Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[Cl:12].C(N=[C:18]=[O:19])CCC.C(Cl)(=O)[C:21](Cl)=[O:22]>ClC1C=CC=CC=1>[Cl:12][C:3]1[CH:4]=[C:5]([S:8]([N:11]=[C:18]=[O:19])(=[O:9])=[O:10])[CH:6]=[CH:7][C:2]=1[N:1]=[C:21]=[O:22]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Nc1ccc(S(N)(=O)=O)cc1Cl
Reactant: CCCCN=C=O
Solvent: Clc1ccccc1
Product: O=C=Nc1ccc(S(=O)(=O)N=C=O)cc1Cl
Temperature: 100 °C

Procedure:
5,7-Dichloro-4-[4-(methylcarbamoyl)-3-chlorobenzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester ##STR38## Dissolve 4-amino-3-chlorobenzenesulfonamide (0.96g, 5mmol) in chlorobenzene (10% solution) and distill the mixture to remove any traces of water. Cool to 100° C. and add n-butyl isocyanate (99mg, 1mmol). Heat to reflux and add, by dropwise addition, oxalyl chloride (1.5mL). Purge with nitrogen at 130°-132° C. for 30 minutes and distill to give 3-chloro-4-isocyanatobenzenesulfonyl isocyanate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:19][CH:20]=3)[C:15](=[O:26])[N:14]2[CH3:27])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:28]=[C:29]1[NH:34][CH2:33][CH2:32][CH2:31][N:30]1[CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH:23]([CH3:24])[CH3:25])=[CH:19][CH:20]=3)[C:15](=[O:26])[N:14]2[CH3:27])[CH2:10][CH2:11][N:38]2[CH2:39][CH2:40][CH:35]([N:30]3[CH2:31][CH2:32][CH2:33][NH:34][C:29]3=[O:28])[CH2:36][CH2:37]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)Oc1ccc2c(c1)C(=O)N(C)C2C(CC=O)c1ccc(Cl)c(Cl)c1
Reactant: O=C1NCCCN1C1CCNCC1
Product: CC(C)Oc1ccc2c(c1)C(=O)N(C)C2C(CCN1CCC(N2CCCNC2=O)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 111 %

Procedure:
3-(3,4-Dichlorophenyl)-3-(5-isopropoxy-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.3 g) was coupled to 4-(2-oxoperhydropyrimidine-1-yl)piperidine (0.135 g) by a method similar to that described in Example 8. The reaction product was not purified by chromatography but converted to the corresponding hydrochloride salt as described in the Example 8 to afford the title compound (0.25 g); mp 192-200° C.; MS: m/z=573(M+1); NMR(CD3SOCD3): 1.24 (d,6, J=5.9), 1.77 (broad,2), 2.19 (m,2), 2.5 (m,2), 2.73 (broad,1l), 3.58 (m,3), 4.39 (m,1), 4.74 (m,2), 7.06 (m,5), 7.79 (d,1, J=8.4). Analysis for C30H38Cl2N4O3.2.0 HCl: Calculated: C, 55.74; H, 6.24, N, 8.67; Found: C, 56.11; H, 6.22; N, 8.60.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li])CCC.CN(CCN(CCN(C)C)C)C.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([C:40](=[O:45])N(OC)C)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>C1COCC1.C(OCC)(=O)C>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([C:40](=[O:45])[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:8][CH3:9])[C:2]=2[F:1])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1ccccc1F
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1F
Reaction time: 0.22 h
Yield: 125.2 %

