Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1C=CC(C(NC2CCN(C)C2)=O)=CC=1OC.[CH2:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28](=[O:40])[C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[C:31]([O:38][CH3:39])[CH:30]=2)[CH2:23][CH2:22]1)[CH3:20]>>[NH2:35][C:32]1[CH:33]=[CH:34][C:29]([C:28]([NH:27][CH:24]2[CH2:23][CH2:22][N:21]([CH2:19][CH3:20])[CH2:26][CH2:25]2)=[O:40])=[CH:30][C:31]=1[O:38][CH3:39]
Reactant: CCN1CCC(NC(=O)c2ccc([N+](=O)[O-])c(OC)c2)CC1
Agent: COc1cc(C(=O)NC2CCN(C)C2)ccc1N
Product: CCN1CCC(NC(=O)c2ccc(N)c(OC)c2)CC1

Procedure:
The title compound was prepared in quantitative yield by an analogous method to the preparation of Intermediate 187, on a 2 g scale utilising N-(1-ethyl-4-piperidyl)-3-methoxy-4-nitro-benzamide (Intermediate 191).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](N2C=CN=C2)=[O:9])=[CH:6][N:5]=[C:4]2[NH:15][CH:16]=[CH:17][C:3]=12.C(N(C(C)C)C(C)C)C.Cl.[CH3:28][O:29][C:30](=[O:33])[CH2:31][NH2:32].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([C:8]([NH:32][CH2:31][C:30]([O:29][CH3:28])=[O:33])=[O:9])=[CH:6][N:5]=[C:4]2[NH:15][CH:16]=[CH:17][C:3]=12
Reactant: O=C(c1cnc2[nH]ccc2c1Cl)n1ccnc1
Reactant: COC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CNC(=O)c1cnc2[nH]ccc2c1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 4-chloro-5-(1H-imidazol-1-ylcarbonyl)-1H-pyrrolo[2,3-b]pyridine(300 mg) in N,N-dimethylformamide (3 ml) were added N-ethyl-N-isopropylpropane-2-amine (0.64 ml) and glycine methylester hydrochloride (305 mg) at ambient temperature. The mixture was warmed immediately to 60° C. and stirred at 60° C. for 2 hours. After to the reaction solution was added water, the mixture was stirred for 1 hour. The precipitated solid was filtered, washed with water, and dried to obtain methyl N-[(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonyl]glycinate (267 mg) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]3[CH:15]([C:16]([O:18]C)=[O:17])[CH2:14][CH2:13][CH2:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[Li].O>C1COCC1.CO.O>[C:1]1([C:7]2[S:8][C:9]3[CH:15]([C:16]([OH:18])=[O:17])[CH2:14][CH2:13][CH2:12][C:10]=3[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C1CCCc2nc(-c3ccccc3)sc21
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1CCCc2nc(-c3ccccc3)sc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of methyl 2-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazole-7-carboxylate (12.0 mg, 0.044 mmol) and LiOH.H2O (2.7 mg, 0.065 mmol) in THF/MeOH/H2O (1 mL, 3:1:1) was stirred at RT for 45 min. The mixture was acidified to pH=3 and extracted with DCM. The comb. org. layers were dried over MgSO4, and conc. in vacuo.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([NH:12]CC2C=CC(OC)=CC=2)[C:5]([N+:22]([O-:24])=[O:23])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>CCOC(C)=O.O>[NH2:12][C:6]1[C:5]([N+:22]([O-:24])=[O:23])=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1c(Cl)ccc([N+](=O)[O-])c1NCc1ccc(OC)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COC(=O)c1c(Cl)ccc([N+](=O)[O-])c1N
Yield: 81.1 %

