@@H:6]([NH:11][C:17](=[O:18])[CH3:16])[C:5]=2[N:4]=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: NC1CCCc2nccnc21
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N[C@@H]1CCCc2nccnc21
Reaction time: 2 h

Procedure:
Following the general procedure, 5,6,7,8-tetrahydroquinoxalin-5-ylamine (263 mg, 1.76 mmol), CALB (45 mg) and EtOAc (7.0 mL) were stirred for 2 hours. The conversion determined from 1H NMR by integration of the peaks at 4.94 ppm (CHNHAc) and 4.01 ppm (CHNH2) was 50%. Flash chromatography of the material on silica gel using 1:4 MeOH:EtOAc followed by 1:1:4 NH4OH:MeOH:EtOAc furnished the (R)-N-(5,6,7,8-tetrahydroquinoxalin-5-yl)acetamide ((157 mg, 47%) in 98% ee (chiral GC method: 130° C. for 180 min, (S)-enantiomerrt=183.5 min, (R)-enantiomerrt=183.7 min); [α]D=−78° (c 1.40, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 1.62-1.75 (m, 1H), 1.85-2.04 (m, 2H), 2.06 (s, 3H), 2.48-2.57 (m, 1H), 2.90-3.13 (m, 2H), 4.96-5.03 (m, 1H), 6.34 (br s, 1H), 8.35 (d, 1H, J=2.4 Hz), 8.39 (d, 1H, J=2.4 Hz); 13C NMR (CDCl3) δ 19.9, 23.6, 29.7, 31.8, 50.6, 142.1, 143.3, 152.0, 154.0, 170.7; MS m/z: 214 (M+Na+). The unreacted (S)-5,6,7,8-tetrahydroquinoxalin-5-ylamine (was isolated in 45% yield (118 mg) and 99% ee ((S)-enantiomerrt=25.9 min, (R)-enantiomerrt=29.0 min); [α]D=+61° (c 0.71, CHCl3); 1H NMR (CDCl3, 300 MHz): δ 1.62-1.79 (m, 1H), 1.80-2.18 (m, 4H), 2.18-2.30 (m, 1H), 2.91-3.01 (m, 2H), 4.07 (dd, 1H, J=8.4, 5.4 Hz), 8.32-8.38 (m, 2H); 13C NMR (CDCl3): δ 19.7, 31.7, 32.2, 51.5, 142.0, 142.5, 152.6, 155.4; MS m/z: 150 (M+H+), 133 (M-NH2).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:5]=1[NH:13][CH2:14][CH2:15][NH:16][C:17]1[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:18]=1[N+:26]([O-])=O)([O-])=O.[H][H].[S:31](=[O:35])(=[O:34])([OH:33])[OH:32]>[Pd].CO>[S:31]([OH:35])([OH:34])(=[O:33])=[O:32].[NH2:26][C:18]1[CH:19]=[CH:20][C:21]([NH2:23])=[CH:22][C:17]=1[NH:16][CH2:15][CH2:14][NH:13][C:5]1[CH:6]=[C:7]([NH2:10])[CH:8]=[CH:9][C:4]=1[NH2:1]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc([N+](=O)[O-])c(NCCNc2cc([N+](=O)[O-])ccc2[N+](=O)[O-])c1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CO
Product: Nc1ccc(N)c(NCCNc2cc(N)ccc2N)c1

Procedure:
150 ml of methanol were introduced into a 0.3 liter autoclave, 16.7 g (0.2 mole) of N,N'-bis-(2,5-dinitrophenyl)-1,2-diaminoethane were dissolved therein and 2 g of palladium on active carbon 10% (Degussa) were added. After the autoclave had been closed and blanketed with nitrogen, hydrogenation was carried out under a pressure of 3 bar and at a temperature of 35 to 40° C. until no more hydrogen was taken up. The mixture was emptied onto a pressure filter, the residue was dissolved in 100 ml of N-methyl pyrrolidone at 100° C., the catalyst was filtered off using a pressure filter and, after cooing of the filtrate to 5-10° C., 9.8 g (0.1 mole) of 80% sulfuric acid were added dropwise. The jelly-like precipitate was stirred with 200 ml of methanol. The crystallized product was filtered off under suction, washed with methanol and dried.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([OH:17])=O)[S:14][C:5]=3[C:4]=2[CH:3]=1.C(Cl)(=O)C([Cl:21])=O.CN(C)C=O>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([Cl:21])=[O:17])[S:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C(O)c1cc2c(s1)-c1cc(Br)ccc1OC2
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc2c(s1)-c1cc(Br)ccc1OC2
Reaction time: 2 h

