Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:18]3[C:14]([S:15][CH2:16][CH2:17]3)=[N:13][C:12]=2[C:19]2[CH:24]=[CH:23][C:22]([NH:25]C(=O)C)=[CH:21][CH:20]=2)=[CH:7][CH:6]=1)(=O)C.Cl.[OH-].[Na+]>>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:18]3[C:14]([S:15][CH2:16][CH2:17]3)=[N:13][C:12]=2[C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1ccc(-c2nc3n(c2-c2ccc(NC(C)=O)cc2)CCS3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(-c2nc3n(c2-c2ccc(N)cc2)CCS3)cc1
Reaction time: 1.75 h

Procedure:
A suspension of 25 g. (0.064 mole) of 5,6-bis-(p-acetamidophenyl)-2,3-dihydroimidazo[2,1-b]thiazole, prepared as in Example 22, in 250 ml. of 6 N hydrochloric acid was refluxed with stirring under nitrogen for 1.75 hours. This solution was chilled, made alkaline with 10% aqueous sodium hydroxide and filtered. The precipitate was washed with a small amount of acetonitrile and recrystallized from acetonitrile with charcoal to give 5,6-bis(p-aminophenyl)-2,3-dihydroimidazo[2,1-b]thiazole, m.p. 205°-206.5° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([OH:8])=[CH:6][CH:5]=[N:4]1)C.OC1N(C)N=CC=1.CS(C1C=CC(C(O)=O)=C(C)C=1C(OC)=O)(=O)=O.[CH:34]([O:37][C:38]([C:40]1[C:41]([CH3:53])=[C:42]([CH:46]=[CH:47][C:48]=1[S:49]([CH3:52])(=[O:51])=[O:50])[C:43](O)=[O:44])=[O:39])([CH3:36])[CH3:35]>>[OH:8][C:7]1[N:3]([CH3:1])[N:4]=[C:5]([C:43](=[O:44])[C:42]2[CH:46]=[CH:47][C:48]([S:49]([CH3:52])(=[O:51])=[O:50])=[C:40]([C:38]([O:37][CH:34]([CH3:35])[CH3:36])=[O:39])[C:41]=2[CH3:53])[CH:6]=1
Reactant: CCn1nccc1O
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1C(=O)OC(C)C
Agent: COC(=O)c1c(S(C)(=O)=O)ccc(C(=O)O)c1C
Agent: Cn1nccc1O
Product: Cc1c(C(=O)c2cc(O)n(C)n2)ccc(S(C)(=O)=O)c1C(=O)OC(C)C
Yield: 45 %

Procedure:
The operation and treatment were conducted in the same manner as in Example 1 except that 1.12 g of 1-ethyl-5-hydroxypyrazole was changed to 0.98 g of 5-hydroxy-1-methylpyrazole, and 2.72 g of 4-methanesulfonyl-3-methoxycarbonyl-2-methylbenzoic acid was changed to 3.00 g of 3-isopropoxycarbonyl-4-methanesulfonyl-2-methylbenzoic acid, to obtain 1.71 g of the desired product. (Yield: 45%, melting point: 192°-194° C.)
Reaction SMILES: Cl.[CH3:2][CH:3]([CH3:40])[CH2:4][C@@H:5]([NH:32]C(=O)OC(C)(C)C)[C:6](=[O:31])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[C:12]([N:18]3[CH2:22][CH2:21][CH2:20][C:19]3=[O:23])[CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:24][C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)[C:9]1=[O:30].[OH-].[Na+]>O1CCCC1>[NH2:32][C@H:5]([CH2:4][CH:3]([CH3:40])[CH3:2])[C:6]([NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[C:12]([N:18]3[CH2:22][CH2:21][CH2:20][C:19]3=[O:23])[CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:24][C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)[C:9]1=[O:30])=[O:31]
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)C[C@@H](N)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Temperature: 48 °C
Reaction time: 0.5 h