Procedure:
A solution of methyl 6-chloro-2-[(4-methoxybenzyl)amino]-3-nitrobenzoate (13.2 g, 37.6 mmol) and TFA (75 mL) was stirred at room temperature for 1.7 h. The mixture was diluted with EtOAc (500 mL) and water (250 mL). Solid NaHCO3 (125 g) was slowly added to the heterogeneous mixture. Saturated aqueous NaHCO3 solution (200 mL) and EtOAc were added and the phases were separated. The organic layer was washed with saturated aqueous NaHCO3 solution (150 mL) and brine (50 mL) then dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (10-40μ silica gel; hexane:EtOAc 5:1) to yield the title compound (7.03 g, 81% yield) as a yellow solid.
Reaction SMILES: [O:1]1[CH2:6][C:5](=[O:7])[NH:4][C:3]2[N:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.C([Li])CCC.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>O1CCCC1.CCCCCC>[O:1]1[CH2:6][C:5](=[O:7])[N:4]([C:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])[C:3]2[N:8]=[CH:9][CH:10]=[CH:11][C:2]1=2
Reactant: O=C1COc2cccnc2N1
Reactant: O=C(Cl)Oc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1COc2cccnc2N1C(=O)Oc1ccccc1
Reaction time: 0.5 h

Procedure:
Under an anhydrous atmosphere, a solution of 10 mmol of 2H-pyrido[3,2-b][1,4]oxazin-3-one in 50 ml of tetrahydrofuran is cooled to −78° C. At that temperature, 11 mmol of a 1.6M solution of n-butyllithium in hexane are added dropwise. After 30 minutes' contact at −78° C., 11 mmol of phenyl chloroformate are added dropwise and stirring is maintained for a further 2 hours. After returning to ambient temperature, the solution is hydrolysed and then extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and evaporated. After purification by chromatography on silica gel (petroleum ether/ethyl acetate: 8/2), the expected product is isolated.
Reaction SMILES: C[O:2][C:3](=[O:49])[CH2:4][N:5]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:14]=[C:13](OCCOCCOCCOCC)[CH:12]=1)[CH2:6][C:7]([O:9]C)=[O:8].[OH-].[Na+].C(CN(C1C=C(OCCCCCCCCCCCCOC2C=CC=CC=2)C=[C:63]([O:87][CH2:88][CH2:89][O:90][CH2:91][CH2:92][O:93][CH2:94][CH2:95][O:96]CC)[CH:62]=1)CC(O)=O)(O)=O>CO.O1CCOCC1>[C:7]([CH2:6][N:5]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:14]=[CH:13][C:12]=1[O:96][CH2:95][CH2:94][O:93][CH2:92][CH2:91][O:90][CH2:89][CH2:88][O:87][CH2:63][CH3:62])[CH2:4][C:3]([OH:2])=[O:49])([OH:9])=[O:8]
Reactant: CCOCCOCCOCCOc1cc(OCCCCCCCCCCCCOc2ccccc2)cc(N(CC(=O)O)CC(=O)O)c1
Reactant: CCOCCOCCOCCOc1cc(OCCCCCCCCCCCCOc2ccccc2)cc(N(CC(=O)OC)CC(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CCOCCOCCOCCOc1ccc(OCCCCCCCCCCCCOc2ccccc2)cc1N(CC(=O)O)CC(=O)O
Yield: 85 %

Procedure:
A solution of 1.15 g (1.67 mmol) of N-[3-[2-[2-(2-ethoxyethoxy)ethoxy]ethoxy]-5-[(12-phenoxydodecyl)oxy]phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester and 1.4 ml (8.4 mmol) of 6 N NaOH in 50 ml of methanol and 10 ml of dioxane was stirred at reflux under argon for 19 hours. After the usual workup the product was crystallized from acetone-hexane to give 0.94 g (85% yield), mp 58°-61°, of N-(carboxymethyl)-N-[3-[2-[2-(2-ethoxyethoxy)-ethoxy]ethoxy]-5-[(12-phenoxydodecyl)oxy]phenyl]glycine.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:8]=[CH:9][N:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)[CH:11]=1)=[O:6].C(N(CC)CC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.O>[Br:18][C:14]1[CH:13]=[C:12]([N:10]2[CH:11]=[C:7]([C:5]3[O:6][CH2:2][CH2:3][N:4]=3)[N:8]=[CH:9]2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(NCCO)c1cn(-c2cccc(Br)c2)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Brc1cccc(-n2cnc(C3=NCCO3)c2)c1
Temperature: 25 °C
Yield: 19 %

