Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[O:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)#[N:2].[Sn]([N:28]=[N+:29]=[N-:30])(C)(C)C.[OH-].[Na+].CCCCCC>C1(C)C=CC=CC=1.O>[NH:28]1[C:1]([CH2:3][C:4]2[CH:5]=[C:6]([NH:10][C:11]([C:13]3[O:14][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:16][CH:17]=3)=[O:12])[CH:7]=[CH:8][CH:9]=2)=[N:2][N:30]=[N:29]1
Reactant: N#CCc1cccc(NC(=O)c2ccc(-c3ccccc3)o2)c1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=C(Nc1cccc(Cc2nnn[nH]2)c1)c1ccc(-c2ccccc2)o1
Reaction time: 0.17 h

Procedure:
To a solution of 5-phenyl-furan-2-carboxylic acid (3-cyanomethyl-phenyl)-amide (70 mg, 0.23 mmol) in toluene (3 ml) was added Me3SnN3 (56 mg, 0.28 mmol). After heating to reflux for 18 h, additional Me3SnN3 (56 mg, 0.28 mmol) and toluene (2 ml) were added and the reaction was heated to reflux for a further 18 h. After this time, 2M NaOH (2 ml) and hexane (2 ml) were added to the reaction mixture and stirred for 10 min. Water (1 ml) was added and the organic layer separated. EtOAc (2 ml) was added to the aqueous layer and the solution stirred for 2 min before the organic layer was separated. The combined organic layers were discarded. The aqueous layer was then acidified to pH 5 with 2M HCl then EtOAc (2.5 ml) was added and the solution stirred for 10 min after which time the organic layer was separated. EtOAc (2.5 ml) was added to the aqueous layer and the solution stirred for 1 hour. The EtOAc layer was separated and these combined organic layers were evaporated in vacuo to give the title compound.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]([NH:10][C@H:11]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:9])[C@H:4]([CH2:6][CH3:7])[CH3:5].C(N(CC)CC)C.[CH2:36]([OH:47])[C@H:37]1[O:43][C:41](=[O:42])[C@H:40]([OH:44])[C@@H:39]([OH:45])[C@@H:38]1[OH:46]>CN(C=O)C>[OH:42][CH:41]1[O:43][C@H:37]([C:36](=[O:9])[OH:47])[C@@H:38]([OH:46])[C@H:39]([OH:45])[C@H:40]1[OH:44].[NH2:2][C@H:3]([C:8]([NH:10][C@H:11]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:9])[C@H:4]([CH2:6][CH3:7])[CH3:5]
Reactant: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: CC[C@H](C)[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a solution of HCl, H-Ile-Phe-OBzl (1.41 g, 3.5 mmol) in freshly distilled DMF (2 ml) neutralized with triethylamine (0.49 ml, 3.5 mmol), δ-gluconolactone (1.25 g, 7 mmol) and TEA (0.98 ml, 7 mmol) were added. The mixture was stirred at 60° C. for 24 hr. δ-gluconolactane (0.63 g, 3.5 mmol) and TEA (0.43 ml, 3.5 mmol) were then added and the mixture was stirred for 24 h more. The mixture was then filtered and the filtrate evaporated under reduced pressure. The residue was purified by preparative chromatography on a silica gel column eluted with the system chloroform-methanol-water (16:6:1): yield 1.1 g (58%) after precipitation in ether-petroleum ether (1:1, v/v); mp 175°-176° C.; [α]54625 =+1.3° (c=1, DMF); Rf(A) =0.53.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[CH3:24][N:25]([C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[S:26]([CH3:29])(=[O:28])=[O:27].[OH-].[Na+]>CN(C=O)C.CO>[CH3:24][N:25]([C:30]1[CH:36]=[CH:35][C:33]([NH:34]/[C:13](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:32][CH:31]=1)[S:26]([CH3:29])(=[O:27])=[O:28]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Reactant: CN(c1ccc(N)cc1)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CN(c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1)S(C)(=O)=O

