Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[CH3:15].[N+:16]([O-])([O-:18])=[O:17].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[C:6]([N+:16]([O-:18])=[O:17])[C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[CH3:15]
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)CCCc1ccc(F)c(C)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)CCCc1cc(C)c(F)cc1[N+](=O)[O-]
Reaction time: 0.33 h

Procedure:
The compound obtained in (2) above (10.9 gm) was added to 6 ml of cold concentrated sulfuric acid, and to the mixture was dropwise added 5.8 gm of potassium nitrate in 15 ml of concentrated sulfuric acid, while maintaining the internal temperature below 5° C. After the addition, the mixture was stirred for a further 20 minutes. The reaction product was poured into ice-cold water and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was subjected to silica gel column chromatography using a hexane-ethyl acetate (90:7) mixed solvent as an eluant to obtain fractions containing the target compound. The fractions were concentrated to produce 7.1 gm of the title compound.
Reaction SMILES: N[C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.C=O.[C:18]([BH3-])#[N:19].[Na+].[C:22](O)(=O)C>CO>[CH3:22][N:19]([CH3:18])[C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1
Reactant: CC(=O)O
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN(C)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl trans-4-aminocyclohexylcarbamate (750 mg, 3.50 mmol), paraformaldehyde (318 mg, 10.5 mmol), and sodium cyanoborohydride (660 mg, 13.5 mmol) in methanol (30 mL) was added acetic acid (catalytic) and the reaction stirred at room temperature for 18 h. The reaction mixture was quenched with water and the layers were separated. The pH of the aqueous layer was adjusted to 10 using 1 M sodium hydroxide followed by extraction with methylene chloride. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to afford the desired product (805 mg, 95%) as a white solid: ESI MS m/z 243 [C13H26N2O2+H]+.
Reaction SMILES: N.Cl[C:3]1[N:8]2[C:9]([CH2:12][CH2:13][CH3:14])=[N:10][CH:11]=[C:7]2[CH:6]=[C:5]([Cl:15])[N:4]=1.NC1N2C(CCC)=NC=C2C=C(Cl)N=1.[CH4:30].[OH2:31]>C1CCCCC1.CO>[Cl:15][C:5]1[N:4]=[C:3]([O:31][CH3:30])[N:8]2[C:9]([CH2:12][CH2:13][CH3:14])=[N:10][CH:11]=[C:7]2[CH:6]=1
Reactant: CCCc1ncc2cc(Cl)nc(Cl)n12
Reactant: O
Reactant: C
Agent: CCCc1ncc2cc(Cl)nc(N)n12
Agent: N
Solvent: C1CCCCC1
Solvent: CO
Product: CCCc1ncc2cc(Cl)nc(OC)n12
Reaction time: 1.5 h

Procedure:
To 25 ml of methanol saturated with ammonia gas was added with stirring 1.00 g (4.35 mmole) of 5,7-dichloro-3-(n-propyl)imidazo[1,5-c]pyrimidine (from Example 36). Stirring was continued at 20° C. for 1.5 hours, at which time the mixture was poured into 50 ml of water and extracted with four 35 ml portions of chloroform. The combined extracts were washed twice with 50 ml portions of water, once with 35 ml of saturated aqueous sodium chloride solution and dried over magnesium sulfate. Concentration provided a residue which was triturated with diethyl ether to provide a yellow solid which was mostly 5-amino-7-chloro-3-(n-propyl)imidazo[1,5-c]pyrimidine. The ether solution was evaporated to provide a yellow solid. The solid was dissolved in cyclohexane, treated with decolorizing charcoal and cooled. The small amount of precipitate formed was 5-amino-7-chloro-3-(n-propyl)imidazo[1,5-c]pyrimidine. Evaporation of the cyclohexane gave yellow solid 7-chloro-5-methoxy-3-(n-propyl)imidazo[1,5-c]pyrimidine, m.p. 76°- 77° C. Analysis: Calculated for C10H12ClN3O: %C, 53.2; %H, 5.4; %N, 18.6; Found; %C, 52.9; %H, 5.4; %N, 18.1.
Reaction SMILES: C(C1(C)N=[C:7]([CH2:9][CH3:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4]1)C.N1C=CCNC1.C(=O)([O-])[O-:22].[Na+].[Na+]>Cl>[NH2:4][C:5]([CH3:11])([CH2:12][CH3:13])[CH2:6][C:7](=[O:22])[CH2:9][CH3:10]
Reactant: O=C([O-])[O-]
Reactant: CCC1=NC(C)(CC)NC(C)(CC)C1
Agent: C1=CNCNC1
Agent: Cl
Agent: [Na+]
Product: CCC(=O)CC(C)(N)CC

