Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Na].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=1[CH3:24].[H-].[Na+].C1(O)C=CC=CC=1>CN(C)C=O>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:2]2[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=2)[C:7]([O:9][CH3:10])=[O:8])=[CH:19][C:18]=1[CH3:24]
Reactant: COC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: Cc1cc(O)ccc1Cl
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: Oc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(Cl)c(C)c2)ccc1[N+](=O)[O-]

Procedure:
Methyl 5-fluoro-2-nitrobenzoate was reacted with the sodium salt of 4-chloro-3-methylphenol (prepared from sodium hydride and the phenol) in dimethylformamide at 100° C. for 2.5 hours and the resulting methyl 5(4-chloro-3-methylphenoxy)-2-nitrobenzoate isolated in the usual way; the ester had a melting point of 85°-87° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([OH:17])[CH2:16][CH2:15][C:10]3(OCC[O:11]3)[CH2:9][CH2:8]2)[N:2]=1.Cl>C1COCC1>[OH:17][C:7]1([C:3]2[N:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:16][CH2:15][C:10](=[O:11])[CH2:9][CH2:8]1
Reactant: OC1(c2cccnn2)CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCC(O)(c2cccnn2)CC1
Reaction time: 8 h
Yield: 52.1 %

Procedure:
To the product from step A (7.79 mmol, 1.84 g) in THF (15 mL) was added HCl (45 mmol, 15 mL). The reaction was stirred overnight and subsequently quenched using Na2CO3. The solution was then extracted using EtOAc (3×100 mL). The organic layers were combined, dried and concentrated in vacuo to afford the desired ketone (780 mg, 52%). MS (M+H)+ 193.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[CH:13]=[N:12][CH:11]=[N:10]1.[CH2:14]=[O:15]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[C:13]([CH2:14][OH:15])=[N:12][CH:11]=[N:10]1
Reactant: C=O
Reactant: Fc1ccc(Br)c(-n2cncn2)c1
Product: OCc1ncnn1-c1cc(F)ccc1Br
Temperature: 150 °C

Procedure:
A suspension of 1-(2-bromo-5-fluorophenyl)-1H-1,2,4-triazole (3.63 g, 15 mmol) in 37% formaline (15 mL) in a sealed vessel was stirred in an oil bath heated at 150° C. for 9.5 h. After cooling, the mixture was extracted with CH2Cl2 (15 mL×2) and the combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The residual crude oil was purified by column chromatography (SiO2, 0–7% MeOH/CH2Cl2) followed by trituration with Et2O to obtain 430 mg of the title compound as white crystalline solid: TLC Rf 0.5 (10% MeOH/CH2Cl2); HPLC rt=1.31 min; LC/MS m/z 272/274 (M+H); 1H NMR (CDCl3, 500 MHz) δ ppm 3.67 (1H, br.s, OH), 4.65 (2H, s, 9-OCH2), 7.13–7.22 (1H, m, 5-CH), 7.29 (1H, dd, J=8, 3 Hz, 3-CH), 7.71 (1H, dd, J=9.0, 5.3 Hz, 6-CH), 8.03 (1H, s, 8-CH); 13C NMR (CDCl3, 125.8 Hz) δ ppm 55.3 (9-OCH2), 116.2 (d, J=3.9 Hz, 1-C), 117.4 (d, J=25 Hz, 3-CH), 119.4 (d, J=22 Hz, 5-CH), 134.7 (d, J=8.3 Hz, 6-CH), 137.0 (d, J=10 Hz, 2-C), 151.3 (8-CH), 156.3 (7-C), 161.8 (d, J=252 Hz, 4-CF); HRMS (ESI) calcd for C9H8FBrN3O (M+H) 271.9835. found 271.9828 (δ −2.5 ppm).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].[H-].[Na+].[CH3:16][O:17][C:18]1[C:23]2[CH2:24][CH2:25][C:26]3[CH:27]=[N:28][C:29](SC)=[N:30][C:31]=3[C:22]=2[CH:21]=[CH:20][CH:19]=1.O>O1CCCC1>[CH3:16][O:17][C:18]1[C:23]2[CH2:24][CH2:25][C:26]3[CH:27]=[N:28][C:29]([NH:6][C:5]4[CH:7]=[C:8]([O:12][CH3:13])[C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=4)=[N:30][C:31]=3[C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: COc1cccc2c1CCc1cnc(SC)nc1-2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc2c1CCc1cnc(Nc3cc(OC)c(OC)c(OC)c3)nc1-2
Reaction time: 0.25 h
Yield: 77.4 %