Procedure:
Prepared analogously to Example 1 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-(N-methyl-N-methylsulphonyl-amino)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:25][C:26](Br)=[O:27].[CH3:29][O:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33][NH2:34]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:25][C:26]([NH:34][CH2:33][C:32]1[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=1[O:30][CH3:29])=[O:27]
Reactant: COc1cccc(CC2NCCc3cc(OC)c(OC)cc32)c1
Reactant: O=C(Br)CBr
Reactant: COc1ccccc1CN
Product: COc1cccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2OC)c1

Procedure:
prepared by reaction of 1-(3-Methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline and 2-bromoacetyl bromide with 2-methoxybenzylamine
Reaction SMILES: [ClH:1].[CH2:2]([C:7]1[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=1)[CH2:3][CH2:4][C:5]#[CH:6].[N:13]([CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[N+:14]=[N-:15]>>[ClH:1].[C:19]1([CH2:18][CH2:17][CH2:16][N:13]2[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][C:7]3[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=3)[N:15]=[N:14]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C#CCCCc1c[nH]c(N)n1
Reactant: [N-]=[N+]=NCCCc1ccccc1
Agent: Cl
Product: Nc1nc(CCCc2cn(CCCc3ccccc3)nn2)c[nH]1
Yield: 34.1 %

Procedure:
4-Pent-4-ynyl-1H-imidazol-2-ylamine hydrochloride (0.050 g, 0.269 mmol) was reacted with (3-azido-propyl)benzene (0.044 g, 0.273 mmol) following the general procedure for click reactions outlined above to produce 4-{3-[1-(3-Phenyl-propyl)-1H-[1,2,3]triazol-4-yl]-propyl}-1H-imidazol-2-ylamine hydrochloride (0.0318 g, 34%) as a pale yellow solid. 1H NMR (300 MHz, DMSO) δ 7.91 (s, 1H), δ 7.29-7.17 (m, 5H), δ 6.62 (s, 2H), δ 6.57 (s, 1H), δ 4.29 (t, 2H), δ 2.59 (t, 2H), δ 2.53 (t, 2H), δ 2.43 (t, 2H) δ 2.09 (m, 2H), δ 1.83 (m, 2H) ppm; 13C NMR (75 MHz, DMSO) δ 163.6, 156.2, 155.1, 147.4, 146.9, 141.4, 129.1, 127.1, 126.7, 122.6, 109.4, 49.4, 32.6, 32.0, 28.1, 24.9, 24.2 ppm; HRMS (ESI) calcd for C17H22N6 (M+) 310.1978, found 310.1977.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9](O)[CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.P([N:34]=[N+:35]=[N-:36])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C1CCN2C(=NCCC2)CC1.ClC1C(Cl)=CC=CC=1C=CC1C=CN=CC=1>C1COCC1>[N:34]([CH:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=1[Cl:1])[CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[N+:35]=[N-:36]
Reactant: OC(Cc1ccncc1)c1cccc(Cl)c1Cl
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Agent: Clc1cccc(C=Cc2ccncc2)c1Cl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NC(Cc1ccncc1)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.7 %

