Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][C:20]([F:29])=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:28])[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+]>>[N:30]([CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][C:20]([F:29])=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:15]=2[O:14]1)=[N+:31]=[N-:32]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3ccc(F)c(-c4ccccc4Cl)c3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: [N-]=[N+]=NCC1Cc2ccc(F)c(-c3ccccc3Cl)c2O1
Yield: 99 %

Procedure:
Treatment of 1-bromo-2-chlorobenzene (5.63 g, 29.4 mmol) with (2-fluoro-6-methyoxyphenyl)boronic acid (5.0 g, 29.42 mol) generally according to the procedure described for Intermediate 37 afforded 2.0 g (29%) of 6-fluoro-2′-chlorobiphenyl-2-yl methyl ether. Treatment of 6-fluoro-2′-chlorobiphenyl-2-yl methyl ether with hydrogen bromide (50 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 395 afforded a brown oil. The oil was reacted with sodium hydride (0.34 g, 14.35 mmol) and allyl bromide (1.74 g, 14.35 mmol) followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 to provide 3-allyl-6-chloro-2′-chlorobiphenyl-2-ol. Treatment of 3-allyl-6-fluoro-2′-methylbiphenyl-2-ol (1.2 g, 4.56 mmol) with m-chloroperoxybenzoic acid (2.36 g, 13.68 mmol, 77%) and potassium carbonate (1.575 g, 11.4 mmol) generally according to the procedure described for Intermediate 9 afforded 0.7 g (55%) of (±)-[7-(2-chlorophenyl)-6-fluoro-2,3-dihydro-1-benzofuran-2-yl]methanol. Treatment (±)-[7-(2-chlorophenyl)-6-fluoro-2,3-dihydro-1-benzofuran-2-yl]methanol (1.5 g, 5.81 mmol) with p-toluenesulfonyl chloride (1.66 g, 8.71 mol) generally according to the procedure described for Intermediate 10 gave 0.9 g (82%) of (±)-[6-fluoro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Treatment of (±)-[6-fluoro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.50 g, 1.15 mmol) with sodium azide (0.4 g, 6.15 mmol) generally according to the procedure described for Intermediate 98 afforded 0.35 g, (99%) of (±)-2-(azidomethyl)-7-(2-chlorophenyl)-6-fluoro-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-7-(2-chlorophenyl)-6-fluoro-2,3-dihydro-1-benzofuran (0.35 g, 1.15 mmol) in tetrahydrofuran (10 mL) with polymer-supported triphenylphosphine (0.60 g, 2.3 mmol) generally according to the procedure described for Example 154 provided 0.170 g (47%) of (±)-{[6-fluoro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. mp 248-250° C.
Reaction SMILES: [OH:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].[CH3:17]O>>[CH3:17][O:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1O
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Product: COc1c(C(=O)O)cccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 93 %

Procedure:
Methyl 2-hydroxy-3-nitrobenzoate (2.85 g, 13.50 mmol) was dissolved in hot methanol (10 mL) at 75° C. to make clear solution and 1N aq. sodium hydroxide (28.3 mL, 28.3 mmol) was added dropwise. The mixture was heated under reflux for 15 minutes and then cooled to room temperature, concentrated to remove the methanol and then cooled in an ice bath. The solution was acidified via the dropwise addition of 1M (aq.) HCl until the pH was ˜1, resulting in the product precipitating out of solution. The solid was collected by filtration, rinsed with water, and dried on the filter to afford the product 2-methoxy-3-nitrobenzoic acid (2.48 g, 12.58 mmol, 93% yield) as a white solid. HPLC (Method N) RT=1.57 minutes.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:35])[N:27]3[C:30]([O:32][CH2:33]Cl)=[O:31])=[CH:22][CH:21]=2)[CH2:11][CH2:10]1.[C:36]([OH:53])(=[O:52])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:35])[N:27]3[C:30]([O:32][CH2:33][O:53][C:36](=[O:52])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:31])=[CH:22][CH:21]=2)[CH2:13][CH2:14]1
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1C(=O)OCCl
Reactant: CCCCCCCCCCCCCCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCC(=O)OCOC(=O)N1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Temperature: 60 °C