Procedure:
Concentrated hydrochloric acid (89.6 mL) was added to the tetrahydrofuran solution of tert-butyl (2R)-4-methyl-1-oxo-1-[2-oxo-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-ylamino]pentan-2-ylcarbamate, and the mixture was stirred at an internal temperature of 48±2° C. for 30 minutes. The resultant mixture was neutralized with 25% aqueous sodium hydroxide solution (172 g) under cooling on an ice bath, and the organic layer was separated, whereby a solution of the title compound in tetrahydrofuran was yielded.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[O:3].[CH2:7](O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:5])[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)C(=O)O
Reactant: CCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCOC(=O)C(C)=O
Temperature: 25 °C
Yield: 76.1 %

Procedure:
A toluene (1 L) solution of pyruvic acid (440 g, 5.0 mol), n-octanol (651 g, 5.0 mol) and p-toluenesulfonic acid monohydrate (2.5 g) was heated and refluxed for 16 hours while removing water under a nitrogen gas stream, thereby obtaining a first reaction solution. Next, the first reaction solution was cooled to room temperature (25° C.). Thereafter, toluene was removed under reduced pressure (40 mmHg) using an evaporator, and the residue was purified by reduced pressure distillation (2 mmHg, 82 to 92° C.), thereby obtaining octyl pyruvate (762 g, yield 76%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Cl:20]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:20][C:5]1[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CC(C)(C)C(=O)Nc1cccc(Cl)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1nc(Cl)ccc1Cl
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of N-(6-chloropyridin-2-yl)pivalamide (2.00 g, 9.40 mmol) in 25 mL THF at −78° C. was added butyllithium 2.5 M in hexanes (9.40 mL, 23.5 mmol) slowly dropwise over 2 min After 5 min, the reaction mixture was warmed to 0° C., then back to −10° C. (ice/brine) and to −20° C. (ice/salt). The reaction mixture was allowed to stir at this temp for 1.5 h. The reaction mixture was cooled to −78° C. and a solution of hexachloroethane (3.34 g, 14.1 mmol) in 7.5 mL THF was added dropwise via syringe. The bath was removed and the reaction mixture warmed to ambient temperature. The reaction mixture was partitioned between satd NH4Cl and Et2O. The organic layer was washed with water once, brine once, and the organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The material was dissolved in DCM and purified by silica gel chromatography, 80 g, 5-50% EA/hexanes. Product-containing fractions were combined and concentrated to give N-(3,6-dichloropyridin-2-yl)pivalamide as a solid. MS (ESI) m/z: calculated: 246.0; Observed: 247.0 (M++1).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].Cl[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1>>[N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[CH2:21][N:7]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: ClCc1ccc2ccccc2n1
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Oc2cc(C)cc(C)c2)n(Cc2ccc3ccccc3n2)c(=O)[nH]c1=O
Yield: 32.4 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 2-chloromethyl quinoline were reacted by the same way with the example 1 to obtain the titled compound (130 mg, yield: 32.4%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]2OCC=C[O:11]2)=[CH:6][C:5]=1[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Cl>C1COCC1>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:5]=1[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCc1cc(C2OC=CCO2)ccc1C(=O)OC
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCc1cc(C=O)ccc1C(=O)OC
Reaction time: 2 h
Yield: 77.5 %

Procedure:
To a solution of 4-[1,3]Dioxin-2-yl-2-pentyl-benzoic acid methyl ester (360 mg, 1.3 mmol) in THF (5.0 mL) is added concentrated HCl (0.55 mL, 6.5 mmol). The reaction is stirred for 2.0 h. The reaction mixture is partitioned between EtOAc (20 mL) and water (20 mL). The organic phase is washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography to afford the title compound as syrup (236 mg, 98%). LC-ES/MS m/e 235.3 (M+1).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:12]=[CH:11][C:10]=1[C@@H:23]1[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>O.ClCCl>[CH3:46][S:47]([O:29][C@H:26]1[CH2:25][CH2:24][C@@H:23]([C:10]2[CH:11]=[CH:12][C:13]([O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17])=[CH:14][C:9]=2[O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[CH2:28][CH2:27]1)(=[O:49])=[O:48]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@@H](O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@@H](OS(C)(=O)=O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reaction time: 24 h