Procedure:
To a solution of 3,4,5-trimethoxyaniline (0.401 g) in tetrahydrofuran at room temperature under nitrogen was added sodium hydride (60% oil dispersion, 0.16 g) in portions over 2-3 minutes. The mixture was stirred for 15 minutes, and then 7-methoxy-2-methylthio-5,6-dihydrobenzo[h]quinazoline (0.258 g) was added, and the mixture was refluxed for 4 hours. The reaction mixture was poured into 300 ml of water, and the resulting yellow precipitate filtered off, washed with pentane, and dried under vacuum, giving 7-methoxy-2-(3,4,5-trimethoxyanilino)-5,6-dihydrobenzo[h]quinazoline (0.3042 g).
Reaction SMILES: [F:1][C:2]1[C:3]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=3)[CH2:15][CH2:14]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[Cl-].[NH4+]>CO.O.[Fe]>[F:1][C:2]1[C:3]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C:21]3[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=3)[NH2:27])[CH2:17][CH2:18]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2
Reactant: Cc1ccc2c(N3CCN(CCc4cccc([N+](=O)[O-])c4)CC3)c(F)ccc2n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)c(F)ccc2n1
Temperature: 25 °C
Yield: 91 %

Procedure:
A solution of 6-fluoro-2-methyl-5-{4-[2-(3-nitrophenyl)ethyl]-1-piperazinyl}quinoline (0.05 g; 1 eq) in methanol (3 mL) was added dropwise to a suspension of iron powder (0.05 g; 7 eq) and ammonium chloride (0.05 g; 7 eq) in water (3 mL). The reactants were heated at reflux for 8 hours, with additional amounts of iron powder (total 0.05 g; 7 eq) and ammonium chloride (0.05 g; 7 eq) added in 3 portions during the reaction. The reaction mixture was cooled to room temperature and filtered using a Millipore filter. The filtrate was concentrated under reduced pressure, diluted with water (5 mL) and a saturated aqueous solution of sodium hydrogen carbonate (2 mL) and extracted into ethyl acetate (3×5 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the title compound in 91% yield (0.04 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:22]OS(C)(=O)=O)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Na+].[I-:29]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:22][I:29])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: [I-]
Reactant: COc1ccc(-n2nc(COS(C)(=O)=O)cc2-c2ccc(Cl)c(Cl)c2)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(-n2nc(CI)cc2-c2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Yield: 96.7 %

