Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[S:7]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:7]1[CH:11]=[CH:10][C:9]([C:2]2[N:3]=[CH:4][NH:5][CH:6]=2)=[CH:8]1
Reactant: OB(O)c1ccsc1
Reactant: Ic1c[nH]cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: c1nc(-c2ccsc2)c[nH]1
Temperature: 25 °C
Yield: 85.2 %

Procedure:
A solution of 4-iodo-1H-imidazole (0.24 g, 1.25 mmol) and Pd(PPh3)4 (72 mg, 0.06 mmol) in DME (12.5 mL) was degased by purging with argon for 10 min. Thiophene-3-boronic acid (0.32 g, 2.50 mmol) and Na2CO3 (2.5 mL of a 2M solution in water) were added. The mixture was heated to reflux for 18 h. After cooling to RT, the solvent was removed under reduced pressure. The residue was subjected to flash chromatography (4% MeOH/CH2Cl2, silica gel) to give 0.16 g of the desired product as an off-white solid. MS(ES+) m/z 151.3 (M+H+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][C:20]([C:22]([N:24]3[CH2:27][CH:26]([O:28][C:29]4[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=4)[CH2:25]3)=[O:23])=[N:19][N:18]=2)=[CH:13][CH:12]=1.[Na].C([O-])(O)=O.[Na+]>ClCCl>[OH:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([CH2:33][C:32]2[CH:31]=[CH:30][C:29]([O:28][CH:26]3[CH2:27][N:24]([C:22]([C:20]4[O:21][C:17]([C:14]5[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=5)=[N:18][N:19]=4)=[O:23])[CH2:25]3)=[CH:36][CH:35]=2)[CH2:2][CH2:3]1
Reactant: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(C=O)cc4)C3)o2)cc1
Reactant: OCC1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(CN5CCC(CO)CC5)cc4)C3)o2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Piperidin-4-ylmethanol (0.04 g, 0.35 mmol) was dissolved in dichloromethane (2 mL) and TEA (0.052 ml, 0.38 mmol) was added. Intermediate 55A (0.11 g, 0.29 mmol) was added followed by addition of sodium triacetoxyhydroborate (0.123 g, 0.58 mmol). The mixture was stirred at RT overnight. Dichloromethane (10 mL) and NaHCO3 (sat. 2 mL) were added and the mixture was filtered through a phase separator and the solvent was removed by evaporation. The product was purified by preparative reverse-phase HPLC at pH 10 to give 81 mg (58%). 1H NMR (600 MHz, DMSO) δ 1.05-1.17 (m, 2H), 1.28-1.39 (m, 1H), 1.57-1.66 (m, 2H), 1.82-1.92 (m, 2H), 2.75-2.84 (m, 2H), 3.19-3.27 (m, 3H), 3.83-3.92 (m, 3H), 4.06-4.13 (m, 1H), 4.37-4.45 (m, 1H), 4.5-4.67 (m, 2H), 5.04-5.19 (m, 2H), 6.85 (d, 2H), 7.16-7.27 (m, 4H), 8-8.05 (m, 2H), MS (APCI+) m/z 479 [M+H]+, LC-purity: 99%.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[NH:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:28][O:29][C:30]1[C:31](=O)[C:32](=[O:36])[C:33]=1[O:34]C>>[CH3:28][O:29][C:30]1[C:33](=[O:34])[C:32](=[O:36])[C:31]=1[NH:2][C:3]1[CH:4]=[C:5]([CH:9]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[NH:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1c(OC)c(=O)c1=O
Reactant: COc1ccc(C(NC(=O)c2ccc(F)cc2)c2cccc(N)c2)cc1
Agent: Cl
Product: COc1ccc(C(NC(=O)c2ccc(F)cc2)c2cccc(Nc3c(OC)c(=O)c3=O)c2)cc1
Yield: 49.7 %

