Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[C:12]([CH3:14])([CH3:13])[CH2:11][C:10]([CH3:16])([CH3:15])[CH2:9][C:8]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([CH3:24])[CH:18]=1)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOCC>[C:6]([C:7]1[C:12]([CH3:14])([CH3:13])[CH2:11][C:10]([CH3:16])([CH3:15])[CH2:9][C:8]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([CH3:24])[CH:18]=1)#[CH:5]
Reactant: Cc1cc(C2=C(C#C[Si](C)(C)C)C(C)(C)CC(C)(C)C2)ccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC(=O)O
Product: C#CC1=C(c2ccc(F)c(C)c2)CC(C)(C)CC1(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 98 %

Procedure:
To a solution of the product from Example 1, Step D above (5 g, 14.6 mmol), and acetic acid (1.3 ml, 21.9 mmol) in THF (15 ml) at 0° C. is added tetrabutylammonium fluoride in THF (1M, 21.9 ml, 21.9 mmol). The resulting solution is stirred for 12 hours at room temperature, diluted with ether and washed with saturated ammonium chloride solution. The ether fraction is dried over MgSO4, and the solvent is removed under reduced pressure. Purification by silica gel chromatography (100% hexane) provides 3.9 g (98%) of 1-(ethynyl)-2-(4-fluoro-3-methylphenyl)-4,4,6,6-tetramethyl-1-cyclohexene: 1H NMR δ=1.0 (s,6), 1.22 (s,6), 1.45 (s,2), 2.15 (s,2), 2.25 (s,3), 2.75 (s,1), 6.95 (t,1), 7.15 (m,2).
Reaction SMILES: [C:1]([C:5]1[O:9][C:8](=[NH:10])[N:7]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[CH3:46][O:47][C:48]1[CH:56]=[CH:55][C:54]([C:57]([F:60])([F:59])[F:58])=[CH:53][C:49]=1[C:50](O)=[O:51]>O1CCCC1.C(OCC)(=O)C>[C:1]([C:5]1[O:9]/[C:8](=[N:10]\[C:50](=[O:51])[C:49]2[CH:53]=[C:54]([C:57]([F:59])([F:60])[F:58])[CH:55]=[CH:56][C:48]=2[O:47][CH3:46])/[N:7]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cn(C[C@H]2CCCO2)c(=N)o1
Reactant: COc1ccc(C(F)(F)F)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(C(F)(F)F)cc1C(=O)/N=c1\oc(C(C)(C)C)cn1C[C@H]1CCCO1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of Example 66A (100 mg, 0.45 mmol) in tetrahydrofuran (4 mL) was added N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (85.0 mg, 0.45 mmol), 1-hydroxybenzotriazole (68.3 mg, 0.45 mmol), triethylamine (93 μL, 0.67 mmol) and 2-methoxy-5-trifluoromethylbenzoic acid (Alfa) (98.0 mg, 0.45 mmol). The mixture was stirred at 60° C. overnight, cooled to room temperature, diluted with ethyl acetate, washed with 1 M aqueous NaHCO3, dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% ethyl acetate in hexanes) to provide the title product. MS (ESI+) m/z 428 (M+H)+; 1H NMR (300 MHz, CDCl3) δ ppm 1.15-1.19 (m, 1H), 1.20 (s, 9H), 1.61-1.72 (m, 1H), 1.83-1.96 (m, 2H), 2.02-2.15 (m, 1H), 3.68 (dd, J=14.3, 7.1 Hz, 1H), 3.75-3.87 (m, 2H), 3.89 (s, 3H), 4.02-4.12 (m, 1H), 4.14-4.25 (m, 1H), 6.53 (s, 1H), 6.97 (d, J=8.7 Hz, 1H), 7.58 (dd, J=8.7, 2.4 Hz, 1H), 8.06 (d, J=2.0 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3](O)=[N:4][CH:5]=[N:6][C:7]=1[CH2:8][O:9][CH3:10].P(Cl)(Cl)([Cl:14])=O>C(Cl)Cl>[Cl:14][C:3]1[C:2]([CH3:1])=[C:7]([CH2:8][O:9][CH3:10])[N:6]=[CH:5][N:4]=1
Reactant: COCc1ncnc(O)c1C
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COCc1ncnc(Cl)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