Procedure:
To a solution of chloromethyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (1.16 g, 2.14 mmol) in dimethyl formamide (20 mL) was added palmitic acid (825 mg, 3.22 mmol) and cesium carbonate (524 mg, 1.61 mmol). The reaction was heated to 60° C. for 5 hours then allowed to cool to room temperature. The reaction was diluted with ethyl acetate (20 mL) and washed with 1:1 water/brine (3×40 mL). The organics were filtered to remove a white precipitate then dried (MgSO4) and concentrated. The crude product was purified by column chromatography on silica eluting with 0.5% Et3N/ethyl acetate to give palmitoyloxymethyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate, Compound-89 (548 mg, 32% over 2 steps). The material was determined to be 83% pure by LCMS.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:9]=1.ClC1C=CC=C(C(OO)=[O:34])C=1>C(Cl)Cl>[OH:1][CH2:2][CH2:3][S:4]([C:5]1[S:6][C:7]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[N:9]=1)=[O:34]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2nc(SCCO)sc2-c2ccc(OC)cc2)cc1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)CCO)sc2-c2ccc(OC)cc2)cc1

Procedure:
5.0 g of 2-(2-hydroxyethylthio)-4,5-bis-(p-methoxyphenyl)-thiazole are dissolved in 100 ml of methylene chloride and, while stirring, 2.56 g of m-chloroperbenzoic acid are added in portions. The mixture is then stirred for 15 minutes and subsequently extracted by shaking twice with dilute sodium carbonate solution. The aqueous phase is then washed with methylene chloride. The organic phases are combined, dried over magnesium sulphate and concentrated to dryness by evaporation. The crude product is dissolved in 10 ml of ethyl acetate, precipitated with 30 ml of diethyl ether, filtered with suction, washed with diethyl ether, dried under reduced pressure and, to purify further, made into a slurry with 50 ml of diethyl ether, filtered again and dried at 0.01 mbar and 100° to constant weight. 2-(2-hydroxyethanesulphinyl)-4,5-bis-(p-methoxyphenyl)-thiazole is obtained in the form of a pale yellow oil, Rf value 0.12 (silica gel thin layer/toluene:ethyl acetate 1:1); IR-spectrum: νSO =1060 cm-1 (3% in CH2Cl2).
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:26])([F:25])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:15]2=[O:24])=[CH:10][CH:9]=1.[CH3:27][O:28][C:29](=[O:41])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:31]=1[S:37](Cl)(=[O:39])=[O:38]>>[CH3:27][O:28][C:29](=[O:41])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:31]=1[S:37]([N:21]1[CH2:20][CH2:19][C:16]2([C:15](=[O:24])[N:14]([C:11]3[CH:12]=[CH:13][C:8]([O:7][C:6]([F:5])([F:25])[F:26])=[CH:9][CH:10]=3)[CH2:18][CH2:17]2)[CH2:23][CH2:22]1)(=[O:38])=[O:39]
Reactant: COC(=O)c1cccc(C)c1S(=O)(=O)Cl
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Solvent: CC(=O)O
Product: COC(=O)c1cccc(C)c1S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1

Procedure:
The title compound was prepared in analogy to example 180 step D from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and 2-Chlorosulfonyl-3-methyl-benzoic acid methyl ester. White solid. MS (ESI): 527.14 (MH+)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:11])=[N:5][C:6]([Cl:10])=[C:7]([Br:9])[N:8]=1.[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[S:20](Cl)(=[O:22])=[O:21]>>[Br:9][C:7]1[N:8]=[C:3]([O:2][CH3:1])[C:4]([NH:11][S:20]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=2[Cl:12])(=[O:22])=[O:21])=[N:5][C:6]=1[Cl:10]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: COc1nc(Br)c(Cl)nc1N
Product: COc1nc(Br)c(Cl)nc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Procedure as for Example 1 (reaction performed at room temperature) using 3-methoxy-5-bromo-6-chloro-2-pyrazinamine (Example 125a) (0.5 g) and 2,3-dichlorobenzenesulphonyl chloride (2.21 g). Yield 3.2 g.
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:11](OCC)(=[O:16])[CH2:12][C:13]([CH3:15])=O.C[O-].[Na+]>CCO>[CH3:15][C:13]1[N:10]=[C:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:9]=[C:11]([OH:16])[CH:12]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: N=C(N)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(O)nc(-c2ccccc2)n1