Procedure:
In a similar manner to that described in Example (46e) N-[(3-aminophenyl)-(4-methoxyphenyl)methyl]-4-fluorobenzamide hydrochloride (674 mg) [prepared as described in step (b) above] and 3,4-dimethoxy-3-cyclobutene-1,2-dione (250 mg) were reacted, to afford the title compound (399 mg) as a yellow solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]([S:7]([CH:10]=[CH2:11])(=[O:9])=[O:8])=[CH2:6].[F:12][C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:14]=1[NH2:15]>ClC1C=CC=CC=1>[F:12][C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:14]=1[N:15]1[CH2:11][CH2:10][S:7](=[O:9])(=[O:8])[CH2:5][CH2:6]1
Reactant: Nc1c(F)cccc1F
Reactant: C=CS(=O)(=O)C=C
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: O=S1(=O)CCN(c2c(F)cccc2F)CC1
Temperature: 110 °C

Procedure:
Aluminum chloride (310 g, 2.3 mol) is added to chlorobenzene (2.5 L) to give a cloudy green suspension. Vinyl sulfone (230 mL, 2.3 mol) is added via funnel, followed by 2,6-difluoroaniline (250 mL, 2.3 mol). The light brown solution is heated to 110° C. Upon completion of the reaction, the heat is removed and the black solution is self-cooled to 70° C. The reaction mixture is then quenched in methylene chloride (4 L) and ice water (5 L), the aqueous phase is extracted with methylene chloride (3 L, 2 L, 2 L, 2 L) and the combined organic layers are concentrated, rediluted with branched octane (3 L), and then cooled to 0° C. for 30 minutes. The solids are filtered and washed with branched octane (2×500 mL) and are then dissolved in methylene chloride (3 L) and loaded onto a silica gel plug (1.8 kg). The column is eluted with dichloromethane (16 L) until clear. The methylene chloride solution is concentrated, and the solids are dissolved in hot ethyl acetate (3 L) followed by the addition of hexanes (900 mL). The black solution is self-cooled to room temperature overnight, and the resulting light amber crystal needles are filtered and washed with hexanes (4×250 mL). The solids are dried under reduced pressure at 50° C. overnight to give the title compound, 1H NMR (CDCl3) δ 7.08 (m, 1H), 6.91 (m, 2H), 3.67 (m, 4H), 3.18 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([OH:14])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.[C:16]1(B(O)O)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.CCN(CC)CC>C(Cl)Cl>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:12]([O:14][C:18]2[CH:17]=[CH:16][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH:13]=[C:4]([C:3]([O:2][CH3:1])=[O:15])[CH:5]=1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: OB(O)c1cccc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Oc2ccc3ccccc3c2)cc(C(=O)OC)c1
Yield: 76 %

Procedure:
A solution of 5-hydroxyisophthalic acid dimethylester (208 mg, 1 mmol) and 2 naphthaleneboronic acid (172 mg, 1 mmol), Cu (OAc)2 (61 mg, 0.5 mmol), Et3N (0.16 ml, 1.2 mmol) in 10 ml methylenechloride was refluxed for overnight. The reaction mixture was purified by silica gel column eluted by 15% Teac in hexane to afford the product (76% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]=[CH:7]2.C(=O)([O-])[O-].[Cs+].[Cs+].[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[N:8]=[CH:7]2
Reactant: Clc1ncc2cccc(Br)c2n1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Brc1cccc2cnc(Oc3ccccc3)nc12
Temperature: 120 °C
Yield: 71.4 %