Procedure:
To a stirred solution of 2-fluoroanisole (6.00 g, 47.6 mmol) and anhydrous THF (125 mL) at −78° C. under nitrogen was added butyllithium (35 mL of a 1.6 M solution in hexanes, 56.0 mmol). After stirring for 13 min, N,N,N′,N′,N″-Pentamethyidiethylenetriamine (12.9 mL, 61.8 mmol) was added dropwise and the reaction stirred at −78° C. After 168 min, a solution of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (16.8 g, 61.7 mmol) in anhydrous THF (40 mL) was added dropwise over 25 min. The reaction was stirred at −78° C. for 35 min and at room temperature for 65 min. The reaction was diluted with ethyl acetate (400 mL) and washed with cold 0.5 N aqueous HCl (2×200 mL), 5% aqueous potassium carbonate (200 mL), water (200 mL), and brine (200 mL) successively. The organic phase was dried over magnesium sulfate, filtered, and the solvent removed to give 20.1 g of a yellow oil. The product was chromatographed on silica gel (350 g), using a step gradient elution of 20% ethyl acetatejheptane to 30% ethyl acetate/heptane, to afford 12.0 g (75%) of the desired product as a white solid.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[C:12]([Cl:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[N:8]=2)[CH2:3][CH2:2]1.OO.C([OH:29])CC>S(=O)(=O)(O)O>[O:29]=[S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[C:12]([Cl:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: Clc1cccc2c(N3CCSCC3)nc(N3CCNCC3)cc12
Reactant: CCCO
Agent: O=S(=O)(O)O
Agent: OO
Product: O=S1CCN(c2nc(N3CCNCC3)cc3c(Cl)cccc23)CC1
Yield: 31 %

Procedure:
1-(1-Oxido-thiomorpholino)-3-piperazino-5-chloro-isoquinoline was prepared analogous to Example 12 from 1-thiomorpholino-3-piperazino-5-chloro-isoquinoline in dilute sulfuric acid by oxidation with hydrogen peroxide. M.p. 215°-217°C (from n-propanol); yield: 31% of theory.
Reaction SMILES: [OH:1][C:2]1([C:14](O)=[O:15])[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH2:3]1.C(OCC)(=O)C.O.Cl>O1CCCC1>[OH:1][C:2]1([CH2:14][OH:15])[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH2:7]1
Reactant: O=C(O)C1(O)C=CC(c2ccccc2)=CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: OCC1(O)C=CC(c2ccccc2)=CC1
Reaction time: 0.5 h
Yield: 29 %

Procedure:
To a solution of 4-hydroxy-4-biphenylcarboxylic acid (2.14 g) in tetrahydrofuran (25 ml) under an argon atmosphere was added slowly 1M borane-THF complex (50 ml). The resulting mixture was stirred for 18 hours before the addition of ethyl acetate (10 ml) and water (100 ml). The resulting mixture was acidified with 2N hydrochloric acid and stirred for 30 minutes. The aqueous layer was extracted with ethyl acetate (2×100 ml). The organic extracts were combined, dried (MgSO4) and evaporated . Recrystallisation from a small volume of ethyl acetate gave 4-hydroxy-4-biphenylmethanol (580 mg): NMR (d6DMSO), δ4.5(s,2H), 6.85(d,2H), 7.35(d,2H), 7.45-7.55(dd,4H), 9.45(s,1H); m/e 201(M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])[CH:11]=[CH:10]2.[CH3:22]O>>[CH3:22][O:19][C:18](=[O:20])[CH:17]([C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[CH:15][CH:16]=[C:7]([OH:6])[CH:8]=2)[CH:13]=1)[CH3:21]
Reactant: CO
Reactant: CC(C(=O)O)c1ccc2cc(O)ccc2c1
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)c1ccc2cc(O)ccc2c1
Yield: 89.5 %

Procedure:
To a solution of methanol (2100 ml) and sulphuric acid (84 ml) was added 2-(6-Hydroxynaphthalen-2-yl)-propionic acid 5 (420 g, 1.944 mmol), and refluxed for 6 hours. Methanol (1000 ml) was distilled off and the cooled reaction mass was poured onto ice water (3000 ml). Crude 6 was filtered, dried and recrystallised from a mixture of ethyl acetate:hexane (1:5) to give pure 6 (400 g, 89.5%) as a white fluffy powder. The melting point found to be 89.5-92° C. The structure was confirmed with IR and NMR.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH3:10])[CH:6]=[C:7]([CH3:9])[CH:8]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:31]N1C(=O)CCC1=O.[I-].[K+]>C1C=CC=CC=1>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[CH2:10][Br:31]
Reactant: Cc1cc(C)cc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: c1ccccc1
Product: Cc1cc(CBr)cc(C(F)(F)F)c1