Procedure:
Benzamidine hydrochloride (1.56 g), ethyl acetoacetate (1.26 ml) and sodium methoxide (30% in MeOH, 3.7 ml) were dissolved in EtOH (10 ml) and the resulting mixture was refluxed overnight. It was cooled down and the white suspension was filtered off. The solid was washed with water and high-vacuum dried. 1.83 g of a white solid were obtained.
Reaction SMILES: C(O)C.[CH3:4][C:5]1[CH:10]=[C:9](Br)[CH:8]=[CH:7][C:6]=1[N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[S:17]([CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27][CH2:26]2)=[O:18]>[C].[Pd].C(N(CC)CC)C>[CH3:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[S@:17]([CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27][CH2:26]2)=[O:18]
Reactant: Cc1cc(Br)ccc1-n1ccnc1S(=O)CCCOc1ccc2c(c1)CCC(=O)N2
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccccc1-n1ccnc1[S@@](=O)CCCOc1ccc2c(c1)CCC(=O)N2
Yield: 131.2 %

Procedure:
In a pressure glass reactor containing ethanol was placed 12 g of 6-{3-[1-(2-methyl-4-bromophenyl)-2-imidazolylsulfinyl]propoxy}-3,4-dihydrocarbostyril. To the resulting solution were added 18 ml of triethylamine and 6 g of a 10% palladium carbon powder. The reactor inside was purged with hydrogen gas and the reactor contents were subjected to a reaction at a pressure of 3 kg/cm2 at 70° C. for 16 hours. The reaction was repeated on the same scale. The reaction mixture obtained from two times of the reaction was filtered to remove the catalyst. The filtrate was extracted with chloroform, washed with 1 N aqueous hydrochloric acid solution thoroughly, washed with an aqueous solution saturated with sodium chloride, dried with anhydrous magnesium sulfate, and subjected to distillation to remove the solvent. The resulting white oil was purified by a silica gel column chromatography (eluant: dichloromethane/ethyl acetate/methanol=30/10/1) to obtain crude crystals. The crude crystals were recrystallized from ethanol to obtain 13.2 g of (S)-(+)-6-{3-[1-(2-methylphenyl)-2-imidazolylsulfinyl]propoxy}-3,4-dihydrocarbostyril.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([Br:16])[CH:15]=1)[CH:11]=O.[Cl-].[NH4+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([Br:16])[CH:15]=1)[CH:11]=[CH2:1]
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1cc(Br)cc(Br)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=Cc1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
Tetrahydrofuran (20 mL) was added to methyltriphenylphosphonium bromide (3.150 g, 8.8 mmol). Then potassium t-butoxide (0.989 g, 8.8 mmol) was added herein small portions with ice-cooling, and the mixture was stirred at room temperature for 1 hr. The resultant slurry was cooled to −78° C. and a tetrahydrofuran (20 mL) solution containing 3,5-dibromobenzaldehyde (1.519 g, 5.8 mmol) was added dropwise. The reaction solution was allowed to warm to room temperature and stirred for 1 hr, and then a saturated ammonium chloride aqueous solution was added to the reaction solution. The product was extracted with ethyl acetate, the solvent was distilled off under reduced pressure, and the residue was purified with silica-gel column chromatography to obtain 3,5-dibromostyrene (1.2 g, 4.6 mmol).
Reaction SMILES: ClC1C(O[C:9](=[O:16])[C@@H:10]2[CH2:14][CH2:13][C:12](=[O:15])[NH:11]2)=C(Cl)C(Cl)=C(Cl)C=1Cl.[CH2:21]([NH2:25])[CH2:22][CH2:23][CH3:24]>O1CCCC1>[CH2:21]([NH:25][C:9](=[O:16])[C@@H:10]1[CH2:14][CH2:13][C:12](=[O:15])[NH:11]1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCN
Reactant: O=C1CC[C@@H](C(=O)Oc2c(Cl)c(Cl)c(Cl)c(Cl)c2Cl)N1
Solvent: C1CCOC1
Product: CCCCNC(=O)[C@@H]1CCC(=O)N1