Procedure:
196.3 g of 2,4,6-triethyl-2,6-dimethyl-1,2,5,6-tetrahydropyrimidine were added dropwise to 300 ml of concentrated hydrochloric acid at 30° - 40° C, with stirring. When all of the tetrahydropyrimidine had been added, the entire mixture was stirred for 4 - 5 hours and then neutralized with sodium carbonate and extracted with benzene. The resulting benzene solution was washed, in turn, with a 5% aqueous solution of sodium carbonate and with water, and was then dried over potassium carbonate. After removing the benzene, the residue was distilled under reduced pressure, giving 72.4 g of 5-amino-5-methyl-3-heptanone (bp 46° - 48° C/2.5 mmHg).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH:10](O)[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:35][O:36][C:37]1[CH:42]=[C:41]([O:43][CH3:44])[N:40]=[C:39]([SH:45])[N:38]=1.[Na].CN(C=O)C>ClCCl>[CH2:1]([O:8][C:9]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:16])[CH:10]([S:45][C:39]1[N:38]=[C:37]([O:36][CH3:35])[CH:42]=[C:41]([O:43][CH3:44])[N:40]=1)[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(OC)nc(S)n1
Reactant: COC(=O)C(O)C(C)(OCc1ccccc1)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C(Sc1nc(OC)cc(OC)n1)C(C)(OCc1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 28.2 %

Procedure:
11 g (25 mmol) of methyl 3-benzyloxy-3-phenyl-2-hydroxybutyrate (comp. 1.1) are dissolved in 50 ml of dichloromethane, 3 g (30 mmol) of triethylamine are added and, while stirring, 3.2 g (28 mmol) of methanesulfonyl chloride are added dropwise. The mixture is stirred at room temperature for 2 hours, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is taken up in DMF and added dropwise to a suspension of 12.9 g (75 mmol) of 4,6-dimethoxypyrimidine-2-thiol and 8.4 g (100 nmol) of sodium DMF at 0° C. After stirring at room temperature for 2 hours and at 60° C. for a further 2 hours, the mixture is poured into 1 1 of ice-water, and the precipitate is filtered off with suction. Drying results in 3.2 g of a white powder.
Reaction SMILES: [O-]CC.[Na+].[Cl:5][C:6]1[C:7]([O:9][C:10](=O)[C:11]=1[Cl:12])=[O:8].Cl.[CH3:15][NH2:16].O>C(O)(=O)C>[Cl:5][C:6]1[C:7]([N:16]([CH3:15])[C:10](=[O:9])[C:11]=1[Cl:12])=[O:8]
Reactant: CN
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CN1C(=O)C(Cl)=C(Cl)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.7 %