Procedure:
To a round bottom flask containing cis-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl) cyclohexanol (200 mg, 0.46 mmol) was added dichloromethane (10 ml) followed by triethylamine (96 μl, 0.69 mmol) and dimethylaminopyridine (catalytic amount). The flask was purged with argon and methane sulfonyl chloride (53 μl, 0.69 mmol) was added with stirring. Stirring was continued for a further 24 hr and the reaction mixture was poured into water and extracted with dichloromethane (4×20 ml). The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated in vacuo. Purification via flash column chromatography (SiO2, ethyl acetate/petrol, 1:9) afforded the title compound as an oil (194 mg, 82%). δH(CDCl3) 0.19 (6H, s), 0.22 (6H, s), 0.97 (9H, s), 1.01 (9H, s), 1.20-1.35 (2H, m), 1.65-1.78 (4H, m), 2.15-2.22 (2H, m), 2.85-2.95 (1H, m), 3.02 (3H, s), 5.06 (1H, s), 6.30 (1H, d), 6.43 (1H, dd), 7.00 (1H, d).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH:13]=[CH:12]2.NC1C=CC2C(=CC=C(CN3CCNCC3=O)C=2)N=1.[Cl:39][C:40]1[CH:41]=[CH:42][C:43]2[CH:47]=[C:46]([S:48](Cl)(=[O:50])=[O:49])[S:45][C:44]=2[CH:52]=1>>[Cl:39][C:40]1[CH:41]=[CH:42][C:43]2[CH:47]=[C:46]([S:48]([N:6]3[CH2:5][CH2:4][N:3]([CH2:8][C:9]4[CH:10]=[C:11]5[C:16](=[CH:17][CH:18]=4)[NH:15][C:14](=[O:19])[CH:13]=[CH:12]5)[C:2](=[O:1])[CH2:7]3)(=[O:50])=[O:49])[S:45][C:44]=2[CH:52]=1
Reactant: O=C1CNCCN1Cc1ccc2[nH]c(=O)ccc2c1
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Agent: Nc1ccc2cc(CN3CCNCC3=O)ccc2n1
Product: O=C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1Cc1ccc2[nH]c(=O)ccc2c1

Procedure:
The title compound is prepared as described in EXAMPLE 101,using 6-(2-oxopiperazin-1-ylmethyl)-1H-quinolin-2-one, minor product from EXAMPLE 67, Part D, and 6-chlorobenzo[b]thiophene-2-sulfonyl chloride, EXAMPLE 1. The crude product is triturated in CH2Cl2 and filtered to provide the title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ11.72 (bs, 1H), 8.33 (s, 1H), 8.18 (s, 1H), 8.07 (d, 1H), 7.78 (d, 1H), 7.58 (dd, 1H), 7.45 (s, 1H), 7.30 (dd, 1H), 7.18 (d, 1H), 6.46 (d, 1H), 4.52 (s, 2H), 3.86 (s, 2H), 3.43 (m, 2H), 3.31 (m, 2H). MS (ion spray) m/z 488, 490, (M+H), Cl pattern.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:19][CH2:18][CH2:17][C:16]4[N:15]([CH3:20])[N:14]=[CH:13][C:12]3=4)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.C1C(=O)N([Br:28])C(=O)C1>CN(C=O)C>[Br:28][C:10]1[N:9]=[C:8]([CH:11]2[CH2:19][CH2:18][CH2:17][C:16]3[N:15]([CH3:20])[N:14]=[CH:13][C:12]2=3)[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=12
Reactant: Cn1ncc2c1CCCC2c1ncc2c(Cl)nccn12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Cn1ncc2c1CCCC2c1nc(Br)c2c(Cl)nccn12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 16 %

