Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([C:14]([O:16][CH3:17])=[O:15])[C:8]2=[O:13].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.C(OCC)(=O)C>CO>[OH:13][C@H:8]1[C:9]2[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:6][C@@H:7]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)C1CCc2c(OC)cccc2C1=O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CCc2c(OC)cccc2[C@@H]1O
Yield: 98 %

Procedure:
A solution of methyl [5-methoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthyl]formate (2.50 g), D-10-camphorsulfonic acid (124 mg), [RuCl2 (S)-binap]2NEt3 (90 mg) [cf. Tetrahedron Letters, Vol. 35, No. 26, pp 4559-4562, 1994], ethyl acetate (23.8 ml) and methanol (1.25 ml) was stirred under hydrogen (90 atm) at 50° C. for 40 hours. The reaction mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give (1R,2S)-methyl [1-hydroxy-5-methoxy-1,2,3,4-tetrahydro-2-naphthyl]formate (2.47 g) as a white powder. mp: 87°-88° C.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](Cl)(Cl)Cl)[N:8]=1.C1C(C(/C=C/C2C=CC(F)=CC=2Cl)=[O:24])=CC=C(F)C=1.[F:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1.C(N(CC)CC)C.Cl>C1(C)C=CC=CC=1>[F:36][C:37]1[CH:43]=[CH:42][C:40]([NH:41][C:13]([C:9]2[N:8]=[C:7]([Cl:6])[CH:12]=[CH:11][CH:10]=2)=[O:24])=[CH:39][CH:38]=1
Reactant: O=C(/C=C/c1ccc(F)cc1Cl)c1ccc(F)cc1
Reactant: Clc1cccc(C(Cl)(Cl)Cl)n1
Reactant: Nc1ccc(F)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)cc1)c1cccc(Cl)n1
Temperature: 135 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
[A1 is N, A2 is Cl—C, A3, A4 and A5 are CH, R1 is 4-fluorophenyl, X is NR2 and R2 is H in the compound of formula I] Concentrated sulfuric acid (98% by weight, 127.5 g, 1.3 mol) is added to 2-chloro-6-trichloromethylpyridin (NP, 231 g, 1 mol) over a period of three hours at 135° C. The resulting mixture is stirred for three hours at 135° C. A viscous melted mass is obtained consisting of a mixture of intermediate IVa1 and Va1 with R1 being H and Hal being Cl, corresponding to a yield of >95% based on NP. This intermediate product shows a strong infrared band at 1770cm−1 indicating a carbonylchloride group. 13C-NNR (TMS/nitromethane-d3): δ=130.2 (CH-5), 135.3 (CH-3), 143.7 (C-2), 151.4 (CCl-6), 151.5 (CH-4), 164.1 (C═O) ppm. The mass is added to a mixture of 4-fluoroaniline (166.4 g 1.5 mol), triethylamine (202.0 g, 2 mol) and toluene (752 g) at temperatures between 20 and 80° C. over a period of 45 minutes. The resulting reaction mixture is heated to temperatures between 80 and 100° C. and stirred for one hour. The mixture is treated with 500 ml of hydrochloric acid (1.0% by weight) at 80° C. and the phases are separated. The resulting solution of N-(4-fluorophenyl) 2-chloro-pyrid-6-ylinecarboxamide in toluene is used for the preparation of N-(4-fluorophenyl) 2-(3-trifluoromethylphenoxy)-pyrid-6-ylinecarboxamide without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:12][CH:13]([OH:16])[CH2:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].C(O)(C)C.[H][H]>[Pd].O>[C:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[O:11][CH2:12][CH:13]([OH:16])[CH2:14][CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CCC(O)COc1ccccc1C(C)(C)C
Agent: [Pd]
Solvent: CC(C)O
Solvent: O
Product: CCC(O)COC1CCCCC1C(C)(C)C
Yield: 73.9 %