Procedure:
7.5 g (20 mmols) of L-pyroglutamic acid pentachlorophenyl ester and 1.75 g (2.4 mmols) of n-butyl amine were stirred in 100 ml of tetrahydrofurane for 5 hours. The solvent was distilled off. The residue was dissolved in methanol and treatment with strongly basic and then with strongly acidic ion exchangers followed. After filtration, methanol was distilled off. The oily residue was dissolved and precipitated with petroleum ether. After a prolonged period of time, the product, which has precipitated in oily form, became solid. It was filtered off, washed with petroleum ether and dried under vacuum.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:17][N:18](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[C:17]([C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6])#[N:18]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(Br)cc(S(F)(F)(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
200 mg (0.61 mmol) of the compound of Example 15A were dissolved in 2.0 ml of DMF, and the mixture was degassed with argon. After addition of 79 mg (0.67 mmol) of zinc cyanide and 42 mg (0.04 mmol) of tetrakis(triphenylphosphine)palladium(0), the reaction was stirred in a microwave oven (Biotage Initiator, with Dynamic Field Tuning) at 120° C. for 30 min. After cooling, solid components were filtered off and the filtrate was separated into its components by preparative HPLC (Method 15). Concentration of the product fractions and drying of the residue under high vacuum gave 115 mg (88% pure, 61% of theory) of the title compound.
Reaction SMILES: C1CNC(=O)C1.[Br:7][Br-]Br.[C:10]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]2([CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:14]=1)(=[O:12])[CH3:11]>O1CCCC1.S(=O)(=O)(O)O>[Br:7][CH2:11][C:10]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]2([CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:14]=1)=[O:12]
Reactant: CC(=O)C1=CC2(CCCC2)c2ccccc21
Agent: O=C1CCCN1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: O=C(CBr)C1=CC2(CCCC2)c2ccccc21
Reaction time: 24 h

Procedure:
Pyrrolidone hydrotribromide [(pyrrolidone)3HBr3 ] is added at about 20° C. to the ketone from step (b) (12 g) in tetrahydrofuran (1500 ml) containing 10 drops of concentrated sulphuric acid. The mixture is stirred for 24 hours. Precipitated salts are removed by filtration and the filtrate is concentrated to a small volume. Water (200 ml) is added and the mixture is extracted three times with diethyl ether. After drying the solvent is evaporated, yielding a semi-crystalline residue. Crystallization from methanol gives the pure bromoacetyl title compound, m.p. 75°-77° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:11][CH:10]([C:12]([OH:14])=O)[CH2:9][S:8]2)[CH:2]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH:23][C:12]([CH:10]2[CH2:9][S:8][CH:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[NH:11]2)=[O:14])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cccc(N)c1
Reactant: O=C(O)C1CSC(c2cccnc2)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc(NC(=O)C2CSC(c3cccnc3)N2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
A mixture of 630 mg of 2-(3-pyridyl)thiazolidine-4-carboxylic acid, 350 mg of m-anisidine, 650 mg of dicyclohexylcarbodiimide and 430 mg of 1-hydroxybenzotriazole in 8 ml of dimethylformamide was stirred overnight at room temperature. The reaction mixture was diluted with 50 ml of ethyl acetate, and the insoluble matter was filtered off. The filtrate was washed with two portions of water, and then with aqueous solution of sodium hydrogen carbonate, water and saturated aqueous solution of sodium chloride in that order, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by preparative thin layer chromatography to give 230 mg of N-(3-methoxyphenyl)-2-(3-pyridyl)thiazolidine-4-carboxamide. This compound was dissolved in ethyl acetate, and 1 ml of 2N hydrogen chloride solution in dioxane was added. The resultant solid was collected by filtration, washed with ethyl acetate and dried to give 250 mg of N-(3-methoxyphenyl)-2-(3-pyridyl)thiazolidine-4-carboxamide dihydrochloride. Melting point 129° C.
Reaction SMILES: O=C1NC2C=C(CN3CCN(C4C=CC(C(O)=O)=CC=4)CC3)C=NC=2N2CCCC[C@@H]12.[O:32]=[C:33]1[NH:38][C:37]2[CH:39]=[C:40]([CH2:43][N:44]3[CH2:49][CH2:48][N:47]([C:50]4[CH:60]=[CH:59][C:53]([C:54]([O:56]CC)=[O:55])=[CH:52][N:51]=4)[CH2:46][CH2:45]3)[CH:41]=[N:42][C:36]=2[N:35]2[CH2:61][CH2:62][CH2:63][CH2:64][C@@H:34]12>>[O:32]=[C:33]1[NH:38][C:37]2[CH:39]=[C:40]([CH2:43][N:44]3[CH2:45][CH2:46][N:47]([C:50]4[CH:60]=[CH:59][C:53]([C:54]([OH:56])=[O:55])=[CH:52][N:51]=4)[CH2:48][CH2:49]3)[CH:41]=[N:42][C:36]=2[N:35]2[CH2:61][CH2:62][CH2:63][CH2:64][C@@H:34]12
Reactant: CCOC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)nc1
Agent: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)cc1
Product: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)nc1