Procedure:
1-(3-Bromo-phenyl)-1H-imidazole-4-carboxylic acid (2-hydroxy-ethyl)-amide (140 mg, 0.45 mmol) was dissolved in CH2Cl2 under argon atmosphere and triethyl amine (321 μL, 2.3 mmol) and para-toluene sulfonic acid (95 mg; 0.5 mmol) were added. After heating for 20 h at reflux the reaction mixture was diluted with water and refluxed for 45 min. After cooling to room temperature the layers were separated and the organic phase was washed with water and dried over Na2SO4. Concentration of the organic layer followed by column chromatography on silica gel with a gradient of 1%-5% MeOH in CH2Cl2 afforded 25 mg (19%) of the title product. HRMS (ESI+): m/z=292.135 [M+H]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[CH2:13][C:14]([NH:16][C@H:17]([C:33]1[NH:34][C:35]([C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=2)=[CH:36][N:37]=1)[CH2:18][CH2:19][CH2:20][CH2:21][NH:22]C(=O)OCC1C=CC=CC=1)=[O:15]>CO.[Pd]>[NH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]([NH:16][C:14](=[O:15])[CH2:13][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:8][C:7]=1[CH3:12])[C:33]1[NH:34][C:35]([C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=2)=[CH:36][N:37]=1
Reactant: COc1ccc2[nH]c(C)c(CC(=O)N[C@@H](CCCCNC(=O)OCc3ccccc3)c3ncc(-c4ccc5ccccc5c4)[nH]3)c2c1
Agent: [Pd]
Solvent: CO
Product: COc1ccc2[nH]c(C)c(CC(=O)N[C@@H](CCCCN)c3ncc(-c4ccc5ccccc5c4)[nH]3)c2c1
Temperature: 25 °C
Yield: 94 %

Procedure:
A stirred solution (0.2 M) of the product from step 3 in MeOH was added to 10% Pd on carbon (17% w/w) and the heterogeneous mixture was stirred under H2 (g) at RT for the weekend. The reaction mixture was filtered through a pad of celite and washed with MeOH. Evaporation of the solvent yielded (94%) the title compound as a solid.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([NH:13][C:14]([C:16]2[CH:17]=[C:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:19]=[CH:20][C:21]=2[F:22])=[O:15])[CH:7]=1.CO.[OH-].[Na+]>C1COCC1>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][C:3]([OH:29])=[O:2])=[CH:7][C:8]=1[NH:13][C:14]([C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:20][C:21]=1[F:22])=[O:15]
Reactant: COC(=O)C=Cc1ccc(Cl)c(NC(=O)c2cc(-c3ccccc3)ccc2F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C=Cc1ccc(Cl)c(NC(=O)c2cc(-c3ccccc3)ccc2F)c1
Reaction time: 3 h

Procedure:
The ester (51) (124 mg, 0.21 mmol) was hydrolysed using Method C, except that MeOH (1.25 mL), THF and 1M NaOH (1.25 mL) were used, and the reaction was stirred for 3 hours. The solvent was removed under a stream of nitrogen gas and the residue acidified with 1N HCl. The solid was filtered and dried to give the title compound. Yield: 91 mg, 76%; LC-MS tr 2.28 min; HPLC Purity: 94%; MS (ES+) m/z 396 (M÷H); 1H NMR (400 MHz; DMSO): δ 6.60 (d, 1H), 7.45-7.75 (m, 7H), 7.80 (d, 2H), 7.95 (m, 1H), 8.10 (d, 1H), 8.15 (s, 1H), 10.25 (s, 1H), 12.55 (br. s, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH2:9])[N:6]=[C:5]([NH2:10])[CH:4]=1.[N:11]([O-])=[O:12].[Na+]>C(O)(=O)C.O>[N:11]([C:4]1[C:5]([NH2:10])=[N:6][C:7]([NH2:9])=[N:8][C:3]=1[O:2][CH3:1])=[O:12]
Reactant: COc1cc(N)nc(N)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1nc(N)nc(N)c1N=O
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
To a stirred solution of 7.0 g (0.05 mol) 6-methoxy-2,4-diaminopyrimidine in 100 ml acetic acid (10% conc. in water) at 50-60° C. was added dropwise over a period of 30 min a solution of 4.55 g (0.07 mol) sodium nitrite in 20 ml water. The solution was stirred at this temperature for a further 30 min and then stirred at room temperature overnight. The filtrate was filtered off with suction, washed with water and dried. 5-Nitroso-2,4-diamino-6-methoxypyrimidine (7.80 g, 92%) was obtained as a violet solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27]C)=[N:7][C:6]=2[CH:5]=[CH:4][N:3]=1.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[OH:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:8]1[N:9]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:10](=[O:12])[C:11]2[C:2]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:3][CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccccc1-c1nc2ccnc(Cl)c2c(=O)n1CCc1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=c1c2c(-c3ccccc3)nccc2nc(-c2ccccc2O)n1CCc1ccccc1
Temperature: 25 °C