Procedure:
To a 500 ml autoclave, 50 g (0.23 mol) of 1-(2-tertbutylphenyloxy)-2-butanol, 150 g of isopropanol and 1.0 g of 5 weight % palladium catalyst supported on active carbon containing 50 weight % water (produced by N. E. Chemcat Co.) were added, and the mixture obtained was reacted at 190° C. at a hydrogen pressure of 70 kg/cm2 for 27 hours until absorption of hydrogen had stopped. After the reaction was finished, the catalyst was filtered to remove it, and the reacted solution was distilled and 38.8 g of 1-(2-tert-butylcyclohexyloxy)-2-butanol (cis:trans=63:37) were obtained in a 74% yield of product.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[NH:13][CH:14]=[CH:15][C:3]=12.Cl.[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]1[NH2:24].[CH:25](N(CC)C(C)C)(C)C>C(O)CCC>[CH3:25][N:24]([C@H:19]1[CH2:20][CH2:21][CH2:22][CH2:23][C@H:18]1[CH3:17])[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[NH:13][CH:14]=[CH:15][C:3]=12
Reactant: CCOC(=O)c1cnc2[nH]ccc2c1Cl
Reactant: C[C@@H]1CCCC[C@@H]1N
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: CCCCO
Product: CCOC(=O)c1cnc2[nH]ccc2c1N(C)[C@H]1CCCC[C@H]1C

Procedure:
In a microwave reaction vessel ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (15 mg) and (1S,2R)-2-methylcyclohexanamine hydrochloride (65.5 mg) were suspended in n-butanol (0.075 mL). To the mixture was added N,N-diisopropylethylamine (0.093 mL). The vessel was sealed and reacted in the microwave reactor at 160° C. for 1 hour. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel with chloroform and methanol (100:0 to 90:10) to give ethyl 4-{methyl[(1S,2R)-2-methylcyclohexyl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (5 mg) as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.Cl[C:13]([O:16]C(=O)OC(Cl)(Cl)Cl)(Cl)Cl>O1CCOCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:13](=[O:16])[O:8][C:7](=[O:9])[C:6]=2[CH:10]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(O)cc1C(=O)O
Solvent: C1COCCO1
Product: O=c1[nH]c2ccc(O)cc2c(=O)o1
Temperature: 25 °C
Yield: 281.9 %

Procedure:
5-Hydroxyanthranilic acid (9.5 g, 62 mmol) was suspended in dioxane (50 mL), bis(trichloromethyl)carbonate (6 g, 20 mmol) was added (slightly exothermic), the suspension was refluxed for 1 h, allowed to cool to rt, the solid was filtered off and washed with dioxane, affording brown crystals (10.1 g, 90%), mp. 236° C. (dec).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([C:16]3[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:18][CH:17]=3)=[O:15])[C:9](=[O:27])[CH2:8]2)=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH2:32](O)[CH3:33]>>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([C:16]3[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22]([O:24][CH2:32][CH3:33])=[O:23])=[CH:18][CH:17]=3)=[O:15])[C:9](=[O:27])[CH2:8]2)=[CH:3][CH:2]=1
Reactant: O=C(O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2=O)cc1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2=O)cc1

Procedure:
A crude sample of the product of Example 62 (3.4 g) was treated with a solution, at 0° C., made by adding thionyl chloride (2.25 g) dropwise to ethanol (45 ml) with stirring at below 0° C. The mixture was stirred at room temperature for 2 hours, heated at gentle reflux for 2 1/2 hours, and evaporated. The residue was treated with water and adjusted to pH6 with aqueous sodium bicarbonate solution. The gum which precipitated was separated and the aqueous solution was adjusted to pH8 and extracted with dichloromethane (2×50 ml). The combined extracts were washed with brine, dried and evaporated. The residue was purified by chromatography using a 10 g. Mega Bond Elut silica gel column, eluting with 5% methanol/dichloromethane/0.5% triethylamine to give the title product as a solid (0.2 g); m.p. 163°-165° C.; NMR(CDCl3) δ8.34(2H,m), 7.97(2H,m), 6.98(2H,m), 6.63(2H,m), 4.89(2H,s), 4.7(2H,s), 4.29(2H,q), 4.1(2H,s), 3.7(2H,m), 3.6(2H,m), 1 31(3H,t); m/e 398(M+H)+ ; calculated for C21H23N3O5 : C, 63.5; M, 5.83; N, 10.6. Found: C, 61.5; H, 5.9; N, 10.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[C:4]([F:10])[CH:3]=1.[CH:11](=O)[CH3:12].[O-:14][C:15]#[N:16].[Na+].N1C(=O)N=CN1>C(O)(C)(C)C.O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:15](=[O:14])[NH:16][C:11]([CH3:12])=[N:9]2)=[C:4]([F:10])[CH:3]=1
Reactant: CC=O
Reactant: NNc1ccc(Cl)cc1F
Reactant: N#C[O-]
Agent: O=c1nc[nH][nH]1
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1nn(-c2ccc(Cl)cc2F)c(=O)[nH]1
Temperature: 2.5 °C
Reaction time: 0.08 h

