Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH:13]([CH3:14])[CH2:12][CH:11]=[C:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:9]1)C1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21].C(=O)([O-])O.[Na+].C(OCC)(=O)C>C1COCC1>[CH3:14][CH:13]1[N:8]([C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])[CH2:9][C:10]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH2:12]1
Reactant: COC(=O)C1=CCC(C)N(Cc2ccccc2)C1
Reactant: C=CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1CC(C(=O)OC)=CCC1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 71 %

Procedure:
To a solution of methyl 1-benzyl-6-methyl-1,2,5,6-tetrahydro-3-pyridinecarboxylate (2.05 g, 8.36 mmol) in THF (15 ml) were added at 0–5° C. allyl chloroformate (1.1 ml, 10.4 mmol). The mixture was immediately raised to room temperature and stirred for 18 hours. After cooled to 0–5° C. a saturated aqueous sodium hydrogen carbonate and ethy acetate were added thereto and the mixture was separated with a separating funnel. The aqueous layer was extracted twice with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified with silica gel (55 g) chromatography (hexane/ethyl acetate=6/1→4/1) to give 1-allyl 3-methyl 6-methyl-5,6-dihydro-1,3(2 H)-pyridinedicarboxylate (1.42 g, 71%).
Reaction SMILES: [CH3:1][C@:2]1([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:6][CH2:5][N:4]([C@@H:7]([C:12]2[CH:13]=[N:14][C:15]([NH:18][NH2:19])=[CH:16][CH:17]=2)[C:8]([F:11])([F:10])[F:9])[CH2:3]1.[F:28][C:29]1[CH:30]=[C:31]2[C:36](=[C:37]([O:39][CH3:40])[CH:38]=1)[N:35]=[C:34]([CH:41]=O)[CH:33]=[CH:32]2>C(Cl)Cl>[CH3:1][C@:2]1([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:6][CH2:5][N:4]([C@@H:7]([C:12]2[CH:13]=[N:14][C:15]([NH:18]/[N:19]=[CH:41]/[C:34]3[CH:33]=[CH:32][C:31]4[C:36](=[C:37]([O:39][CH3:40])[CH:38]=[C:29]([F:28])[CH:30]=4)[N:35]=3)=[CH:16][CH:17]=2)[C:8]([F:9])([F:10])[F:11])[CH2:3]1
Reactant: COc1cc(F)cc2ccc(C=O)nc12
Reactant: CC(C)(C)OC(=O)N[C@@]1(C)CCN([C@@H](c2ccc(NN)nc2)C(F)(F)F)C1
Solvent: ClCCl
Product: COc1cc(F)cc2ccc(/C=N/Nc3ccc([C@H](N4CC[C@](C)(NC(=O)OC(C)(C)C)C4)C(F)(F)F)cn3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
To a solution of tert-butyl (S)-3-methyl-1-((S)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (1.00 g, 2.57 mmol) in DCM (15 mL) was added 6-fluoro-8-methoxyquinoline-2-carbaldehyde (0.5269 g, 2.568 mmol) and the reaction mixture was stirred at ambient temperature overnight. The reaction was concentrated under reduced pressure and the residue purified by chromatography (C18, 300 g, 10% MeCN/water to 95% MeCN/water over 25 column volumes) to give tert-butyl (S)-3-methyl-1-((S)-2,2,2-trifluoro-1-(6-((E)-2-((6-fluoro-8-methoxyquinolin-2-yl)methylene)hydrazinyl)pyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (1.132 g, 1.963 mmol, 76.45% yield).
Reaction SMILES: O=[C:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](O)=O)[CH2:3][CH2:4][C:5]([OH:7])=O.[C:21]1(=[O:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[C:5]1(=[O:7])[CH2:4][CH2:3][CH2:2][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1.[C:21]1(=[O:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(O)CCCCCCCCCCC(=O)CCC(=O)O
Agent: O=C1CCCCCCCCCCC1
Product: O=C1CCCCCCCCCCCCCC1

Procedure:
4-oxo-pentadecanedioic acid IV is obtainable at the yield of 66.2% based on the moles of cyclododecanone through the referential examples 1 and 2 and Example 1 as mentioned later. Alternatively, the compound IV is obtainable at the yield of 60.8% based on the moles of cyclododecanone through Examples 5 and 7. Further combined with the Referential Example 3, the overall yields of cyclopentadecanone from cyclododecanone are 39.7% and 36.4%, respectively. This fact shows that this invention provides increased yield as another improved advantage in addition to the before-mentioned advantage of avoiding employment of polyphosphoric acid for conversion to ketone.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[C:6]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:21]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=2)[CH2:1]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=Cc1ccccc1
Reactant: NC(=O)c1ccc(Oc2cccc3c2CCNC3)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: NC(=O)c1ccc(Oc2cccc3c2CCN(Cc2ccccc2)C3)nc1
Yield: 23.7 %

