Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[NH:6][N:5]=[C:4]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:3]=1.Cl[CH2:15][C:16]1[CH:35]=[CH:34][C:19]([O:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:27][C:26]1[O:25][C:24]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[N:23][C:22]=1[CH2:21][O:20][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][S:1][C:2]2[NH:6][N:5]=[C:4]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:3]=2)=[CH:35][CH:34]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: CCOC(=O)CCc1n[nH]c(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1n[nH]c(SCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 3-(5-mercapto-1H-1,2,4-triazol-3-yl)propionate (450 mg), 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (700 mg), potassium carbonate (370 mg) and N,N-dimethylformamide (20 ml) was stirred at room temperature for 2 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[5-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylthio]-1H-1,2,4-triazol-3-yl]propionate was obtained as crystals (600 mg, yield 56%) from a fraction eluted with ethyl acetate-hexane (3:2, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 114–115° C.
Reaction SMILES: CS(O)(=O)=[O:3].[N:6]1([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([O:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][NH:24][C:25](=[O:34])[CH2:26][S:27][CH2:28][CH2:29][O:30][C:31](=[O:33])[CH3:32])[CH:14]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.ClC1C=C(C=CC=1)C(OO)=O>ClCCCl>[N:6]1([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([O:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][NH:24][C:25](=[O:34])[CH2:26][S:27]([CH2:28][CH2:29][O:30][C:31](=[O:33])[CH3:32])=[O:3])[CH:14]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CC(=O)OCCSCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: CS(=O)(=O)O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCCl
Product: CC(=O)OCCS(=O)CC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Temperature: -10 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
77 μl of methanesulfonic acid was added to a solution of 0.50 g of N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-acetoxyethylthio)acetamide (prepared as described in Example 2) in 5.5 ml of 1,2-dichloroethane, and the resulting mixture was cooled to -10° C. 0.28 g of 3-chloroperoxybenzoic acid (purity: 80%) was then added, and the reaction mixture was stirred, whilst keeping the temperature in the range from -10° C. to -5° C., for 2 hours. At the end of this time, it was washed with a 10% w/v aqueous solution of sodium hydrogensulfite, with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 1:9 by volume mixture of ethanol and chloroform as the eluent, to give 0.38 g (yield 73%) of the title compound as an oil.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][C:4](=O)[CH3:5].Cl.Cl.[CH2:10]([NH:17][NH2:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(O)(=O)C>[CH2:10]([N:17]1[C:4]([CH3:5])=[CH:3][C:2]([CH3:1])=[N:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)CC(C)=O
Reactant: NNCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: Cc1cc(C)n(Cc2ccccc2)n1
Yield: 92 %

Procedure:
Dissolve 2,4-pentanedione (5.09 g, 50.8 mmol) and benzylhydrazine dihydrochloride (10.91 g, 55.9 mmol) in acetic acid (40 mL). Slowly add triethylamine (15.6 mL, 0.112 mol) and stir the mixture for 18 hr. Concentrate the solution then dilute the residue with saturated aqueous sodium bicarbonate and extract 3 times with ethyl acetate. Dry (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 40:60 hexanes:ethyl acetate), to give 1-benzyl-3,5-dimethyl-1H-pyrazole as a yellow oil (8.703 g, 92%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:18])[CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CC(C)=O>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:18][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(O)cc2C1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NC1Cc2ccc(Oc3ccccc3)cc2C1
Yield: 90 %

Procedure:
2-(tert-butoxycarbonylamino)-5-hydroxyindan (100 mg, 0.40 mmol) synthesized in the above Reference Production Example 1 was dissolved in acetone (2 ml), to which potassium carbonate (58 mg, 0.45 mmol) and benzylbromide (48 μl, 0.40 mmol) were added, and the mixture was heated to reflux for 3 hours. The reaction mixture was extracted with ether and dried, and then the solvent was distilled off under reduced pressure to obtain 2-(tert-butoxycarbonylamino)-5-phenoxyindan (120 mg, 0.36 mmol) having the following physical properties:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([O-:6])=[O:5].[Ca+2:7].[NH2:8][CH2:9][CH2:10][C:11]([O-:13])=[O:12].[CH3:14][C:15]1([CH3:22])[CH:20]([OH:21])[C:18](=[O:19])[O:17][CH2:16]1>CO>[CH3:14][C:15]([CH:20]([OH:21])[C:18]([NH:1][CH2:2][CH2:3][C:4]([O-:6])=[O:5])=[O:19])([CH2:16][OH:17])[CH3:22].[CH3:14][C:15]([CH:20]([OH:21])[C:18]([NH:8][CH2:9][CH2:10][C:11]([O-:13])=[O:12])=[O:19])([CH2:16][OH:17])[CH3:22].[Ca+2:7]
Reactant: NCCC(=O)[O-]
Reactant: CC1(C)COC(=O)C1O
Agent: [Ca+2]
Solvent: CO
Product: CC(C)(CO)C(O)C(=O)NCCC(=O)[O-]