Procedure:
A solution of 5-trifluoromethyl-m-xylene (3.4 g) and dibenzoyl peroxide (0.25 g) in 100 ml of benzene at reflux is treated with N-bromosuccinimide (4.4 g) in portions. The mixture is heated until a negative potassium iodide test is obtained. The reaction mixture is cooled and concentrated in vacuo. The residue is triturated with n-hexane and the solids are removed by filtration. The filtrate is evaporated to give the oily crude benzyl bromide.
Reaction SMILES: [C:1]([OH:6])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].C(=O)([O-])[O-].[K+].[K+].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.C(OCC)(=O)C>CN(C)C=O.O>[C:1]([O:6][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)(=[O:5])/[CH:2]=[CH:3]/[CH3:4]
Reactant: C/C=C/C(=O)O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C/C=C/C(=O)OCc1ccc(OC)cc1
Reaction time: 0.5 h
Yield: 103.4 %

Procedure:
Crotonic acid (17.2 g, 200 mmol) was dissolved in N,N-dimethylformamide (100 ml) with cooling in an ice bath under nitrogen, and powdered potassium carbonate (15.2 g, 110 mmol) was added. The mixture was stirred for 30 minutes, and 4-methoxybenzyl chloride (29.8 g, 190 mmol) was then added dropwise over 15 minutes. The reaction mixture was stirred at mom temperature for four hours and at 45° C. for 14 hours. Ethyl acetate (500 ml) and water (200 ml) were added to the reaction liquid. The separated organic layer was washed with water (100 ml×2) and brine (100 ml). The aqueous layer was extracted with ethyl acetate (100 ml). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a crude product of the title compound (40.51 g, yield: 98.2%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:11](=[O:15])[NH:10][C:9]([NH2:16])=[N:8][C:7]1=2.CN(C)C=O.[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:22]([O:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:11](=[O:15])[NH:10][C:9]([NH2:16])=[N:8][C:7]1=2)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc2c(ncn2COCCO)c(=O)[nH]1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)OCCOCn1cnc2c(=O)[nH]c(N)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 9-(2-hydroxyethoxymethyl)guanine (4.6 g), dry dimethylformamide (46 ml), acetic anhydride (16 ml) and dry pyridine (24 ml) was stirred at room temperature overnight. The resulting white solid was removed by filtration and dissolved in warm dimethylformamide (100 ml), pyridine (10 ml) and acetic anhydride (8 ml) added and the mixture stirred for 18 hr. The white solid formed was removed by filtration, washed with ethyl acetate and recrystallized from dimethylformamide to give 9-(2-acetyloxyethoxymethyl)guanine (3.3 g), m.p. 240°-241° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:19][CH3:20])=[CH:5][C:6]2[CH:12]([CH2:13][O:14][CH2:15][CH2:16][OH:17])[O:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:18]=1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)([O-:23])=[O:22]>C(N(CC)CC)C>[N+:21]([C:24]1[CH:25]=[CH:26][C:27]([S:30]([O:17][CH2:16][CH2:15][O:14][CH2:13][CH:12]2[C:6]3[CH:5]=[C:4]([O:19][CH3:20])[C:3]([O:2][CH3:1])=[CH:18][C:7]=3[CH2:8][CH2:9][CH2:10][O:11]2)(=[O:32])=[O:31])=[CH:28][CH:29]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc2c(cc1OC)C(COCCO)OCCC2
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)C(COCCOS(=O)(=O)c1ccc([N+](=O)[O-])cc1)OCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
To a mixture of 3.00 g (10.6 mmoles) of 2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)methoxy]ethanol and 1.63 ml (11.7 mmoles) of triethylamine is added 2.59 g (11.7 mmoles) of p-nitrobenzenesulfonyl chloride. The reaction mixture is stirred at room temperature for 1 hour and then heated at 50° for 30 minutes. To this is added an additional 0.5 g of p-nitrobenzenesulfonyl chloride and 0.5 ml of triethylamine. After stirring at room temperature for 30 minutes, the reaction mixture is extracted with aqueous sodium bicarbonate and brine. The organic layer is filtered through sodium sulfate and taken to dryness. The residue is chromatographed on silica gel using 1% methanol methylene chloride as eluant to give 1.56 g (32%) 2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)methoxy]ethyl 4-nitrobenzene sulfonate. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[N:16][C:17](Cl)=[C:18]([F:23])[CH:19]=2)[N:14]([CH2:25][CH3:26])[CH:13]=1)=[O:11])[CH3:8]>C(O)C>[CH2:7]([O:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[N:16][C:17]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)=[C:18]([F:23])[CH:19]=2)[N:14]([CH2:25][CH3:26])[CH:13]=1)=[O:11])[CH3:8]
Reactant: C1CNCCN1
Reactant: CCOC(=O)c1cn(CC)c2nc(Cl)c(F)cc2c1=O
Solvent: CCO
Product: CCOC(=O)c1cn(CC)c2nc(N3CCNCC3)c(F)cc2c1=O