5-Methyl-6-[(methyloxy)methyl]-4-pyrimidinol (Intermediate 48, 2.10 g, 13.62 mmol) was dissolved in DCM (20 ml), treated with phosphorus oxychloride (12.04 ml, 129 mmol) and the resulting mixture was heated under reflux for 3 hours, allowed to cool to room temperature and left to stand overnight. The solvent was removed under reduced pressure, the residue taken up in ice water and the pH was adjusted to 7 using aqueous 2M sodium hydroxide solution. The mixture was extracted with chloroform (×3) and the chloroform layers were separated, combined, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by SP4 Biotage column chromatography eluting with a gradient of 0-50% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a yellow oil (2.14 g);
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=2)=[O:22])=[CH:16][CH:15]=1)#[CH:13].C(N(CC)CC)C>CN(C=O)C.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.[Cu]I>[NH2:11][C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([C:13]#[C:12][C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=4)=[O:22])=[CH:18][CH:19]=3)=[N:7][N:6]2[CH:8]=1
Reactant: C#Cc1ccc(NC(=O)Nc2cccc(C)c2)cc1
Reactant: Nc1cn2nc(I)ccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc(NC(=O)Nc2ccc(C#Cc3ccc4nc(N)cn4n3)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a nitrogen bubbled solution of 6-iodo-imidazo[1,2-b]pyridazin-2-ylamine (260 mg, 1 mmol, 1 eq) and 1-(4-ethynylphenyl)-3-(3-methylphenyl)urea (375 mg, 1.5 eq) in DMF (5 mL) was added triethylamine (0.56 mL, 4 eq), bis(triphenylphosphine)palladium(II) dichloride (70.2 mg, 0.1 eq), and copper(I) iodide (38.1 mg, 0.2 eq). The reaction mixture was stirred at room temperature for 10 minutes and then partitioned between saturated aq NaHCO3 and i-PrOH—CHCl3 (1:4). The aqueous layer was extracted once more with i-PrOH—CHCl3 (1:4). The two organic layers were combined, washed with brine, and dried with anhydrous Na2SO4. The upper clear liquid was decanted, concentrated with silica gel, and the solid mixture was chromatographed (eluted from DCM to MeOH-DCM 1:15). The product fractions were collected and concentrated. The solid residue was triturated with EtOAc-Hex (1:1) and gave 1-{4-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)ethynyl]phenyl}-3-(3-methylphenyl)urea as a brown solid upon filtration in amount of 133 mg.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][C:14](=[O:17])[CH2:15][CH3:16])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([Cl:12])=[CH:7][CH:6]=2.N1C=CC=CC=1.[C:24](Cl)(=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>O1CCCC1>[Cl:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]=[C:3]([NH:13][C:14](=[O:17])[CH2:15][CH3:16])[C:2]([NH:1][C:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[N:11]2
Reactant: CCCCCC(=O)Cl
Reactant: CCC(=O)Nc1nc2ccc(Cl)cc2nc1N
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCC(=O)Nc1nc2cc(Cl)ccc2nc1NC(=O)CC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A suspension of 50 parts of 3-amino-6-chloro-2-propionamidoquinoxaline in 1000 parts of pyridine was cooled to 5° in an ice bath. A solution of 96 parts of hexanoyl chloride in 88 parts of tetrahydrofuran was added as quickly as possible with good cooling to prevent the temperature from rising above 25°. The reaction mixture was stirred for 10 minutes and then poured into 2500 parts of ice water. The yellow gum which separated was removed by filtration and washed with water and then dissolved in 2700 parts of methylene chloride. The methylene chloride solution was washed in succession with 1000 parts each of water, 5% aqueous hydrochloric acid, water, 10% aqueous sodium carbonate, and water. The methylene chloride solution was dried (MgSO4) and evaporated. The residue was recrystallized from 1:4 ethyl acetate-benzene, the solid filtered off, and washed with ether to yield 8 parts of 6-chloro-3-hexanamido-2-propionamidoquinoxaline, m.p. 158°-160°, as a colorless solid.