Procedure:
reacting the anhydrous calcium beta-alaninate with dl-pantolactone in methanol at a temperature of from about 55° to about 65° C. for from about 6 to about 9 hours and therafter cooling and filtering the reaction product and removing methanol to obtain dl-calcium pantothenate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH2:20][OH:21])[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH2:20][O:21][S:30]([CH3:29])(=[O:32])=[O:31])[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2cc(CO)c(=O)n(CC(C)C)n2)cc1F
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
To an ice-cold solution of 6-(3-fluoro-4-methyl-phenyl)-4-hydroxymethyl-2-isobutyl-2H-pyridazin-3-one (1.08 g, 3.73 mmol) in methylene chloride (20 mL) were added triethylamine (491 mg, 4.85 mmol) and methanesulfonyl chloride (513 mg, 4.48 mmol), and the mixture was stirred for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, and then, the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from chloroform-hexane to yield the title compound as a colorless crystalline powder (964 mg, 70.4%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[C:8]([OH:14])[CH:7]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].[Br:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1F.Cl>CN1C(=O)CCC1>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[C:8]([O:14][C:28]2[CH:27]=[C:26]([Cl:29])[CH:25]=[CH:24][C:23]=2[Br:22])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(CC)c(O)c1
Reactant: Fc1cc(Cl)ccc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)Cc1ccc(CC)c(Oc2cc(Cl)ccc2Br)c1
Temperature: 120 °C

Procedure:
step 1—To a solution of ethyl 4-ethyl-3-hydroxyphenylacetate (12a, 1.000 g; 4.8 mmol) and NMP (10 mL) was added K2CO3 (1.99 g; 14.4 mmol) and 1-bromo-4-chloro-2-fluorobenzene (1.106 g; 5.28 mmol). The reaction was heated to 120° C. and monitored by TLC. After 8 h the reaction was cooled to RT and 10% HCl was added. The mixture was extracted with EtOAc and the combined extracts were washed with H2O and brine. The extracts were dried (Na2SO4) filtered and evaporated. The crude product was chromatographed with SiO2 and eluted with a gradient of hexane/EtOAc (100:0 to 60:40) to afford [3-(2-bromo-5-chloro-phenoxy)-4-ethyl-phenyl]-acetic acid ethyl ester.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Cl)[C:5]=1[NH:12][C:13](=[O:29])[CH2:14][CH:15]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)([CH3:3])[CH3:2].[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1.[I-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:31]2[NH:30][CH:34]=[CH:33][N:32]=2)[C:5]=1[NH:12][C:13](=[O:29])[CH2:14][CH:15]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)([CH3:3])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CC(C)c1cccc(CCl)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1cccc(Cc2ncc[nH]2)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Temperature: 90 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
A suspension of 500 mg (1.23 mmol) of N-(2-isopropyl-6-chloromethylphenyl)-2-(9H-xanthen-9-yl)acetamide [prepared as described in Preparation 28(iv)], 847 mg (12.3 mmol) of imidazole and 277 mg (1.9 mmol) of sodium iodide in 10 ml of N,N-dimethylformamide was stirred at 90° C. for 2 hours and then the temperature was lowered to room temperature. The resulting mixture was diluted with ethyl acetate. The diluted mixture was washed several times with water and once with a saturated aqueous solution of sodium chloride. The organic phase was dried over anhydrous sodium sulfate, and then the solvent was removed by distillation under reduced pressure. The resulting residue was triturated with a mixture of diethyl ether and hexane, and the resulting crystallized product was collected to give 471 mg (yield 88%) of the title compound as crystals, melting at 193°-195° C. (after recrystallization from a mixture of methanol, diethyl ether and hexane).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].OS(O)(=O)=O.[O:12]=[S:13]1(=[O:44])[C:19]2[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:18]=2[N:17]([C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][CH:27]=2)[C:16](=O)[C:15]([CH2:40][CH2:41][CH2:42][CH3:43])([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:14]1>C1COCC1>[O:44]=[S:13]1(=[O:12])[C:19]2[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:18]=2[N:17]([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:16][C:15]([CH2:40][CH2:41][CH2:42][CH3:43])([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:14]1
Reactant: CCCCC1(CCCC)CS(=O)(=O)c2cc(OC)ccc2N(c2ccc([N+](=O)[O-])cc2)C1=O
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCC1(CCCC)CN(c2ccc(N)cc2)c2ccc(OC)cc2S(=O)(=O)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 27.5 %