Procedure:
To a suspension of 8-bromo-4H-thieno[3,2-c]chromene-2-carboxylic acid 3bp (1.50 g, 4.82 mmol, 1 equiv) in dichloromethane (45 mL) at 24° C. was sequentially added oxalyl chloride (3.1 mL, 6.3 mmol, 1.3 equiv, 2.0 M in dichloromethane) and N,N-dimethylformamide (56 μL, 0.72 mmol, 0.15 equiv), as in General Procedure B. After 2 hr, the clear yellow solution was concentrated in vacuo (˜20 mm Hg) to afford crude 4bp.
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6]1[C:7]([N+:14]([O-])=O)=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10]>[Fe].C(O)(=O)C>[NH2:14][C:7]1[C:6]([O:5][CH3:4])=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[O:10]
Reactant: COc1cccc(C=O)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cccc(C=O)c1N
Reaction time: 3 h
Yield: 85 %

Procedure:
To a 1:1 mixture of ethanol and acetic acid was added 3-methoxy-2-nitrobenzaldehyde (1 eq) and Fe dust (3 eq) was added in portions. The reduction was complete in 3 h. The reaction mixture was filtered and then concentrated and partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate and dried and concentrated to give 2-amino-3-methoxybenzaldehyde in 85% yield. ES/MS m/z 151 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:19])[C:10]2[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=2[Cl:18])[CH:5]=[CH:4][CH:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:16][C:15]1[CH:14]=[C:13]([Cl:17])[CH:12]=[C:11]([Cl:18])[C:10]=1[C:9]([NH:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([NH:1][CH:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)[N:7]=1)=[O:19]
Reactant: CN1CCC(=O)CC1
Reactant: Nc1cccc(NC(=O)c2c(Cl)cc(Cl)cc2Cl)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN1CCC(Nc2cccc(NC(=O)c3c(Cl)cc(Cl)cc3Cl)n2)CC1
Yield: 38.3 %

Procedure:
Using a method similar to Example 104 using N-(6-amino-pyridin-2-yl)-2,4,6-trichloro-benzamide (Preparation 55, 375 mg, 1.18 mmol), 1-methyl-4-piperidone (270 mg, 0.29 mL, 2.37 mmol), 1,2-dichloroethane (15 mL), powdered molecular sieves 4 Å (1 g), glacial acetic acid (0.21 g, 0.20 mL, 3.54 mmol), sodium triacetoxyborohydride (625 mg, 2.95 mmol) gives the title compound (187 mg, 45% yield): dihydrochloride salt: mass spectrum (ion spray): m/z=412.0 (M+1), 1H NMR δ (CDCl3) 7.78 (s, 1H), 7.56 (d, 1H), 7.45 (t, 1H), 7.36 (s, 2H), 6.18 (d, 1H), 4.26 (d, 1H), 3.55 (m, 1H), 2.73 (d, 2H), 2.28 (s, 3H), 2.11 (m, 4H), 1.50 (m, 2H).
Reaction SMILES: [C:1]1(C)C=CC=CC=1.[CH2:8]([O:15][C:16]([NH:18][C@H:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)(=O)C>[CH2:8]([O:15][C:16]([N:18]1[CH:19]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])[C:25](=[O:27])[O:26][CH2:1]1)=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Cc1ccccc1
Agent: C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)CCC1C(=O)OCN1C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
To 1 liter of toluene were added 300 g of DL-N-benzyloxycarbonylglutamic acid, 48 g of paraformaldehyde and 12 g of p-toluenesulfonic acid monohydrate, and azeotropic dehydration was then carried out for 1 hour. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the oily substance thus obtained was dissolved in 500 ml of ethyl acetate, after which the resulting solution was washed with water and then dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure to obtain oily DL-3-benzyloxycarbonyl-4-(2-carboxyethyl)oxazolidin-5-one.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([F:8])[N:5]2[N:9]=[C:10]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:11]([C:12]([N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:13])=[C:4]2[CH:3]=1.[CH3:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O>[C:17]([O:16][C:15]([N:14]([CH3:22])[C:12]([C:11]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[N:9][N:5]2[C:6]([F:8])=[CH:7][C:2]([C:32]3[CH:33]=[C:34]([CH:38]=[CH:39][C:31]=3[CH3:30])[C:35]([OH:37])=[O:36])=[CH:3][C:4]=12)=[O:13])=[O:21])([CH3:20])([CH3:19])[CH3:18]
Reactant: CN(C(=O)OC(C)(C)C)C(=O)c1c(-c2ccc(F)cc2)nn2c(F)cc(Cl)cc12
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(C(=O)O)cc1-c1cc(F)n2nc(-c3ccc(F)cc3)c(C(=O)N(C)C(=O)OC(C)(C)C)c2c1
Temperature: 95 °C
Reaction time: 18 h