Procedure:
Compound 76B was prepared using a procedure analogous to that described in connection with Compound 73B except that (S)-ethyl 6-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinate was used instead of (S)-ethyl 4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzoate to yield the title compound as a white solid. [M+H] calc'd for C22H26N6O3, 423; found, 423.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:6]=[CH:7][N:8]=1.Cl[CH2:21][C:22]1[N:23]=[C:24](/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[CH:30]=2)[O:25][CH:26]=1>>[CH3:35][C:31]1[CH:30]=[C:29](/[CH:28]=[CH:27]/[C:24]2[O:25][CH:26]=[C:22]([CH2:21][O:19][C:16]3[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][N:5]4[CH:6]=[CH:7][N:8]=[C:4]4[CH2:3][CH2:2][OH:1])=[CH:18][CH:17]=3)[N:23]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: OCCc1nccn1CCCCc1ccc(O)cc1
Reactant: Cc1cccc(/C=C/c2nc(CCl)co2)c1
Product: Cc1cccc(/C=C/c2nc(COc3ccc(CCCCn4ccnc4CCO)cc3)co2)c1
Yield: 63.5 %

Procedure:
Using 4-[4-[2-(2-hydroxyethyl)-1H-imidazol-1-yl]butyl]phenol (260 mg) and (E)-4-chloromethyl-2-[2-(3-methylphenyl)ethenyl]oxazole (257 mg), the same reaction as Example 1 was carried out to yield the titled compound (290 mg) as colorless crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[N:15]1[C:24]2[C:19](=[CH:20][C:21]([F:44])=[C:22](OS(C3C(C(C)C)=CC(C(C)C)=CC=3C(C)C)(=O)=O)[N:23]=2)[C:18](=[O:45])[C:17]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:16]1.C(OCC)(=O)C.O>C(Cl)Cl.C(OCC)C>[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[N:15]1[C:24]2[C:19](=[CH:20][C:21]([F:44])=[C:22]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)[N:23]=2)[C:18](=[O:45])[C:17]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:16]1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(OS(=O)(=O)c3c(C(C)C)cc(C(C)C)cc3C(C)C)c(F)cc2c1=O
Reactant: C1CNCCN1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(N3CCNCC3)c(F)cc2c1=O
Yield: 91.2 %

Procedure:
In 4 ml of methylene chloride was dissolved 270 mg of anhydrous piperazine, and 400 mg of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-7-(2,4,6-triisopropylbenzenesulfonyloxy)-1,8-naphthyridine-3-carboxylate was added to the resulting solution, after which the resulting mixture was subjected to reaction with ice-cooling for 1 hour. To the reaction mixture were added 20 ml of ethyl acetate and 10 ml of water, and the organic layer was separated, washed successively with 10 ml of saturated aqueous sodium hydrogencarbonate solution and 10 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the crystalline material thus obtained was added 5 ml of diethyl ether, after which crystals were collected by filtration to obtain 250 mg (yield 91.2%) of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylate having a melting point of 208°-211° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].C(N(CC)CC)C.[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>C(Cl)Cl>[OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cc(O)ccc1O
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Oc1ccc(O)c(C=O)c1
Temperature: -8 °C

Procedure:
To a cooled (-8° C.), stirred suspension of 2,5-dihydroxybenzaldehyde (13 g, 93.6 mmol) in of CH2Cl2 (65 ml) (dried over 4A sieves) (65 ml) was added triethylamine (6.5 ml, 46.8 mmol) to give a deep red solution. Pivaloyl chloride (5.6 g, 46.8 mmol) was added portionwise keeping the temperature below 0° C. After the addition was complete the reaction was allowed to warm to ambient temperature and stirred overnight. The reaction was washed with 2N aqueous HCl, water, saturated aqueous NaHCO3 and dried (MgSO4). The organic solution was filtered and evaporated and the residue purified by chromatography (eluant: CH2Cl2 /hexane) to give the title product as a colourless oil which crystallized on standing (4.7 g, 45% based on limiting reagent).