Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22](I)=[N:23][C:24]=2[Cl:28])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH:37]#[C:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([C:37]#[C:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[N:23][C:24]=2[Cl:28])(=[O:3])[CH3:2]
Reactant: C#CCCCCCCC
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCCCCCC#Cc1nc(Cl)c2ncn([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Yield: 89 %

Procedure:
In 12 ml of 1,4-dioxane were suspended 2.15 g (4 mmole ) of 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-6- chloro-2-iodopurine , 56 mg (0.08 mmole) of bis(triphenylphosphine)palladium dichloride and 15 mg (0.08 mmole ) of cuprous iodide, and 1.2 ml of triethylamine and 0.75 ml of 1-nonyne were added to the suspension. The mixture was stirred and caused to react at room temperature (25° C.) for 12 hours. The reaction solution at this time had a transparent pale brown color, which was paler than those in the aforementioned (i) or (ii). After the reaction, the solution was concentrated, and 200 ml of ethyl acetate was added to the residue to obtain a solution, which was distributed and washed several times with an aqueous EDTA.2Na solution and a saturated brine solution, respectively to remove copper ions. The organic layer was subjected to silica gel column chromatography in the same manner as in (i) to remove colored materials and other by-products and to produce 1.90 g (yield 89%) of 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-6-chloro-2-(1-nonynyl)purine as a viscous material.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:9]=3[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28](O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(O)(=O)C>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([O:17][C:14]2[CH:15]=[CH:16][C:9]3[CH2:8][CH2:7][N:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:12][CH2:11][C:10]=3[CH:13]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1ccc2c(c1)CCN(C1CCCC1)CC2
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)CCN(C2CCCC2)CC3)CC1

Procedure:
3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E4) (1.1 g, 4.8 mmol), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1.15 g, 5.7 mmol), di-tert-butyl azodicarboxylate (1.31 g, 5.7 mmol) and triphenylphosphine (1.5 g, 5.7 mmol) were stirred at room temperature for 16 hours in tetrahydrofuran (20 ml). The mixture was acidified with acetic acid and applied to a SCX ion exchange cartridge (Varian bond-elute, 10 g) and washed with methanol and then a mixture of 0.880 ammonia:methanol (1:9). The combined basic fractions were concentrated in vacuo and the resulting residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (1:9:90) to afford the title product (E5a); MS (ES+) m/e 415 [M+H]+.
Reaction SMILES: [ClH:1].[C:2]([C:4]1([NH:9][C:10](=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:8][CH2:7][CH2:6][CH2:5]1)#[N:3].C1(=O)CCCC1>C(O)C>[NH2:9][C:4]1([C:2]#[N:3])[CH2:8][CH2:7][CH2:6][CH2:5]1.[C:10]([Cl:1])(=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCC(=O)NC1(C#N)CCCC1
Reactant: Cl
Solvent: O=C1CCCC1
Solvent: CCO
Product: CCCCC(=O)Cl
Product: N#CC1(N)CCCC1

Procedure:
9.39 g (39 mmol) of a freshly prepared solution of hydrogen chloride in ethanol (15.15 percent by weight) was added to 6.80 g (30 mmol) of N-(1-cyanocyclopentyl)-pentanamide (prepared from cyclopentanone by means of a Strecker synthesis to give 1-aminocyclopentanecarbonitrile and acylation with pentanoyl chloride, content 85.7 percent) in 28 g of anhydrous ethanol. The mixture was heated to 50° C. under nitrogen and stirred at this temperature for 3.1 hours. It was then cooled to 1° C. and left to stand at this temperature for 1 hour. The product which had precipitated out was filtered off, washed with 10 ml of ice-cold ethanol and dried at 40° C./24 mbar. The yield of the product was 4.05 g (58 percent) of colorless crystals, content 98.3 percent (HPLC).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([NH:11][C:12]2[S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl[C:22](=[O:26])[CH:23]([Cl:25])[CH3:24]>ClCCCl>[S:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=[C:12]1[NH:11][C:5]1[CH:6]=[CH:7][C:8]([C:22](=[O:26])[CH:23]([Cl:25])[CH3:24])=[CH:9][CH:10]=1
Reactant: CC(Cl)C(=O)Cl
Reactant: c1ccc(Nc2nc3ccccc3s2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(Cl)C(=O)c1ccc(Nc2nc3ccccc3s2)cc1
Temperature: 80 °C
Yield: 96.7 %