Procedure:
To a degassed mixture containing tert-butyl 5-chloro-7-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbonyl(methyl)carbamate (0.060 g, 0.14 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (0.047 g, 0.18 mmol), sodium carbonate (0.043 g, 0.43 mmol), dioxane (1.2 mL) and water (0.24 mL) was added tetrakis(tiphenylphosphine)palladium(0) (0.005 g, 0.004 mmol). The mixture was stirred at 95° C. for 18 h. The mixture was cooled to room temperature, filtered to remove solids and adjusted to below pH 4 with 1N aqueous hydrochloric acid (2.0 mL). Water was added (10 mL) and the aqueous portion was extracted with ethyl acetate (2×15 mL). The combined organic portions were washed with brine (20 mL) and dried over magnesium sulfate. The mixture was filtered and concentrated to afford 3-(3-(tert-butoxycarbonyl(methyl)carbamoyl)-7-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl)-4-methylbenzoic acid as a residue which was used without further purification. LCMS retention time: 2.725 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3OH/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3OH/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 522 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[NH:4][CH2:3]1.[CH:23]([N:26]=[C:27]=[O:28])([CH3:25])[CH3:24]>ClCCCl>[CH:23]([NH:26][C:27]([N:4]1[CH2:3][C:2]([CH3:22])([CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:13]=1)=[O:28])([CH3:25])[CH3:24]
Reactant: CC(C)N=C=O
Reactant: CC1(C)CNC(c2ccc(C(F)(F)F)cc2)c2ccccc21
Solvent: ClCCCl
Product: CC(C)NC(=O)N1CC(C)(C)c2ccccc2C1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 25-mL round-bottomed flask was charged with 4,4-dimethyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (366 mg, 1.2 mmol), iso-propyl isocyanate (141 μL, 1.4 mmol), DCE (5 mL) and stirred at RT for 1 h. Then the solvent was removed under vacuum and the product was purified by recrystallization from a mixture of ether/hexane. MS (ESI, positive ion) m/z: 391 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[O:15][CH3:16])=[CH:12][C:11](I)=[CH:10][CH:9]=2)=[O:4].[OH-].[Na+].[C:20](O)(=[O:22])C>CO.O>[CH:20]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]=[CH:6][C:5]([C:3]([OH:2])=[O:4])=[C:14]2[O:15][CH3:16])=[O:22]
Reactant: COC(=O)c1cnc2ccc(I)cc2c1OC
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1c(C(=O)O)cnc2ccc(C=O)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the suspension of 6-iodo-4-methoxy-quinoline-3-carboxylic acid methyl ester (example 1d) (5.91 g, 17.2 mmol) in methanol (20 mL) was slowly added the solution of sodium hydroxide (2.76 g, 69 mmol) in water (10 mL). The mixture was stirred at room temperature for 3 hours. The solution was adjusted pH=5.0 using aqueous acetic acid solution. After adding more water, the solid was collected by filtration, washed with water and dried to obtain 6-formyl-4-methoxy-quinoline-3-carboxylic acid. LC-MS m/e 330 (MH+)
Reaction SMILES: C(OC([NH:8][C@H:9]([CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[CH2:10][N:11]1[C:16](=[O:17])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[F:26])=[C:14]([CH3:27])[N:13]([CH2:28][C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=2[F:36])[C:12]1=[O:37])=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:8][C@H:9]([CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[CH2:10][N:11]1[C:16](=[O:17])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[F:26])=[C:14]([CH3:27])[N:13]([CH2:28][C:29]2[C:30]([F:36])=[CH:31][CH:32]=[CH:33][C:34]=2[F:35])[C:12]1=[O:37]
Reactant: COc1cccc(-c2c(C)n(Cc3c(F)cccc3F)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)C3CCCCC3)c2=O)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3F)c(=O)n(C[C@H](N)C3CCCCC3)c2=O)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To compound 2c (300 mg, 0.5 mmol) in dichloromethane (DCM, 2 mL) was added TFA (2 mL) and the reaction mixture was stirred at ambient temperature for 1 hour. Volatiles were evaporated and the residue was partitioned between saturated NaHCO3/water and EtOAc. The organic layer was dried (sodium sulfate), evaporated, purified by reverse phase HPLC (C-18 column, 15-75% ACN/water) to give compound 2d. MS (CI) m/z 502.20 (MH+).
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38]S(CC1C=CC=CC=1)(=O)=O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:49][C:50]([F:67])([F:66])[C:51]1[CH:52]=[C:53]([CH:59]=[C:60]([C:62]([F:65])([F:64])[F:63])[CH:61]=1)[CH2:54][S:55](Cl)(=[O:57])=[O:56]>>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:55]([CH2:54][C:53]1[CH:52]=[C:51]([C:50]([F:67])([F:66])[F:49])[CH:61]=[C:60]([C:62]([F:65])([F:64])[F:63])[CH:59]=1)(=[O:57])=[O:56])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: O=S(=O)(Cl)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 79 %