Procedure:
1-(2,3-dichlorophenyl)-2-(pyridin-4-yl)ethanol (7) (6.20 g, 23.2 mmol) in THF (100 mL) was added diphenyl phosphorazidate (6.00 mL, 27.8 mmol), and DBU (4.20 mL, 23.1 mmol) at 0° C. The mixture was stirred at room temperature overnight. The mixture was heated at 50° C. for 1.5 hour. The solvents were evaporated under reduced pressure. The residue was diluted with water, and extracted with ethyl acetate (3×). The pooled organic layer was dried over magnesium sulfate. The mixture was filtered. Silica gel was added to the filtrate, and the solvents were evaporated under reduce pressure. Purification by chromatography on silica gel (60% hexane, 40% ethyl acetate) gave a 4:1 mixture of products: 4-(2-azido-2-(2,3-dichlorophenyl)ethyl)pyridine (8) (4 parts, 3.82 g, 10.6 mmol, 46% yield), and 4-(2,3-dichlorostyryl)pyridine (9) (1 part).
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([C:7]2([C:10]([O:12][CH3:13])=[O:11])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[Br:15]N1C(=O)CCC1=O>C(#N)C.O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:15][CH2:14][C:1]1[CH:2]=[CH:3][C:4]([C:7]2([C:10]([O:12][CH3:13])=[O:11])[CH2:9][CH2:8]2)=[CH:5][CH:6]=1
Reactant: COC(=O)C1(c2ccc(C)cc2)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: O
Product: COC(=O)C1(c2ccc(CBr)cc2)CC1
Temperature: 80 °C
Reaction time: 0.67 h
Yield: 58.4 %

Procedure:
To a stirred solution of methyl 1-(p-tolyl)cyclopropanecarboxylate (3 g, 15.77 mmol) in acetonitrile (42 mL), was added N-bromosuccinimide (2.807 g, 15.77 mmol) followed by benzoyl peroxide (0.164 g, 0.473 mmol). The reaction was stirred at 80° C. for 2 hours 40 minutes and then allowed to cool to room temperature. The reaction mixture was diluted with water and extracted with dichloromethane (×3). The combined organic extracts were washed with brine and dried (magnesium sulfate), filtered and concentrated under reduced pressure to afford a red oil. The crude material was purified by silica gel column chromatography eluting with 0-9% ethyl acetate in iso-hexane to afford the title compound (2.478 g, 58%).
Reaction SMILES: [C:1]([C:9]1[C:10]([NH:15][C:16](=[O:19])[CH2:17][Cl:18])=[CH:11][NH:12][C:13]=1[CH3:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O-])([O-])=O.[K+].[K+].COS(OC)(=O)=O>CC(=O)CC>[C:1]([C:9]1[C:10]([NH:15][C:16](=[O:19])[CH2:17][Cl:18])=[CH:11][N:12]([CH3:20])[C:13]=1[CH3:14])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1[nH]cc(NC(=O)CCl)c1C(=O)c1ccccc1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CCC(C)=O
Product: Cc1c(C(=O)c2ccccc2)c(NC(=O)CCl)cn1C
Temperature: 25 °C

Procedure:
N-(4-benzoyl-5-methyl(1H)-pyrrol-3-yl)2-chloroacetamide (0.019 mole) was dissolved in butan-2-one (60 ml) and K2CO3 (4.5 g) and dimethylsulphate (0.037 mole) were added to the obtained solution. The reaction mixture was maintained at the reflux temperature for 5 hours and at room temperature overnight. An inert atmosphere was maintained throughout the process. The inorganic salts were filtered and the clear solution was evaporated under vacuum to yield a residue which upon crystallization from methanol gave the compound of the title.
Reaction SMILES: [C:1]1(=[O:12])[O:7][C:5](=O)[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1.[CH2:13]([NH2:17])[CH2:14][CH:15]=[CH2:16]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:13]([N:17]1[C:1](=[O:12])[CH2:2][C:3]2[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5]1=[O:7])[CH2:14][CH:15]=[CH2:16]
Reactant: C=CCCN
Reactant: O=C1Cc2ccccc2C(=O)O1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C=CCCN1C(=O)Cc2ccccc2C1=O
Temperature: 160 °C
Yield: 37.7 %