Procedure:
Sodium ethoxide (3.56 g, 50 mmol) was added to a solution containing 2,3-dichloromaleic anhydride (5.56 g, 33.3 mmol) and methylamine hydrochloride (3.50 g, 55.0 mmol) in 40 mL of acetic acid. The mixture was stirred under a CaCl2 drying tube at 25° C. for 16 hours and then refluxed for 4 hours. The cooled mixture was poured into water (350 mL) and extracted with EtOAc (3×75 mL). The combined organic extracts were washed with 100 mL portions of saturated aqueous NaHCO3, water and brine and dried (MgSO4). The solvent was evaporated under reduced pressure. The residue was recrystallized from ethanol to give 3.82 g (64%) of 2,3-dichloro N-methylmaleimide as white crystals. Concentration of the mother liquor and chromatography of the residue by radial preparative layer chromatography (Chromatotron, Harrison Research), gave an additional 0.81 g of 2,3-dichloro N-methylmaleimide, raising the yield to 77%.
Reaction SMILES: [C:1]1(C([O-])=O)[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[CH:2]=1.[NH2:12][N+:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[C:14]=1[NH2:20].[CH:21]([N:24](C(C)C)CC)(C)C.CCN=C=NCCCN(C)C>ClCCl.CN(C)C=O>[Cl:19][C:15]1[C:14]2[N:13]([N:12]=[C:21]([NH:24][C:1]3[CH:2]=[C:3]([CH3:8])[CH:4]=[C:5]([CH3:7])[CH:6]=3)[N:20]=2)[CH:18]=[CH:17][N:16]=1
Reactant: Nc1c(Cl)ncc[n+]1N
Reactant: Cc1cc(C)cc(C(=O)[O-])c1
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(Nc2nc3c(Cl)nccn3n2)c1
Reaction time: 1 h
Yield: 53.7 %

Procedure:
To a solution of 3,5-dimethylisothiocyanate (200 mg, 1.2 mmol) in dichloromethane and N,N-dimethylformamide (1:1) (5.0 mL) are added 1,2-diamino-3-chloro-pyrazinium mesitylenate (0.59 g, 0.0017 mol) and diisopropylethyl-amine (791 mg, 6.1 mmol). The reaction mixture is stirred for 1 hour. EDCI (93 mg, 5 mmol) is added and the solution stirred for 2 hours at room temperature before being concentrated to dryness. The residue is taken up in water and stirred for 5 minutes and the solid precipitated was filtered, washed with water, dried to get the product as a light brown solid (0.25 g, 75%). TLC: pet ether/ethyl acetate (6/4) Rf—0.4. LCMS (method A): mass found (M+H+, 274.0), Rt (min): 4.47 area % 98.0 (max), 98.47 (254 nm); 1H NMR (400 MHz, DMSO-d6): δ 9.99 (s, 1H), 8.95 (d, J=4.28 Hz, 1H), 7.91 (d, J=4.32 Hz, 1H), 7.28 (s, 2H), 6.58 (s, 1H), 2.24 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[C:10](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: Cc1ccc(Cl)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(C)ccc1Cl
Yield: 103.8 %

Procedure:
50 g (350.65 mmol) of 2-chloro-5-methylphenol is dissolved in 450 ml of acetone and mixed with 96.5 g (701.3 mmol) of potassium carbonate under nitrogen. After 43.6 ml of methyl iodide (2 equivalents) is added, it is refluxed for three hours. After cooling, the reaction mixture is filtered, the filter residue is washed with acetone, and the filter is spun in until a dry state is reached (bath temperature 30° C.). Since the residue still contains potassium carbonate, it is taken up in a little diethyl ether and filtered again. After the solvent is spun off, 57 g (103.8%) of the desired compound is obtained, which is used as crude product in the next stage.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Cl)[CH:3]=1.[H-].[Na+].[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][C@@H:21]([OH:24])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].O>CN(C=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][C@@H:21]([O:24][CH2:8][C:4]2[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=2)[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](OCc2cccnc2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 54.7 %