Procedure:
To LiAlH4 (5.76 g, 151 mmol) were added THF (200 ml). The reaction mixture was cooled to 0° C. and H2SO4 (4.06 ml, 76 mmol) were added slowly with a syringe. After the addition was completed the reaction was stirred for 10 minutes, Then 1,1-dioxo-3,3-dibutyl-4-oxo-5-(4-nitrophenyl)-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 104; 2.57 g, 5.06 mmol) dissolved in THF (50 ml) was added at 0° C. After vigorous stirring for 1 hour the cooling bath was removed and the reaction was heated to 40° C. overnight. Then Na2SO4.10H2O (3–4 teaspoons), water (8 ml), NaOH (15%, aq) (8 ml), water (25 ml) and MeOH (30 ml) were added in that order. The precipitate was removed by filtration and rinsed with DCM/MeOH. The solvent was dried, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography using DCM:EtOAc, 9:1 then 3:1 as eluent to give the title compound 0.6 g (27%). M/z 431.3.
Reaction SMILES: [CH:1]1([C:5]2[N:6]=[C:7](/[CH:10]=[CH:11]/[C:12]3[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=3)[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(O[C:23]1[CH:34]=[C:27]2[CH2:28][C:29]([O:31][C:32](=[O:33])[C:26]2=[CH:25][CH:24]=1)=[O:30])(=O)C>C1(C)C=CC=CC=1>[C:29]([O:31][C:24]1[CH:23]=[CH:34][C:27]([CH2:28][C:29]([NH:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12](/[CH:11]=[CH:10]/[C:7]3[S:8][CH:9]=[C:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)[N:6]=3)[CH:13]=2)=[O:30])=[C:26]([CH:25]=1)[C:32]([OH:31])=[O:33])(=[O:30])[CH3:28]
Reactant: CC(=O)Oc1ccc2c(c1)CC(=O)OC2=O
Reactant: Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Solvent: Cc1ccccc1
Product: CC(=O)Oc1ccc(CC(=O)Nc2cccc(/C=C/c3nc(C4CCC4)cs3)c2)c(C(=O)O)c1
Yield: 148.2 %

Procedure:
A mixture composed of 0.58g of (E)-3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]benzeneamine, 0.48g of 5-acetoxyhomophthalic anhydride and 50 ml of toluene was heated on a steam bath for 0.5 hr. The mixture was cooled and the solids that formed were isolated by filtration to yield 0.77 g of (E)-5-acetoxy-2-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid; m.p. 176°-179° C. after trituration with hot acetonitrile.
Reaction SMILES: O.[OH-].[Na+].[F:4][C:5]1[C:6]([CH2:14][C:15]#[N:16])=[CH:7][C:8]2[O:12][CH2:11][O:10][C:9]=2[CH:13]=1.Br[CH2:18][CH2:19]Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[F:4][C:5]1[C:6]([C:14]2([C:15]#[N:16])[CH2:19][CH2:18]2)=[CH:7][C:8]2[O:12][CH2:11][O:10][C:9]=2[CH:13]=1
Reactant: N#CCc1cc2c(cc1F)OCO2
Reactant: ClCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#CC1(c2cc3c(cc2F)OCO3)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
A flask was charged with water (10 mL), followed by a rapid addition of NaOH (10 g, 0.25 mol) in three portions over a 5 min period. The mixture was allowed to cool to room temperature. Subsequently, the flask was charged with toluene (6 mL), tetrabutyl-ammonium bromide (50 mg, 0.12 mmol), (6-fluoro-benzo[1,3]dioxol-5-yl)-acetonitrile (600 mg, 3.4 mmol) and 1-bromo-2-chloroethane (1.7 g, 12 mmol). The mixture stirred vigorously at 50° C. overnight. The cooled flask was charged with additional toluene (20 mL). The organic layer was separated and washed with water (30 mL) and brine (30 mL). The organic layer was removed in vacuo to give the crude product, which was purified by column chromatography on silica gel (5-10% ethyl acetate/petroleum ether) to give 1-(6-fluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonitrile (400 mg, 60%). 1H NMR (300 MHz, CDCl3) δ 6.73 (d, J=3.0 Hz, 1H), 6.61 (d, J=9.3 Hz, 1H), 5.98 (s, 2H), 1.67-1.62 (m, 2H), 1.31-1.27 (m, 2H).
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:42])[N:24]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[F:41])[CH2:25][CH2:26][CH2:27][C:28](=[O:34])[N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:20]=[C:19]([Cl:43])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>ClCCl>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[Cl:43][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=1)[C:23]([N:24]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[F:41])[CH2:25][CH2:26][CH2:27][C:28](=[O:34])[N:29]1[CH2:30][CH2:31][CH2:32][CH2:33]1)=[O:42]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCC(=O)N2CCCC2)c2ccccc2F)c1)c1ccncc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)c1ccccc1F)N1CCCC1
Reaction time: 1 h

