Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C@:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:10][CH2:9]2)=[C:4]([F:31])[CH:3]=1.[CH3:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:24]([O:23][CH2:22][C@:19]1([CH3:21])[S:18][CH2:17][CH2:16][N:15]2[C:11]([C:8]3([C:5]4[CH:6]=[CH:7][C:2]([C:36]5[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=5)=[CH:3][C:4]=4[F:31])[CH2:10][CH2:9]3)=[N:12][N:13]=[C:14]2[CH2:20]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@]1(C)Cc2nnc(C3(c4ccc(Br)cc4F)CC3)n2CCS1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cn1cc(-c2ccc(C3(c4nnc5n4CCS[C@@](C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)c(F)c2)cn1
Temperature: 25 °C
Yield: 100.2 %

Procedure:
A solution of the compound (3.86 g, 7.32 mmol) obtained in Example 81-1), 1-methyl-1H-pyrazole-4-boronic acid pinacol ester (1.68 g, 8.06 mmol), tetrakis(triphenylphosphine)palladium(0) (850 mg, 0.73 mmol), and potassium carbonate (2.02 g, 14.65 mmol) in 1,2-dimethoxyethane (50 mL) and water (25 mL) was heated to reflux overnight with stirring. The reaction mixture was cooled to room temperature, water (20 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate:methanol=100:0 to 70:30) to obtain the title compound (3.87 g, quant.) as a yellow solid.
Reaction SMILES: [OH-].[K+].C(OC([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:13]=2[O:12][CH2:11][CH2:10][CH2:9]1)=O)C>O.COCCO>[N+:19]([C:17]1[CH:16]=[CH:15][C:14]2[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]=2[CH:18]=1)([O-:21])=[O:20]
Reactant: CCOC(=O)N1CCCOc2cc([N+](=O)[O-])ccc21
Agent: [K+]
Agent: [OH-]
Solvent: COCCO
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)OCCCN2
Temperature: 100 °C
Yield: 93.4 %

Procedure:
1.00 M of Potassium hydroxide in Water (38 mL) was added to 3-Nitro-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid ethyl ester (1.967 g, 7.388 mmol) in 2-Methoxyethanol (80 mL) at 80° C. and further heated at 100° C. for 3 h. The solution was cooled and diluted with 200 mL water and was extracted with EtOAc (3×100 mL). The organic extract was washed with water (2×50 mL) and brine (100 mL), dried over sodium sulfate and concentrated to give 3-Nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene as a yellow solid (1.34 g, 93%). 1H-NMR (CDCl3): 7.79 (s, 1H), 7.76 (d, 1H, J=8.8 Hz), 6.69 (d, 1H, J=8.8 Hz), 4.34 (s, 1H), 4.25 (t, 2H, J=5.9 Hz), 3.49 (m, 2H), 2.09 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([OH:14])=O)[S:11][C:7]=2[C:6]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:34][CH2:35][C:36](=[O:43])[CH2:37][C:38]1[S:39][CH:40]=[CH:41][CH:42]=1.C(N(CC)CC)C>CN(C=O)C.O>[O:43]=[C:36]([CH2:37][C:38]1[S:39][CH:40]=[CH:41][CH:42]=1)[CH2:35][NH:34][C:12]([C:10]1[S:11][C:7]2[C:6]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1)=[O:14]
Reactant: NCC(=O)Cc1cccs1
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)O)nc12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(N2CCOCC2)c2sc(C(=O)NCC(=O)Cc3cccs3)nc12
Reaction time: 48 h
Yield: 16.7 %

Procedure:
0.41 g 4-Methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid and 0.14 g 1,1′-carbonyl-diimidazole in 11 ml DMF were stirred at room temperature for 16 hours. 0.16 g 1-amino-3-thiophen-2-yl-propan-2-one hydrochloride and 0.23 ml triethylamine were added and stirring was continued for two days at room temperature. Water was added and the mixture was extracted with ethylacetate. Chromatography on silicagel with ethylacetate/hexane 3:7–7:3 to yielded 0.06 g (18%) 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid (2-oxo-3-thiophen-2-yl-propyl)-amide as a yellow solid; MS (ISP): m/e=432 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([C:12]3[C:13]([NH2:18])=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:22][CH2:23][S:24](Cl)(=[O:26])=[O:25].O>C1COCC1>[C:1]1([C:7]2[S:11][C:10]([C:12]3[C:13]4=[N:18][S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][N:14]4[CH:15]=[CH:16][CH:17]=3)=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1-c1ccc(-c2ccccc2)s1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=CC=C(c3ccc(-c4ccccc4)s3)C2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
A mixture of 3-(5-phenylthiophen-2-yl)pyridin-2-amine (250 mg) in dehydrated THF (10 mL) was added to a mixture of sodium hydride (60%, 198 mg) and 2-chloroethanesulfonyl chloride (485 mg) in dehydrated THF (10 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was added to water, and the resulting precipitate was washed with water and diisopropyl ether to give the title compound (262 mg) as a yellow solid. The obtained solid was crystallized from acetonitrile to give a yellow solid.
Reaction SMILES: [H-].[Na+].CCCCC.[C:8]([O:17]C)(=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14].[C:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])[CH3:20]>CO.O1CCCC1>[C:22]1([C:19](=[O:21])[CH2:20][C:8](=[O:17])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([CH3:14])[CH3:15])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(=O)c1ccccc1
Reactant: COC(=O)CCCCC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CCCCC(=O)CC(=O)c1ccccc1

