Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[C:6]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])#[CH:7].[CH2:20]([Sn:24](Cl)([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23]>C1COCC1>[CH2:29]([Sn:24]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:25][CH2:26][CH2:27][CH3:28])[C:7]#[C:6][CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:30][CH2:31][CH3:32]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: C#CC1CCCN1C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](C#CC1CCCN1C(=O)OC(C)(C)C)(CCCC)CCCC
Temperature: -30 °C
Yield: 61.2 %

Procedure:
n-Butyllithium (1.6M in hexanes, 12.3 mL) was added over 2 minutes to a stirred solution of tert-butyl 2-ethynylpyrrolidine-1-carboxylate (3.65 g) in anhydrous THF (80 mL) at −78° C. under nitrogen and then the mixture was allowed to warm to −30° C. over one hour. Tributyltin chloride (6.41 g) was then added dropwise at −30° C. and the mixture was allowed to warm to −10° C. and quenched by addition of saturated sodium bicarbonate solution. The layers were separated and the organic layer was dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-5% to give tert-butyl 2-tributylstannanylethynylpyrrolidine-1-carboxylate (5.54 g) as a colourless oil.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>CO.[Pd]>[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[C:20]1[CH:21]=[CH:22][C:23]([C:24]2[NH:13][C:12]3[CH:11]=[CH:10][CH:9]=[C:5]([C:6]([NH2:8])=[O:7])[C:4]=3[N:3]=2)=[CH:26][CH:27]=1
Reactant: NC(=O)c1cccc(N)c1N
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NC(=O)c1cccc2[nH]c(-c3ccc(C4CCCCN4)cc3)nc12
Reaction time: 18 h

Procedure:
A mixture of 2,3-diaminobenzamide dihydrochloride (1 g), 4-pyridin-2-ylbenzaldehyde (0.82 g) and 10% Pd/C (0.3 g) in methanol (30 mL) at reflux was stirred for 18 hours, cooled, filtered through diatomaceous earth (Celite®) and concentrated. The concentrate was crystallized from methanol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[NH2:32][CH2:33][CH2:34][CH2:35][S:36][C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([NH:32][CH2:33][CH2:34][CH2:35][S:36][C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1)=[O:9]
Reactant: O=C(O)c1cnccn1
Reactant: NCCCSc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: O=C(NCCCSc1ccncc1)c1cnccn1
Yield: 34 %

Procedure:
To a solution of 1.00 g (8.06 mmol) of 2-pyrazinecarboxylic acid and 1.21 g (10.5 mmol) of N-hydroxysuccinimide in 70 ml of methylene chloride, 1.85 g (9.67 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) was added with stirring under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Further, 1.94 g (8.06 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate and water, and dried. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethyl acetate) to give 0.751 g of the desired compound (34.0% yield, colorless powder).
Reaction SMILES: [CH3:1][S:2]([C:4]1[S:8][C:7]([N:9]=[C:10]=[O:11])=[N:6][N:5]=1)=[O:3].[CH2:12]([NH:16][CH:17]([CH2:20][O:21][CH3:22])[CH:18]=[O:19])[CH2:13][CH2:14][CH3:15]>C1C=CC=CC=1>[CH2:12]([N:16]([CH:17]([CH2:20][O:21][CH3:22])[CH:18]=[O:19])[C:10]([NH:9][C:7]1[S:8][C:4]([S:2]([CH3:1])=[O:3])=[N:5][N:6]=1)=[O:11])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCNC(C=O)COC
Reactant: CS(=O)c1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: CCCCN(C(=O)Nc1nnc(S(C)=O)s1)C(C=O)COC