Procedure:
A mixture of piperazine (0.86 g), the above ester (1.0 g) and ethanol (20 ml) was refluxed for 2.5 hrs. The solvent was evaporated, and the residue was extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous sodium sulfate, and chloroform was evaporated. The residue was purified by chromatography to give 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].P(=O)([O-])[O-].C([Li])CCC.[C:17](OC)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1.CCCCCC.C(O)(=O)C>[O:24]=[C:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)c1ccccc1
Agent: O=[PH]([O-])[O-]
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COP(=O)(CC(=O)c1ccccc1)OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 51.1 %

Procedure:
A solution of 74.5 g (600 mmoles) dimethyl methylphosphonate (Aldrich) in 750 ml dry tetrahydrofuran was cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution was added 265 ml of 2.34 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 30 minutes at such a rate that the reaction temperature never rose above -65°. After an additional 5 minutes stirring at -78°, 41 g (300 mmole) of methyl benzoate was added dropwise at a rate that kept the reaction temperature less than -70° (10 minutes). After 1 hour at -78° the reaction mixture was allowed to warm to ambient temperature, neutralized with 35 ml acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 75 ml water, the aqueous phase extracted with 300 ml portions of ether (3x), the combined organic extracts were backwashed (50 cc H2O), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled, b.p. 130°-5° (0.4 mm) to give 35 g (29%) dimethyl 2-oxo-2-phenylethylphosphonate (2a).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([CH:15]=O)[CH:3]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([NH2:25])[CH:19]=1.S(=O)(O)[O-].[Na+]>CN(C=O)C.O>[Br:17][C:18]1[CH:23]=[CH:22][C:21]2[N:24]=[C:15]([C:4]3[CH:3]=[C:2]([CH3:1])[N:6]([CH2:7][C:8]4[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=4)[N:5]=3)[NH:25][C:20]=2[CH:19]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: Cc1ccc(Cn2nc(C=O)cc2C)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Cn2nc(-c3nc4ccc(Br)cc4[nH]3)cc2C)cc1
Temperature: 110 °C