Procedure:
A stirring solution of 80.3 grams (0.500 mole) of 4-chloro-2-fluorophenylhydrazine in 180 ml of tert-butanol/water (88/12) is cooled to 0 to 5° C., and a solution of 23.4 grams (0.525 mole) of acetaldehyde in 54 grams of tert-butanol/water (88/12) is added dropwise during a 20 minute period. Upon completion of addition, the reaction mixture is stirred for five minutes, and a slurry of 39.8 grams (91.5% pure--0.560 mole--12% molar excess) of sodium cyanate in 90 grams of water is added in one portion. Additional water is used to wash any of the remaining slurry of sodium cyanate from its container into the reaction mixture. The reaction mixture is cooled to 0 to 5° C., and 39.3 grams (0.655 mole--5% equivalent excess, based on equivalents of sodium cyanate and its sodium carbonate impurity) of acetic acid is added dropwise during a 15 minute period. Upon completion of addition, the reaction mixture is stirred for about two hours during which time it is allowed to warm to about 20° C. Upon completion of the two hour stirring time, the reaction mixture is cooled to 10° C., and 321 grams (0.537 mole) of a 12.4% aqueous solution of sodium hypochlorite is added dropwise during a 40 minute period. Upon completion of addition, the reaction mixture is stirred for an additional 40 minutes. The tert-butanol/water medium is then distilled from the reaction mixture by slowly heating the reaction mixture to about 100° C. Upon completion of the distillation, the pot residue is washed with water and dried, yielding 1-(4-chloro-2-fluorophenyl)-4,5-dihydro-3-methyl,-1,2,4-triazol-5(1H)-one.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[C:15]([CH3:22])[CH:14]=1>>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:11][C@@H:7]2[CH2:8][CH2:9][CH2:10][C@@H:6]2[N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:18])=[C:15]([CH3:22])[CH:14]=1
Reactant: Cc1cc(Cl)ccc1C(=O)O
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Product: Cc1cc(Cl)ccc1C(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, light brown viscous oil, MS: m/e=307.2 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 4-chloro-2-methylbenzoic acid.
Reaction SMILES: [Cl:1][CH:2]([CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3](Cl)=[O:4].[NH2:15][CH2:16][CH2:17][CH:18]1[O:22][CH2:21][CH2:20][O:19]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][CH:2]([CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([NH:15][CH2:16][CH2:17][CH:18]1[O:22][CH2:21][CH2:20][O:19]1)=[O:4]
Reactant: O=C(Cl)C(Cl)COCc1ccccc1
Reactant: NCCC1OCCO1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(NCCC1OCCO1)C(Cl)COCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 65.9 %

Procedure:
A solution of 69.63 g of 2-chloro-3-(phenylmethoxy)propanoyl chloride (prepared according to the procedure described in Inorg. Chem., 31. 2422, 1992) (0.299 mol) in 90 ml of CHCl3 was added to a solution of 35.49 g of 2-(2-aminoethyl)-1,3-dioxolane (prepared according to the procedure described in EXAMPLE 4) (0.303 mol) and to 60.3 g of triethylamine (83 ml; 0.596 mol) in 100 ml of CHCl3 under inert atmosphere, keeping the temperature at 0°-5° C. The reaction mixture was stirred for 5 h at 25° C., then was washed with H2O. The organic phase was dried and evaporated to dryness, the residue was purified by flash chromatography. 61.68 g of the desired product (0.197 mol) were obtained.
Reaction SMILES: [O:1]1[CH2:11][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:12]1(=[O:18])[NH:16][C:15](=[O:17])[CH2:14][CH2:13]1>C(O)C.N1C=CC=CC=1>[C:15]1(=[O:17])[N:16]([CH2:11][CH:2]([OH:1])[CH2:3][O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:12](=[O:18])[CH2:13][CH2:14]1
Reactant: O=C1CCC(=O)N1
Reactant: c1ccc(OCC2CO2)cc1
Solvent: CCO
Solvent: c1ccncc1
Product: O=C1CCC(=O)N1CC(O)COc1ccccc1
Reaction time: 24 h
Yield: 72.2 %