Procedure:
Combine 6-(1,2,3,4-tetrahydro-isoquinolin-5-yloxy)-nicotinamide (100 mg, 0.3 7 mmol), benzaldehyde (39 μL, 0.38 mmol), sodium triacetoxyborohydride (101 mg, 0.48 mmol), acetic acid (22 μL, 0.39 mmol), and 1,2-dichloroethane (5 mL) then stir at room temperature for 18 hours. Dilute the reaction with saturated aqueous sodium bicarbonate solution and extract with dichloromethane (3×25 mL). Dry the combined dichloromethane extracts with sodium chloride/magnesium sulfate, filter, and concentrate on a rotary evaporator to yield 45 mg of the crude product. The crude product is purified by flash column chromatography on silica gel eluting with (0.5% conc. ammonium hydroxide/5% ethanol) to (1% conc. ammonium hydroxide/10% ethanol) in chloroform to yield 6-(2-benzyl-1,2,3,4-tetrahydro isoquinolin-5-yloxy)-nicotinamide (31 mg, 0.09 mmol): m/z=360.1 (M+1); 3H NMR (DMSO-d6, 300.00 MHz): 8.56 (s, 1H); 8.16-8.12 (m, 1H); 7.38-7.15 (m, 6H); 6.94-6.89 (m, 3H); 6.17 (s, 2H); 3.74-3.61 (m, 4H); 2.69-2.66 (m, 4H), HPLC=99% (30/70 to 90/10 ACN/(0.1% TFA in water), Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nm).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[C:13]([N:14]4[C:19]=2[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[S:16][CH2:15]4)=[CH:12][C:11]([C:24]([O:26]C)=[O:25])=[CH:10][CH:9]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>O1CCCC1.CO>[CH:1]1([C:7]2[C:8]3[C:13]([N:14]4[C:19]=2[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[S:16][CH2:15]4)=[CH:12][C:11]([C:24]([OH:26])=[O:25])=[CH:10][CH:9]=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CSc1ccccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CSc1ccccc1-3
Temperature: 25 °C
Reaction time: 15 h
Yield: 33.9 %

Procedure:
To a solution of methyl 11-cyclohexyl-5-thia-6a-azabenzo[a]fluorene-8-carboxylate (100 mg, 0.26 mmol) in tetrahydrofuran (2 ml) and methanol (2 ml) was added 4N aqueous sodium hydroxide solution (2 ml), and the mixture was stirred at room temperature for 15 hr. 2N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate=2:1-1:1) to give 11-cyclohexyl-5-thia-6a-azabenzo[a]fluorene-8-carboxylic acid (32 mg, yield 33.3%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[F:17][C:18]([F:27])([F:26])[C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22]>>[F:17][C:18]([F:26])([F:27])[C:19]1[CH:20]=[C:21]([NH:22][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[CH:23]=[CH:24][CH:25]=1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: Nc1cccc(C(F)(F)F)c1
Product: O=c1[nH]c2nccc(Nc3cccc(C(F)(F)F)c3)c2c2ccccc12
Yield: 34 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 3-(trifluoromethyl)aniline (140 mg, 0.87 mmol) to provide 194 (52 mg, 34% yield) as a white solid. LC-MS (M+H=356, obsd.=356).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]1[CH2:13][CH2:14][OH:15].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[C:21](Cl)=[O:22]>N1C=CC=CC=1>[CH3:30][O:29][C:25]1[CH:24]=[C:20]([CH:19]=[C:18]([O:17][CH3:16])[C:26]=1[O:27][CH3:28])[C:21]([NH:1][CH2:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]1[CH2:13][CH2:14][OH:15])=[O:22]
Reactant: NCC1c2ccccc2CCN1CCO
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: c1ccncc1
Product: COc1cc(C(=O)NCC2c3ccccc3CCN2CCO)cc(OC)c1OC
Reaction time: 8 h