Procedure:
To a solution of 5-methyl-1-(4-methylbenzyl)-1H-pyrazole-3-carbaldehyde (Step 2, 700 mg, 3.27 mmol) in DMF (25 mL) was added 4-bromo-o-phenylenediamine (1.2 g, 6.53 mmol) followed by sodium bisulfite (679 mg, 6.53 mmol), and the resulting mixture was heated at 110° C. for 5 h. After being cooled to rt, the reaction mixture was diluted with water. The aqueous phase was extracted with ethyl acetate (3×50 mL), and the combined organics were washed with water (1×50 mL) and brine (1×50 mL), dried (Na2SO4), filtered, and concentrated to dryness. The crude material was then purified with an ISCO CombiFlash Companion using gradient elution from 0% to 50% EtOAc in hexanes to afford the title compound as a mixture of regioisomers as a light yellow solid (600 mg, 48%): 1H NMR (300 MHz, DMSO-d6) δ 11.76 (m, 1H), 11.60 (s, 1H), 7.35-7.77 (m, 2H), 7.27-7.30 (m, 1H), 7.13 (d, 2H), 7.04 (d, 2H), 6.69 (s, 1H), 5.36 (s, 2H), 2.27 (s, 3H), 2.24 (s, 3H); ES-MS m/z 381.20, HPLC RT (Method B) 3.20 min.
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH2:4][CH3:5].[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O[CH:18]=[C:19]([C:25]([O:27]CC)=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])C>C1(C)C=CC=CC=1>[CH2:7]([N:14]1[C:3]([CH2:4][CH3:5])=[C:2]([CH3:1])[CH:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:25]1=[O:27])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCc1ccccc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCC(=O)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C)c(CC)n(Cc2ccccc2)c1=O

Procedure:
A toluene solution (50 mL) of 3-pentanone (5.00 g, 58.1 mmol) and benzylamine (6.23 g, 58.1 mmol) was heated and refluxed under azeotropic dehydration for 3 hours. After that, diethyl ethoxymethylenemalonate (12.56 g, 58.1 mmol) was added, and the mixture was further continued to be heated and refluxed for 5 hours. The solvent was removed by distillation under reduced pressure, and the residue was refined with silica gel (300 g) column chromatography (ethyl acetate-hexane of 1:5 in mixing ratio and then those of 1:3 and 2:1), and pale yellow oily matter (AA06, 1.92 g, 11.0%) was obtained.
Reaction SMILES: [CH:1]([C:3]1[C:4]([OH:13])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=[O:2].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)([O-:16])=[O:15].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:1]([C:3]1[C:4]([O:13][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=2)=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=[O:2]
Reactant: COC(=O)c1cccc(C=O)c1O
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C=O)c1OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
A mixture of 5.0 g of methyl 3-formyl-2-hydroxybenzoate, 11.7 g of 4-nitrobenzyl bromide, 11.7 g of potassium carbonate and 70 ml of dimethylformamide is stirred at room temperature for 1 hour. The reaction mixture is poured into water and the aqueous mixture is extracted with ethyl acetate. The extract is dried and evaporated to remove solvent to give 8.70 g of methyl 3-formyl-2-(4-nitrobenzyloxy)benzoate as colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:41]=[CH:40][C:5]2[NH:6][C:7]([CH:9]([O:32][CH:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)[C:10]3[CH:11]=[C:12]([C:16]#[C:17][CH2:18][CH2:19][CH2:20][N:21]4C(=O)C5C(=CC=CC=5)C4=O)[CH:13]=[CH:14][CH:15]=3)=[N:8][C:4]=2[CH:3]=1.O.NN.O.[C:46]([OH:51])(=[O:50])[C:47]([OH:49])=[O:48]>C(O)C.CC(C)=O>[C:46]([OH:51])(=[O:50])[C:47]([OH:49])=[O:48].[F:1][C:2]1[CH:41]=[CH:40][C:5]2[NH:6][C:7]([CH:9]([O:32][CH:33]3[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]3)[C:10]3[CH:11]=[C:12]([C:16]#[C:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH:13]=[CH:14][CH:15]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CN1CCC(OC(c2cccc(C#CCCCN3C(=O)c4ccccc4C3=O)c2)c2nc3cc(F)ccc3[nH]2)CC1
Agent: NN
Agent: O=C(O)C(=O)O
Solvent: CC(C)=O
Solvent: CCO
Solvent: O
Product: CN1CCC(OC(c2cccc(C#CCCCN)c2)c2nc3cc(F)ccc3[nH]2)CC1