Procedure:
A dispersion of 16.9 G (0.4 mole) of 56% by weight sodium hydride in mineral oil is slurried with n-pentane under nitrogen, the supernatant liquid is removed by suction with a sintered glass tip tube. This process is repeated three times before 500 ml of dry tetrahydrofuran and 75.8 G (0.48 mole) of methyl isooctanoate are added. The resultant mixture is heated to reflux temperature with agitation. A total of 48 G (0.4 mole) of acetophenone is added to the above refluxing mixture over a 3 hour period of time. The system is maintained at reflux temperature for an additional one half hour after the acetophenone addition is completed. Approximately 20 ml of methanol is added to the above mixture at room temperature to destroy any unreacted sodium hydride. The reaction mixture is then poured into a vigorously stirred mixture of 75 ml of concentrated hydrochloric acid and 250 G of ice. When most of the ice has melted the solution is extracted twice with 242 ml of heptane per extraction. The combined heptane extracts are successively washed with water, 10% sodium carbonate solution and again with water. The heptane solution is dried with sodium sulfate, filtered, the volatiles removed at reduced pressure and the residue distilled to yield 1-phenylisodecane-1,3-dione.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:8]=[CH:9][N:10](C(=O)C)[C:11]=2[CH:12]=[C:13]([OH:15])[CH:14]=1)=[O:5])[CH3:2].[C:19]1([CH:25]2[CH2:27][CH:26]2[CH2:28]OS(C)(=O)=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=[C:13]([O:15][CH2:28][CH:26]2[CH2:27][CH:25]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)OCC1CC1c1ccccc1
Reactant: CCOC(=O)c1cc(O)cc2c1ccn2C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCC2CC2c2ccccc2)cc2[nH]ccc12

Procedure:
1-Acetyl-6-hydroxy-1H-indole-4-carboxylic acid ethyl ester 275(a) (0.2 g) obtained according to Krutosikova, Alzbeta et al. (Collection of Czechoslovak Chemical Communications (1988), 53(8), 1770–8) was heated with methanesulfonic acid 2-phenyl-cyclopropylmethyl ester (1.5 eq) and potassium carbonate (10 eq) in DMF (2 mL) during 12 h at 90° C. The volatiles were removed in vacuo. Flash Chromatography afforded a white solid (96 mg).
Reaction SMILES: [CH3:1][C:2](=[O:6])[C:3](=[O:5])[CH3:4].[C:7]1(C)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1>[OH:5][C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:4])[C:2](=[O:6])[CH3:1]
Reactant: CC(=O)C(C)=O
Reactant: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)C(C)(O)c1ccccc1
Yield: 56.6 %