Reaction SMILES: [NH2:1][CH:2]([CH3:26])[CH2:3][C:4]1[N:8]2[C:9]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:10]=3[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])=[N:12][CH2:13][C:7]2=[N:6][N:5]=1.C=O.[C:29](O)(=O)C.C([BH3-])#N.[Na+]>C(#N)C>[CH3:29][NH:1][CH:2]([CH3:26])[CH2:3][C:4]1[N:8]2[C:9]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:10]=3[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])=[N:12][CH2:13][C:7]2=[N:6][N:5]=1
Reactant: CC(N)Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Product: CNC(C)Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
A solution of 0.001 mole of 1-(2-aminopropyl)-8-chloro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in acetonitrile is successively treated with 0.001 mole each of formaldehyde, acetic acid and sodium cyanoborohydride at room temperature. The mixture is concentrated in vacuo and the residue treated with 25% aqueous ethylene diamine (5 ml.) and methanol (10 ml.) and refluxed under nitrogen for 2 hours. This mixture is concentrated and the residue mixed with water and extracted with chloroform. The chloroform extracts were filtered, evaporated, and crystallized to give 1-[2-(methylamino)propyl]-8-chloro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:34][C:35]1[CH:36]=[N:37][C:38]2[C:43]([C:44]=1[C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[C:47]([O:53][CH3:54])[C:46]=1[O:55][CH3:56])=[CH:42][C:41]([Cl:57])=[CH:40][CH:39]=2>ClCCl>[C:15]([C:12]1[CH:11]=[C:7]([CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:13]=1[OH:14])[C:8]([NH:34][C:35]1[CH:36]=[N:37][C:38]2[C:43]([C:44]=1[C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[C:47]([O:53][CH3:54])[C:46]=1[O:55][CH3:56])=[CH:42][C:41]([Cl:57])=[CH:40][CH:39]=2)=[O:10])([CH3:17])([CH3:16])[CH3:18]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: COc1ccc(-c2c(N)cnc3ccc(Cl)cc23)c(OC)c1OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(-c2c(NC(=O)c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)cnc3ccc(Cl)cc23)c(OC)c1OC
Temperature: 0 °C
Yield: 47.6 %

Procedure:
To a solution of 3,5-di-tert-butyl-4-hydroxybenzoic acid (220 mg) in dichloromethane (20 ml) was dropwise added dicyclohexylcarbodiimide (DCC) (180 mg) under stirring at 0° C. The mixture was stirred at 0° C. for 15 minutes. Then, 3-amino-6-chloro-4-(2,3,4-trimethoxyphenyl) quinoline (250 mg) was added to this mixture. The resultant mixture was stirred at 0° C. for an hour and at room temperature for two days. After the residue was filtered off, the filtrate was diluted with water and extracted with dichloromethane. The dichloromethane layer was washed with an aqueous sodium hydroxide solution, diluted with hydrochloric acid and water in this order and dried (MgSO4). The solvent was removed and the residue was purified by a silica gel column chromatography with hexane-ethyl acetate (3:1, V/V), and then crystallized from isopropyl ether to obtain 3-(3,5-di-tert-butyl-4-hydroxybenzamido)-6-chloro-4-(2,3,-4-trimethoxyphenyl) quinoline (199 mg, 47.6%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2([C:17]([O:19][CH3:20])=[O:18])[CH:10]([C:11](=O)[CH2:12][CH2:13][CH:14]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:31][NH2:32]>CO>[CH2:1]([N:8]1[CH2:16][C:15]2([C:17]([O:19][CH3:20])=[O:18])[CH:10]([C:11](=[N:31][NH2:32])[CH2:12][CH2:13][CH:14]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(=O)CCC2c1ccccc1OC
Reactant: NN