Procedure:
A solution of 2-(5-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)isoindole-1,3-dione (example 438B, 170 mg) and hydrazine hydrate (200 μL) in ethanol (2.5 mL) is stirred a room temperature overnight. Water is added and the aqueous phase is extracted by diethyl ether. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (dichloromethane/methanol/ammonia from 95/5/0.5 to 90/10/1)) to afford the free base. One equivalent of oxalic acid in acetone is added to the free base to afford 5-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylamine oxalate as a white crystalline solid melting at 150° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.CO[CH:14]1[CH2:18][CH2:17][CH:16](OC)O1.C(O)(=O)C>C(Cl)Cl>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([CH3:10])=[N:7][C:6]=3[CH:11]=2)[CH:14]=[CH:18][CH:17]=[CH:16]1
Reactant: COC1CCC(OC)O1
Reactant: Cc1nc2cc(N)ccc2o1
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1nc2cc(-n3cccc3)ccc2o1
Yield: 40 %

Procedure:
5-Amino-2-methylbenzoxazole (30.0 g, 0,203 mol) and 2,5-dimethoxytetrahydrofuran (30.0 g, 0.227 mol) were combined with 90 mL of acetic acid and the solution was heated at reflux for 1 hr. The mixture was evaporated to a red slurry and mixed with hexane to give a dark solid. The solid was dissolved in methylene chloride and extracted with basic water. The organic phase was removed, dried, and evaporated to a brown solid. Recrystallization from hexane/heptane afforded 18 g (45% yield) of product, m.p. 115°-121° C.
Reaction SMILES: C(OC(Cl)=O)C(C)C.[C:9]([NH:12][C:13]1[C:21]([Cl:22])=[CH:20][C:16]([C:17]([OH:19])=O)=[C:15]([O:23][CH3:24])[CH:14]=1)(=[O:11])[CH3:10].CN1CCOCC1.[F:32][C:33]([F:43])([F:42])[C:34]1[CH:39]=[CH:38][C:37]([NH:40][NH2:41])=[CH:36][CH:35]=1>C1COCC1.C(OCC)(=O)C>[F:32][C:33]([F:42])([F:43])[C:34]1[CH:35]=[CH:36][C:37]([N:40]([C:17](=[O:19])[C:16]2[CH:20]=[C:21]([Cl:22])[C:13]([NH:12][C:9](=[O:11])[CH3:10])=[CH:14][C:15]=2[O:23][CH3:24])[NH2:41])=[CH:38][CH:39]=1
Reactant: NNc1ccc(C(F)(F)F)cc1
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)N(N)c1ccc(C(F)(F)F)cc1
Reaction time: 8 h

Procedure:
Iso-butylchloroformate (1.6 ml, 16.4 mmol) was added dropwise to a solution of 4-(acetylamino)-5-chloro-2-methoxybenzoic acid (4 g, 16.4 mmol) and 4-methylmorpholine (1.8 ml, 16.4mmol) in 400 ml of anhydrous THF at 0° C. and stirred for 0.5 h at room temperature before addition of 4-(trifluoromethyl)phenylhydrazine (2.9 g, 16.4 mmol) dissolved in 80 ml of the same solvent. The reaction mixture was stirred 8 h, diluted with ethyl acetate (1 vol), washed with water, saturated NaHCO3 solution, and brine. Concentration gave a solid which was recrystallized from acetonitrile 5.7 g (86%); mp 217°-219° C.; IR(KBr, ν=cm-1) 3410, 3286, 1704, 1670, 1500, 1338, 1238, 1104; 1H NMR (300 MHz, DMSO-d6) δ2.15 (3H, s), 3.88 (3H, s), 6.88 (2H, d, J=8.5 Hz), 7.49 (2H, d, J=8.5 Hz), 7.68 (1H, s), 7.76 (1H, s), 8.61 (1H, br. s), 9.62 (1H, br. s) 10.01 (1H, br. s); MS(ESI)m/z: 400 (M--H-)