Procedure:
A stirred solution of methanesulfonic acid 5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-ylmethyl ester (8.80 g, 0.0206 mol) and NaI (4.64 g, 0.0309 mol) in acetone (175 mL) was refluxed for 90 min. The thick reaction slurry was cooled to rt, quenched with H2O (200 mL) and extracted with EtOAc (3×75 mL). The organic layer was dried with Na2SO4, filtered and concentrated to a dark oil. The crude oil was purified by column chromatography (silica gel, 85:15 hexane/EtOAc) to obtain 9.15 g (97%) of the title compound after two steps. HPLC: Rt=11.03 (Method E). MS (ES+): mass calculated for C17H13Cl2IN2O, 459.10; m/z found 460.9 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.37 (d, J=2.0 Hz, 1H), 7.34 (d, J=8.3 Hz, 1H), 7.18 (d, J=8.8 Hz, 2H), 6.95 (dd, J=6.3, 2.0 Hz, 1H), 6.88 (d, J=9.1 Hz, 2H), 6.55 (s, 1H), 4.47 (s, 2H), 3.83 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][C@@H:12]([O:14][CH2:15][CH3:16])[C@H:11]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:19][CH:18]=2)[C@@H:10]([O:35][CH2:36][C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=2)[CH2:9]1)=O)(C)(C)C.Cl>>[CH2:28]([O:27][CH2:26][CH2:25][CH2:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([C@H:11]2[C@H:12]([O:14][CH2:15][CH3:16])[CH2:13][NH:8][CH2:9][C@@H:10]2[O:35][CH2:36][C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=2)=[CH:22][CH:21]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](OCc2ccc3ccccc3c2)[C@H]1c1ccc(OCCCOCc2ccccc2)cc1
Agent: Cl
Product: CCO[C@@H]1CNC[C@H](OCc2ccc3ccccc3c2)[C@H]1c1ccc(OCCCOCc2ccccc2)cc1

Procedure:
reacting the product of step g) with hydrochloric acid to yield (3R,4S,5S)-4-[4-(3-benzyloxy-propoxy)-phenyl]-5-ethoxy-3-(naphthalen-2-ylmethoxy)-piperidine.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][N:32]=[CH:31][C:30]=2[Br:35])=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[Br:35][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][C:29]=1[O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][C@H:17]([NH:16][C:2]2[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=3)[N:3]=2)[C:18]([OH:20])=[O:19])=[CH:27][CH:26]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: N[C@@H](Cc1ccc(Oc2ccncc2Br)cc1)C(=O)O
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(Oc2ccncc2Br)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 109c, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(3-bromo-pyridin-4-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) in DMSO to provide the title compound in good yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][C@@H:10]([CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][OH:12])[C:6]([N+:22]([O-:24])=[O:23])=[CH:5][CH:4]=1.Cl[Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].N1C=CN=C1>CN(C=O)C>[CH3:30][C:29]([Si:26]([CH3:28])([CH3:27])[O:12][CH2:11][C@@H:10]([NH:9][C:7]1[C:6]([N+:22]([O-:24])=[O:23])=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=1)[CH2:13][O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc([N+](=O)[O-])c(N[C@H](CO)COCc2ccccc2)n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(N[C@@H](COCc2ccccc2)CO[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.4 %

Procedure:
To a solution of (2R)-2-{[6-(methyloxy)-3-nitro-2-pyridinyl]amino}-3-[(phenylmethyl)oxy]-1-propanol (675.8 g) in DMF (2.37 L) was added chloro(1,1-dimethylethyl)dimethylsilane (382.0 g) in portions. Then, imidazole (331.2 g) was added in portions and the mixture was stirred at room temperature for 1.5 h. The reaction mixture was evaporated and the resulting orange gum was partitioned between EtOAc (3 L) and H2O (3 L). The layers were separated and the aqueous was extracted with EtOAc (2.5+2 L). The organic layers were combined, dried over MgSO4 (˜500 g), filtered and evaporated to give an orange oil. The crude product was purified by column chromatography (10 kg silica, 9:1 heptane:EtOAc) to give N-((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-{[(phenylmethyl)oxy]methyl}ethyl)-6-(methyloxy)-3-nitro-2-pyridinamine (774.7 g, 100%) as a bright yellow solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][NH:8][C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH:16][NH:17][C:18](=[O:37])[C@H:19]([CH2:31][CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[CH2:20][N:21]([O:24]C3CCCCO3)[CH:22]=[O:23])[C:10]=2[F:38])[N:6]=1.CC(O)=O>O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][NH:8][C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH:16][NH:17][C:18](=[O:37])[C@H:19]([CH2:31][CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[CH2:20][N:21]([OH:24])[CH:22]=[O:23])[C:10]=2[F:38])[N:6]=1
Reactant: Cc1nc(NCc2csc(N)n2)c(F)c(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)n1
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc(NCc2csc(N)n2)c(F)c(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)n1
Yield: 19.3 %