Procedure:
A suspension of 3-picolylchloride hydrochloride (1.84 g, 11.2 mmol) in DMF (50 ml) was added to a stirred slurry of sodium hydride (60% dispersion in oil, 0.45 g, 11.2 mmol) in DMF at 0° C. under nitrogen. The mixture was stirred at 0° C. for 0.25 h and then added to a mixture of (3R)-N-tert-butyloxycarbonylpyrrolidin-3-ol (2.0 g, 10.7 mmol) and sodium hydride (60% dispersion in oil, 0.45 g, 11.2 mmol) in DMF at 0° C. under nitrogen (mixture stirred for 0.2 h at 0° C. prior to the addition). The reaction mixture was stirred at room temperature for 2.5 h. Water (200 ml) was added and the mixture extracted with ethyl acetate (1×200 ml), dried (Na2SO4) and evaporated in vacuo. The crude product was chromatographed on silica gel, eluting with Et2 O/MeOH (95:5), to give the desired product (1.63 g, 55%), δ (250 MHz, d4 -MeOH), 1.46 (9H, s, OC(Me)3), 1.95-2.18 (2H, m, CH2), 3.34-3.51 (4H, m, 2 of CH2), 4.22 (1H, m, CHOCH2Ar), 4.59 (2H, s, OCH2Ar), 7.43 (1H, dd, J=4.7 and 7.8 Hz, Ar--H), 7.48 (1H, d, J=7.9 Hz, Ar--H), 8.45-8.51 (2H, m, 2 of Ar--H).
Reaction SMILES: [Na].[CH2:2]([OH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15](Br)[CH:16]=1>O.[Cu]>[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:16]=1
Reactant: Brc1cncc(Br)c1
Reactant: OCc1ccccc1
Agent: [Cu]
Agent: [Na]
Solvent: O
Product: Brc1cncc(OCc2ccccc2)c1
Temperature: 70 °C
Yield: 56.9 %

Procedure:
Under a nitrogen atmosphere, small pieces of sodium (1.48 g, 64.4 mmol) were added to benzyl alcohol (17.11 g, 158.0 mmol), and the mixture was stirred and heated at 70° C. for 18 h. To the stirring, viscous mixture was added 3,5-dibromopyridine (5.00 g, 21.1 mmol), copper powder (255 mg, 4.0 mmol), and benzyl alcohol (15 mL). The mixture was further heated at 100° C. for 48 h. The reaction mixture was allowed to cool to ambient temperature, diluted with water (50 mL), and extracted with diethyl ether (5×50 mL). The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation. Vacuum distillation removed excess benzyl alcohol, bp 68-72° C. at 2.6 mm Hg. Further vacuum distillation afforded 3.17 g (38.0%) of 3-bromo-5-benzyloxypyridine as a white, crystalline solid, mp 64-66° C.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1)([O-:14])=[O:13].[Cl-].[Li+].C(N(C(C)C)CC)(C)C.C(OC(C)C)(C)C>O1CCCC1>[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][CH:3]([C:2](=[O:1])[CH2:9][CH2:10][CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCCC(=O)CC(=O)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)OC(C)C
Product: CCCC(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)OCC
Temperature: 25 °C
Yield: 73.5 %

Procedure:
127.7 g of ethyl 3-oxohexanoate are dissolved in 700 ml of tetrahydrofuran. 174.5 g of 4-nitrobenzyl bromide and 35 g of lithium chloride are added and the mixture is stirred at room temperature. 286 ml of diisopropylethylamine are then introduced dropwise, which causes a slight exothermic effect. The mixture is then stirred for 3 hours at room temperature and thereafter for 10 hours under reflux. The solvents are evaporated off under vacuum and the residue is taken up with water and then extracted with chloroform. The organic phase is separated after settling has taken place and then washed with dilute hydrochloric acid solution, dried over magnesium sulphate and evaporated under vacuum. The oily residue obtained is taken up with isopropyl ether and the crystals formed are filtered off. The mother liquors are concentrated under vacuum and the residue is heated to 130° C. at 20 mm of mercury in order to remove the residual starting materials. 174 g of ethyl 2-(4-nitrobenzyl)-3-oxohexanoate are thereby obtained in the form of an oil, which is used without further purification for the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(O)(=O)C.ClC(Cl)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>[Na+].[Cl-]>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: Nc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccnc2)CC1
Reaction time: 16 h
Yield: 47 %