Procedure:
To a solution of 8-chloro-3-(1-methyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)imidazo[1,5-a]pyrazine (1.0 g, 3.5 mmol) in DMF (20 mL) was added NBS (600 mg, 3.4 mmol) dropwise in DMF (20 mL) at 0° C. The mixture was stirred about 10 min under this condition, and then was poured into ice-water. The solid was filtered and dried under high vacuum to give 1-bromo-8-chloro-3-(1-methyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)imidazo[1,5-a]pyrazine (200 mg, 15.6%). MS-ESI (m/z): 368 (M+1)+ (Acq Method: 10-80AB_2 min_220 &254.1 cm; Rt: 1.04 min)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[CH2:10][CH2:11][CH3:12].Br[CH:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15]([O:17][CH3:18])=[O:16].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[OH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([O:1][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]([O:17][CH3:18])=[O:16])=[C:3]([CH2:10][CH2:11][CH3:12])[CH:4]=1
Reactant: CCCc1cc(CO)ccc1O
Reactant: COC(=O)C(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1cc(CO)ccc1OC(C(=O)OC)c1ccccc1
Yield: 82.6 %

Procedure:
To a solution of 0.484 g (2.91 mmol) of the product of Step F dissolved in 12 mL of acetone were added 0.667 g (2.91 mmol) of methyl 2-bromo-2-phenylacetate, 0.804 g (5.82 mmol) of anhydrous K2CO3 and the mixture was stirred and heated at reflux for 5 hours. The mixture was then cooled, filtered and evaporated in vacuo. The residual oil was purified on a silica gel flash chromatography column eluted with 30% ethyl acetate/hexane to afford 0.756 g (83%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[S:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[ClH:36]>CO.O.C(O)(C)C>[ClH:36].[CH3:23][O:22][C:18]([CH2:19][CH2:20][N:13]1[CH2:12][CH2:11][N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([S:3][C:2]([F:1])([F:16])[F:17])[CH:5]=2)[CH2:15][CH2:14]1)=[O:21]
Reactant: FC(F)(F)Sc1cccc(N2CCNCC2)c1
Reactant: C=CC(=O)OC
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: [OH-]
Solvent: CC(C)O
Solvent: CO
Solvent: O
Product: COC(=O)CCN1CCN(c2cccc(SC(F)(F)F)c2)CC1
Reaction time: 48 h
Yield: 80 %