Procedure:
A mixture of 8-bromo-2-chloroquinazoline (Ark Pharm Inc, Libertyville Ill.; 0.550 g, 2.259 mmol), cesium carbonate (0.883 g, 2.71 mmol), and phenol (0.234 g, 2.485 mmol) in 3 mL DMSO was sealed and heated to 120° C. for 2 h. The reaction was then partitioned between water and EtOAc. The organic layer was sequentially washed with water (2×), and saturated aq. NaCl (1×), then dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography using 0-20% EtOAc/hexane. The material-containing fractions were concentrated to afford 8-bromo-2-phenoxyquinazoline (0.486 g, 1.614 mmol, 71% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ ppm 9.25 (1H, s), 8.15 (1H, dd, J=7.6, 1.4 Hz), 7.87 (1H, dd, J=8.0, 1.4 Hz), 7.34-7.50 (5H, m), 7.26-7.31 (1H, m). m/z (ESI, +ve) 302.9 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH2:8][S:9][CH3:10])[NH2:6].[Cl:12][C:13]1[CH:14]=[C:15]([NH:20][CH:21]([C:23](O)=[O:24])[CH3:22])[CH:16]=[CH:17][C:18]=1[Cl:19]>>[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH2:8][S:9][CH3:10])[NH:6][C:23](=[O:24])[CH:21]([CH3:22])[NH:20][C:15]1[CH:16]=[CH:17][C:18]([Cl:19])=[C:13]([Cl:12])[CH:14]=1
Reactant: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Reactant: COC(=O)[C@@H](N)CCSC
Agent: Cl
Product: COC(=O)[C@H](CCSC)NC(=O)C(C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure D and using L-methionine methyl ester hydrochloride (Sigma) and N-(3,4-dichlorophenyl)-D,L-alanine (from Example A above), the title compound was prepared as a mixture of diastereomers. The reaction was monitored by tlc (Rf=0.35 in 43% EtOAc/hexanes) and purification of this compound was by flash chromatography with 43% EtOAc/hexanes.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl.Cl.N1CCCCC1>>[CH:2]([C:3]1[CH:11]=[CH:10][C:8]([O:9][CH2:12][CH:14]2[O:16][CH2:15]2)=[C:5]([O:6][CH3:7])[CH:4]=1)=[O:1]
Reactant: COc1cc(C=O)ccc1O
Reactant: ClCC1CO1
Agent: Cl
Solvent: C1CCNCC1
Product: COc1cc(C=O)ccc1OCC1CO1
Reaction time: 4 h

Procedure:
A mixture of 50 g. of vanillin, 77 ml. of epichlorohydrin and 0.33 g. of piperidine hydrochloride is heated at 95°-100°C. for 4 hours. The excess epichlorohydrin is removed by evaporation under reduced pressure and the residue is distilled at 178°-183°C./0.6-0.7 mm. The distilled product is stirred rapidly with 400 ml. of aqueous N-sodium hydroxide solution for 4 hours, and the solid is extracted from the mixture with 400 ml. of chloroform. The chloroform solution is dried and evaporated to dryness and there is thus obtained as residue 1-(4-formyl-2-methoxyphenoxy)-2,3-epoxypropane, a pale yellow solid which is used without further purification. A solution of 5 g. of 1-(4-formyl-2-methoxyphenoxy)-2,3-epoxypropane and 50 ml. of isopropylamine in 50 ml. of chloroform is heated under reflux for 18 hours. The mixture is evaporated to dryness and the residue is crystallised from a mixture of benzene and petroleum ether (b.p. 60°-80°C.). There is thus obtained 1-[2-methoxy-4-(N-isopropyliminomethyl)phenoxy]-3-isopropylamino-2-propanol. A mixture of the above compound, 75 ml. of concentrated aqueous hydrochloric acid and 75 ml. of water is heated under reflux for 4 hours. The aqueous hydrochloric acid is removed by evaporation and the residue is partitioned between 100 ml. of chloroform and 100 ml. of aqueous 2N-hydrochloric acid. The aqueous acidic layer is separated, made alkaline with sodium carbonate and extracted twice with 100 ml. of chloroform each time. The combined extracts are dried and evaporated to dryness. The residual basic oil is converted to the oxalate thereof by conventional means, and the oxalate is crystallised from a mixture of methanol and water. The oxalate is reconverted to the free base by conventional means, and the base is crystallised from a mixture of ethyl acetate and petroleum ether (b.p. 60°-80°C.). There is thus obtained 3-isopropylamino-1-(4-formyl-2-methoxyphenoxy)-2-propanol, m.p. 56°-58°C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[CH3:2].C(O[C:19]1(OCC)[CH2:23][CH2:22][CH2:21][N:20]1[CH3:24])C>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5](=[C:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH3:24])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:15])[CH3:2]
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOC1(OCC)CCCN1C
Solvent: c1ccccc1
Product: CCOC(=O)C(=C1CCCN1C)c1ccc([N+](=O)[O-])cc1