Procedure:
A mixture of 15 gm (0.1 mole) of 2,3-epoxypropoxybenzene (prepared as described in Example I) and 9.9 gm (0.1 mole) of succinimide in 100 mL ethanol having 10 drops of pyridine was heated to reflux for 4 hours. After standing 24 hours at room temperature a white crystalline product separated. This material was collected, air-dried and recrystallized from 700 mL ethyl acetate:hexane (6:1) to give 18 gm (72%) of white crystals: mp 130°. The NMR spectrum and the elemental analyses were consistent with the assigned structure.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][C@@H:7]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:6]2)#[N:2].C(O)(=O)C.C1COCC1.I([Cl:35])(=O)=O.I(Cl)(=O)=O.I(Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>C(Cl)Cl>[Cl:35][C:11]1[CH:12]=[C:3]([C:1]#[N:2])[CH:4]=[C:5]2[C:10]=1[NH:9][CH2:8][CH:7]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:6]2
Reactant: N#Cc1ccc2c(c1)C[C@H](NS(=O)(=O)c1ccccc1)CN2
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N#Cc1cc(Cl)c2c(c1)CC(NS(=O)(=O)c1ccccc1)CN2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.7 %

Procedure:
To a suspension of racemate 1G (313.4 mg, 1 mmol) in a mixed solvent of acetic acid (3 mL), THF (3 mL) and CH2Cl2 (3 mL) at RT was added benzyltrimethylammonium tetrachloroiodate (419 mg, 1 mmol). After addition, the mixture was stirred at RT for 30 min to become a clear yellow solution which was concentrated in vacuo. The residue was triturated with CH2Cl2 and H2O and the resultant solid filtered and washed with CH2Cl2 and H2O, dried in vacuo to give the title compound as an off-white solid (204 mg, 59%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([NH:7][C:8](=[O:32])[CH2:9][CH2:10][N:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[CH2:20][CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23][CH2:24][C:12]2=3)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.C(Cl)[Cl:43]>>[ClH:43].[CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([NH:7][C:8](=[O:32])[CH2:9][CH2:10][N:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[CH2:20][CH2:21][NH:22][CH2:23][CH2:24][C:12]2=3)=[CH:5][CH:4]=1
Reactant: ClCCl
Reactant: COc1ccc(NC(=O)CCn2c3c(c4ccccc42)CCN(C(=O)OC(C)(C)C)CC3)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(NC(=O)CCn2c3c(c4ccccc42)CCNCC3)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84 %

Procedure:
tert-butyl 6-[3-(4-methoxyanilino)-3-oxopropyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.110 g, 0.238 mmol) was disolved in CH2Cl2 (5 mL) and trifluoroacetic acid (2.0 mL, 2.96 g, 26.0 mmol, 109 equiv.) was added. The resulting solution was stirred at rt for 2.5 h. The reaction mixture was concentrated to dryness, and the residue was partitioned between EtOAc and 1N NaOH. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The crude product (0.0805 g) was combined with EtOAc (2 mL), and 1M HCl in Et2O (2 mL) and the salt was collected by filtration. The salt was dried under vacuum over P2O5. N-(4-methoxyphenyl)-3-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)propanamide hydrochloride (0.0796 g) was obtained in 84% yield. 1H NMR (300 MHz, CD3OD) δ 2.76, 3.13-3.17, 3.28-3.39, 3.74, 4.55, 6.82, 7.08, 7.18, 7.26, 7.44, 7.47; MS (ESI+) for C22H25N3O2 m/z 364.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C([Li])CCC.CCCCCC.[CH3:20][C:21]([CH3:23])=[O:22].[CH3:24][S:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1>CCOCC>[OH:22][C:21]([C:5]1[CH:6]=[CH:7][C:2]([CH:30]([C:29]2[CH:32]=[CH:33][C:26]([S:25][CH3:24])=[CH:27][CH:28]=2)[OH:31])=[N:3][CH:4]=1)([CH3:23])[CH3:20]
Reactant: CC(C)=O
Reactant: Brc1ccc(Br)nc1
Reactant: CSc1ccc(C=O)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CSc1ccc(C(O)c2ccc(C(C)(C)O)cn2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2,5-dibromopyridine (5.12 g, 1 eq) in ether at −78° C., was added n-butyllithium in hexane (1.05 eq) slowly. The resulting yellow-orange precipitate was strirred 30 min. Then acetone (1.54 ml, 1.05 eq) was added. The solution was kept at −78° C. for another 30 min. n-Butyllithium in hexane (1.1 eq) was slowly syringed to the resulting orange suspension. The suspension was then stirred 1 h at −78° C. Following this, 4-(methylthio)benzaldehyde (2.85 ml, 1.1 eq.) was added. The resulting suspension was warmed to −35° C. and quenched with a solution of NH4Cl (sat.). Water and EtOAc were added and the organic layer dried over MgSO4, evaporated and purified by flash chromatography (EtOAc) to give [5-(1-Hydroxy-1-methylethyl)-2-pyridinyl][4-(methylthio)phenyl]methanol.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][C:17](=[O:27])[CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)=[O:9])=[CH:4][CH:3]=1.Cl[C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl.[O:42]1CCOC[CH2:43]1>>[N:26]([C:23]1[CH:22]=[CH:21][C:20]([O:19][CH2:18][C:17]([O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][C:8](=[O:9])[CH2:7][O:6][C:5]2[CH:4]=[CH:3][C:2]([N:1]=[C:43]=[O:42])=[CH:29][CH:28]=2)=[O:27])=[CH:25][CH:24]=1)=[C:31]=[O:33]
Reactant: C1COCCO1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(OCC(=O)OCCOCCOC(=O)COc2ccc(N)cc2)cc1
Product: O=C=Nc1ccc(OCC(=O)OCCOCCOC(=O)COc2ccc(N=C=O)cc2)cc1
Temperature: 80 °C