Procedure:
The Grignard reagent (6.13 moles) was added to 480 g of 2,3-butanedione dissolved in 1.95 L of THF and 3.25 L of PhMe while maintaining the temperature at -6° C.±4° C. After the reaction was complete, it was quenched with 5% sulfuric acid to pH=4.5±1, then worked up as in Example I to give 689 g of crude product. Vacuum distillation (88°-93° C., 1.2-3 mm Hg) gave 3-hydroxy-3-phenylbutan-2-one in 56.6% yield.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.C(N(CC)CC)C.Cl[C:30]([O:32][CH3:33])=[O:31]>ClCCl>[F:11][C:10]([F:13])([F:12])[C:6]1[CH:5]=[C:4]([CH:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:2][NH:1][C:30](=[O:31])[O:32][CH3:33])[CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)NC(CN)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NCC(NC(=O)OC(C)(C)C)c1cccc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
Of the compound from Example 101A, 500 mg (1.64 mmol) were introduced in dichloromethane together with 320 μl (2.30 mmol) of triethylamine, with ice cooling, and 152 μl (1.97 mmol) of methyl chloroformate were added. The ice bath was removed and the mixture was stirred for a further 1 h. The solvent was removed on a rotary evaporator and the residue was purified by preparative HPLC [Method 20]. The product fractions were combined and freed from the solvents on a rotary evaporator, and the residue was dried in an HV. This gave 428 mg (72% of theory) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][N:37]=[C:36]([C:40]#[N:41])[CH:35]=1)=[O:33])(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:17])[CH3:18])[CH3:15])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][N:37]=[C:36]([C:40]#[N:41])[CH:35]=1)=[O:33])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Reactant: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(C#N)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-(isoproyl-methyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J37) (500 mg, 1.44 mmol) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert-butyl ester (Example K3) (355 mg, 1.44 mmol) according to the general procedure M. Obtained as a light orange oil (670 mg, 90%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[CH:9][C:10]=1[C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[O:4].NC1SC=CC=1C(=O)C1C=CC=CC=1Cl.[Br:35]CC(Br)=O.BrBr>N.N1C=CC=CC=1.C(O)(=O)C.C(O)CCC>[Br:35][C:8]1[S:7][C:6]2[NH:5][C:3](=[O:4])[CH2:2][N:1]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[C:10]=2[CH:9]=1
Reactant: NCC(=O)Nc1sccc1C(=O)c1ccccc1Cl
Reactant: O=C(Br)CBr
Agent: BrBr
Agent: N
Agent: Nc1sccc1C(=O)c1ccccc1Cl
Solvent: CC(=O)O
Solvent: c1ccncc1
Solvent: CCCCO
Product: O=C1CN=C(c2ccccc2Cl)c2cc(Br)sc2N1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
220 g (0.746 mol) of 2-amino-N-[3-(2-chlorobenzoyl)thiophen-2-yl]acetamide (prepared by reacting 2-amino-3-(2-chlorobenzoyl)thiophene with bromoacetylbromide and subsequently piping in gaseous ammonia) are added at 110° C. to a mixture of 1.8 l of n-butanol and 150 ml of glacial acetic acid. The mixture is refluxed for 1 hour, cooled to ambient temperature and 330 ml of pyridine and 57 ml (178.8 g, 1.12 mol) of bromine are added with cooling. Then the mixture is stirred for another 0.5 to 2 hours, cooled to 5 to 10° C. and stirred for a further 2 hours at this temperature. The product that crystallises out is isolated by filtration, washed with 50% ethanol and dried overnight in vacuo at 60° C.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[C:36]([F:40])=[CH:35][C:34]=1[F:41])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:28]([F:31])([F:30])[F:29])=[N:19][C:20]([C:21](=[O:27])[NH:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:14]2[CH2:13]1)=[O:11])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:23]([NH:22][C:21]([C:20]1[N:19]=[C:18]([C:28]([F:29])([F:30])[F:31])[N:15]2[CH2:16][CH2:17][N:12]([C:10](=[O:11])[CH2:9][C@H:8]([NH2:7])[CH2:32][C:33]3[CH:38]=[C:37]([F:39])[C:36]([F:40])=[CH:35][C:34]=3[F:41])[CH2:13][C:14]=12)=[O:27])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCNC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCNC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@H](N)Cc1cc(F)c(F)cc1F)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
(R)-[3-(1-Butylcarbamoyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 43a (120 mg, 0.198 mmol) was dissolved in 10 mL of dichloromethane, and trifluoroacetic acid (452 mg, 3.97 mmol) was then added to the solution. The reaction mixture was stirred at room temperature for 2 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid butylamide 43 (70 mg, yield 70%) as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH3:20])[C:3]1=[O:21].[CH2:22]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)[CH2:23][CH2:24][CH2:25][CH3:26]>>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH3:20])[C:3](=[O:21])[CH:2]([NH:1][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:28][CH:29]=2)[N:8]=1
Reactant: CCCCCc1ccc(C(=O)Cl)cc1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2F)c2ccccc21
Product: CCCCCc1ccc(C(=O)NC2N=C(c3ccccc3F)c3ccccc3N(C)C2=O)cc1

Procedure:
The procedure of Example 134 was carried out using equivalent amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one and 4-n-pentylbenzoyl chloride. The product was purified by chromatography on silica gel (5% (v/v) Et2O in CH2Cl2 elution). The combined product fractions were evaporated to dryness in vacuo to give the title compound which was dried at 65° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[C:12]([O:17][CH3:18])=[N:13][CH:14]=[CH:15][CH:16]=2)O)=[CH:5][CH:4]=1>C(O)(=O)C.[C].[Pd]>[CH3:18][O:17][C:12]1[C:11]([CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: COc1ccc(C(O)c2cccnc2OC)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc(Cc2cccnc2OC)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 75.7 %