Procedure:
5-Methylsulfinyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-butylamino-3-methoxypropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 30 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. This residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-butyl-3-(5-methylsulfinyl-1,3,4-thiadiazol-2-yl)ureido]-3-methoxypropionaldehyde.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)[C:3]=1[C:16]#[N:17].C(O[CH:26](OCC1C=CC=CC=1)[N:27]([CH3:29])[CH3:28])C1C=CC=CC=1>C1(C)C=CC=CC=1>[N+:13]([C:9]1[CH:8]=[C:7]([C:4]2[C:3]([C:16]#[N:17])=[C:2]([N:1]=[CH:26][N:27]([CH3:29])[CH3:28])[NH:6][N:5]=2)[CH:12]=[CH:11][CH:10]=1)([O-:15])=[O:14]
Reactant: N#Cc1c(-c2cccc([N+](=O)[O-])c2)n[nH]c1N
Reactant: CN(C)C(OCc1ccccc1)OCc1ccccc1
Solvent: Cc1ccccc1
Product: CN(C)C=Nc1[nH]nc(-c2cccc([N+](=O)[O-])c2)c1C#N

Procedure:
In 8 ml of toluene, 229 mg (1.00 mmol) of 5-amino-3-(3-nitro-phenyl)-1H-pyrazole-4-carbonitrile and 317 μl of N,N-dimethylformamide dibenzylacetal are boiled overnight. Cooling, filtering the suspension and washing with hexane yield N'-[3-(3-nitrophenyl)-4-cyano-1H-pyrazol-5-yl]-N,N-dimethylformamidine; m.p. 221-225° C.; TRet (Grad22-100)=8.7.
Reaction SMILES: [CH3:1][N:2]([CH:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1)[C:3]([C:5]1[S:6][C:7]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[C:21](=NOC)[CH2:20][CH2:19]3)=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:9]=1)=[O:4].[O:35]1CCOCC1.CC(C)=O>Cl>[CH3:1][N:2]([CH:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1)[C:3]([C:5]1[S:6][C:7]([C:16]2[CH:17]=[C:21]3[C:22](=[CH:23][CH:24]=2)[C:18](=[O:35])[CH2:19][CH2:20]3)=[C:8]([C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)[CH:9]=1)=[O:4]
Reactant: C1COCCO1
Reactant: CON=C1CCc2cc(-c3sc(C(=O)N(C)C4CCN(C)CC4)cc3-c3ccncc3)ccc21
Agent: Cl
Solvent: CC(C)=O
Product: CN1CCC(N(C)C(=O)c2cc(-c3ccncc3)c(-c3ccc4c(c3)CCC4=O)s2)CC1
Yield: 67 %

Procedure:
The product of step 3 (476 mg 1 mmol) was dissolved in 5N hydrochloric acid (10 ml), dioxane (10 ml) and acetone (5 ml) and heated at 80° C. for 2 hours. The resulting solution was concentrated in vacuo and co-evaporated with ethanol (×3) to afford a crude solid. This was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The aqueous phase was re-extracted with ethyl acetate (×2), and the combined organic extracts were washed with water (×3), brine, dried and evaporated in vacuo to a crude solid. This was purified by column chromatography (1:9:40 0.880 ammonia:thanol:dichloromethane) to afford title product (300 mg, 67%); MS (AP+) m/e 446 [M+H]+
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:32])[C:13]([N:14]3[CH2:19][C@H:18]([C:20]([F:23])([F:22])[F:21])[CH2:17][C@H:16]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[C:33]([O:37][C:38]([NH:40][C:41]1[S:45][C:44]([C:46]2[C:51]([F:52])=[CH:50][CH:49]=[CH:48][C:47]=2[F:53])=[N:43][C:42]=1[C:54](O)=[O:55])=[O:39])([CH3:36])([CH3:35])[CH3:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:32][C:54]([C:42]3[N:43]=[C:44]([C:46]4[C:51]([F:52])=[CH:50][CH:49]=[CH:48][C:47]=4[F:53])[S:45][C:41]=3[NH:40][C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])=[O:55])[C:13]([N:14]3[CH2:19][C@H:18]([C:20]([F:22])([F:21])[F:23])[CH2:17][C@H:16]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@@H](NC(=O)OC(C)(C)C)C[C@@H](C(F)(F)F)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1nc(-c3c(F)cccc3F)sc1NC(=O)OC(C)(C)C)c2N1C[C@@H](NC(=O)OC(C)(C)C)C[C@@H](C(F)(F)F)C1
Temperature: 45 °C
Reaction time: 14 h