Procedure:
[(2R)-3-[2-(6-{[(2-Amino-1,3-thiazol-4-yl)methyl]amino}-5-fluoro-2-methyl-4-pyrimidinyl)hydrazino]-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (114 mg, 0.2 mmol) in 4:1 AcOH:water (5 mL) was stirred at room temperature overnight. The solvents were removed in vacuo, and the resulting crude product was purified by RP-HPLC to provide [(2R)-3-[2-(6-{[(2-amino-1,3-thiazol-4-yl)methyl]amino}-5-fluoro-2-methyl-4-pyrimidinyl)hydrazino]-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide (18 mg, 18%). LCMS: (M+H)+: 481.2.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH:31]([NH:34][CH2:35][CH3:36])([CH3:33])[CH3:32]>>[CH2:35]([N:34]([CH:31]([CH3:33])[CH3:32])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:21][CH:22]=3)=[CH:13][C:11]=2[CH:12]=1)[CH3:36]
Reactant: CCNC(C)C
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1
Product: CCN(CCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1)C(C)C

Procedure:
The product from Example 23D and isopropyl(ethyl)amine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.83 (m, 1H), 7.74 (d, J=8.1, 2H), 7.58 (m, 2H), 7.53 (d, J=8.1 Hz, 2H), 6.80 (s, 1H), 3.3-3.8 (m, 15H), 1.41 (m, 9H); MS (DCI) m/z 421 (M+H)+;
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCc1cc2c(NCCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Reactant: c1c[nH]cn1
Product: CCc1cc2c(NCCc3ccc4c(c3)OCO4)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-ethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-ethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl.Cl.[CH3:3][C@@:4]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[O:8][C:7]2=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]2[CH2:5]1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][S:42](Cl)(=[O:44])=[O:43])=[CH:36][CH:35]=1>O>[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([CH2:40][CH2:41][S:42]([N:19]2[CH2:18][CH2:17][N:16]([CH2:15][C@:4]3([CH3:3])[O:8][C:7]4=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]4[CH2:5]3)[CH2:21][CH2:20]2)(=[O:44])=[O:43])=[CH:38][CH:39]=1
Reactant: C[C@]1(CN2CCNCC2)Cn2cc([N+](=O)[O-])nc2O1
Reactant: O=S(=O)(Cl)CCc1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@]1(CN2CCN(S(=O)(=O)CCc3ccc(Cl)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.2 %

Procedure:
A mixture of (S)-2-methyl-6-nitro-2-(piperazin-1-ylmethyl)-2,3-dihydroimidazo[2,1-b]oxazole dihydrochloride prepared in Example 408 (236 mg, 0.88 mmol) and DMF (3 ml) was added potassium carbonate (500 mg, 3.62 mmol) and 2-(4-chlorophenyl)ethanesulfonyl chloride (240 mg, 1 mmol) in this order followed by stirring at room temperature overnight. To the reaction mixture, water was added, and the solution was extracted with ethyl acetate. The organic phase was washed with water three times and saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=50/1) to afford (S)-2-{4-[2-(4-chlorophenyl)ethanesulfonyl]piperazin-1-ylmethyl}-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (100 mg, yield 26%) as a white powder.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:25][C:18]3([NH:22]C(=O)N[C:19]3=[O:24])[CH2:17][O:16]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-:26].[Na+].Cl>O>[NH2:22][C:18]1([C:19]([OH:24])=[O:26])[CH2:25][CH:15]([C:12]2[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:14][CH:13]=2)[O:16][CH2:17]1
Reactant: [OH-]
Reactant: CCCCCCCCc1ccc(C2CC3(CO2)NC(=O)NC3=O)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCCCCCCc1ccc(C2CC(N)(C(=O)O)CO2)cc1
Temperature: 100 °C
Yield: 60.4 %