Procedure:
5-Chloro-2-(2-methoxy-phenyl)-3-phenethyl-3H-pyrido[4,3-d]pyrimidin-4-one, phenylboronic acid (1.1 equiv.), palladium tetrakis(triphenylphosphine) (7 mol %) and 2N aqueous Na2CO3 (4 equiv.) were combined in dioxane (0.5 mL) and heated in a microwave for 15 minutes to 140° C. The reaction mixture was cooled to room temperature, diluted with water and extracted (3×) with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous MgSO4 and filtered. The crude products were purified on preparative TLC using 1:1 ethyl acetate:hexane. The desired product can be obtained by using the methyl ether deprotection conditions employing BCl3 and isolation conditions found in the final step of Example 1. 1H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 8.78 (d, 1H), 7.53 (m, 2H), 7.46 (m, 3H), 7.37 (t, 1H), 7.29 (d, 1H), 7.13 (m, 3H), 6.97 (m, 2H), 6.77 (m, 2H), 4.30 (t, 2H), 2.79 (t, 2H). MS m/z 420.4 (M+H)+.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][O:4][C:3]2=[O:21].ClC1C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C(O)(C)(C)C>[CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH:8]=[CH:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][O:4][C:3]2=[O:21]
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)OC[C@@H]12
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: CC(C)(C)O
Product: C[C@]12CCC(=O)C=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)OC[C@@H]12
Yield: 53.4 %

Procedure:
415 mg of 16-oxaandrost-4-ene-3,17-dione, 768 mg of 2,3,5,6-tetrachloro-1,4-benzoquinone and 30 ml of t-butanol were refluxed overnight. The insoluble matters were removed from the reaction mixture, the solvent was distilled out, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium bicarbonate solution, water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled out, and the resultant crude product was purified by TLC [developing solvent; chloroform: acetone (39:1)) to obtain 220 mg of 16-oxaandrosta-4,6-diene-3,17-dione.
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([CH2:21][OH:22])[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:23]1([C:29](Cl)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[CH2:1]([S:17][CH2:18][CH:19]([CH2:21][O:22][C:29]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCSCC(O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCSCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 98.3 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar and drying tube, a solution of 70 grams (0.2 mole) (±)-1-S-hexadecylthioglycerol in 300 milliliters of pyridine was added, followed by the addition of 76.0 grams (0.27 mole) triphenylmethyl chloride. The reaction mixture was stirred at room temperature. After 36 hours, the pyridine was removed in vacuo and the resulting oil was dissolved in 450 milliliters of CHCl3. The solution was extracted twice with 500 milliliter portions of 5% HCl, twice with 500 milliliter portions of water and the nonaqueous solution was dried over anhydrous sodium sulfate. The drying agent was filtered, the solvent was removed in vacuo, the residue was dissolved in 500 milliliters of hexanes, and the solution was placed at -5° Centigrade for 24 hours. The resulting precipitate was redissolved in 500 milliliters of acetone and reprecipitated as before. The final precipitate was filtered and dried under vacuum to give 113 grams (94%) of product, (mp 61°-62° Centigrade). 1H-NMR (CDCl3): delta, 0.7-1.7[m, 31H, (CH2)14CH3 ], 2.3-2.8(m, 4H, CH2 --S--CH2), 3.25[d, 2H, CH2 --O--C(C6H5)3 ], 3.6-4.0(m, 1H, CH2 --CH--CH2), 7.0-7.6[m, 15H, C(C6H5)3 ].
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:35]=[CH:34][C:13]2=[C:14]3[C:19](=[C:20]([NH2:22])[N:21]=[C:12]2[CH:11]=1)[N:18]=[CH:17][C:16]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[CH3:33])=[CH:15]3)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[NH2:22][C:20]1[C:19]2[N:18]=[CH:17][C:16]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=3[CH3:33])=[CH:15][C:14]=2[C:13]2[CH:34]=[CH:35][C:10]([CH2:9][OH:8])=[CH:11][C:12]=2[N:21]=1
Reactant: COc1ccc(CCc2cnc3c(N)nc4cc(CO[Si](C)(C)C(C)(C)C)ccc4c3c2)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(CCc2cnc3c(N)nc4cc(CO)ccc4c3c2)c(C)c1