Procedure:
A solution of 20.6 g. of 1-aminomethyl-2-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinoline and 27.6 g. of 3,4,5-trimethoxybenzoyl chloride in 130 ml. of pyridine is left to stand overnight. The thus-precipitated 1-(3,4,5-trimethoxybenzamidomethyl)-2-[2-(3,4,5-trimethoxybenzoyloxy)-ethyl]-1,2,3,4-tetrahydroisoquinoline is filtered, washed with ether, and extracted with methanol; m.p. 236°-238°. The pyridine filtrate is evaporated, the residue is taken up in chloroform and washed several times with 5% potassium bicarbonate solution. After drying and evaporation, 1-(3,4,5-trimethoxybenzamidomethyl)-2-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinoline is obtained in this way; m.p. 138°-140° (from ethyl acetate).
Reaction SMILES: C([NH:4][C:5]1[CH:14]=[C:13]2[C:8]([NH:9][C:10](=[O:22])[C:11](=[O:21])[N:12]2[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:7][CH:6]=1)(=O)C.[N+:23]([O-])([O-:25])=[O:24].[K+]>S(=O)(=O)(O)O>[NH2:4][C:5]1[CH:14]=[C:13]2[C:8]([NH:9][C:10](=[O:22])[C:11](=[O:21])[N:12]2[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(=O)Nc1ccc2[nH]c(=O)c(=O)n(C3CCCCC3)c2c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Nc1cc2c(cc1[N+](=O)[O-])[nH]c(=O)c(=O)n2C1CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
20.6 g (68 mmol) of 7-acetamido-1-cyclohexyl-2,3(1H,4H)-quinoxalinedione were dissolved in 250 ml of concentrated sulfuric acid. Then, at 0°-5° C., 7.2 g (71 mmol) of potassium nitrate were added a little at a time. The mixture was then stirred at 0° C. for 30 min and at room temperature for 2 h and subsequently poured into 1.5 1 of ice-water and then heated on a water bath for 4 h. The resulting precipitate was filtered off with suction. The filtrate was adjusted to pH 6 with a little ammonia solution and was extracted with methylene chloride. The organic phase was dried and concentrated under reduced pressure. This residue and the first precipitate were combined to yield 13.4 g (64%) of the product. Melting point>260° C.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([O:7][C@H:8]2[CH2:12][CH2:11][C@@H:10]([O:13][Si](C(C)(C)C)(C)C)[CH2:9]2)=[CH:3][CH:2]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)C>[C:1]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=[CH:5][C:4]([O:7][C@H:8]2[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]2)=[CH:3][CH:2]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](Oc2ccc(-c3ccccc3)cc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O[C@@H]1CC[C@H](Oc2ccc(-c3ccccc3)cc2)C1
Yield: 100 %