Procedure:
(4-Aminophenoxy)-acetic acid 2-{2-[2-(4-aminophenoxy)-acetoxy]-ethoxy}-ethyl ester (200 grams, 495 mmoles) was dissolved in dry 1,4-dioxane (2000 ml) under nitrogen atmosphere and cooled to below 10° C. A solution of triphosgene (250 grams, 842.45 mmoles) in dry 1,4-dioxane (600 ml) was added. The mixture was heated slowly to 80° C. and maintained at that temperature for 2 hours. The condenser was then arranged for distillation and the solvent was removed by distillation at atmospheric pressure until the volume of the reaction mixture had been reduced to approximately one third. Fresh dry 1,4-dioxane (600 ml) was added and distilled off under vacuum. The residue was re-evaporated two times from dry 1,4-dioxane (1.2 L), then dry toluene (600 ml) and charcoal (20 g) were added. The solution was filtered hot, and toluene was distilled off under vacuum to give pure (4-isocyanato-phenoxy)-acetic acid 2-{2-[2-(4-isocyanato-phenoxy)-acetoxy]-ethoxy}-ethyl ester (4.5 g) as a light yellow syrup. The product was characterized by 1H NMR (CDCl3) δ 3.65 (t, 2H, CH2), 4.35 (t, 2H, CH2), 4.65 (s, 2H, CH2), 6.75 (d, 2H, Ar), 7.00 (d, 2H, Ar).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:27])=[CH:4][C:5]([F:26])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:19])=[C:15]([Cl:18])[N:16]=3)[C:11](=[O:20])[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:9]2)[CH:7]=1.Cl[CH2:29]CCl.CO.C=O>[Pd].C(O)(=O)C>[Cl:18][C:15]1[N:16]=[C:17]2[C:12]([C:11](=[O:20])[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:9][N:8]2[C:6]2[CH:7]=[C:2]([NH:1][CH3:29])[C:3]([F:27])=[CH:4][C:5]=2[F:26])=[CH:13][C:14]=1[F:19]
Reactant: CCOC(=O)c1cn(-c2cc(N)c(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Reactant: ClCCCl
Agent: [Pd]
Agent: C=O
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)c1cn(-c2cc(NC)c(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Reaction time: 16 h

Procedure:
Ethyl 1-(5-amino-2,4-difluorophenyl)-7-chloro-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (500 mg) was added to a mixture of 10 ml of 1,2-dichloroethane, 5 ml of methanol and 0.5 ml of acetic acid together with 100 mg of 37% formalin. Using 0.08 g of 10% palladium on carbon, hydrogenation was carried out for 16 hours. After the catalyst was filtered off, the filtrate was concentrated in vacua. The residue was dissolved in 50 ml of chloroform, washed with an aqueous solution of 50% sodium carbonate, dried over anhydrous magnesium sulfate, and then concentrated in vacua. The residue was subject to chromatography using 20 g of silica gel (eluting solution: chloroform) to give 150 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[NH2:32][CH2:33][CH2:34][C:35]1[N:39]=[CH:38][NH:37][CH:36]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:32][CH2:33][CH2:34][C:35]3[N:39]=[CH:38][NH:37][CH:36]=3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: NCCc1c[nH]cn1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Product: Cc1cc(F)ccc1-c1nc(NCCc2c[nH]cn2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 30.9 %

