Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[C:11]([C:19]([OH:21])=O)=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].C[N:25](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[C:11]([C:19](=[O:21])[NH2:25])=[CH:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Cn1cc(C(=O)O)c2cc(Cl)ccc21
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Cn1cc(C(N)=O)c2cc(Cl)ccc21
Reaction time: 16 h

Procedure:
To a mixture of 1-tert-butoxycarbonylmethyl-5-chloro-1H-indole-3-carboxylic acid (400 mg, 1.29 mmol) in CH2Cl2 (6 mL) were added successively NH4Cl (138 mg, 2.58 mmol), HBTU (1.22 g, 3.23 mmol) and DIPEA (0.902 mL, 5.17 mmol). Stirring was continued at RT for 16 h. Additional aliquots of NH4Cl (2 equiv) and DIPEA (4 equiv) were added to the reaction mixture. After stirring for 4 h, the reaction mixture was diluted with CH2Cl2 and the solution was washed with water (2×), 0.1N aqueous HCl (2×), saturated aqueous NaHCO3 (2×) and brine, dried (Phase separator) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc/c-hexane gradient 2:1 to 1:0) to give the title compound as a white solid. TLC Rf (EtOAc/c-hexane 2:1)=0.20; MS (LC/MS): 309 [M+H]+, 617 [2M+H]+; tR (HPLC conditions b): 4.75 min.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]([C:25]2[N:26]=[C:27]([N:30]3[CH2:33][CH:32]([OH:34])[CH2:31]3)[O:28][CH:29]=2)=[O:24])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.[CH3:35][S:36](Cl)(=[O:38])=[O:37].C(N(CC)CC)C>C(Cl)Cl>[Si:1]([O:18][CH:19]1[CH2:20][N:21]([C:23]([C:25]2[N:26]=[C:27]([N:30]3[CH2:33][CH:32]([O:34][S:36]([CH3:35])(=[O:38])=[O:37])[CH2:31]3)[O:28][CH:29]=2)=[O:24])[CH2:22]1)([C:14]([CH3:15])([CH3:17])[CH3:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](OC1CN(C(=O)c2coc(N3CC(O)C3)n2)C1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](OC1CN(C(=O)c2coc(N3CC(OS(C)(=O)=O)C3)n2)C1)(c1ccccc1)c1ccccc1
Reaction time: 0.17 h
Yield: 79.5 %