Procedure:
Aluminium(III)chloride (0.666 mol) was added portionwise at RT to a solution of N-phenyl-2-benzothiazolylamine (0.222 mol) and 1,2-dichloro-1-propanone (0.233 mol) in 1,2-dichloroethane (500 ml) and the mixture was stirred and heated at 80° C. for 2 hours. The mixture was poured into ice and extracted with CH2Cl2. The organic layer was decanted, dried filtered and the solvent was evaporated, yielding 68 g of (±)-1-[4-(2-benzothiazolylamino)phenyl]-2-chloro-1-propanone (95.7%) (interm. 22).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)#[N:2].[CH2:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH2:11]1.C([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][C:25]=1[O:32][CH3:33])(=O)C>>[OH:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]2[CH:16]3[CH:15]([C:14]4[CH:13]=[CH:12][CH:11]=[CH:10][C:19]=4[CH2:18][CH2:17]3)[C:5]3[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][C:6]=3[NH:9]2)=[CH:26][C:25]=1[O:32][CH3:33]
Reactant: N#Cc1ccc(N)cc1
Reactant: C1=Cc2ccccc2CC1
Reactant: COc1cc(C=O)ccc1OC(C)=O
Product: COc1cc(C2Nc3ccc(C#N)cc3C3c4ccccc4CCC23)ccc1O

Procedure:
6-(4-Hydroxy-3-methoxy-phenyl)-5,6,6a,7,8,12b-hexahydro-benzo[k]phenanthridine-2-carbonitrile was prepared according to the protocol described in Example 2 using 4-cyanophenyl amine instead of 4-amino-benzamidine mono HCl salt, 1,2-dihydronapthalene and 4-acetoxy-3-methoxybenzaldehyde. Mass spectrum 400 (M+1).
Reaction SMILES: C1N=C[N:3]([C:6](N2C=NC=C2)=[S:7])C=1.[NH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.C([O-])(=O)C.[NH4+]>C(#N)C.CO>[N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[NH:13][C:6]([NH2:3])=[S:7]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc2ccccc2n1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC#N
Solvent: CO
Product: NC(=S)Nc1ccc2ccccc2n1
Reaction time: 1 h
Yield: 41 %

Procedure:
1.496 g (8.394 mmol) N,N′-thiocarbonyldiimidazole was dissolved in 30 mL acetonitrile, and 1.210 g (8.394 mmol) 2-amino-quinoline dissolved in 15 mL acetonitrile was added dropwise at room temperature. After 1 hr a precipitate deposited, and stirring was performed for an additional 12 hr. The solid was filtered off, and without further purification was reacted directly with 1.294 g (16.789 mmol) ammonium acetate in 50 mL methanol for 5 hr at 40° C. After mass spectrometric analysis the solvent was removed under vacuum, and the batch was dissolved in dichloromethane and shaken out with water (1×50 mL). The organic phase was dried over magnesium sulfate and filtered, and the solvent was removed under vacuum. The crude product was purified by column chromatography on silica gel (column Ø=3 cm, h=15 cm), first with dichloromethane as eluent, then with methanol to increase the polarity, and finally with pure methanol. The clean fraction was purified and the solvent was removed under vacuum, resulting in a total of 0.70 g (3.445 mmol, 41%) N-quinolin-2-yl-thiourea.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH2:3][CH3:4].[Br:7][C:8]1[CH:9]=[C:10]([C:14](=[O:16])[CH3:15])[CH:11]=[CH:12][CH:13]=1>>[Br:7][C:8]1[CH:9]=[C:10]([C:14]([OH:16])([CH2:1][CH2:2][CH2:3][CH3:4])[CH3:15])[CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: CCCC[Mg]Cl
Product: CCCCC(C)(O)c1cccc(Br)c1