Procedure:
8-(4-Octylphenyl)-7-oxa-1,3-diazaspiro[4.4]nonane-2,4-dione (0.5 g, 1.452 mmol) and sodium hydroxide (10.89 ml, 21.77 mmol) were combined in water (8.54 ml) and equipped with a reflux condensor. The mixture was heated at about 100° C. for about 72 h. The reaction was cooled and acidified with concentrated HCl until pH=4-5. The product was collected by vacuum filtration and dried under vacuum. The residue was purified by flash column chromatography (1″×6″ of silica) eluting with 1:1 EtOAc/(6:3:1 CHCl3/MeOH/NH4OH). The product fractions were combined. The solvents were removed under reduced pressure and the residue triturated with ether. The resulting solid was collected by vacuum filtration and washed with ether to provide 3-amino-5-(4-octylphenyl)tetrahydrofuran-3-carboxylic acid (0.280 g, 0.877 mmol, 60.4% yield) as a white solid:
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([NH:40][CH2:41][C:42]([O:44]C(C)(C)C)=[O:43])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]3[C:33]4=[N:34][O:35][N:36]=[C:32]4[C:31]([N+:37]([O-:39])=[O:38])=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)[CH2:14][CH2:13][N:12]([CH2:49][C:50]([O:52]C(C)(C)C)=[O:51])[CH2:11][CH2:10]1)=[O:7])(C)(C)C.Cl.CCOCC>O1CCOCC1>[C:50]([CH2:49][N:12]1[CH2:13][CH2:14][N:15]([CH2:18][CH:19]([NH:40][CH2:41][C:42]([OH:44])=[O:43])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]3[C:33]4=[N:34][O:35][N:36]=[C:32]4[C:31]([N+:37]([O-:39])=[O:38])=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)[CH2:16][CH2:17][N:9]([CH2:8][C:6]([OH:7])=[O:5])[CH2:10][CH2:11]1)([OH:52])=[O:51]
Reactant: CC(C)(C)OC(=O)CNC(Cc1ccc(Nc2ccc([N+](=O)[O-])c3nonc23)cc1)CN1CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C(O)CNC(Cc1ccc(Nc2ccc([N+](=O)[O-])c3nonc23)cc1)CN1CCN(CC(=O)O)CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.9 %

Procedure:
To a solution of Compound 16 (15.7 mg, 0.02 mmol) in 1,4-dioxane (1 mL) at 0-5° C. was added 4M HCl(g) in 1,4-dioxane (1 mL) dropwise over ˜15 min. The resulting mixture was allowed to warm to room temperature. Ether (˜15 mL) was added to the reaction mixture and stirred for 10 min. The resulting mixture was placed in the freezer for 1 h. The solid residue was filtered and washed with ether and quickly dissolved in 18μΩ deionized water. Evaporation of the aqueous solution gave pure Compound 17 (12.4 mg, 90%) as an orange solid. 1H NMR (CD3OD) δ 2.82-3.48 (m, 13H), 3.78-4.08 (m, 10H), 6.76 (d, 1H), 7.40-7.55 (m, 4H), 8.51 (d, 1H). HRMS (Positive ion FAB) Calcd for C27H34N8O9 [M+H]+ m/z 615.2527. Found: [M+H]+ m/z 615.2520. Analytical HPLC (tR=3.6 min, Method 2).
Reaction SMILES: [CH3:1][C:2]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:27]=[C:28]([C:29]([F:32])([F:31])[F:30])[C:21]=23)[CH:15]=1)([CH2:12][CH3:13])[CH2:3][NH:4]C(=O)OC(C)(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][N:27]=[C:28]([C:29]([F:31])([F:32])[F:30])[C:21]=23)[CH:15]=1)([CH2:12][CH3:13])[CH2:3][NH2:4]
Reactant: CCC(C)(CNC(=O)OC(C)(C)C)c1cccc(-c2ccnc3c2c(C(F)(F)F)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)(CN)c1cccc(-c2ccnc3[nH]nc(C(F)(F)F)c23)c1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 75.7 %