Procedure:
To a solution of 1-[4-(3-t-butyldiphenylsilyloxyazetidine-l-carbonyl)-1,3-oxazol-2-yl]-3-hydroxyazetidine (1.68 g, 3.53 mmol) (obtained as described in Reference Example 74(1)) in methylene chloride (84 ml) were added methanesulfonyl chloride (820 μl, 10.6 mmol) and triethylamine (1.49 ml, 10.6 mmol) in an ice bath and the mixture was stirred for 10 minutes and then at room temperature for 0.5 hour. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using methylene chloride:ethyl acetate (1:1) as the eluant to afford 1-[4-(3-t-butyldiphenylsilyloxyazetidine-1-carbonyl)-1,3-oxazol-2-yl]-3-methanesulfonyloxyazetidine (1.56 g, yield 80%) as a pale yellow solid.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([CH2:51][CH2:52][CH3:53])[N:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:9]=1[C:10](OC)=[O:11])(OC)=[O:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:2][CH2:1][C:5]1[N:6]=[C:7]([CH2:51][CH2:52][CH3:53])[N:8]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31]([C:32]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]=[N:29][N:28]=3)=[CH:19][CH:20]=2)[C:9]=1[CH2:10][OH:11]
Reactant: CCCc1nc(C(=O)OC)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCc1nc(CO)c(CO)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
4,5-Dicarbomethoxy-2-n-propyl-1-[(2'-(N-triphenylmethyl-(1H-tetrazol-5-yl))biphenyl-4-yl)methyl]imidazole (9.88 g, 14.1 mmol, 1 eq) was dissolved in a minimum of THF and to this solution, lithium aluminum hydride (1.0M in THF) (15.48 mL, 15.48 mmol, 1.1 eq) was slowly added dropwise. The mixture was allowed to stir at room temperature overnight after which It was quenched by the Steinhardt procedure (Fieser & Fieser V.1, p.584) as follows: to the reaction mixture water (0.66 mL) was first carefully added followed by 15% NaOH (0.66 mL) followed by water (1.97 mL). After stirring for 72 h, a very fine suspension of particulate had formed which was slowly filtered through Celite™. The filtrate was dried (MgSO4) and the solvent removed in vacuo to yield 8.83 g of a yellow glass which could not be recrystallized. This Intermediate was suitable for further transformation. NMR (DMSO-d6) δ 7.82 (d, 1H,J=9Hz); 7.68-7.28 (m,12H); 7.05 (d,2H,J=9Hz); 6.87 (d,6H,J=9Hz); 5.16 (s,2H); 4.94 (t,1H,J=7Hz); 4.66 (t,1H,J=7Hz); 4.37 (d,2H,J=7Hz); 4.32 (d,2H,J=7Hz); 2.34 (t,2H,J=7Hz); 1.52 (t of q,2H,J=7,7Hz); 0.77 (t,3H,J=7Hz). IR (neat) 3300 br; 3061; 1027; 1006; 909; 732; 699 cm-1. Anal. calcd. for C41H38N6O2.H2O: C, 74.07; H, 6.06; N, 12.64. Found: C, 74.06; H, 5.95: N, 11.86.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[F:9][C:10]1[C:18]2[C:14](=[CH:15][N:16]([CH3:19])[N:17]=2)[C:13](/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:12][CH:11]=1.O>CS(C)=O>[F:9][C:10]1[C:18]2[C:14](=[CH:15][N:16]([CH3:19])[N:17]=2)[C:13]([CH:20]2[CH2:4][CH:21]2[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:12][CH:11]=1
Reactant: CCOC(=O)/C=C/c1ccc(F)c2nn(C)cc12
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1CC1c1ccc(F)c2nn(C)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
Under nitrogen atmosphere, to a suspension of sodium hydride (290 mg, 7.25 mmol) in dimethyl sulfoxide (45 mL) was added trimethylsulfoxonium iodide (1.73 g, 7.86 mmol) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added a solution of ethyl (2E)-3-(7-fluoro-2-methyl-2H-indazol-4-yl)acrylate (1.50 g, 6.04 mmol) in dimethyl sulfoxide (15 mL) at 0° C., and the mixture was stirred at 70° C. for 27 hr. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=15/85-+50/50) to give the title compound (1.20 g, yield 76%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][S:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[CH:12]([C:13](=O)[CH2:14][C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[CH2:17][CH2:18][C:19]2=[O:29])[CH2:11]1)=[O:4].Cl.[NH2:34][OH:35]>>[F:1][C:2]([F:31])([F:32])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][S:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[CH:12](/[C:13](=[N:34]/[OH:35])/[CH2:14][C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[CH2:17][CH2:18][C:19]2=[O:29])[CH2:11]1)=[O:4]
Reactant: NO
Reactant: C[C@]12CC[C@H](SCCCNC(=O)C(F)(F)F)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: Cl
Product: C[C@]12CC[C@H](SCCCNC(=O)C(F)(F)F)CC1/C(=N/O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 49.1 %

Procedure:
Following the procedure described in Example 1 and starting from 3β-(3-trifluoroacetamidopropylthio)androstane-6,17-dione (395 mg) and hydroxylamine hydrochloride (65 mg), 3β-(3-trifluoroacetamidopropylthio)-6-(E)-hydroxyiminoandrostane-17-one (200 mg, 50%) was obtained. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 10.40 (1H, s), 9.42 (1H, t), 3.23 (4H, m), 2.55-0.90 (23H, m), 0.76 (3H, s), 0.67 (3H, s).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:16][CH:15]=[C:14]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:13]=2.[Cl:38][CH2:39][C:40](Cl)=O>ClCCl>[CH2:31]([O:30][C:14]1[CH:15]=[CH:16][C:17]2[C:18]3[N:19]([CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:40]([CH2:39][Cl:38])=[N:8][C:9]=3[CH:10]=[N:11][C:12]=2[CH:13]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)NCCNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCn1c(CCl)nc2cnc3cc(OCc4ccccc4)ccc3c21
Temperature: 25 °C
Yield: 15.5 %