Procedure:
Grignard coupling of butylmagnesium chloride with 1-(3-bromophenyl)ethanone followed by flash chromatography (0-25% ethyl acetate/hexanes gradient), gave 2-(3-bromophenyl)hexan-2-ol as a yellow oil. Yield (0.99 g, 51%): 1H NMR (400 MHz, CDCl3) δ 7.59 (t, J=2.0 Hz, 1H), 7.30-7.37 (m, 2H), 7.19 (t, J=8.0 Hz, 1H), 1.70-1.84 (m, 2H), 1.52 (s, 3H), 1.64 (brs, 1H), 1.18-1.30 (m, 3H), 1.02-1.14 (m, 1H), 0.84 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[C:8]2[CH2:12][CH2:13][OH:14])[CH3:2].N1C2C(=CC=CC=2)C(CCO)=C1.[CH2:27]([O:29][C:30]([CH:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([CH:32]1[CH2:37][CH2:36][C:35]2([C:9]3[NH:10][C:11]4[C:7]([C:8]=3[CH2:12][CH2:13][O:14]2)=[CH:6][CH:5]=[CH:4][C:3]=4[CH2:1][CH3:2])[CH2:34][CH2:33]1)=[O:31])[CH3:28]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: CCc1cccc2c(CCO)c[nH]c12
Agent: OCCc1c[nH]c2ccccc12
Product: CCOC(=O)C1CCC2(CC1)OCCc1c2[nH]c2c(CC)cccc12

Procedure:
Following the procedure of example 24.A. except using 2-(7-ethyl-1H-indol-3-yl)-ethanol as the 3-indolethanol component and 4-oxo-cyclohexane carboxylic acid ethyl ester as ketone component afforded the title compound as an oil. ESI (+) MS m/e=342 (MH+), ESI (−) MS m/e=340 (MH−).
Reaction SMILES: [OH:1][N:2]1C(=O)C2=CC=CC=C2C1=O.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][Cl:18]>>[ClH:18].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][O:1][NH2:2]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: COc1ccccc1CCl
Product: COc1ccccc1CON
Product: Cl

Procedure:
Prepared by a similar procedure as described for preparation 18, starting from N-hydroxyphthalimide and 2-methoxybenzyl chloride (Aldrich). 13C-NMR (DMSO-d6) δ 157.5, 130.8, 130.7, 121.5, 120.3, 111.1, 70.8, 55.4.
Reaction SMILES: C[O:2][C:3](=[O:35])[C@H:4]([CH2:31][CH2:32][S:33][CH3:34])[NH:5][C:6](=[O:30])[C@H:7]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:8][CH2:9][C@@H:10]([NH:14][C:15](=[O:22])[C@@H:16]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1)[CH:11]([CH3:13])[CH3:12].[Li+].[OH-]>CO.O>[NH:17]1[C:18](=[O:21])[CH2:19][CH2:20][C@H:16]1[C:15]([NH:14][C@@H:10]([CH:11]([CH3:13])[CH3:12])[CH2:9][NH:8][C@H:7]([C:6]([NH:5][C@H:4]([C:3]([OH:35])=[O:2])[CH2:31][CH2:32][S:33][CH3:34])=[O:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]
Reactant: COC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1ccccc1)NC[C@@H](NC(=O)[C@@H]1CCC(=O)N1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC[C@@H](NC(=O)[C@@H]1CCC(=O)N1)C(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product of Step E was dissolved in 15 mL of methanol and a solution of 60 mg of LiOH in 7 mL of water added. The mixture was stirred for 3 h at room temperature under argon, diluted with water and filtered. The filtrate was neutralized with 10% citric acid and cooled. The product was isolated by filtration and further purified by reverse phase HPLC. Lyophilization gave the title compound as a white solid. 1H-NMR (D2O) δ7.40 (3H, m), 7.29 (2H, m), 4.36 (1H, dd, J=4.9, 8.5 Hz), 4.29 (1H, m), 4.22 (1H, dd, J=6.2, 8.7 Hz), 3.96 (1H, dd, J=7, 13 Hz), 3.33 (1H, dd, J=6.4, 14.3 Hz), 3.20 (3H, m), 2.54 (1H, m), 2.44 (2H, m), 2.39 (1H, m), 2.32 (1H, m), 2.09 (2H, m), 2.06 (3H, s), 1.92 (1H, m), 1.87 (1H, m), 0.92 (3H, d, J=7.8 Hz), 0.90 (3H, d, J=7.8 Hz).
Reaction SMILES: C([O:8][NH:9][C:10](=[O:38])[CH2:11][CH:12]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH2:36][CH3:37])[CH:28]=1)[N:13]1[C:17](=[O:18])[C:16]2=[CH:19][C:20]([N+:23]([O-])=O)=[CH:21][CH:22]=[C:15]2[C:14]1=[O:26])C1C=CC=CC=1.C(OCC)(=O)C>C(OCC)(=O)C.CO.O1CCCC1.[OH-].[OH-].[Pd+2]>[NH2:23][C:20]1[CH:19]=[C:16]2[C:17](=[O:18])[N:13]([CH:12]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH2:36][CH3:37])[CH:28]=3)[CH2:11][C:10]([NH:9][OH:8])=[O:38])[C:14](=[O:26])[C:15]2=[CH:22][CH:21]=1
Reactant: CCOc1cc(C(CC(=O)NOCc2ccccc2)N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)ccc1OC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2C(=O)c3ccc(N)cc3C2=O)ccc1OC
Yield: 102 %