Procedure:
A solution of (2-{3-chloro-5-[(2-fluoro-phenyl)-(4-oxo-4-pyrrolidin-1-yl-butyl)-carbamoyl]-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester (0.025 g) in mixture of trifluoroacetic acid (1 ml) and dichloromethane (1 ml) was stored at room temperature for 1 h and then the solvent removed under reduced pressure. The residue was subjected to preparative hplc to give the title compound (0.024 g) as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[CH:3]=1.[NH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=O)=[CH:13][CH:12]=1>O>[CH3:9][C:4]1[CH:5]=[CH:6][C:7]2[O:8][C:15]([C:14]3[CH:18]=[CH:19][C:11]([NH2:10])=[CH:12][CH:13]=3)=[N:1][C:2]=2[CH:3]=1
Reactant: Cc1ccc(O)c(N)c1
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: O
Product: Cc1ccc2oc(-c3ccc(N)cc3)nc2c1
Temperature: 190 °C
Yield: 90.3 %

Procedure:
A mixture of 2-amino-p-cresol (1.5 g, 12 mmol), 4-aminobenzoic acid (1.67 g, 12 mmol) and 40 g polyphosphoric acid was heated at 190° C. under nitrogen for 6 h. The reaction mixture was cooled to room temperature and 300 ml water was added to the viscous liquid. The solid that precipitated was collected by filtration and dissolved in 200 ml ethyl acetate. The ethyl acetate solution was washed sequentially with 100 ml saturated aqueous sodium bicarbonate solution, 100 ml water and 100 ml brine, dried (anhydrous sodium sulfate) and concentrated under reduced pressure to yield the title compound as an off-white solid (2.43 g, 89% yield).
Reaction SMILES: [CH2:1](Br)[CH3:2].[CH3:4][CH2:5][C@@H:6]([C:17]([O-:19])=[O:18])[C@H:7]([CH2:15][OH:16])[CH2:8][C:9]1[N:13]([CH3:14])[CH:12]=[N:11][CH:10]=1.[Na+].O>CS(C)=O>[CH3:4][CH2:5][C@H:6]([C:17]([O:19][CH2:1][CH3:2])=[O:18])[C@H:7]([CH2:15][OH:16])[CH2:8][C:9]1[N:13]([CH3:14])[CH:12]=[N:11][CH:10]=1
Reactant: CC[C@@H](C(=O)[O-])[C@H](CO)Cc1cncn1C
Reactant: CCBr
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)[C@@H](CC)[C@H](CO)Cc1cncn1C
Temperature: 25 °C
Reaction time: 60 h

Procedure:
9.80 mmoles of ethylbromide (1068 mg) were added dropwise within about an hour to a solution containing 9.80 mmoles (2432 mg) of pilocarpic acid sodium salt in 60 ml of dimethyl sulfoxide. The solution was stirred at room temperature for 48-72 hours and poured into 100 ml of distilled water. The mixture was extracted with two portions of each 150 ml of ethyl acetate. The combined ethyl acetate extracts were washed with 150 ml of distilled water, with 150 ml of 2% sodium bicarbonate solution and with 150 ml of distilled water. The ethyl acetate extracts were dried on calcium sulfate (30 min) and the ethyl acetate evaporated under reduced pressure, and the pilocarpic acid ethyl ester obtained was crystallized from a chloroform/ petroleum ether-mixture, whereby 448 mg (1.76 mmoles) of the ester were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[C:5]([NH2:19])=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1.[F:21][C:22]([F:33])([F:32])[C:23]([F:31])([F:30])[C:24]([F:29])([F:28])[C:25](O)=O>C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][CH:10]=2)=[CH:6][C:5]2[NH:19][C:25]([C:24]([F:28])([F:29])[C:23]([F:30])([F:31])[C:22]([F:33])([F:32])[F:21])=[N:20][C:4]=2[CH:3]=1
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Nc1cc(Cl)c(Oc2ccc(C(F)(F)F)cc2)cc1N
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(Oc2cc3[nH]c(C(F)(F)C(F)(F)C(F)(F)F)nc3cc2Cl)cc1
Yield: 43 %