Procedure:
(Tert-butyldimethylsilyloxy)methyl)-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-5-amine (from step 5) (1.0 equiv.) and TBAF (1.1 equiv.) in THF is stirred at ambient temperature overnight. The reaction is quenched with saturated NaHCO3. The two phases are separated, and the aqueous layer is extracted twice with Et2O. The combined organic layers are washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The crude material is purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-5% MeOH/DCM to give 5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)methanol (2-1) as a white solid. 1H NMR (acetone-d6): δ 8.79 (s, 1H), 8.73 (s, 1H), 8.35 (d, 1H), 7.61 (s, 1H), 7.33 (d, 1H), 7.09 (d, 1H), 6.75 (d, 1H), 6.68 (dd, 1H), 6.57 (br s, 2H), 4.47 (d, 2H), 4.32 (t, 1H), 3.58 (s, 3H), 3.17 (t, 2H), 3.04 (t, 2H), 2.30 (s, 3H). LRMS [M+H]=374.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH:16]([CH3:17])[CH2:15][O:14][CH2:13][C:12]1=[O:18])[C:5]([OH:7])=O.[Cl:19][C:20]1[CH:33]=[CH:32][C:23]2[NH:24][C:25]([C@@H:27]([NH2:31])[CH2:28][O:29][CH3:30])=[N:26][C:22]=2[CH:21]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH:16]([CH3:17])[CH2:15][O:14][CH2:13][C:12]1=[O:18])[C:5]([NH:31][C@H:27]([C:25]1[NH:24][C:23]2[CH:32]=[CH:33][C:20]([Cl:19])=[CH:21][C:22]=2[N:26]=1)[CH2:28][O:29][CH3:30])=[O:7]
Reactant: COC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: CC1COCC(=O)N1c1ccc(C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COC[C@H](NC(=O)c1ccc(N2C(=O)COCC2C)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1f from 3-chloro-4-(5-methyl-morpholin-3-on-4-yl)-benzoic acid and (1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethylamine with TBTU and TEA in DMF.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:11]2[CH2:13][CH2:12]2)=O)=[CH:5][CH:4]=1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:15]3[N:14]([CH:18]=[CH:17][N:16]=3)[CH:12]=[CH:13][CH:11]=2)=[CH:7][CH:8]=1
Reactant: c1c[nH]cn1
Reactant: COc1ccc(C(=O)C2CC2)cc1
Product: Oc1ccc(-c2cccn3ccnc23)cc1

Procedure:
Combine 25 g (0.14 mol) of cyclopropyl 4-methoxyphenyl ketone with 50 g (0.73 mol) of imidazole, and heat to 200°-225° C. for 24 hr. Isolation from 200 g of silica gel using 2% methanol/methylene chloride followed by crystallization from methanol provides the title compound.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:17]=3[CH:18]=[CH:19][N:20]4[CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])[N:12]=2)=[CH:7][C:6]=1[C:32]([F:35])([F:34])[F:33])[CH3:3].[OH-].[Na+:37]>C(O)C>[CH3:3][CH:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:17]=3[CH:18]=[CH:19][N:20]4[CH2:25][CH2:26][C:27]([O-:29])=[O:28])[N:12]=2)=[CH:7][C:6]=1[C:32]([F:35])([F:34])[F:33])[CH3:1].[Na+:37]
Reactant: CCOC(=O)CCn1ccc2c(-c3noc(-c4ccc(OC(C)C)c(C(F)(F)F)c4)n3)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3ccn4CCC(=O)[O-])no2)cc1C(F)(F)F
Temperature: 50 °C
Yield: 69.6 %