Procedure:
Homophthalic anhydride (1.5 g, 9.25 mmol), 3-buten-1-amine (1.129 ml, 11.10 mmol), and 4 A molecular sieves (300 mg) were combined in toluene (15 ml) and heated to 160° C. in a microwave for 40 minutes. The reaction mixture was diluted with CH2Cl2 and the slurry was filtered over CELITE. The filtrate was concentrated in vacuo and the resulting residue was purified by column chromatography (gradient elution, 10-20% EtOAc/Hexane) to afford the title compound (0.75 g, 36%) as an oil. LCMS (ES+) m/z 216.03 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:22])([C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[CH2:3][CH2:4][SiH:5]([CH:9]([CH3:11])[CH3:10])[CH:6]([CH3:8])[CH3:7].C([Br:26])C=C>Cl[Pd]Cl>[F:22][C:2]([F:1])([C:12]([F:20])([F:21])[C:13]([F:18])([F:19])[C:14]([F:15])([F:16])[F:17])[CH2:3][CH2:4][Si:5]([Br:26])([CH:9]([CH3:11])[CH3:10])[CH:6]([CH3:8])[CH3:7]
Reactant: C=CCBr
Reactant: CC(C)[SiH](CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(C)C
Agent: Cl[Pd]Cl
Product: CC(C)[Si](Br)(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(C)C
Temperature: 60 °C

Procedure:
In an oven-dried round-bottom flask equipped with a stir bar and cooled under N2, 3,3,4,4,5,5,6,6,6-nonafluorohexyldiisopropylsilane (10.1 g, 27.8 mmol) was dissolved in allyl bromide (20 mL), and PdCl2 (50 mg) was added. The solution was heated to 60° C. for 15 hr, then cooled, and concentrated via rotary evaporation. The resulting suspension was dissolved in pentane, filtered to remove residual catalyst, and then solvent was removed to yield (3,3,4,4,5,5,6,6,6-nonafluorohexyldiisopropylsilyl)bromide (12.1 g) as a pale brown liquid. The bromide was treated under anhydrous conditions with 1.2 eq. (based on initial silane) of ethynylmagnesium bromide and heated to 40° C. for 6 hr. The reaction was quenched with water and dilute sulfuric acid, pentane was added, and the organic layer was separated. The organic layer was washed with water (6×50 mL), dried over MgSO4, filtered, and concentrated via rotary evaporation. Further purification via flash chromatography using hexane yielded pure (3,3,4,4,5,5,6,6,6-nonafluorohexyldiisopropylsilyl)acetylene (9.90 g, 25.6 mmol, 92%) as a colorless liquid. Analysis of the product provided the following data: 1H-NMR (200 MHz, CDCl3) δ=2.4 (s, 1H), 2.2 (m, 2H), 1.1 (m, 14H), 0.8 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:10])=[N:4][C:5]([OH:9])=[N:6][C:7]=1[OH:8].[C:11]1([N:17]=[C:18]=[S:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)(=O)C>[OH-].[Na+]>[OH:9][C:5]1[N:6]=[C:7]([OH:8])[C:2]([NH:1][C:18]([NH:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[S:19])=[C:3]([OH:10])[N:4]=1
Reactant: S=C=Nc1ccccc1
Reactant: Nc1c(O)nc(O)nc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Oc1nc(O)c(NC(=S)Nc2ccccc2)c(O)n1
Temperature: 60 °C

Procedure:
75 g of 5-amino-2,4,6-trihydroxypyrimidine was dissolved in 1.5 to 5% sodium hydroxide with vigorous overhead stirring producing a violet solution. The reaction was heated to 60° C. and 63 ml phenyl isothiocyanate was added dropwise over 1.5 hours. The reaction turned pale yellow. The reaction was stirred an additional 2 hours at 60° C., cooled and acidified with glacial acetic acid producing a light yellow precipitate. This was filtered to yield about 75 g of N-(2,4,6-trihydroxy-5-pyrimidyl)-N'-phenylthiourea.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>O1CCOCC1>[N:11]1([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cnccc1N1CCCC1
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
4-Chloro-3-nitropyridine (2.02 g, 12.7 mmol) was suspended in 15 ml of 1,4-dioxane. The suspension was cooled a little in an ice bath, and then pyrrolidine (2.1 ml, 25.3 mmol ) was added dropwise thereto. The temperature of the suspension was returned to room temperature, and the suspension was stirred for 30 minutes, followed by removal of the solvent by distillation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 2.34 g of a yellow solid (yield: 95.4%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27].C(O)(=O)C.Cl>O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27]
Reactant: CCOC(=O)CCCCCCOc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC1(C2CCCC2)Cc2cc(OCCCCCCC(=O)O)c(Cl)c(Cl)c2C1=O
Yield: 80.9 %