Procedure:
Boil 50 g of 4-nitrophenylacetic acid ethyl ester and 41.4 g of 2,2-diethoxy-1-methylpyrrolidine under reflux for 3 hours in 250 ml of benzene. Distil off the benzene before recrystallizing the resulting residue from diethyl ether/petroleum ether to obtain the title compound at a yield of 52.6 g (77% of theory) in the form of red crystals of m.p. 82° to 83°.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.[CH3:6][C:7]([Si:10]([CH3:19])([CH3:18])[O:11][CH2:12][CH2:13][O:14][CH2:15]CO)([CH3:9])[CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:5][CH2:1][CH2:15][O:14][CH2:13][CH2:12][O:11][Si:10]([C:7]([CH3:9])([CH3:8])[CH3:6])([CH3:19])[CH3:18]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)[Si](C)(C)OCCOCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCOCCBr
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.2 %

Procedure:
18.2 g of carbon tetrabromide is added over 15 minutes at −15°/−20° C. to a mixture containing 11.2 g of the product of Stage A and 14.4 g of triphenylphosphine in 100 cm3 of methylene chloride. Agitation is carried out for 1 hour 15 minutes at −15° C., the solvent is evaporated off, followed by taking up in pentane, agitating at ambient temperature, separating, washing with pentane and drying at 50° C. under reduced pressure. 10.1 g of expected product is obtained.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:20])[CH:16]=2)[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:21]([O-])([OH:23])=[O:22].O>C(O)(=O)C>[C:1]([O:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:20])[C:16]=2[N+:21]([O-:23])=[O:22])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: O=C(Oc1ccc2cc(O)ccc2c1)c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: O=C(Oc1ccc2c([N+](=O)[O-])c(O)ccc2c1)c1ccccc1

Procedure:
The thus obtained 6-hydroxy-2-naphthyl benzoate was dispersed in acetic acid, nitric acid was added dropwise to the dispersion while keeping it at 15° C., and water was further added thereto, followed by stirring. The thus obtained deposit was recrystallized from ethanol/acetic acid to obtain 6-hydroxy-5-nitro-2-naphthyl benzoate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:19]([O-:21])=[O:20])[C:5]([CH:8](C(OCC)=O)C(OCC)=O)=[N:6][CH:7]=1.[OH-].[Na+]>Cl>[Br:1][C:2]1[CH:3]=[C:4]([N+:19]([O-:21])=[O:20])[C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 95 %

Procedure:
diethyl (5-bromo-3-nitropyridin-2-yl)propanedioate (6.8 g, 18.8 mmol) was refluxed in 290 ml of 6M HCl overnight. The reaction mixture was allowed to cool down to room temperature, and the mixture was neutralized with NaOH in an ice bath to pH 10. The solution was extracted with dichloromethane (DCM), dried, and evaporated to a yellow solid, 3.88 g, in 95% yield.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][C:4](=[O:6])[OH:5].[F:17][CH2:18]C(OC(=O)CF)=O.C(N(CC)CC)C>C1C=CC=CC=1.CN(C)C1C=CN=CC=1>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([CH2:18][F:17])=[O:9])[CH2:3][C:4](=[O:6])[OH:5]
Reactant: O=C(CF)OC(=O)CF
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)CF
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of Boc-Asp-OH (8.11 mmol) and fluoroacetic anhydride (16.2 mmol) in benzene (30 ml) was treated with triethylamine (16.2 mmol) at room temperature. The catalyst 4-dimethylaminopyridine (0.41 mmol) was added to the solution and the reaction stirred for about 2 h at room temperature. About 100 ml benzene was added to the reaction mixture. The organic solution was washed with 1N HCl (2×50 ml), saturated NaHCO3 (2×50 ml), and saturated NaCl (2×50 ml), followed by drying over anhydrous MgSO4. The solvent was then removed by evaporation under reduced pressure. The resulting oil was applied to a 2.5×80 cm column of silica gel (60-200 mesh). The title compound was eluded with 2% methanol in chloroform.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1.Cl.[NH2:15][OH:16]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[CH2:12][CH2:11][C:10](=[N:15][OH:16])[CH2:9][CH2:8]1
Reactant: NO
Reactant: O=C1CCN(Cc2cccs2)CC1
Agent: Cl
Product: ON=C1CCN(Cc2cccs2)CC1