Procedure:
To a suspension of ethyl 3-(4-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)propanoate (D72) (81 mg, 0.17 mmol) in ethanol (8 mL) was added aqueous sodium hydroxide (2M, 0.8 mL, 1.6 mmol) and the reaction heated to 50° C. to dissolve the reagents before heating at 40° C. for 1 h. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (20 mL) and water (20 mL) and acidified with aqueous hydrochloric acid (2M). The aqueous phase was extracted with further ethyl acetate (2×20 mL) and the combined organic extracts dried (phase separator) and concentrated in vacuo. The solid was then dissolved in acetonitrile and water with addition of an equimolar amount of sodium hydroxide (2M) before the solution was freeze-dried to give the title compound (57 mg). δH (d6-DMSO, 400 MHz): 8.44 (1H, dd), 8.35 (1H, d), 7.93 (1H, dd), 7.74 (1H, d), 7.65-7.54 (2H, m), 7.31 (1H, app. t), 7.00 (1H, dd) 4.99 (1H, septet), 4.38 (2H, t), 2.34 (2H, t), 1.36 (6H, d). MS (ES): C23H20F3N3O4 requires 459; found 460 (MH+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]23[CH2:18][CH2:17][C:14]([NH:19]C(=O)OC(C)(C)C)([CH2:15][CH2:16]2)[CH2:13][CH2:12]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].FC(F)(F)C(O)=O>O.C(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]23[CH2:18][CH2:17][C:14]([NH2:19])([CH2:15][CH2:16]2)[CH2:13][CH2:12]3)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)NC12CCC(c3ccc(S(C)(=O)=O)cc3)(CC1)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1ccc(C23CCC(N)(CC2)CC3)cc1
Yield: 95.9 %

Procedure:
To a 100 mL round-bottomed flask equipped with magnetic stirring was added tert-butyl 4-(4-(methylsulfonyl)phenyl)bicyclo[2.2.2]octan-1-ylcarbamate (170 mg, 448 μmol), 2 mL of CH2Cl2, ca. 5 drops of water, and trifluoroacetic acid (2 mL, 27 mmol). The reaction mixture was stirred at ambient temperature for 3.5 h, after which time the mixture was concentrated in vacuo. NaOH (ca. 50 mL of a 1M aq. solution) was added to the mixture, and the aqueous layer was extracted with CH2Cl2 (3×15 mL). The organic layers were combined, dried over K2CO3, filtered, and concentrated in vacuo to give 4-(4-(methylsulfonyl)phenyl)bicyclo[2.2.2]octan-1-amine (mass=120 mg, Mass Spec. m/z+ion=280.2) The crude reaction product was taken onto the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C=O)C>[OH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:3][CH:4]=1
Reactant: OCc1ccc(O)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
To a 500 mL round bottomed flask with a stirring bar and an argon inlet was added 4-hydroxybenzyl alcohol (7.50 g, 60.42 mmol), Cs2CO3 (29.53 g, 90.63 mmol), DMF (100 mL), and ethyl bromoacetate (11.09 g, 66.46 mmol). This mixture was stirred at ambient temperature for 2 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc and water. The layers were separated and the organic phase was washed with two additional portions of water. Drying (MgSO4), filtration and removal of the solvent in vacuo, gave an oil. This material was chromatographed on 250 g of silica gel using 1:1 EtOAc-hexane as eluant. There was obtained ethyl 2-(4-hydroxymethyl-phenoxy)acetate 35-4 (7.47 g, 59%) as an oil. 1H NMR (CDCl3): δ 1.29 (t, J=7 Hz, 3H), 2.07 (br s, 1H), 4.26 (q, J=7 Hz, 2H), 4.58 (s, 2H), 4.60 (s, 2H), 6.88 (d, J=9 Hz, 2H), 7.27 (d, J=9 Hz, 2H).