Procedure:
To the methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (Step 6, Example 1) was added 3,5-bis(trifluoromethyl)benzylsulfonyl chloride according to the procedure in Example 1 Step 7 to generate the product in 79% yield.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=[O:3])C.[Na+].C([BH3-])#N.[Na+].[C:19]([O:23][C:24]([C:26]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([C:26]1([NH2:31])[CH:30]=[CH:29][O:3][CH:28]=[CH:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)C1(N)CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)(C)OC(=O)C1(N)C=COC=C1

Procedure:
An alternative route for the preparation of some 1,3,4-trisubstituted cyclopentanes within the scope of the instant invention is given in Scheme 11. Reductive alkylation, using for example sodium triacetoxyborohydride or sodium cyanoborohydride, of a cycloalkyl amino-acid 11-2, such as 1-aminocyclopentane carboxylic acid t-butyl ester (Z=single bond) or a heterocyclic amino-acid, such as 4-aminopyran-4-yl carboxylic acid t-butyl ester (Z=O) with the ketone-alcohol 11-1 (Scheme 4) gives 11-3 and 11-4 as a mixture of C-1 isomers which may be separated. These intermediates can then be converted to the final product(s) 11-5 and/or 11-6 as described in Scheme 5.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=O.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O.CCOC(C)=O.C(=O)([O-])[O-].[Na+].[Na+]>[Cl:1][CH2:2][CH2:3][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1
Reactant: O=C(CCl)c1c[nH]c2ncccc12
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: ClCCc1c[nH]c2ncccc12
Reaction time: 16 h