Procedure:
Triethylamine (24.0 mL, 172.58 mmol) was added to a solution of tert-butyl 2-[(3-amino-7-benzyloxyquinolin-4-yl)amino]ethylcarbamate (35.25 g, 86.29 mmol) in dichloromethane (400 mL), and the reaction was stirred at ambient temperature. Chloroacetyl chloride (6.87 mL, 86.29 mmol) was quickly added at ambient temperature, and the reaction was stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethanol (500 mL) and stirred for two days at ambient temperature. The mixture was concentrated under reduced pressure and the residue was recrystallized from dichloromethane to afford 6.23 g of tert-butyl 2-[7-benzyloxy-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethylcarbamate. The mother liquor was divided into two portions which were separately purified by normal phase prep HPLC on silica gel (eluting with 2 N ammonia in methanol/chloroform in a 33-minute gradient from 0:100 to 5:95) and combined to provide an additional 24.21 g of product.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10](Cl)=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[CH3:13][O:14][C:15]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:16]=1[CH2:17][N:18]1[C:27]2[C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[CH:24]=[CH:23][C:22]=2[N:21]=[C:20]([NH:32][NH2:33])[C:19]1=[O:34].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:3][P:4]([CH2:9][C:10]([NH:33][NH:32][C:20]1[C:19](=[O:34])[N:18]([CH2:17][C:16]2[CH:35]=[CH:36][C:37]([O:39][CH3:40])=[CH:38][C:15]=2[O:14][CH3:13])[C:27]2[C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[CH:24]=[CH:23][C:22]=2[N:21]=1)=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(CC(=O)Cl)OCC
Reactant: COc1ccc(Cn2c(=O)c(NN)nc3ccc4ccccc4c32)c(OC)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOP(=O)(CC(=O)NNc1nc2ccc3ccccc3c2n(Cc2ccc(OC)cc2OC)c1=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.2 %

Procedure:
A solution of (diethoxyphosphoryl)acetyl chloride (480 mg, 2.2 mmol) in dry tetrahydrofuran (10 ml) was added to a mixture of 1-(2,4-dimethoxybenzyl)-3-hydrazinobenzo[f]quinoxalin-2(1H)-one (750 mg, 2 mmol) and dry triethylamine (220 mg, 2.2 mmol) in dry tetrahydrofuran (40 ml). The mixture was stirred at room temperature for 1.5 h and filtered. The filtrate was evaporated to give 1.1 g of the title compound as a crude product.
Reaction SMILES: [ClH:1].C([N:9]1[CH:14]2[CH2:15][CH2:16][CH2:17][CH:10]1[CH2:11][C:12](=[O:18])[CH2:13]2)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[ClH:1].[CH:10]12[NH:9][CH:14]([CH2:15][CH2:16][CH2:17]1)[CH2:13][C:12](=[O:18])[CH2:11]2
Reactant: O=C1CC2CCCC(C1)N2Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: O=C1CC2CCCC(C1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
9-benzyl-9-azabicyclo[3.3.1]nonan-3-one hydrochloride (38.8 g) was dissolved in 450 mL of glacial acetic acid. 13.5 Grams of 10% Pd/C (Degussa catalyst E101—containing 50% water) was added. After the appropriate evacuation & purge cycles, the mixture was agitated under 62 psi of H2 at rt overnight. TLC (3% MeOH in CH2Cl2 on silica gel) indicated that the reaction was complete. The reaction mixture was filtered through Celite and concentrated by rotary evaporation under vacuum. The product was redissolved in 0.12 N HCl (250 mL) and the solution was concentrated in vacuo. This was repeated once more with 0.12 N HCl (250 mL). The product was then dissolved in 1 N HCl and concentrated to dryness under vacuum. A sticky brown solid was obtained. The material was recrystallized once from isopropanol and once from EtOH to give 9-azabicyclo[3.3.1]nonan-3-one hydrochloride as a tan granular solid (18.8 g; 73.6% yield) after drying under high vacuum (0.1-1.0 mTorr) overnight.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:5]([C:10]#[N:11])=[N:6][CH:7]=[CH:8][CH:9]=1)#[N:2].[CH3:12][O-:13].[Na+]>CO>[CH3:12][O:13][C:1]1[CH:3]=[C:4]2[C:5](=[C:10]([NH2:11])[N:2]=1)[N:6]=[CH:7][CH:8]=[CH:9]2
Reactant: C[O-]
Reactant: N#CCc1cccnc1C#N
Agent: [Na+]
Solvent: CO
Product: COc1cc2cccnc2c(N)n1
Yield: 9.4 %