Procedure:
A solution of 4-chloro-5-[4-(trifluoromethyl)phenoxy]benzene-1,2-diamine (200 mg, 0.66 mmol) in heptafluorobutanoic acid (3 ml) was stirred overnight at 80° C. in an oil bath. The solution was diluted with ethyl acetate (100 ml), washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Pre-TLC with 10% ethyl acetate in petroleum ether to produce 5-chloro-2-(heptafluoropropyl)-6-[4-(trifluoromethyl)phenoxy]-1H-1,3-benzodiazole as a white solid (135.2 mg, 43%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)[OH:4].O=[C:16]([CH3:33])[CH2:17][O:18][C:19]1[CH:32]=[CH:31][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])=[CH:21][CH:20]=1.C1C=CC=CC=1.[BH4-].[Na+]>CO>[CH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][C:5]=1[CH:3]([OH:4])[CH2:2][NH:1][CH:16]([CH3:33])[CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])=[CH:31][CH:32]=1
Reactant: CC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: NCC(O)c1ccc2ccccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: CC(COc1ccc(CC2SC(=O)NC2=O)cc1)NCC(O)c1ccc2ccccc2c1

Procedure:
A procedure similar to that described in Preparation 10, below, was followed, but using 520 mg of 2-amino-1-(2-naphthyl)ethanol [prepared as described in Preparation 8], 650 mg of 5-[4-(2-oxopropoxy)benzyl]thiazolidine-2,4-dione [prepared as described in Preparation 9], 150 ml of benzene, 100 ml of absolute methanol and 1.25 g of sodium borohydride, to give the title compound in crude form. This crude product was then purified by column chromatography through silica gel, using a 5:1 by volume mixture of ethyl acetate and ethanol as the eluent, to give 490 mg of the title compound melting at between 115° C. and 145° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:13](=[O:19])[NH:14]2)#[CH:9]>[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:27][O:26][C:25]1[CH:24]=[CH:23][NH:22][C:21]=1/[CH:20]=[C:12]1\[C:13](=[O:19])[NH:14][C:15]2[C:11]\1=[C:10]([C:8]#[C:9][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH:18]=[CH:17][CH:16]=2
Reactant: C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2
Reactant: Brc1ccccn1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#Cc3ccccn3)c21

Procedure:
Using Method J above, 2-bromopyridine (44.9 mg, 0.28 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-ethynyl-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 5) (50 mg, 0.19 mmol) using DPPFPdCl2 (7.7 mg) (Aldrich) and CuI (2 mg) (Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent and heating at reflux for 2 days, yielding (Z)-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-4-[(2-pyridinyl)ethynyl]-2H-indol-2-one. (Yield 30 mg, 47%).
Reaction SMILES: [CH:1]1[C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=[C:3]([OH:12])[CH:2]=1.[OH-].[K+].Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>O>[CH2:19]([O:18][C:16]([O:12][C:3]1[CH:4]=[CH:5][C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])=[CH:1][CH:2]=1)=[O:17])[CH3:20]
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)Oc1ccc(/C=C/C(=O)O)cc1
Yield: 98.4 %

Procedure:
67 g (0.41 mol) p-cumaric acid are added to a mixture of 50.4 g (0.90 mol) potassium hydroxide and 600 ml water. 53.1 g (0.50 mol) ethyl chloroformate are added dropwise at 0° C. The reaction temperature rises to 10° C. The reaction mixture is subsequently allowed to react for 2 hours at 25° C. and acidified to pH=1 with 200 ml hydrochloric acid 7N. The product is filtered off, washed with water and dried under vacuum to give 95.3 g of (2E)-3-{4-[(ethoxycarbonyl)oxy]phenyl}acrylic acid as white powder.