Procedure:
1-(2-Thiopheneyl)methyl-4-piperidone oxime is prepared from 1-(2-thiopheneyl)methyl-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH:18]3[CH:13]([N:14](C(OCC4C=CC=CC=4)=O)[CH2:15][CH2:16][CH2:17]3)[CH2:12][CH2:11]2)=[N:3][CH:2]=1.[BrH:29]>C(O)(=O)C>[BrH:29].[N:10]1([C:4]2[C:5]3[CH:9]=[CH:8][NH:7][C:6]=3[N:1]=[CH:2][N:3]=2)[CH:18]2[CH:13]([NH:14][CH2:15][CH2:16][CH2:17]2)[CH2:12][CH2:11]1
Reactant: O=C(OCc1ccccc1)N1CCCC2C1CCN2c1ncnc2[nH]ccc12
Agent: Br
Solvent: CC(=O)O
Product: c1nc(N2CCC3NCCCC32)c2cc[nH]c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of the racemic product of Example 1 (1.77 g, 4.69 mmol) in 33% HBr in acetic acid (30 mL) was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated to a crude solid/liquid mixture. Ethanol (35 mL) was added, and the resulting suspension was stirred at ambient temperature. The solids were filtered, rinsing the filter cake with ethanol. The filtered solids were dried on the high vacuum until constant weight was achieved to afford the desired product (HBr salt) as a grey solid. LRMS calc'd for C13H18N5[M+H]+, 244; found 244. 1H NMR (500 MHz, DMSO-D6) δ 12.7 (br s, 1H), 9.21 (br s, 2H), 8.35 (s, 1H), 7.47 (s, 1H), 6.85 (s, 1H), 4.56 (br s, 1H), 4.30-3.76 (br m, 4H), 3.20-3.02 (br m, 2H), 2.60 (br pentet, 1H), 2.33-2.24 (br m, 1H), 2.22-2.14 (br m, 1H), 1.82-1.74 (br m, 1H), 1,74-1.52 (br m, 2H).
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[F:21][C:22]([F:35])([F:34])[C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[NH2:26]>ClCCl.N1C=CC=CC=1>[F:21][C:22]([F:34])([F:35])[C:23]1[CH:24]=[C:25]([NH:26][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:26][C:25]2[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=[C:23]([C:22]([F:21])([F:34])[F:35])[CH:24]=2)=[O:13])[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1SSc1ccccc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 8 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 3,5 -bis (trifluoromethyl) aniline (2.66 g, 11.6 mmol) in 21 mL of pyridine. The crude product was recrystallized from ethyl acetate-hexanes (1:9) to yield 0.34 g of the title compound, mp 213°-214° C.
Reaction SMILES: [F:1][C:2]([F:16])([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)[C:3](OCC)=[O:4].[NH3:17]>CO>[F:1][C:2]([F:16])([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)[C:3]([NH2:17])=[O:4]
Reactant: N
Reactant: CCOC(=O)C(F)(F)Oc1cccc(F)c1
Solvent: CO
Product: NC(=O)C(F)(F)Oc1cccc(F)c1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture of ethyl 2,2-difluoro-2-(3-fluorophenoxy)acetate (3.5 g, 14.9 mmol), MeOH (10 mL) and ammonia (5.09 g) in a 20 mL of sealing tube was stirred at 100° C. for 24 h. The mixture was cooled to rt and concentrated in vacuo to give the title compound, which was used for next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=2[Cl:19])[N:12]=[C:11]([C:21]([OH:23])=[O:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:28][N:29]([CH3:34])[CH2:30][CH:31](O)[CH3:32]>>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=2[Cl:19])[N:12]=[C:11]([C:21]([O:23][CH:31]([CH3:32])[CH2:30][N:29]([CH3:34])[CH3:28])=[O:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(OCc2ccccc2)c2c(Cl)cc(Cl)cc2n1
Reactant: CC(O)CN(C)C
Solvent: O=S(Cl)Cl
Product: CC(CN(C)C)OC(=O)c1cc(OCc2ccccc2)c2c(Cl)cc(Cl)cc2n1