Procedure:
To a mixture of 3-amino-4-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (86.6 mg, 0.189 mmol), 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (89.5 mg, 0.251 mmol), and HATU (221.8 mg, 0.5833 mmol) was added DMF (2.0 mL) followed by DIPEA (164.3 mg, 1.271 mmol). The reaction mixture was stirred at 45° C. for 14 h, and then concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a dark semi-oil (110.3 mg, 73%). LCMS calc. for C36H42F5N6O7S (M+H)+: m/z=797.3. found 797.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[Br:9]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][Br:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(Br)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc(Br)c1
Reaction time: 15 h
Yield: 67.8 %

Procedure:
m-bromotoluene (25.33 g; 148.1 mmol), N-bromosuccinimide (26.36 g; 148.1 mmol), and benzoyl peroxide (0.3 g) were added to carbon tetrachloride (200 ml), and the mixture was heated under reflux for 3 hours. The white crystals that precipitated were filtered off, and the filtrate was concentrated under reduced pressure. The residue was taken up in n-hexane (200 ml), and the mixture was left to stand for 15 hours at room temperature. The white crystals that precipitated were filtered off, and the filtrate was concentrated, to thereby yield a yellow oily compound (25.1 g). The compound was analyzed by 1H-NMR and found to be a mixture of the target compound, the starting compound, and a dibromo compound (4.34:1.03:1.00). The yield based on the result of 1H-NMR analysis was 67.9%.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[CH2:10]([O:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[CH3:11].C1C=CC=CC=1>O>[CH3:2][C:1](=[N:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([O:12][CH2:10][CH3:11])=[O:21])=[CH:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)c1ccc(N=C(C)c2ccccc2)cc1

Procedure:
A solution of acetophenone (44 ml), ethyl-p-aminobenzoate (60 g), benzene (100 ml) was refluxed in the presence of molecular sieve (100 g) with continuous removal of water. The crude product was purified by crystallizing it from ethanol to give N-(α-methyl benzylidene)-p-carbethoxy aniline (XI). XI had a m.p. of 87° C.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:24]([O:25]C(=O)C)=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7](=[O:20])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1.[NH2:31][CH2:32][C:33]([OH:35])=[O:34].C(=O)([O-])[O-].[K+].[K+]>CC#N.O>[OH:25][C:24]1[C:4]2[O:3][C:2]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[C:6]([C:7](=[O:20])[C:8]3[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=3)[C:5]=2[CH:21]=[CH:22][C:23]=1[O:29][CH3:30]
Reactant: COc1cc(C(=O)c2c(Br)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Reactant: NCC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cc(C(=O)c2c(NCC(=O)O)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Reaction time: 0.33 h
Yield: 53.3 %

Procedure:
A mixture of 2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzofuran (50 mg, 0.10 mmol), glycine (18 mg, 0.29 mmol) and potassium carbonate (29 mg, 0.21 mmol) in a mixture of MeCN/water 80:20 (5 mL) was refluxed for six hours. Solvent was distilled and the residue was taken in water:dichloromethane 1:2 (30 mL) and stirred for 20 minutes. Aqueous layer was separated, washed with dichloromethane (20 mL) and acidified with 2 drops of concentrated HCl and was diluted with dichloromethane (50 mL) and was stirred for 30 minutes. The organic layer was separated and dried over magnesium sulfate and solvent was distilled to afford the title compound as yellow powder (23 mg, 51%); 1H NMR (300 MHz, Acetone d6) δ 9.09(b, 1H, NH), 6.97(s, 2H, benzoyl Hs), 6.74(d, 1H, J=8.53 Hz), 6.45(d, 1H, J=8.48 Hz), 4.48(d, 2H, J=4.28 Hz), 3.82(s, 6H, 2×OMe), 3.79(s, 3H, OMe), 3.78(s, 3H, OMe).
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[Br:16]N1C(=O)CCC1=O.O>CN(C=O)C>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([Br:16])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCn1c2ccccc2c2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c2ccccc2c2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 12 h
Yield: 80.9 %