Procedure:
A mixture of ethyl 7-[(6,7-Dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]heptanoate (16 g., 0.035 mole), acetic acid (100 ml.) and 6N hydrochloric acid (50 ml.) is stirred and refluxed for 6 hours. The mixture is poured into water (400 ml.) where upon the product slowly solidifies. The product is removed by filtration, dried and recrystallized from a mixture of tetrahydrofuran, ether and petroleum ether (50, 100 and 200 ml., respectively) to give 7-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]heptanoic acid 12.1 g., m.p. 107°-110° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH:32]([CH3:34])[CH3:33])=[C:11]([CH2:13][CH2:14][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([CH3:31])([CH3:30])[C:25]([O:27]CC)=[O:26])=[CH:19][CH:18]=2)O)[N:12]=1.O.[OH-].[Li+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH:32]([CH3:34])[CH3:33])=[C:11]([CH2:13][CH:14]=[CH:15][C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24]([CH3:30])([CH3:31])[C:25]([OH:27])=[O:26])=[CH:21][CH:22]=2)[N:12]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C(O)CCc2nc(-c3ccccc3Cl)oc2C(C)C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)c1oc(-c2ccccc2Cl)nc1CC=Cc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.3 %

Procedure:
The resulting propionic acid derivative (25 mg, 0.053 mmol) was dissolved in a mixture of ethanol (2 mL) and water (1 mL). To the solution was then added lithium hydroxide monohydrate (6 mg). The mixture was stirred for 20 hours at room temperature, and after cooling with ice, cooled with ice, neutralized by addition of diluted hydrochloric acid, and then subjected to extraction using ethyl acetate. The organic layer was collected, washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The ethyl acetate was distilled off under reduced pressure, to give 15 mg of the desired compound as colorless oil residue (yield 63%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)(O)[O-].[Na+].[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>C(OCC)(=O)C.O>[C:19]([C:18]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[O:23])([CH3:22])([CH3:21])[CH3:20]
Reactant: COC(=O)c1c(N)cccc1O
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(O)cccc1NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 78.1 %

Procedure:
A solution of methyl 2-amino-6-hydroxybenzoate (prepared according to Comess et al, US2004 167128, 3.8 g) and sodium bicarbonate (2.52 g) in ethyl acetate (75 mL) and water (17.5 mL) was stirred at room temperature and pivaloyl chloride (3.51 g) was added dropwise. The resultant mixture was stirred at room temperature for 1 hour. A further amount of pivaloyl chloride (1.75 g) was added and the mixture was stirred at room temperature for 2.5 hours. A further amount of pivaloyl chloride (1 g) was added and the mixture was stirred at room temperature for 4 hours and 20 minutes. Ethyl acetate and saturated aqueous sodium bicarbonate solution were added and the layers were separated. The organic phase was washed with brine, dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 5-25% to give methyl 2-tert-butylcarbonylamino-6-hydroxybenzoate (4.46 g) as a white solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:23](I)[CH3:24].[H-].[Na+].C(OCC)(=O)C>C1COCC1.O>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:23][CH3:24])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCI
Reactant: CC(C)(C)[Si](C)(C)OCCCNC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)OCc1ccccc1
Reaction time: 15 h
Yield: 80 %