Procedure:
Following the general procedure outlined in Example 217, the product of Example 48 (150 mg, 0.34 mmol) and histamine (187 mg, 1.68 mmol) were reacted to give the desired product 50 mg (31%). LC-MS: 477.0 (MH+, m/z), 1.59 (Rt, min).
Reaction SMILES: [CH3:1]N(C)C=O.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[NH:17][CH:18]=[CH:19][N:20]=2)=[CH:11][CH:10]=1)([O-:8])=[O:7].[H-].[Na+].O.[C:24]([O:27][CH2:28][CH3:29])(=O)C>>[CH3:1][C@@:28]1([CH2:29][N:20]2[CH:19]=[CH:18][N:17]=[C:16]2[S:15][C:12]2[CH:13]=[CH:14][C:9]([N+:6]([O-:8])=[O:7])=[CH:10][CH:11]=2)[CH2:24][O:27]1
Reactant: CN(C)C=O
Reactant: CCOC(C)=O
Reactant: O=[N+]([O-])c1ccc(Sc2ncc[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: C[C@@]1(Cn2ccnc2Sc2ccc([N+](=O)[O-])cc2)CO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To N,N-dimethylformamide (5 ml) solution of 2-(4-nitrophenylthio)imidazole (500 mg) was added sodium hydride (90 mg) at 0° C., then reaction mixture was stirred at a room temperature for 30 minutes. After being cooled again the reaction mixture to 0° C., 2-methyl-2-oxiranylmethyl(S)-4-nitrobenzenesulfonate (618 mg) was added and stirred at a room temperature for 3.5 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was taken by separation. The ethyl acetate layer was washed with water and an aqueous solution being saturated with sodium chloride, then dried over anhydrous sodium sulfate. The residue obtained by removal of the solvent by distillation was purified by use of a silica gel column chromatography (eluent: dichlormethane/ethyl acetate=17/3), there was obtained (R)-1-(2-methyl-2-oxiranylmethyl)-2-(4-nitrophenylthio)imidazole (604 mg, yield: 91%) as yellow oily product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:6][CH:5]=1.[NH2:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[C:21](Cl)[N:20]=1>C(O)CC(C)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:21]3[N:20]=[C:19]([NH2:18])[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=3)[CH2:13][CH2:12]2)=[N:6][CH:5]=1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: COC(=O)c1ccc(NC2CCNCC2)nc1
Solvent: CC(C)CCO
Product: COC(=O)c1ccc(NC2CCN(c3nc(N)c4cc(OC)c(OC)cc4n3)CC2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.5 %

Procedure:
Compound (40) (1.18 g, 5 mmol) was added to a solution of 4-amino-2-chloro-6,7-dimethoxyquinazoline (1.0 g, 4 mmol) in isoamyl alcohol (10 mL) at 25° C. The mixture was stirred at 120 C. for 12 h. The reaction mixture was then cooled to room temperature and the desired product was filtered and rinsed with acetone to give 1.5 g (68%) of the title compound; 1H NMR (DMSO) δ 12.37 (s, 1H), 8.74 (d, 2H, J=6.3), 8.57 (d, 1H, J=2.2), 7.80 (m, 1H), 7.76 (s, 1H), 7.62 (s, 1H), 7.60 (d, 1H, J=8.8), 6.56 (d, 1H, J=8.9), 4.57 (m, 2H), 4.20 (m, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 3.76 (s, 3H), 3.42 (m, 2H), 2.03 (m, 2H), 1.51 (m, 2H); 13C NMR (DMSO) δ 165.6, 161.3, 160.2, 155.1, 151.0, 150.6, 146.6, 136.8, 136.4, 113.1, 107.9, 105.2, 101.5, 99.3, 56.2, 55.9, 51.2, 46.6, 43.4, 30.9; HRMS (FAB) m/z 439.2083 (M+H)+ (C22H26N6O4 requires 439.2094); Anal. (C22H26N6O4 ·1HCl) C, H, N.