Procedure:
A stirred solution of 2-chloro-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethanone (12.5 g) in TFA at room temperature is treated with triethylsilane (72 mL, 7 eq.), stirred for 16 h, diluted with EtOAc and saturated sodium carbonate to pH 8. The phases are separated and the organic phase is dried over MgSO4 and concentrated in vacuo. The resultant residue is purified by flash chromatography (silica gel, 10% EtOAc in ether as eluent) to give the title pyrrolo[2,3-b]pyridine compound, identified by NMR and mass spectral analyses.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:21][CH:20]2[C:8]([CH3:33])([CH:9]3[CH:17]([CH:18]([OH:22])[CH2:19]2)[CH:16]2[C:12]([CH3:31])([CH:13]([CH:23]([CH3:30])[CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:14][CH2:15]2)[CH:11]([OH:32])[CH2:10]3)[CH2:7][CH2:6]1.[Br:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38](O)=[O:39].C(N1CCOCC1)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38]([NH:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:21][CH:20]2[C:8]([CH3:33])([CH:9]3[CH:17]([CH:18]([OH:22])[CH2:19]2)[CH:16]2[C:12]([CH3:31])([CH:13]([CH:23]([CH3:30])[CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:14][CH2:15]2)[CH:11]([OH:32])[CH2:10]3)[CH2:7][CH2:6]1)=[O:39]
Reactant: COC(=O)CCC(C)C1CCC2C3C(O)CC4CC(OCCN)CCC4(C)C3CC(O)C12C
Reactant: O=C(O)c1cccc(Br)c1
Agent: CCN1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCC(C)C1CCC2C3C(O)CC4CC(OCCNC(=O)c5cccc(Br)c5)CCC4(C)C3CC(O)C12C
Temperature: 25 °C
Reaction time: 20.5 h
Yield: 47 %

Procedure:
932 mg of methyl 4-[3-(2-aminoethoxy)-7,12-dihydroxy-10,13-dimethylhexadecahydrocyclopenta[a]phenanthren-17-yl]pentanoate (Example 1d) and 402 mg of 3-bromobenzoic acid are dissolved in 20 ml of anhydrous DMF and first 656 mg of O[(cyano(ethoxycarbonyl)methylene)amino]-1,1,3,3-tetramethyluronium tetrafluoroborate (TOTU) (Proceedings of the 21st European Peptide Symposium, Peptides 1990, Editors E. Giralt and D. Andreu, Escom, Leiden, 1991) and then 760 μL of N-ethylmorpholine are added at 0° C. The reaction mixture is stirred at RT for 20.5 hours and then poured into 100 ml of a 10% aqueous NaHCO3 solution. It is extracted 3 times using 150 ml of EA each time. The extract is dried over Na2SO4 and the solvent is removed in vacuo. Chromatography on silica gel using EA yields 610 mg of a viscous oil.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:24])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1)[CH3:12]>>[CH2:11]([O:13][C:14](=[O:24])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=2)=[O:10])[CH:18]=1)[CH3:12]
Reactant: O=C(O)c1cccc(Br)n1
Reactant: CCOC(=O)COc1cccc(N)c1
Product: CCOC(=O)COc1cccc(NC(=O)c2cccc(Br)n2)c1

Procedure:
6-Bromo-pyridine-2-carboxylic acid (250 mg, 1.24 mmol) was coupled to aniline (64)(241 mg, 1.24 mmol) using Method C to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][CH:4]=1.ClC1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=1.[OH-].[K+]>CS(C)=O>[OH:7][C:6]1[CH:8]=[CH:9][C:3]([O:2][C:1]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)=[CH:4][CH:5]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: COc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 0 °C
Yield: 29.9 %