Procedure:
To a 1 L round bottom flask was added 3-(cyanomethyl)picolinonitrile (63.6 mmol), MeOH (500 mL), followed by sodium methoxide (76.3 mmol). The mixture was heated at reflux for 18 h, after which time the solvent was removed. The residue was diluted with water (400 mL) and extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The resultant crude residue was purified by silica gel to yield 6-methoxy-1,7-naphthyridin-8-amine (1.05 g, 5.99 mmol, 9.4%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.50 (d, J=2.75 Hz, 1H), 7.95 (d, J=8.24 Hz, 1H), 7.48 (dd, J=8.25, 4.40 Hz, 1H), 7.05 (s, 2H), 6.16 (s, 1H), 3.79 (s, 3H).
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[C:27]([Br:29])[C:26]([OH:30])=[C:25]([Br:31])[CH:24]=2)=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:33][C:34](=[O:45])[C@H:35](O)[CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[C:27]([Br:29])[C:26]([O:30][C@@H:35]([CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:34]([OH:45])=[O:33])=[C:25]([Br:31])[CH:24]=2)=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1Br
Reactant: COC(=O)[C@H](O)CCc1ccccc1
Product: O=C(O)[C@H](CCc1ccccc1)Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1Br

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzo[b]thiophen-3-yl)-3,5-dibromo-biphenyl-4-ol, and (R)-(−)-2-hydroxy-4-phenylbutyric acid methyl ester, in substantially the same manner, as described in Example 1, steps g-h, and was obtained as a white solid, mp 85-87° C.; MS m/e 709 (M−H)+;
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:17][NH:18][CH:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([F:29])[CH:25]=2)[CH2:20]1)C1C=CC=CC=1>[Pd].CO>[NH2:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:17][NH:18][CH:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([F:29])[CH:25]=2)[CH2:20]1
Reactant: O=C(N[C@@H]1CCCC[C@H]1CNC1CCc2cc(F)ccc2C1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: N[C@@H]1CCCC[C@H]1CNC1CCc2cc(F)ccc2C1
Reaction time: 3.5 h

Procedure:
A mixture of benzyl((1R,2S)-2-{[((2RS)-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino]methyl}cyclohexyl)carbamate (280 mg, 0.68 mmol) and 10% palladium on charcoal (56 mg) in methanol (20 mL) was shaken under an atmosphere of hydrogen (55 psig) for 3.5 hours. The mixture was filtered, the solid was washed with methanol, and the filtrates were concentrated. The residual oil (120 mg, 64%) was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]=1[C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[C:27](OCC)(=[O:29])[CH3:28]>>[C:27]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]=1[C:19](=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)(=[O:29])[CH3:28]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2cc([N+](=O)[O-])ccc21
Product: CCOC(=O)n1c(C(=O)c2ccccc2)c(NC(C)=O)c2cc([N+](=O)[O-])ccc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 2 (Method A) from 3-amino-2-benzoyl-1-(ethoxycarbonyl)-5-nitroindole (step 2). tlc: Rf=0.2 (50% ethyl acetate in hexanes)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([OH:25])=O.[NH2:37][CH2:38][CH2:39][CH2:40][OH:41]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([NH:37][CH2:38][CH2:39][CH2:40][OH:41])=[O:25]
Reactant: NCCCO
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCCCO)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with 3-amino-1-propanol.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([N:29]3[CH2:34][CH2:33][CH:32]([O:35][C:36]4[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:37]=4[F:44])[CH2:31][CH2:30]3)=[C:20]([NH:25][CH:26]3[CH2:28][CH2:27]3)[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[CH:26]1([NH:25][C:20]2[N:21]=[C:22]3[CH2:23][CH2:24][NH:15][CH2:16][C:17]3=[N:18][C:19]=2[N:29]2[CH2:30][CH2:31][CH:32]([O:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:37]=3[F:44])[CH2:33][CH2:34]2)[CH2:27][CH2:28]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: COc1ccc(OC2CCN(c3nc4c(nc3NC3CC3)CCN(Cc3ccccc3)C4)CC2)c(F)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(OC2CCN(c3nc4c(nc3NC3CC3)CCNC4)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 6-benzyl-N-cyclopropyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (5 mg, 8.10 μmol) and Pd(OH)2 on carbon, (20 wt %, 1 mg, 7.12 μmol) in THF (80 μL) was stirred under atmosphere of hydrogen gas (balloon) at rt. After 1 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (4.6 mg, 100%) as a yellow film; ESI-MS m/z [M+H]+ 414.4.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[OH:14][C:15]1[CH:23]=[C:19]([C:20]([OH:22])=[O:21])[C:18]([NH2:24])=[CH:17][CH:16]=1>CN(C)C=O>[NH2:24][C:18]1[CH:17]=[CH:16][C:15]([O:14][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])=[CH:23][C:19]=1[C:20]([OH:22])=[O:21]
Reactant: Nc1ccc(O)cc1C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(N)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.5 %