Procedure:
N-(m-trifluoromethylthiophenyl)-piperazine (7 g, 0.0267 g.mol) and freshly distilled methyl acrylate (2.55 g, 0.0295 g.mol.) are introduced in a 50 ml round bottomed flask provided with a stirrer and reflux condenser. The temperature rises slightly. The mixture is allowed to cool and 0.1 ml of a 40% solution of benzyltrimethylammonium hydroxide in methyl alcohol is then added with stirring. The mixture is allowed to stand for 2 days at ambient temperature. Boiling isopropyl alcohol (60 ml) is then added and the mixture is acidified by addition of concentrated hydrochloric acid (2.3 ml). The solvents are removed on a water-bath in vacuo and the residue is treated twice with benzene (50 ml each time) which is distilled off to remove water azeotropically. The residue is then taken up in isopropyl alcohol (50 ml) and the solution is filtered hot and allowed to stand several hours in a refrigerator. The precipitate formed is separated and dried in vacuo over phosphorous pentoxide. N-(β-methoxycarbonyl-ethyl)-N'-(m-trifluoromethylthiophenyl)-piperazine hydrochloride (8.2 g, 80% yield) is thus obtained as a white crystalline powder, m.p. 180° C, soluble in water.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[Na+].[CH:18]1[C:31]2[NH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[S:23][C:22]=2[CH:21]=[CH:20][CH:19]=1.O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([N:30]2[C:31]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[S:23][C:24]3[C:29]2=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(Br)cc1
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCc1ccc(N2c3ccccc3Sc3ccccc32)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of tris(dibenzylideneacetone)dipalladium (Pd2(dba)3) (0.30 g, 0.33 mmol) and bis(diphenylphosphino)ferrocene (DPPF) (0.22 g, 0.40 mmol) in dry toluene (60 ml) under nitrogen atmosphere was added 4-(butyl)phenylbromide (3.21 g, 15.1 mmol) at room temperature, and the resultant mixture was stirred for 10 min., sodium tert-butoxide (4.0 g) and phenothiazine (3.0 g, 15.1 mmol) were added to this solution and stirred at 90° C. overnight under nitrogen. The reaction mixture was poured into water (80 ml), extracted three times with ether (100 ml×3) and dried over anhydrous magnesium sulfate. The product was purified by flash column chromatography using 5% ethyl acetate in hexane as eluant and was isolated in 81% (4.03 g) yield as a pale yellow solid.1H NMR (CDCl3, 500 MHz) δppm: 7.41 (d, J=7.0 Hz, 2H), 7.29 (d, J=8.0 Hz, 2H), 7.0 (dd, J=7.5 Hz, J=1.5 Hz, 2H), 6.7-6.9 (m, 4H), 6.20 (d, J=7.5 Hz, 2H), 2.72 (t, J=7.5 Hz, 2H, CH2), 1.7 (m, 2H, CH2), 1.44 (m, 2H, CH2), 0.99 (t, J=7.0 Hz, 3H, CH3).
Reaction SMILES: C(N(C(C)C)C(C)C)C.[C:10]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12][CH2:11]1.[CH:18]1[C:28]2[CH:27]=[CH:26][C:25]3[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=3[CH:23]([CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[C:22]=2[CH:21]=[CH:20][CH:19]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:29]1[C:25]2[CH:26]=[CH:27][C:28]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[CH:23]([CH:33]3[CH2:34][CH2:35][N:36]([C:14](=[O:15])[CH2:13][CH2:12][CH2:11][C:10]([OH:16])=[O:17])[CH2:37][CH2:38]3)[C:24]=2[CH:32]=[CH:31][CH:30]=1
Reactant: O=C1CCCC(=O)O1
Reactant: C1=Cc2ccccc2C(C2CCNCC2)c2ccccc21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CCCC(=O)N1CCC(C2c3ccccc3C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.04 gram (0.36 millimole) of 4-dimethylaminopyridine, 0.94 gram (7.26 millimoles) of ethyl diisopropylamine, and 0.41 gram (3.63 millimoles) of glutaric anhydride were added successively to a solution of 1.00 gram (3.63 millimoles) of 4-(5H-dibenzo[a,d]cyclohepten-5-yl)-piperidine and the resulting mixture stirred at ambient temperature for two hours. The reaction mixture was diluted with 100 milliliters of methylene chloride and washed with aqueous hydrochloric acid and then with brine. The washed solution was dried over magnesium sulfate, the drying agent filtered and the solution evaporated in vacuo whereupon a foam was produced which when triturated with hot acetonitrile produced white crystals. The crystals were recrystallized from hot acetic acid/acetonitrile to obtain 4-(5H-dibenzo[a,d]cyclohepten-5-yl)-δ-oxo-1-piperidinepentanoic acid product, m.p. 180°-186° C. The product had elemental analyses as follows:
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:3]=1[NH:4][S:5]([CH3:8])(=[O:7])=[O:6].C(N(CC)CC)C.[F:23][S:24]([C:27]1[CH:28]=C(S(Cl)(=O)=O)[CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25]>O1CCCC1>[NH2:1][C:2]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:3]=1[N:4]([NH:4][S:5]([CH3:8])(=[O:7])=[O:6])[S:5]([C:8]1[CH:30]=[CH:31][CH:32]=[C:27]([S:24]([F:23])(=[O:25])=[O:26])[CH:28]=1)(=[O:7])=[O:6]
Reactant: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1N
Reactant: O=S(=O)(F)c1cccc(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)NN(c1ccc([N+](=O)[O-])cc1N)S(=O)(=O)c1cccc(S(=O)(=O)F)c1
Temperature: 5 °C
Yield: 166.2 %