Procedure:
Treatment of 4-benzyloxy-5,7-dichloroquinoline-2-carboxylic acid (1.5 g, Example 33b) with thionyl chloride (15 ml) followed by 1-dimethylamino-2-propanol (1.71 ml) as described in Example 33c gave 2-dimethylamino-1-methylethyl 4-benzyloxy-5,7-dichloroquinoline-2-carboxylate (1.47 g). δ (360 MHz, DMSO-d6) 1.34 (3H, d, CHCH3), 2.22 (6H, s, N(CH3)2), 2.45 and 2.62 (2H, 2dd, CH2N), 5.29 (1H, m, CO2CH), 5.58 (2H, s, OCH2), 7.41 (3H, m, m,p-ArH), 7.59 (2H, d, 0-ArH), 7.69 (1H, s, 3-H), 7.85 (1H, d, 6-H) and 8.12 (1H, d, 8-H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:6].CS[C:15]1[NH:20][C:19](=[O:21])[C:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)=[CH:17][N:16]=1>N1C=CC=CC=1>[CH3:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:15]1[NH:20][C:19](=[O:21])[C:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)=[CH:17][N:16]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: CSc1ncc(Cc2ccc(Cl)c(Cl)c2)c(=O)[nH]1
Reactant: CN(CCCN)c1ccccn1
Solvent: c1ccncc1
Product: CN(CCCNc1ncc(Cc2ccc(Cl)c(Cl)c2)c(=O)[nH]1)c1ccccn1

Procedure:
2-[N-(3-aminopropyl)-N-methylamino]pyridine (0.66 g) and 2-methylthio-5-(3,4-dichlorobenzyl)pyrimid-4-one (1.0 g) were heated together under reflux in pyridine (2.5 ml) for 24 hr. After stripping, the residue was recrystallised three times from ethanol/water to give 2-[3-(N-methyl-N-pyrid-2-ylamino)propylamino]-5-(3,4-dichlorobenzyl)pyrimid-4-one 0.25H2O, 1.0 g (70%) mp 104°-6° C.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH3:21])[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:6]([C:12](=[O:14])[CH:13]=1)[C:7]([O:9]CC)=[O:8])[CH3:2].Cl>[OH-].[Na+]>[CH2:1]([C:3]1[N:4]([CH3:21])[C:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:6]([C:12](=[O:14])[CH:13]=1)[C:7]([OH:9])=[O:8])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccccc2)n(C)c(CC)cc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCc1cc(=O)c(C(=O)O)c(-c2ccccc2)n1C
Yield: 100.8 %

Procedure:
2.2 gms of ethyl 6-ethyl-1-methyl-2-phenyl-4-oxonicotinate is suspended in 35 ml of 5% aqueous sodium hydroxide solution. The resulting suspension is heated on a steambath for 4 hours, cooled and acidified with dilute HCl to yield 2.0 gms of 6-ethyl-1-methyl-2-phenyl-4-oxonicotinic acid. mp (CH3CN)=244°-5°.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH2:11](Br)[C:12]#[CH:13].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:13]([N:6]1[CH2:7][CH2:8][CH:3]([C:2]([F:10])([F:9])[F:1])[CH2:4][CH2:5]1)[C:12]#[CH:11]
Reactant: C#CCBr
Reactant: FC(F)(F)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C#CCN1CCC(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 32 %

Procedure:
4-Trifluoromethylpiperidine (2.0 g, 13 mmol) was added to a solution of propargyl bromide (80 wt. % 5.4 g, 36 mmol) in ethanol (30 ml). Potassium carbonate (5.4 g, 39 mmol) was added and the mixture was stirred at room temperature for 20 hours. The mixture was filtered and the solids washed with ethyl acetate. The filtrate was evaporated in vacuo, diluted with sodium hydrogen carbonate (sat, 50 ml) and extracted with ethyl acetate (2×40 ml). The extracts were washed with brine, dried (MgSO4) and evaporated in vacuo to provide 1-propargyl-4-trifluoromethylpiperidine as a brown oil (795 mg, 32%). (ES+) 192 ([MH]+).