Procedure:
(1R*,3S*)-[3-(Biphenyl-4-yloxy)-cyclopentyloxy]-tert-butyldimethylsilane (0.25 g, 0.67 mmol) was dissolved in 2 mL of THF and tetrabutylammonium fluoride (0.67 mL, 1M in THF) and stirred at room temperature for 2 hours. The solution was diluted with 15 mL of diethyl ether and washed with 1N HCl (2×15 mL). The organic layer was dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography (silica gel, hexanes/ethyl acetate 3:1, Rf0.09) to give the product (100%). 1H-NMR (200.15 MHz, CDCl3): δ 7.58–7.26 (m, 7H), 6.95 (d, 2H, J=8.9), 4.92–4.84 (m, 1H), 4.40–4.38 (m, 1H), 2.18–1.92 (m, 7H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17](B(O)O)[CH:16]=1>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][O:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:17]1[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=1)[N:11]=[C:10]2[OH:12]
Reactant: OB(O)c1cccnc1
Reactant: COc1ccc2nc(Cl)nc(O)c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: COc1ccc2nc(-c3cccnc3)nc(O)c2c1
Temperature: 105 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
To a mixture of 2-chloro-6-methoxyquinazolin-4-ol (1.20 g, 5.7 mmol, 1.0 eq.), pyridin-3-ylboronic acid (1.27 g, 8.6 mmol, 1.5 eq.), K2 CO3 (2.37 g, 17.1 mmol, 3.0 eq.) in dioxane (100 mL) and 1H2O (10 ml) was added Pd(PPh3)2Cl2 (230 mg, 0.29 mmol, 0.05 eq.) under N2 atmosphere. The resulting mixture was stirred at 105° C. under N2 atmosphere overnight. After reaction was completed, the mixture was cooled to room temperature, and the resultant precipitate was removed by filtration. The filtrate was concentrated in vacuo and the residue was partitioned between H2O (30 mL) and ethyl acetate (100 mL×3). The combined organic layers were washed with brine, dried over MgSO4. After filtration and evaporation, the crude product was obtained, which was combined with the filter cake and dried in vacuo to give 1.35 g of 6-methoxy-2-(pyridin-3-yl) quinazolin-4-ol as a gray solid. LCMS m/z=254.1 (M+1) (Method B) (retention time=1.39 min). The crude product was used for the next step without further purification.
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(C)(C)OC(=O)C1(N)CCCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
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: [OH:1][C:2]([CH3:13])([C:8]#[C:9][CH:10]([CH3:12])[CH3:11])[C:3]([O:5]CC)=[O:4].O.[OH-].[Na+].Cl>C1COCC1>[OH:1][C:2]([CH3:13])([C:8]#[C:9][CH:10]([CH3:11])[CH3:12])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(O)C#CC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C#CC(C)(O)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To a stirred solution of ethyl 2-hydroxy-2,5-dimethyl-3-hexynoate from the previous step (0.35 g, 1.9 mmol) in 2 mL THF was added H2O (2 mL) and 1 N NaOH solution (2 mL). The reaction was stirred at ambient temperature for 3 h. The mixture was acidified with 1N HCl (2 mL) and extracted twice with Et2O (10 mL). The organic layers were washed with brine, dried over anhydrous MgSO4, and filtered. The filtrate solvent was removed on a rotary evaporator to give 2-hydroxy-2,5-dimethy-3-hexynoic acid as a white solid (0.272 g, 92%). 1H NMR, 400 MHz, CDCl3, 4.81 ppm (br, s, 1H); 2.56-2.62 ppm (m, 1H); 1.70 ppm (s, 3H); 1.17 ppm (d, J=3.18 Hz, 6H).
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[C:11]([NH:12][CH2:13][C:4]2=[CH:3][CH:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.C(N(CC)CC)C.[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)([O-:23])=[O:22]>C(Cl)Cl.C(OCC)(=O)C>[N+:21]([C:24]1[CH:25]=[CH:26][C:27]([C:28]([N:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]3[CH:1]=[CH:2][CH:3]=[C:4]3[CH2:13]2)=[O:29])=[CH:31][CH:32]=1)([O-:23])=[O:22]
Reactant: c1ccc2c(c1)NCc1cccn1-2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2cccn2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5 mmol of 4,5-dihydro-pyrrolo-[1,2-a]quinoxaline in 50 ml of methylene chloride under argon is added 10 mmol of triethylamine followed by ice bath cooling. A solution of 5 mmol of 4-nitrobenzoyl chloride in 10 ml of methylene chloride is added dropwise. Following complete addition, the ice bath is removed and the reaction mixture stirred at room temperature for 2 hours. The volatiles are removed in vacuo to give a residue which is dissolved in ethyl acetate. The solution is washed with water, 1N HCl, NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography to give the desired product (from ethyl acetate) as a solid, m.p. 174°-178° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6][C:7](=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([CH:16]=O)[CH:3]=1.C([O-])(=O)C.[NH4+:22]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:14][CH:15]=1)[N:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:22]=[CH:16]2
Reactant: CCOC(=O)C(=O)Nc1ccc(Cl)cc1C=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CCOC(=O)c1ncc2cc(Cl)ccc2n1
Temperature: 115 °C
Yield: 87.3 %

Procedure:
To a solution of ethyl 2-(4-chloro-2-formyl-anilino)-2-oxo-acetate (0.14 g, 0.55 mmol, 1 eq) in 5.5 mL of acetic acid was added ammonium acetate (0.42 g, 5.4 mmol, 10 eq). After heating at 115° C. for 1 h, the mixture was concentrated then diluted with H2O and extracted with ethyl acetate. The organic layer was concentrated and the residue was purified on silica gel column chromatography (hex:EtoAc 3:2) to give ethyl 6-chloroquinazoline-2-carboxylate (0.11 g, 0.48 mmol, 88%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH:7]1[C:12]([S:13](Cl)(=[O:15])=[O:14])=[CH:11][CH:10]=[C:9]([I:17])[CH:8]=1.Cl.S1C(N)=NC=N1>N1C=CC=CC=1>[I:17][C:9]1[CH:8]=[CH:7][C:12]([S:13]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)(=[O:15])=[O:14])=[CH:11][CH:10]=1
Reactant: Nc1nccs1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Agent: Cl
Agent: Nc1ncns1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1nccs1)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 37.9 %