Solvent: CO
Solvent: O
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(=NN)CCC2c1ccccc1OC
Yield: 101.4 %

Procedure:
A solution of 166.6 g (0.424 mol) of methyl (3aRS,4SR,7aRS)-2-benzyl-4-(2-methoxyphenyl)-7-oxo-octahydroisoindole-3a-carboxylate and of 84.5 g (1.69 mol) of hydrazine hydrate in 2.8 dm3 of methanol is brought to reflux for two hours. After concentrating the methanol under reduced pressure, the residue was taken up in 2 dm3 of dichloromethane, washed with four times 1 dm3 of distilled water, dried over magnesium sulphate and concentrated under reduced pressure. 175.2 g of methyl (3aRS,4SR,7aRS)-2-benzyl-7-hydrazono-4-(2-methoxyphenyl)octahydroisoindole-3a-carboxylate were thus obtained in the form of a yellow oil, the characteristics of which were as follows:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH:20](OCC)=[O:21].[H-].[Na+]>COCCOC>[CH:20]([CH:14]([CH2:13][C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:21]
Reactant: CCOC(=O)CCc1cc(OC)c(OC)c(OC)c1
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C=O)Cc1cc(OC)c(OC)c(OC)c1
Yield: 44 %

Procedure:
Ethyl 3-(3,4,5-trimethoxyphenyl)propionate was reacted with ethyl formate and sodium hydride in 1,2-dimethoxyethane to give crude ethyl 2-formyl-3-(3,4,5-trimethoxyphenyl)-propionate in 44% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][NH:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].Cl.Cl[CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1.C(N(CC)C(C)C)(C)C>C(O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][NH:20][CH:21]3[CH2:26][CH2:25][N:24]([CH2:29][C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)[CH2:23][CH2:22]3)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: ClCc1cccnc1
Reactant: CCOC(=O)c1oc2cccc(OCCCNC3CCNCC3)c2c1C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1oc2cccc(OCCCNC3CCN(Cc4cccnc4)CC3)c2c1C
Temperature: 70 °C
Reaction time: 8 h
Yield: 42.6 %

Procedure:
A mixture of 3-methyl-4-[3-(piperidin-4-ylamino)-propoxy]-benzofuran-2-carboxylic acid ethyl ester (15 mg), 3-(chloromethyl)pyridine hydrochloride (8 mg) and N,N-diisopropylethylamine (22 μl) in ethanol (1.5 ml) was stirred overnight at 70° C. The reaction mixture was dissolved in ethyl acetate and washed with saturated ammonium chloride solution and water. The organic solvent was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica gel column chromatography (dichloromethane-MeOH) to afford 3-methyl-4-[3-(1-pyridin-3-ylmethyl-piperidin-4-ylamino)-propoxy]-benzofuran-2-carboxylic acid ethyl ester (8 mg) as a colorless oil. FAB-MS: m/z 452 (MH+); 1H-NMR (CDCl3): δ 1.43 (3H, t, J=7 Hz), 1.60 (2H, m), 2.00 (4H, m), 2.20 (2H, quintet, J=6.5 Hz), 2.70 (1H, m), 2.72 (3H, s), 2.86 (2H, br d, J=12 Hz), 2.99 (2H, t, J=7 Hz), 3.49 (2H, s), 4.15 (2H, t, J=6 Hz), 4.43 (2H, q, J=7 Hz), 6.59 (1H, d, J=8 Hz), 7.11 (1H, d, J328 Hz), 7.22 (1H, m), 7.29 (1H, t, J=8 Hz), 7.66 (1H, brd, J=8 Hz), 8.48 (1H, m), 8.51 (1H, br s).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[CH3:36][C:37]([OH:41])([CH:39]=[CH2:40])[CH3:38]>>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH2:40][CH2:39][C:37]([OH:41])([CH3:38])[CH3:36])[N:7]=2)=[C:9]([C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: C=CC(C)(C)O