Procedure:
3-Benzyloxycarbonylamino-1-propanol t-butyldimethylsilyl ether (10.1 g) was dissolved in THF (250 ml), and to the resulting solution were added under ice-cooling ethyl iodide (5.1 ml) and a 60% sodium hydride (as a mineral oil dispersion) (2.0 g). The resultant mixture was stirred under ice-cooling for 30 minutes and then at room temperature for 15 hours. Ethyl acetate and water were added to the reaction solution obtained. The organic layer so separated was washed with water and then dried over magnesium sulfate. The solvent was evaporated off from the solution, and the residue was purified by a silica gel chromatography, thus affording the titled compound (8.5 g; 80%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([N+:9]([O-:11])=[O:10])=[C:5]([CH3:12])[N:4]([CH2:13][CH2:14][CH3:15])[C:3]1=[O:16].[CH2:17]([O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O)[CH3:18].N1CCCCC1>C(O)C>[CH2:17]([O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1/[CH:22]=[CH:12]/[C:5]1[N:4]([CH2:13][CH2:14][CH3:15])[C:3](=[O:16])[N:2]([CH3:1])[C:7](=[O:8])[C:6]=1[N+:9]([O-:11])=[O:10])[CH3:18]
Reactant: CCCn1c(C)c([N+](=O)[O-])c(=O)n(C)c1=O
Reactant: CCOc1ccccc1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCn1c(/C=C/c2ccccc2OCC)c([N+](=O)[O-])c(=O)n(C)c1=O
Yield: 75.1 %

Procedure:
A mixture of 3,6-dimethyl-5-nitro-1-propyl-1H-pyrimidine-2,4-dione (6.25 g, 27.5 mmol), 2-ethoxybenzaldehyde (4.24 mL, 30.3 mmol), piperidine (2.83 mL, 28.6 mmol) and 3 Å molecular sieves (8.75 g) in ethanol (125 mL) was refluxed for 5 hours. The resulting suspension was filtered and the filtrate was evaporated under reduced pressure. The residue was triturated with isopropyl ether and the precipitate collected by filtration and dried under vacuum to yield 6-[(E)-2-(2-ethoxyphenyl)vinyl]-3-methyl-5-nitro-1-propyl-1H-pyrimidine-2,4-dione (7.42 g, 75%) as a yellow solid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:33]=[CH:32][C:28](C(O)=O)=[CH:27][CH:26]=2)[CH:20]=1.[NH:34]1[CH2:39][CH2:38][CH2:37][CH:36]([OH:40])[CH2:35]1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:16]([N:34]2[CH2:39][CH2:38][CH2:37][CH:36]([OH:40])[CH2:35]2)=[O:18])[N:8]([C:6](=[O:7])[C:28]2[CH:27]=[CH:26][C:25]([C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)=[CH:33][CH:32]=2)[CH2:12]1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: OC1CCCNC1
Reactant: O=C(O)c1ccc(-c2cccnc2)cc1
Product: CON=C1C[C@@H](C(=O)N2CCCC(O)C2)N(C(=O)c2ccc(-c3cccnc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 4-(3-pyridinyl)benzoic acid, and (3RS)-3-piperidinol, the title compound was obtained in 84% purity by HPLC. MS(ESI+): m/z=423.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH3:10])=[CH:5][C:4]=1[CH2:11][CH2:12][C:13]([OH:15])=O.[Cl-].[Al+3].[Cl-].[Cl-]>S(Cl)(Cl)=O.O>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH3:10])=[C:5]2[C:4]=1[CH2:11][CH2:12][C:13]2=[O:15]
Reactant: COc1c(C)cc(C)cc1CCC(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: O
Product: COc1c(C)cc(C)c2c1CCC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
A solution of 3-(2-methoxy-3,5-dimethylphenyl)propionic acid (8.80 g, 42.2 mmol) in thionyl chloride (80 mL) was refluxed for 1.5 hours. After cooling, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in 1,2-dichloroethane (100 mL). To this solution was added anhydrous aluminum chloride (5.80 g, 43.5 mmol) gradually at 0° C. and the mixture was stirred at room temperature for 1.0 hour. After completion of the reaction, the reaction mixture was poured in iced water and extracted with 1,2-dichloroethane. The organic layer was washed serially with 1N-hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and water, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide 6.90 g of the title compound. Yield 86%.