Procedure:
Imidazole (1.8 g, 26.1 mmol) and tert-butyldimethylsilyl chloride (3.95 g, 26.1 mmol) were added to a solution of the commercially available 5-hydroxyanthranilic acid (1.0 g, 6.54 mmol) in dimethylformamide (40 ml) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature and stirred for 18 hours. Aqueous work-up afforded an impure sample of 2-amino-5-(tert-butyl-dimethyl-silanyloxy)-benzoic acid (1.74 g) that was used in Step (ii) without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([N+:20]([O-])=O)=[CH:18][CH:19]=2)[CH2:10][C:9]1([CH3:24])[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.[Ni]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH2:10][C:9]1([CH3:24])[CH3:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1(C)C
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1(C)C
Reaction time: 4 h
Yield: 84.5 %

Procedure:
2,2-Dimethyl-4-(6-nitro-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (14.63 g, 43.5 mmol) was dissolved in THF (400 mL) to which Raney Nickel (6.8 g) was added. The reaction mixture was shaken under a hydrogen atmosphere (50 psi) for 4 hours. The catalyst was removed by filtration and the solvent evaporated to give 4-(6-amino-pyridin-3-yl)-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester as a purple solid (11.26 g, 84.5 %). 1H NMR δ (400 MHz, CDCl3) 7.63 (d, J=2.4 Hz, 1H), 7.06 (dd, J=2.9, 8.8 Hz, 1H), 6.51 (d, J=8.8 Hz, 1H), 3.68 (m, 2H), 3.16 (m, 2H), 2.98 (s, 2H), 1.48 (s, 9H), 1.43 (s, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([NH:13][C:14]2[C:15]3[CH:23]=[C:22](Cl)[N:21]=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:32]1[N:36]([CH3:37])[CH:35]=[N:34][CH:33]=1)CCC>>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([NH:13][C:14]2[C:15]3[CH:23]=[C:22]([C:32]4[N:36]([CH3:37])[CH:35]=[N:34][CH:33]=4)[N:21]=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Reactant: Clc1cc2c(Nc3ccc(OCc4ccccc4)cc3)ncnc2cn1
Product: Cn1cncc1-c1cc2c(Nc3ccc(OCc4ccccc4)cc3)ncnc2cn1

Procedure:
Prepared according to Procedure B from 4-(4-benzyloxyanilino)-6-chloropyrido[3,4-d]pyrimidine and 5-(tri-n-butylstannyl)-N-methylimidazole (prepared according to the published method: Acta Chem. Scand., (1993), 47(1), 57); δH [2H6]-DMSO 10.00 (1H,s), 9.15 (1H,s), 8.65 (1H,s), 8.60 (1H, s), 7.80 (1H,s), 7.61(2H,d), 7.50 (1H,s), 7.25-7.49 (5H,m), 7.10 (2H,d), 5.13 (2H,s), 3.98 (3H,s); m/z (M+1)+409.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH:11]12[O:16][CH:15]1[CH2:14][CH2:13][CH2:12]2>C1COCC1.[Cu]I>[F:1][C:2]1[CH:3]=[C:4]([C@H:14]2[CH2:13][CH2:12][CH2:11][C@@H:15]2[OH:16])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Fc1cc(F)cc([Mg]Br)c1
Reactant: C1CC2OC2C1
Agent: [Cu]I
Solvent: C1CCOC1
Product: O[C@H]1CCC[C@@H]1c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
A flask was charged with (3,5-difluorophenyl)magnesium bromide (149 mL, 149 mmol) and copper (I) iodide (1.901 g, 9.98 mmol). To this reaction mixture, 6-oxabicyclo[3.1.0]hexane (12.53 g, 149 mmol) dissolved in THF (25 mL) was added dropwise. The reaction mixture warmed upon the addition of the epoxide. The reaction was stirred at rt for 2 h at rt. The reaction mixture was quenched by the addition of a solution of ammonium chloride. Ether was added and the organic layer was collected, dried (Na2SO4) and concentrated. The crude product was purified by column chromatography on silica gel to afford (1S,2R)-2-(3,5-difluorophenyl)cyclopentanol (26.5 g, 134 mmol, 90% yield).