Procedure:
A mixture of N-Benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-(4-nitrophthalimido)propionamide (2.3 g, 4.42 mmol) and Pd(OH)2/C (600 mg) in ethyl acetate/methanol/tetrahydrofuran (150 mL each) was shaken under hydrogen. After 24 hours the suspension was filtered through a pad of Celite, and then was washed with methanol (30 mL) and methylene chloride (30 mL). The filtrate was concentrated in vacuo to give an oil. The oil was stirred with ethyl acetate (10 mL) to afford 3-(4-aminophthalimido)-3-(3-ethoxy-4-methoxyphenyl)-N-hydroxypropionamide as a yellow solid (1.8 g, 100% yield): mp, 193.0-195.0° C.; 1H NMR (DMSO-d6) δ1.31 (t, J=6.9 Hz, 3H, CH3), 3.05 (d, J=7.9 Hz, 2H, CH2), 3.71 (s, 3H, CH3), 3.96 (q, J=7.0 Hz, 2H, CH2), 5.57 (t, J=7.9 Hz, 1H, NCH), 6.47 (br s, 2H, NH2), 6.77 (dd, J=2.0, 8.3 Hz, 1H, Ar), 6.83-6.88 (m, 3H, Ar), 6.99 (br s, 1H, Ar), 7.45 (d, J=8.3 Hz, 1H, Ar), 8.78 (br s, 1H, OH), 10.55 (1H, NH); 13C NMR (DMSO-d6) δ14.69, 34.51, 49.75, 55.45, 63.73, 106.82, 111.74, 112.38, 116.32, 116.73, 119.60, 124.89, 131.85, 134.18, 147.62, 148.42, 155.00, 166.111, 167.70, 168.00; Anal Calcd for C20H21N3O6: C, 60.14; H, 5.30; N, 10.52. Found: C, 60.00; H, 5.34; N, 10.30.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[S:23][C:22]([CH2:24]O)=[CH:21][CH:20]=3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:51]1[CH2:54][CH:53]([C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:52]1.C(N(CC)C(C)C)(C)C>>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[S:23][C:22]([CH2:24][N:51]4[CH2:54][CH:53]([C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:52]4)=[CH:21][CH:20]=3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CNC1
Reactant: OCc1ccc(-c2noc(-c3ccc(Oc4ccccc4)cc3)n2)s1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CN(Cc2ccc(-c3noc(-c4ccc(Oc5ccccc5)cc4)n3)s2)C1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1f) using {5-[5-(4-phenoxyphenyl)-1,2,4-oxadiazol-3-yl]-2-thienyl}methanol (97 m g, 0.28 mmol) that was obtained in Example 5 (5a), carbon tetrabromide (0.19 g, 0.56 mmol), triphenylphosphine (0.15 g, 0.56 mmol), ethyl 3-azetidinecarboxylate hydrochloride (70 mg, 0.42 mmol), and N,N-diisopropylethylamine (0.18 ml, 1.1 mmol). Subsequently, the crude product of the title compound thus obtained was purified by thin layer chromatography on a silica gel plate using a mixed solvent of ethyl acetate and hexane (4:3) as the developing solvent to afford the title compound (93 mg) in a yield of 72% as a colourless oily product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)N(C)N=2)C=CC=1OC>>[CH:24]1([CH2:23][N:13]2[N:12]=[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14]2=[O:21])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: BrCC1CCCCC1
Agent: COc1ccc(C2=NN(C)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(CC3CCCCC3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound 1 and bromomethylcyclohexane as described for compound 8. Purified by chromatography (dichloromethane). Crystallized from petroleum ether (60-95° C.). M.p. 137-139° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[CH2:15]([NH2:21])[C:16]1[O:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CC(O)C>[O:20]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH2:15][NH:21][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: NCc1ccco1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(C(=O)O)c(NCc2ccco2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.8 %