Procedure:
40 ml of dimethyl sulfoxide, 5.0 g of hydroquinone monomethyl ether, 5.0 g of 2-chloro-5-trifluoromethylpyridine and 2.3 g of potassium hydroxide were reacted at 150° C. for 3 hours with stirring. After cooling, the reaction product was added to a suitable amount of ice-water, and extracted with methylene chloride. The extract was washed with water and dried over anhydrous sodium sulfate, followed by distilling off the methylene chloride. The residue containing 2-(4-methoxyphenoxy)-5-trifluoromethylpyridine was mixed with 5.0 g of pyridine hydrochloride and heated at 140°-160° C. for 2 hours with stirring. After cooling the system, the reaction product was added to a suitable amount of ice-water and extracted with methylene chloride. This methylene chloride layer was back-extracted with a 5% sodium hydroxide aqueous solution, and the extract was acidified with 30% concentrated hydrochloric acid to obtain a solid material. This solid material was filtered out and dried to obtain 2.1 g of 2-(4-hydroxyphenoxy)-5-trifluoromethylpyridine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:5]=[CH:4][C:3]=1[C:20](=[O:22])[CH3:21].Br[CH2:24][C:25]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:26]=1[O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(#N)C>[C:20]([C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:7][C:2]=1[O:1][CH2:24][C:25]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:26]=1[O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])(=[O:22])[CH3:21]
Reactant: CCOC(=O)COc1c(C)cccc1CBr
Reactant: CC(=O)c1ccc(OCc2ccc3ccccc3n2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCOC(=O)COc1c(C)cccc1COc1cc(OCc2ccc3ccccc3n2)ccc1C(C)=O
Temperature: 50 °C

Procedure:
1-[2-Hydroxy-4-(quinolin-2-ylmethoxy)-phenyl]-ethanone (185 mg, 0.63 mmol, example 58) is dissolved in 2:1 DMF/acetonitrile (6 mL). Ethyl (2-bromomethyl-6-methyl-phenoxy)-acetate (272 mg, 0.95 mmol, example 43b) and K2CO3 (177 mg, 1.26 mmol) are added and the contents are heated to 50° C. for 2 days. The reaction is cooled to r.t. and the volume reduced under a nitrogen stream at 40° C. The contents are partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer is further extracted with ethyl acetate (2×50 mL). The organic fractions are combined and washed with brine (3×75 mL), dried over MgSO4 and concentrated. The crude material is dissolved in 1:1 dichloromethane/methanol, preadsorbed onto silica gel, and purified by flash chromatography (silica, 20% ethyl acetate in hexanes) to give the title compound. MS (ion spray) 500 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.CC1C=CC(S(O[CH2:19][CH2:20][CH2:21][NH:22][C:23]2[C:24](=[O:40])[N:25]([C:36]([CH3:39])([CH3:38])[CH3:37])[S:26](=[O:35])(=[O:34])[C:27]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=O)=O)=CC=1>CCOC(C)=O>[C:36]([N:25]1[C:24](=[O:40])[C:23]([NH:22][CH2:21][CH2:20][CH2:19][O:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[C:27]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[S:26]1(=[O:34])=[O:35])([CH3:37])([CH3:38])[CH3:39]
Reactant: Cc1ccc(S(=O)(=O)OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Reactant: Oc1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)N1C(=O)C(NCCCOc2ccncc2)=C(c2ccccc2)S1(=O)=O
Yield: 35 %

Procedure:
The title compound was prepared as described for Example 12 from 4-hydroxypyridine and 3-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]propyl 4-methylbenzenesulfonate with a reaction time of 15 mins. EtOAc was added to the reaction mixture and the mixture was washed with water, brine and evaporated. The residue was purified twice by silica gel column chromatography (Horizons Biotage) using 50-80% EtOAc in hexane then 50% EtOAc in DCM as eluent to give the title compound (0.035 g, 35%). 1H NMR (500 MHz CDCl3): δ 8.44 (d, 2H), 7.54-7.48 (m, 2H), 7.48-7.41 (m, 3H), 6.75 (d, 2H), 5.64 (t, 1H), 3.91 (t, 2H), 3.114-3.08 (m, 2H), 1.90-1.82 (m, 2H), 1.74 (s, 9H); 13C NMR (125 MHz CDCl3): δ 164.5, 159.8, 151.4, 135.2, 131.8, 129.9, 128.9, 125.2, 110.3, 107.6, 65.7, 61.8, 41.9, 28.8, 27.9; Mass Spectrum: M+H+ 416.