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Product: CC(C)(O)CCc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 247 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.15 g, 0.278 mmol) and 2-methyl-3-buten-2-ol (0.087 ml, 0.835 mmol), the title compound was obtained as a solid (164 mg, 57% yield); 1H NMR (400 MHz, DMSO-d6) ppm 10.75 (s, 1H), 8.48 (d, J=5.31 Hz, 1H), 7.55 (m, 1H), 7.46 (m, 4H), 7.30 (t, J=8.33 Hz, 1H), 6.64 (d, J=5.31 Hz, 1H), 4.29 (s, 1H), 2.87 (m, 2H), 1.76 (m, 2H), 1.42 (s, 9H), 1.12 (s, 6H); MS (ESI): 592 [M+H]+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=O.O.O[N:15]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:36][C:37]1([C:43]2[CH:44]=[C:45]([NH:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH:46]=[CH:47][CH:48]=2)[CH:42]2[CH:38]1[CH2:39][NH:40][CH2:41]2.C(N(CC)CC)C>>[NH3:15].[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[C:10]([N:40]1[CH2:41][CH:42]2[CH:38]([C:37]2([C:43]2[CH:44]=[C:45]([NH:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH:46]=[CH:47][CH:48]=2)[CH3:36])[CH2:39]1)=[O:12]
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Reactant: On1nnc2ccccc21
Reactant: O=C(O)C1Cc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(C(=O)C3Cc4ccccc4C3)CC21
Product: N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 46 %

Procedure:
To a solution of 2-indane carboxylic acid (E. D. Bergmann and E. Hoffrnann, J. Org. Chem., 1961, 26, 3555, 100 mg, 0.62 mmol) in N,N-imethylformamide (13 ml) was added 1-hydroxybenzotriazole monohydrate (100 mg, 0.66 mmol) and 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (170 mg, 0.88 mmol). After stirring at room temperature for 5 min the mixture was treated with the hydrochloride salt of N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (Preparation 53, 200 mg, 0.66 mmol) and triethylamine (133 mg, 1.32 mmol). The reaction mixture was stirred at room temperature for 72 h before concentrating in vacuo. Water (10 ml) was added and the reaction mixture was extracted with ethyl acetate (2×15 ml). The combined organic extracts were washed with water (10 ml) and saturated brine (10 ml), dried (Na2SO4), filtered and concentrated in vacuo to give a light brown oil. The residue was purified by chromatography using a Sep-Pak™ cartridge packed with silica gel (10 g) eluting with dichloromethane:ethanol:0.88 ammonia (300:8:1) to afford the title compound as a white foam (117 mg, 43%).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][CH:10]=[CH:11][C:6]=2[N:5]2[N:12]=[C:13]([CH3:15])[CH:14]=[C:4]2[N:3]=1.[Na].[CH2:17]([OH:19])[CH3:18]>O>[CH2:17]([O:19][C:2]1[C:7]2[CH:8]=[N:9][CH:10]=[CH:11][C:6]=2[N:5]2[N:12]=[C:13]([CH3:15])[CH:14]=[C:4]2[N:3]=1)[CH3:18]
Reactant: Cc1cc2nc(Cl)c3cnccc3n2n1
Reactant: CCO
Agent: [Na]
Solvent: O
Product: CCOc1nc2cc(C)nn2c2ccncc12
Reaction time: 12 h

Procedure:
2.2 g. of 5-chloro-2-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidine are added to a solution of 0.5 g. of sodium in 30 ml. of ethanol. The solution is refluxed with stirring for 12 hours. 10 ml. of water are added and the crystalline 5-ethoxy-2-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidine is filtered off, yield: 1.4 g. (61%); m.p. 156.2° (methanol).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH2:1]([O:9][C:21]([C:20]1[CH:19]=[CH:18][C:17]([C:14]2[CH:15]=[CH:16][C:11]([OH:10])=[CH:12][CH:13]=2)=[CH:25][CH:24]=1)=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCOC(=O)c1ccc(-c2ccc(O)cc2)cc1
Yield: 87.5 %

Procedure:
Fifteen grams of n-octanol, 7.5 g of 4-(4'-hydroxyphenyl)benzoic acid and 7.0 g of p-toluenesulfonic acid were dissolved with 100 ml of toluene in a three necked flask with a dehydration apparatus, and the mixture was refluxed for 15 hours. Water was added to the mixture to separate a toluene layer. Ten grams of 4-(4'-octyloxycarbonylphenyl)phenol (A) were obtained by removing the toluene layer under reduced pressure followed concentration. (s)-4-(1-chloro-2-methylpropylcarbonyloxy) benzoic acid dispersed in 20 ml of carbon tetrachloride was reacted with 5 ml of thionyl chloride by refluxing for 3 hours. After removing the solvent (s)-4-(1-chloro-2-methylpropylcarbonyloxy)benzoic chloride (AC) was obtained. 1.5 g of (AC) was dissolved with mixed solvent of 80 ml of carbon tetrachloride and 10 ml of pyridine, and then 1.7 g of (AB) was added to the mixed solution with cooling and the mixture was allowed to stand overnight to obtain crystals.
Reaction SMILES: Br[C:2]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[Cl:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26][NH:25]2.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26][N:25]2[C:2]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12]
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Reactant: O=C1CNc2cc(Cl)ccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CN(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)c2cc(Cl)ccc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
The mixture of rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (200 mg, 0.55 mmol) (from example 1c supra), 6-Chloro-3,4-dihydro-1H-quinoxalin-2-one (100 mg, 0.55 mmol) and K2CO3 (150 mg, 1.09 mmol) in acetonitrile (3 mL) was stirred at room temperature for 2 hour. The mixture was concentrated in vacuo and purified by flash column chromatography to give 110 mg 6-Chloro-4-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-3,4-dihydro-1H-quinoxalin-2-one. MS: [M+H]+=472.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[CH3:10][O:11][C:12]1[CH:30]=[CH:29][C:15]([CH2:16][O:17][C:18](SC2N=C(C)C=C(C)N=2)=[O:19])=[CH:14][CH:13]=1>>[CH3:10][O:11][C:12]1[CH:30]=[CH:29][C:15]([CH2:16][O:17][C:18]([N:5]2[CH2:6][C@H:2]([OH:1])[CH2:3][C@H:4]2[C:7]([OH:9])=[O:8])=[O:19])=[CH:14][CH:13]=1
Reactant: COc1ccc(COC(=O)Sc2nc(C)cc(C)n2)cc1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Product: COc1ccc(COC(=O)N2C[C@H](O)C[C@H]2C(=O)O)cc1

Procedure:
In the same manner as described in Reference Example 1-1 but using 10 g of trans-4-hydroxy-L-proline and 23.2 g of S-p-methoxybenzyloxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine, trans-1-(p-methoxybenzyloxycarbonyl)-4-hydroxy-L-proline was obtained.
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[CH:27]([NH:29][CH2:30][C:31]1[S:35][C:34]2=[CH:36][N:37]=[CH:38][N:33]2[C:32]=1[CH3:39])=[O:28]>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:37]3[CH:36]=[C:34]4[S:35][C:31]([CH2:30][NH:29][CH:27]=[O:28])=[C:32]([CH3:39])[N+:33]4=[CH:38]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: Cc1c(CNC=O)sc2cncn12
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Product: Cc1c(CNC=O)sc2cn(CC3=C(C(=O)[O-])N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)c[n+]12
Yield: 3.8 %

Procedure:
The same procedure as in Example 1 was repeated except that 91.3 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 100 mg of 2-(formylamino)methyl-3-methylimidazo[5,1-b]thiazole were used, thereby obtaining 4 mg of the title compound.