Procedure:
5.00 g of N-ethylcarbazole was dissolved in 130 ml of dehydrated DMF in a flask whose atmosphere was replaced with argon. This solution was cooled to 0° C., 4.60 g of N-bromosuccinimide was charged as 5 divided fractions for 3 hours. After raising the temperature to room temperature and stirring for 12 hours, the reaction liquid was thrown into iced water and filtrated. The residue was washed with water and methanol, and dried under reduced-pressure to give 6.28 g crude product. It was purified with silica gel column chromatography (eluent: cyclohexane containing 0.1% triethylamine), and 5.68 g of N-ethyl-3-bromo carbazole was obtained.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:11][N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C@@H:5]2[CH2:4]1.Cl[C:13]1[N:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:1][CH2:2][C@@H:3]1[CH2:11][N:6]2[CH2:7][CH2:8][N:9]([C:13]3[N:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=3)[CH2:10][C@@H:5]2[CH2:4]1
Reactant: OC[C@H]1C[C@H]2CNCCN2C1
Reactant: Fc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: OC[C@H]1C[C@H]2CN(c3ncc(F)cn3)CCN2C1
Yield: 43.5 %

Procedure:
A mixture of 1.38 g (8.84 mmol) of (7S,8aS)-7-hydroxymethyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine, 1.30 g (9.87 mmol) of 2-chloro-5-fluoropyrimidine (Dunaiskis, A. et al., Org. Prep. Proc. Int., 1995, 27, 600-602), and 2.85 g (26.9 mmol) of sodium carbonate and 90 mL of water was heated at 95° C. for 16 hours. The solution was cooled and extracted with chloroform (2×), the combined organic phase was dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 9:1 chloroform:methanol gave 0.97 g (43%) of the title compound. Mp 123-124° C. m/z (MH+) 253. 13C NMR (CDCl3): δ 30.9, 37.1, 43.8, 48.8, 51.3, 57.5, 62.6, 67.2, 144.9, 145.2, 149.9, 153.2, 158.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:30][CH3:31])[CH:26]=3)[CH2:21]2)=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:39][CH2:40][N:41]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1.O>CN(C)C=O>[N:41]1([CH2:40][CH2:39][O:19][C:16]2[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][NH:10][CH2:9][C:7]3[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[CH:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[C:25]([O:30][CH3:31])[CH:26]=4)[CH2:21]3)=[CH:14][CH:15]=2)[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: ClCCN1CCCCCC1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1CNCCc1ccc(O)cc1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1CNCCc1ccc(OCCN3CCCCCC3)cc1)C2
Temperature: 60 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
To a solution of 4-{2-{[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]methylamino}ethyl}phenol (160 mg) in N,N-dimethylformamide (3 ml) were sequentially added potassium carbonate (100 mg) and 1-(2-chloroethyl)azepane (110 mg), and the solution was stirred for 2 hours at 60° C. Water was added thereto followed by stirring, the solution was extracted with ethyl acetate, then sequentially washed with water and brine, and the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (157 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[N:3]([C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:4]=[N:5][C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1nc[nH]c1-c1ccccc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 79.6 %

Procedure:
To a solution of 4-methyl-5-phenylimidazole (250 mg, 1.58 mmol) in 5 mL DMF at rt, were added TEA (242 μL, 1.74 mmol) and TrCl (485 mg, 1.74 mmol). The mixture was stirred at rt for 20 h, then was diluted with EtOAc, washed with H2O (2×) and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 50% EtOAc/hexanes gradient) to afford 504 mg of Intermediate 20.1 as a white solid.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=2)[NH:13][CH:12]=1)=[O:10])=[O:5])C.[OH-].[Na+]>C(O)C>[F:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[C:9]([C@@H:7]1[CH2:8][C@H:6]1[C:4]([OH:5])=[O:3])=[O:10]
Reactant: CCOC(=O)[C@@H]1C[C@H]1C(=O)c1c[nH]c2ccc(F)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1C[C@H]1C(=O)c1c[nH]c2ccc(F)cc12
Yield: 60.7 %