Procedure:
A mixture of 3-aminopyridine (2.60 g, 27.60 mmol, 1.0 equiv; commercially available) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (5.50 g, 27.60 mmol, 1.0 equiv; commercially available) in conc. acetic acid (1.57 mL, 1.66 g, 27.60 mmol, 1.0 equiv) and dichloroethane (50 mL) was stirred at rt for 4 h. Sodium triacetoxyborohydride (7.02 g, 33.12 mmol, 1.2 equiv) was added in one portion and the reaction mixture stirred for an additional time period of 16 h. To the reaction mixture was added a sat. solution of NaCl (2×50 mL) and the crude extracted with ethyl acetate (3×100 mL). The combined organic phases were washed over a sat. solution of Na2CO3 (50 mL), dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified with silica column chromatography eluting with a gradient of dichloromethane/methanol (10:0→4:1) to yield 3.60 g (47%) of the title compound in 90% purity according to 1H NMR. 1H NMR (360 MHz, CDCl3): δ 1.28-1.41 (m, 2H), 1.47 (s, 9H), 2.04 (dd, J=12.8 Hz, J=2.6 Hz, 2H), 2.93 (t, J=12.3 Hz, 2H), 3.44 (br s, 1H), 3.58 (br s, 1H), 4.07 (d, J=10.7 Hz, 2H), 6.83-6.91 (m, 1H), 7.08 (dd, J=8.2 Hz, J=4.5 Hz, 1H), 7.96 (d, J=3.6 Hz, 1H), 8.02 (d, J=2.5 Hz, 1H). MS (ESI): 278.5 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:29](OC)(OC)(OC)[CH2:30][CH2:31][CH3:32]>>[CH2:30]([C:29]1[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:31][CH3:32]
Reactant: CCCC(OC)(OC)OC
Reactant: CCOC(=O)CCCCCCCCCCCNc1c(N)cnc2ccccc12
Product: CCCc1nc2cnc3ccccc3c2n1CCCCCCCCCCCC(=O)OCC
Yield: 93.1 %

Procedure:
The general method described in Step 3 of Example 15 was used to cyclize ethyl 12-(3-aminoquinolin-4-ylamino)dodecanoate (30.4 g, 78.8 mmol) by reaction with trimethyl orthobutyrate (13.4 g, 90.6 mmol) to provide ethyl 12-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)dodecanoate (32.1 g) as a solid that was used directly in the next step without further purification.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[CH2:21]([C:23]1[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26])[CH3:22]>C(Cl)(Cl)(Cl)Cl>[Br:1][CH:21]([C:23]1[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26])[CH3:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccccc1C(=O)OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccccc1C(C)Br
Temperature: 80 °C
Yield: 82.1 %

Procedure:
N-Bromosuccinimide (10.7 g) and azodiisobutyronitrile (catalytic) were added to a solution of methyl 2-ethylbenzoate (10 g) in carbon tetrachloride (50 ml), and the resulting mixture was heated at 80° C. for 6 hours under reflux. After cooling, the reaction mixture was filtered and the filtrate was concentrated to give methyl 2-(1-bromoethyl)benzoate (12 g), almost pure by GC and NMR, as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][N:3]=1.Cl.[NH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([OH:21])=[CH:13][CH:12]=1.CC(C)([O-])C.[K+]>CN1C(=O)CCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([O:21][C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([NH2:10])=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Fc1ccnc(Cl)c1
Reactant: Nc1ccc(O)c2ccccc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Nc1ccc(Oc2ccnc(Cl)c2)c2ccccc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.3 %

Procedure:
To a stirred solution of 2-chloro-4-fluoropyridine (1.261 g, 9.58 mmol) and 4-amino-1-naphthol hydrochloride (2) (750 mg, 3.83 mmol) in NMP (40 mL), at −20° C., was added potassium tert-butoxide (1.290 g, 11.50 mmol). The reaction mixture was allowed to warm to RT. After 2.5 hr, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL then 2×80 mL). The combined organic extracts were washed with brine (150 mL), dried and evaporated in vacuo. The crude product was subjected to SCX capture and release eluting with 1% NH3 in MeOH solution and the solvent was removed in vacuo to give 4-(2-chloropyridin-4-yloxy)naphthalen-1-amine (3) (1.019 g, 92%) as a brown solid: m/z 271 (M+H)+ (ES+).
Reaction SMILES: N[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11](=[O:15])[CH2:12][CH2:13][Cl:14])=[CH:4][CH:3]=1.[F:16][B-](F)(F)F.N#[O+].ClC1C=CC=CC=1Cl>C(Cl)Cl>[Cl:14][CH2:13][CH2:12][C:11]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([F:16])[CH:10]=2)[CH2:6][CH2:7]1)=[O:15]
Reactant: F[B-](F)(F)F
Reactant: Nc1ccc2c(c1)N(C(=O)CCCl)CC2
Agent: N#[O+]
Solvent: Clc1ccccc1Cl
Solvent: ClCCl
Product: O=C(CCCl)N1CCc2ccc(F)cc21
Temperature: 10 °C
Yield: 19.5 %