Procedure:
2'-Amino-4'-nitromethanesulfonanilide (30.4 g; 0.13 mole) was dissolved in dry tetrahydrofuran (ca. 700 ml) and then triethylamine (13.1 g; 0.13 mole) was added and the solution was chilled to 5° C. While stirring and maintaining a temperature <10° C., m-fluorosulfonylbenzenesulfonyl chloride (33.8 g; 0.13 mole) was added dropwise. After the addition, the reaction was kept at the ice bath temperature for one hour and then stirring continued at room temperature for an additional hour. The reaction solution was poured into ice cold water (about 2 liters) while stirring and scratching vigorously. The product was filtered and dried to yield 50.6 g (85 percent) beige solid, m.p. 204° to 209° C. A small sample (1 g) was recrystallized from ethanol (150 ml) to yield a beige solid, m.p. 224° to 226° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:29][O:30][C:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)=[O:32]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH3:29][O:30][C:31](=[O:32])[C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)[CH:38]=1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: COC(=O)c1cccc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)c1

Procedure:
In analogy to Example 5, 6-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 56, step 4) was reacted with 3-methoxycarbonyl-phenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as a white solid. MS (m/e, ISP neg. ion)=548.2 [M−H+]
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[CH2:17]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22]2)[CH3:18]>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:22]1[C:21]2[C:25](=[CH:26][CH:27]=[C:19]([CH2:17][CH3:18])[CH:20]=2)[NH:24][C:23]1=[O:28])([CH3:3])[CH3:2]
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Reactant: CCc1ccc2c(c1)CC(=O)N2
Product: CCc1ccc2c(c1)C(=Cc1cc(C(C)C)c(OC)c(C(C)C)c1)C(=O)N2

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 5-ethyl-2-oxindole to give 0.3 g of 3-(3,5-diisopropyl-4-methoxybenzylidene)-5-ethyl-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[C:3]([O:5][NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:4].[H-].[Na+].[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=[C:19]1[S:27](Cl)(=[O:29])=[O:28]>>[CH3:1][C:2]([CH3:15])([CH3:14])[C:3]([O:5][N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[S:27]([C:19]1[O:18][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=1)(=[O:28])=[O:29])=[O:4]
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: CC(C)(C)OC(=O)NOC(=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(OC(=O)C(C)(C)C)S(=O)(=O)c1cc2ccccc2o1

Procedure:
N-[(tert-Butoxy)carbonyl]1-benzofuran-2-sulfonamido 2,2-dimethylpropanoate (55) is prepared from [(tert-butoxy)carbonyl]amino 2,2-dimethylpropanoate, sodium hydride and 1-benzofuran-2-sulfonyl chloride according to Scheme 2. (4.0 g, 87%), 1H NMR (250 MHz, DMSO-d6) δ ppm 8.06 (1H, d, 0.8 Hz), 7.92 (1H, d, 7.3 Hz), 7.81 (1H, dd, 8.5, 0.8 Hz), 7.64 (1H, ddd, 8.5, 7.2, 1.4 Hz), 7.42-7.53 (1H, m), 1.37 (9H, s), 1.28 (9H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:21]=[CH:20][C:15]3[C:16]([CH3:19])=[N:17][O:18][C:14]=3[C:13]=2[C:22]([O:24]C)=[O:23])[N:4]=1.[OH-].[Na+]>O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[CH:21]=[CH:20][C:15]3[C:16]([CH3:19])=[N:17][O:18][C:14]=3[C:13]=2[C:22]([OH:24])=[O:23])[N:6]=1
Reactant: COC(=O)c1c(Oc2nc(OC)cc(OC)n2)ccc2c(C)noc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(OC)nc(Oc2ccc3c(C)noc3c2C(=O)O)n1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 73 %

Procedure:
While heating and stirring 1.0 g of methyl 6-(4,6-dimethoxypyrimidin-2-yl)oxy-3-methylbenzisoxazol-7-carboxylate in 20 ml of N,N-dimethylsulfoxide at 70° C., 1.7 ml of a 2N sodium hydroxide aqueous solution was dropwise added thereto over a period of 10 minutes. Then, the mixture was further heated and stirred at 70° C. for 30 minutes. The mixture was returned to room temperature, then poured into water and extracted with diethyl ether. The aqueous layer was acidified with 10% hydrochloric acid, and precipitated crystals were extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. It was then concentrated under reduced pressure, and the crystals thereby obtained were washed with isopropyl ether to obtain 0.7 g (yield: 71%) of the desired compound.