Procedure:
To a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (1.71 g) in 2-propanol (10 ml) were added furfurylamine (714 mg) and diisopropylethylamine (950 mg), and the mixture was stirred at room temperature for 10 min. The reaction mixture was poured into 2% aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, and the precipitate was collected by filtration. The precipitate was dissolved in ethanol (10 ml), 2 M aqueous sodium hydroxide solution (10 ml) was added and the mixture was stirred at room temperature for 5 hr. The reaction mixture was adjusted to pH 3 with 1 M hydrochloric acid, and the precipitated crystals were collected by filtration to give the object compound (1.75 g) as a powder.
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[CH:2]=1.Cl.[OH-:9].[Na+]>>[CH2:2]([C:3]1[C:7](=[O:9])[CH2:6][CH2:5][CH:4]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: [OH-]
Reactant: Cc1cccnc1
Agent: Cl
Agent: [Na+]
Product: CCCCCC1=CCCC1=O
Temperature: 25 °C
Yield: 80.8 %

Procedure:
In accordance with Example 6, the reaction with dropping addition was carried out by using 7.42 g (0.080 mol) of 3-picoline and 5.54 g (0.053 mol) of a 35% hydrochloric acid. After the dropping addition was finished, the resultant mixture was stirred for 5 hours under heating at the same temperature. After the reaction was finished, the mixture was cooled to the room temperature and neutralized with an aqueous solution of sodium hydroxide. Then, the resultant organic layer was analyzed in the same manner as in Example 1. As the result, 65.2 g of 2-pentyl-2-cyclopentenone were obtained (yield: 80.8%).
Reaction SMILES: C(O[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[CH:6]=1)C.[C:13](OC(C)(C)C)(=O)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].S(=O)(=O)(O)O>CCCCCCC.O>[CH3:11][C:7]1[CH:6]=[C:5]([C:4](=[O:12])[CH3:13])[CH:10]=[CH:9][N:8]=1
Reactant: CCOC(=O)c1ccnc(C)c1
Reactant: CC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)(O)O
Agent: [Li+]
Solvent: O
Solvent: CCCCCCC
Product: CC(=O)c1ccnc(C)c1
Reaction time: 2 h