Procedure:
260 mg (2.2 mmol) of 6-amino-1-(3-chloropropionyl)indoline (prepared as described in Preparation 6) were dissolved in 10 ml of methylene chloride, and 450 mg (2.0 mmol) of nitrosonium tetrafluoroborate were added to the resulting solution while ice-cooling so that the internal temperature was maintained at 10° C. or lower. The mixture was then stirred while ice-cooling for 30 minutes. At the end of this time, 10 ml of 1,2-dichlorobenzene were added to the mixture, and the mixture was stirred at 90° C. for 1 hour. The solvent was then removed from the reaction mixture by distillation under reduced pressure and the resulting residue was purified by silica gel column chromatography, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 97 mg (0.39 mmol) of the title compound as crystals (yield: 20%).
Reaction SMILES: C([O:4][Si:5]([CH2:10][CH3:11])([CH2:8][CH3:9])[CH2:6][CH3:7])(=O)C.S[C:13]1[CH:18]=CN=CC=1>C(#N)C>[CH2:6]([Si:5]([O:4][Si:5]([CH2:6][CH3:7])([CH2:8][CH3:9])[CH2:10][CH3:11])([CH2:18][CH3:13])[CH2:8][CH3:9])[CH3:7]
Reactant: CC[Si](CC)(CC)OC(C)=O
Reactant: Sc1ccncc1
Solvent: CC#N
Product: CC[Si](CC)(CC)O[Si](CC)(CC)CC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To the resulting solution of mesylate (4) is added 4-mercaptopyridine (129 mg; 1.4 equivalents) and acetonitrile (2 ml) and stirred under ice cooling for 1 hour. The reaction mixture is poured into ice-water and adjusted at pH 6.0. The organic layer is separated, washed with aqueous sodium hydrogen carbonate and water, dried, and concentrated in vacuum to give pyridyl sulfide (7) as foamy residue.
Reaction SMILES: [F:1][CH:2]([F:30])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([O:18][C:19]2[CH:24]=[N:23][C:22]([C:25](=[O:29])[N:26]([CH3:28])[CH3:27])=[CH:21][N:20]=2)[CH:17]=1)[C:11]([O:13]C)=[O:12])[CH3:6].[OH-].[Na+].C(O)(=O)C.Cl>O.CN1C(=O)CCC1>[F:30][CH:2]([F:1])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([O:18][C:19]2[CH:24]=[N:23][C:22]([C:25](=[O:29])[N:26]([CH3:27])[CH3:28])=[CH:21][N:20]=2)[CH:17]=1)[C:11]([OH:13])=[O:12])[CH3:6]
Reactant: COC(=O)c1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(O[C@@H](C)COC(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CC(=O)O
Product: C[C@@H](COC(F)F)Oc1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(C(=O)O)c1
Temperature: 0 °C
Yield: 86.9 %

Procedure:
To methyl 3-[(2S)-1-(difluoromethoxy)propan-2-yl]oxy-5-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxy-benzoate (76.3 g, 179 mmol) was added NMP (534 mL), water (305 mL) and the solution was stirred at 0° C. 2N sodium hydroxide (152 mL, 305 mmol) was charged dropwise and the reaction stirred for 4 hours. Acetic acid (41 mL, 718 mmol) was charged dropwise followed by water (1068 mL) and 1N HCl (400 mL) was added until pH 3 was reached and some material oiled out. The aqueous layer was extracted with toluene (3×988 mL) and combined with the material that oiled out which was dissolved in ethyl acetate (988 mL) and the combined organic layers were washed with water (988 mL), saturated aqueous brine (988 mL), dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with 5% MeOH in dichloromethane to afford the title compound (64 g).