Procedure:
tert-butyl 2-methyl-2-(3-(3-(trifluoromethyl)-1-trityl-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)butylcarbamate (148 mg, 0.2142 mmol) was dissolved in dry DCM (2 mL) and cooled in an ice-bath. triethylsilane (99.63 mg, 136.9 μL, 0.8568 mmol) was added followed slowly dropwise by TFA (2 mL,). The resulting mixture was stirred at 0° C. for ˜1 hour 50 minutes. The reaction mixture was concentrated under reduced pressure to give a light brown solid/gum. This material was partitioned with ether and brine. The ether layer was washed with 1M HCl (2×10 mL) and the combined aqueous layer was basified with saturated NaHCO3 and extracted with EtOAc (3×10 mL). The combined EtOAc was dried over Na2SO4, filtered and concentrated under reduced pressure to give a colourless gum (56.5 mg). This material was purified by column chromatography (4.5% MeOH/0.5% NH4OH in DCM, ˜75 mL silica, loaded in DCM) to give a white powder (15 mg, 20% Yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9](CC1C=CC=CC=1)[CH2:8]2)=[O:4].C([O-])(O)=O.[Na+].[CH2:26]([O:33][C:34](Cl)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9]([C:34]([O:33][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:35])[CH2:8]2)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)CN(Cc1ccccc1)C2
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc2c(c1)CN(C(=O)OCc1ccccc1)C2
Temperature: 30 °C

Procedure:
2-Benzyl-2,3-dihydro-1H-isoindole-5-carboxylic acid methyl ester (3.9 g) and NaHCO3 (12.3 g) are suspended in CH2Cl2 (50 mL) and the mixture is treated with benzylchloroformate (Z—Cl) (10.8 mL). The mixture is warmed to 30° C. and after 10 min the reaction mixture is added to a mixture of water (150 mL) with NaHCO3 (12.3 g), the organic phase is separated, dried and evaporated. To the residue are added MeOH and the crystalline solid is collected and dried. 3.79 g of the title compound are obtained with MP 59-65° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:14]2[NH:22][C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[CH:15]=2)=[CH:10][CH:11]([CH3:13])[CH3:12])[CH:6]=[CH:7][CH:8]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([C:14]2[NH:22][C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH:11]([CH3:13])[CH3:12])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(=CC(C)C)c2cc3cccnc3[nH]2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cccc(C(CC(C)C)c2cc3cccnc3[nH]2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.9 %

Procedure:
A solution of 2-(1-(3-methoxy-phenyl)-3-methyl-but-1-enyl)-1H-pyrrolo[2,3-b]pyridine (1.3 g, 4.5 mmol) in methanol (30 mL) was treated with 10% palladium on carbon (130 mg). The reaction was stirred for 16 h at 25° C. under a balloon filled with hydrogen gas. The reaction mixture was filtered through a pad of celite and washed with methanol (2×30 mL). The filtrate was concentrated in vacuo. Silica gel column chromatography (20 g, petroleum ether/ethyl acetate 15:1) afforded 2-(1-(3-methoxy-phenyl)-3-methyl-butyl)-1H-pyrrolo[2,3-b]pyridine (900 mg, 68%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ ppm 10.54 (br. s., 1H), 8.16 (t, 1H, J=3.6 Hz), 7.83 (d, 1H, J=7.8 Hz), 7.24 (t, 1H, J=8.1 Hz), 7.02 (dd, 1H, J1=7.8 Hz, J2=4.8 Hz), 6.91-6.74 (m, 3H), 6.32 (s, 1H), 4.20 (t, 1H, J=7.5 Hz), 3.73 (s, 3H), 2.10-1.95 (m, 2H), 1.60-1.51 (m, 1H), 0.96 (d, 3H, J=4.2 Hz), 0.89 (s, 3H, J=4.2 Hz).