Procedure:
To a solution of 2-methyl-isonicotinic acid ethyl ester (3.20 g) and tert-butyl acetate in n-heptane at −5° C. was slowly added lithium hexamethyldisilazide (46.5 mL; 1 M solution in THF). After stirring for 2 h, a solution of sulfuric acid (4.13 mL) in water (20 mL) was added within 20 min keeping the reaction temperature below 10° C. After the addition was completed, the reaction mixture was heated to reflux overnight. Extraction over a sat. solution of NaHCO3 (100 mL) with ethyl acetate (3×50 mL) and drying of the combined organic phases over Na2SO4 provided after evaporation of the organic solvent the title compound as a light brown liquid (2.40 g, 92%), which was used for the consecutive step without any further purification, MS (ESI+): m/z=136.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[CH3:9].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl.CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][C:8]=1[CH3:9])[C:13](=[O:15])[CH2:12][CH2:11][CH2:10]2
Reactant: COc1cc(CCCC(=O)O)ccc1C
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1cc2c(cc1C)C(=O)CCC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
A solution of 5.6 g (26.9 mmol) of 4-(3-methoxy-4-methylphenyl)butanoic acid in 100 mL of CH2Cl2 was cooled in ice and treated dropwise with 25 mL of trifluoroacetic anhydride. After stirring at 0° C. for 1 hour, the solution was diluted with Et2O and washed twice with 5% NaOH, then with saturated NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure left the crude product. Chromatography on silica gel, eluting with CH2Cl2 gave 2.79 g (54.7% yield) of the product as a white solid, mp 104-107° C. The structure was confirmed by NMR and mass spectroscopy. MS m/z 191 (M+H+).
Reaction SMILES: B(F)(F)F.[CH3:5][CH2:6][O:7][CH2:8][CH3:9].NC1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[N:15]C=1.N(OC(C)(C)C)=[O:20].CCCCC>C(COC)OC>[C:6]([O:7][C:8]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[N:15][CH:9]=1)(=[O:20])[CH3:5]
Reactant: CCOCC
Reactant: COc1ccc(N)cn1
Reactant: CC(C)(C)ON=O
Agent: FB(F)F
Solvent: COCCOC
Solvent: CCCCC
Product: COc1ccc(OC(C)=O)cn1

Procedure:
To 47.6 mL of boron trifluoride etherate (387 mmol, Aldrich) cooled to −10° C. under N2 was added 24 g (193 mmol, Aldrich)) of 5-amino-2-methoxypyridine dissolved in 100 mL of dimethoxyethane. Then tert-butyl nitrite (20.2 mL, 193 mmol, Aldrich) was added at a rate which kept the temperature below 0° C. After 1 hour at −10° C. pentane (400 mL) was then added to the reaction mixture, the pentane solution was decanted, and the residue was washed with cold ether and dissolved in 200 mL of acetic anhydride. The resulting solution was heated to 100° C.±5° C. for 1 hour. The solvent was removed under vacuum, and the residue was suspended in saturated aqueous Na2CO3(200 mL) and extracted with ethyl ether (3×200 mL). The ether solution was dried (MgSO4), the solvent was removed in vacuo, and the residue was chromatographed on silica gel, eluting with 95:5 to 80:20 hexane:ethyl acetate to give 7.3 (20.7%) g of the title compound. MS (CI/NH3) m/e: 168 (M+H)+, 185 (M+NH4)+. 1H NMR (CDCl3 300 MHz) δ.2.30 (s, 3H), 3.92 (s, 3H), 6.75 (d, J=9.0 Hz 1H), 7.35 (dd, J=2.5,9.0 1H), 7.95 (d, J=3.0 Hz 1H). Anal. calcd. for C8H9NO3 C, 57.48; H, 5.43; N, 8.38. Found: C, 57.46; H, 5.40; N, 7.99.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].ClC1C=CC(SC)=CC=1C(O)=O.[CH3:36][N:37]([C:39](ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:38].F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:36][N:37]([CH3:39])[C:38]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:17][CH2:18][CH3:19])[N:16]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Agent: CSc1ccc(Cl)c(C(=O)O)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(N(C)C)n1
Temperature: 150 °C
Yield: 231.9 %

Procedure:
A solution was prepared using 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol), 2-chloro-5-(methylthio)benzoic acid (0.404 g, 2.0 mmol), HATU (1.50 g, 0.040 mmol), triethylamine (1.0 mL, 13.6 mmol) and anhydrous DMF (10 mL). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.035 g (42% yield) of pure product as the undesired product: MS (ES) m/z 377 (M+).