Procedure:
Prepared using general procedure 42. To a stirring solution of 2-aminothiazole (13.2 g, 132.2 mmol) and pyridine (20 mL) under N2, at 0° C., was added pipsyl chloride (20.0 g, 55.1 mmol). The mixture was stirred at ambient temperature for 17 hours. CH2Cl2/MeOH-2/1 (100 mL) was added. The mixture was filtered and the filtrate was purified via silica gel chromatography using 5% MeOH in CH2Cl2. The solid was triturated with CH2Cl2 to obtain the desired sulfonamide as a white solid (8.4 g, 20.9 mmol, 38% yield).
Reaction SMILES: Br.C[O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[CH:11]=[N:12][N:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=23)[N:5]=1>>[N:12]1[N:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]2=[C:10]([C:6]2[N:5]=[C:4]([OH:3])[CH:9]=[CH:8][N:7]=2)[CH:11]=1
Reactant: COc1ccnc(-c2cnn3ccccc23)n1
Agent: Br
Product: Oc1ccnc(-c2cnn3ccccc23)n1
Temperature: 100 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
48% Aqueous hydrogen bromide (19.50 mL) was added to 3-(4-methoxypyrimidin-2-yl) pyrazolo[1,5-a]pyridine (Preparation 4a, 0.30 g, 1.32 mmol) and the resulting mixture was heated to 100° C. with stirring. After 3 hours, the mixture was cooled and the resultant precipitate was filtered and dried in vacuo to give the title compound (0.28 g, 99%) as the hydrobromide salt.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:7]([O:9]CC)=[O:8].C(O)C.Cl>O>[F:3][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:7]([OH:9])=[O:8]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC)cc1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1F

Procedure:
A solution of 3.8 g of potassium hydroxide in 15 ml of water is added to a mixture of 3.5 g of ethyl 3-fluoro-4-hexadecylaminobenzoate, 30 ml of water and 30 ml of ethanol. Upon heating, a clear solution is formed and after 20 hours, the hot solution is acidified with concentrated hydrochloric acid and cooled. The precipitate is collected and recrystallized from ethanol and then from chloroform to yield 3-fluoro-4-(hexadecylamino)benzoic acid as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[N:11][C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([CH:32]=3)[CH2:19][CH2:20][C:21]3[CH:29]=[C:25]([NH:26][C:27]=1[N:28]=2)[CH:24]=[CH:23][C:22]=3[CH2:30]O.[N:33]1([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[N:11][C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([CH:32]=3)[CH2:19][CH2:20][C:21]3[CH:29]=[C:25]([NH:26][C:27]=1[N:28]=2)[CH:24]=[CH:23][C:22]=3[CH2:30][N:36]1[CH2:37][CH2:38][N:33]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34][CH2:35]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: OCc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 63 %

Procedure:
The desired compound was prepared according to the procedure of Example B191 step A, using [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methanol trifluoroacetate and tert-butyl piperazine-1-carboxylate as the starting materials in 63% yield. LCMS for C28H34ClN6O2(M+H)+: m/z=521.3.
Reaction SMILES: I[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=[CH:14][C:9]=3[O:8][CH2:7][CH2:6][N:5]2[CH:19]=1.[CH:20]([N:23]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[N:24]1)([CH3:22])[CH3:21].ClCCl.C([O-])(=O)C.[K+].C(#N)C>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:20]([N:23]1[C:27]([C:2]2[N:3]=[C:4]3[C:10]4[CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=[CH:14][C:9]=4[O:8][CH2:7][CH2:6][N:5]3[CH:19]=2)=[CH:26][CH:25]=[N:24]1)([CH3:22])[CH3:21]
Reactant: COC(=O)c1ccc2c(c1)-c1nc(I)cn1CCO2
Reactant: CC(C)n1nccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: COC(=O)c1ccc2c(c1)-c1nc(-c3ccnn3C(C)C)cn1CCO2

Procedure:
A mixture of methyl 2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate (370.1 mg, 1.000 mmol), 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (354 mg, 1.50 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (40.8 mg, 0.0500 mmol) and 2.0 M of Potassium acetate in water (1.00 mL) in Acetonitrile (12 mL, 230 mmol) was degassed. The reaction was microwaved on 200 watts, 140° C. for 30 minutes. The reaction mixture was partitioned between water and ethyl acetate, filtered, the organic layer was washed with water, brine, dried over MgSO4 and concentrated in vacuum. The residue was purified on 12 g silica column eluting with 35-40% ethyl acetate in heptane. Yield 119 mg (34%). MS: (ESI+): 353.1.