Procedure:
The crude trans-2-(5-fluoro-3-indolylcarbonyl)cyclopropanecarboxylic acid ethyl ester (0.55 g, 2 mmol) was suspended in ethanol and sodium hydroxide solution (4 ml, 1N, 4 mmol) was added. The resultant solution was stirred for 4 hr at 20° and 0.5 hr at reflux. The ethanol was removed in vacuo and the residue mixed with water. The mixture was extracted with ethyl acetate. The aqueous layer was separated and made acidic with 12 N HCl. The precipitate was collected and air dried to give trans-2-(5-fluoro-3-indolylcarbonyl)cyclopropanecarboxylic acid as an off-white solid (0.30 g), mp 276-277 dec. LC/MS mw=247; retention time 1.19 min. Mol wt calc1d for C13H10FNO2: 247.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]1=[O:30])(=[O:14])=[O:13])[CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[CH2:37]([O:44][C:45](=[O:48])[CH2:46]Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH2:46][C:45]([O:44][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:48])[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:17]1=[O:30])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(CBr)OCc1ccccc1
Reactant: C[C@@H](C(=O)OC(C)(C)C)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H](C(=O)OC(C)(C)C)N1CC[C@H](N(CC(=O)OCc2ccccc2)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 115.5 %

Procedure:
To a solution of tert-butyl (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate (1 g) in DMF (20 ml) was added potassium carbonate (0.92 g) and benzyl-2-bromoacetate (0.33 g), and the mixture was stirred under nitrogen at room temperature for 72 h. The reaction mixture was filtered, concentrated under reduced pressure, and the residue partitioned between water and DCM. The organic layer was isolated, dried (over magnesium sulphate and purified by SPE (silica, cyclohexane:ethyl acetate 2:1) to give the title compound (1.0 g) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[C:19]1([C:25]#[CH:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:26]#[C:25][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: C#Cc1ccccc1
Product: CN1C(=O)CC[C@]2(C)c3ccc(C#Cc4ccccc4)cc3CC[C@@H]12

Procedure:
A 1 g portion of (4aR)-(10bR)-4,10b-dimethyl-8-bromo-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one was reacted with 0.4 mL of phenylacetylene in a process substantially similar to that of Example 281 to obtain the desired title product in pure form. mp 205°-208°. FDMS 329.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[C:30]([C:33]1[CH:34]=[C:35](O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])[CH3:31]>>[C:30]([C:33]1[CH:38]=[C:37]([CH:36]=[CH:35][CH:34]=1)[O:29][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1)(=[O:32])[CH3:31]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(F)cc3)CC2)c1
Reactant: CC(=O)c1cccc(O)c1
Product: CC(=O)c1cccc(OC(CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(F)cc2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3-acetylphenol: ESMS m/e: 516.9 (M+H)+.
Reaction SMILES: FC1C=CC(C2C=NC(N3CCN(S(C[C@H](C(C)C)[C:25]([OH:27])=[O:26])(=O)=O)CC3)=NC=2)=CC=1.C([C@@H]1COC(=O)N1C(=O)[C@H:45]([CH2:49][S:50]([N:53]1[CH2:58][CH2:57][N:56]([C:59]2[CH:64]=[CH:63][C:62]([C:65]3[CH:70]=[CH:69][C:68]([Cl:71])=[CH:67][CH:66]=3)=[CH:61][N:60]=2)[CH2:55][CH2:54]1)(=[O:52])=[O:51])[CH:46]([CH3:48])[CH3:47])C1C=CC=CC=1>>[Cl:71][C:68]1[CH:69]=[CH:70][C:65]([C:62]2[CH:63]=[CH:64][C:59]([N:56]3[CH2:55][CH2:54][N:53]([S:50]([CH2:49][C@H:45]([CH:46]([CH3:47])[CH3:48])[C:25]([OH:27])=[O:26])(=[O:51])=[O:52])[CH2:58][CH2:57]3)=[N:60][CH:61]=2)=[CH:66][CH:67]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)O
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ccc(-c3ccc(Cl)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ccc(-c3ccc(Cl)cc3)cn2)CC1)C(=O)O
Yield: 33 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluoro-phenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-3-methylbutyric acid, from 4-(R)-benzyl-3-(2-(R)-{4-[5-(4-chlorophenyl)pyridin-2-yl]piperazine-1-sulfonyl methyl}-3-methylbutyryl)-oxazolidin-2-one (0.312 g), to give the title compound as a white solid (0.077 g, 33%)