Procedure:
To a solution of mesityl bromide (0.77 g) in tetrahydrofuran(2.6 mL) was added tert-butyllithium (1.48 mol/L solution in pentane, 5.3 mL) at −78° C. under an argon atmosphere, and the mixture was stirred for 1 hour. To the reaction mixture was added a solution of 2-methoxypyridine (0.33 g) in tetrahydofuran (3 mL). The temperature was raised to 0° C., and the mixture was stirred for 1 hour. The temperature was raised to room temperature, and the reaction mixture was stirred for additionally 1 hour. To the reaction mixture was added a solution of 4-methoxybenzaldehyde (0.57 g) in tetrahydrofuran (4.2 mL), and the mixture was stirred for 1 hour. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with diethyl ether. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/1-2/1) to give 4-methoxyphenyl 2-methoxypyridin-3-yl methanol (0.43 g). To a solution of the obtained 4-methoxyphenyl 2-methoxypyridin-3-yl methanol (0.41 g) in acetic acid (2.1 mL) was added 10% palladium carbon powder (0.21 g), and the mixture was stirred for 10 hours at room temperature under a hydrogen atmosphere. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1-4/1) to give 2-methoxy-3-(4-methoxybenzyl)-pyridine (0.29 g). To a solution of the obtained 2-methoxy-3-(4-methoxybenzyl)pyridine (0.023 g) in dichloromethane (0.5 mL) was added boron trichloride (1 mol/L solution in dichloromethane, 0.06 mL) at 0° C. The temperature was raised to room temperature, and the mixture was stirred for 1 hour. After boron trichloride (1 mol/L solution in dichloromethane, 0.06 mL) was added to the reaction mixture, the mixture was stirred for additionally 15 hours. To the reaction mixture was added water, and the mixture was extracted with a mixture of dichloromethane and ethanol (10/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: dichloromethane/methanol=8/1) to give 3-(4-methoxy-benzyl)-1H-pyridin-2-one (0.0017 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:6][CH2:5]2.BrN1C(=[O:18])CCC1=O.O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:6][CH:5]2[OH:18]
Reactant: O=C1OCc2cc(Br)ccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1OC(O)c2cc(Br)ccc21
Reaction time: 4 h

Procedure:
A mixture of 13.3 gm 5-bromophthalide and 12.7 gm N-bromosuccinimide in 480 ml carbon tetrachloride was irradiated with a tungsten floor lamp and refluxed for 3 hours. The reaction was followed by NMR. The succinimide was filtered off and the cake washed with carbon tetrachloride. The solvent was removed in vacuo leaving a residue of 19.2 gm, to which was added 100 ml water. This mixture was refluxed with stirring for 4 hours, then the mixture was cooled and the product filtered off, washed neutral with water and dried. Wt=9.9 gm.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])NC1SC(SCC(C)(C)C(O)=O)=CN=1.[NH2:36][C:37]1[S:38][C:39]([S:42][C:43]2([C:47]([OH:49])=[O:48])[CH2:46][CH2:45][CH2:44]2)=[CH:40][N:41]=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])[NH:36][C:37]1[S:38][C:39]([S:42][C:43]2([C:47]([OH:49])=[O:48])[CH2:44][CH2:45][CH2:46]2)=[CH:40][N:41]=1
Reactant: Nc1ncc(SC2(C(=O)O)CCC2)s1
Reactant: CC(C)(CSc1cnc(NC(=O)N(CCOCc2ccccc2Cl)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCOCc2ccccc2Cl)C(=O)Nc2ncc(SC3(C(=O)O)CCC3)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 3-{2-[3-[2-(2-chloro-benzyloxy)-ethyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid using 1-(2-amino-thiazol-5-ylsulfanyl)-cyclobutanecarboxylic acid prepared using the procedure for the preparation of 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.[Br:10][C:11]1[CH:12]=[C:13]([SH:17])[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:10][C:11]1[CH:12]=[C:13]([S:17][CH2:3][CH2:4][N:5]2[CH2:9][CH2:8][CH2:7][CH2:6]2)[CH:14]=[CH:15][CH:16]=1
Reactant: Sc1cccc(Br)c1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1cccc(SCCN2CCCC2)c1
Temperature: 25 °C
Yield: 31.4 %

Procedure:
1-(2-chloroethyl)pyrrolidine hydrochloride (1.0 equiv., 8.82 mmol) and 3-bromothiophenol (1.5 equiv., 13.23 mmol) were dissolved in acetonitrile (100 mL). Potassium carbonate (10.0 equiv., 88.2 mmol) was added to the reaction while stirring. The reaction was kept in oil bath at 80° C. to reflux for 18 h. The reaction was then cooled to room temperature and filtered to remove excess inorganics, and the organics were extracted with saturated NaHCO3 and brine. The organics were dried over Na2SO4 then concentrated under reduced pressure. The resulting crude oil was purified by flash chromatography using 4:6 EtOAc/hexanes. The fractions were concentrated to afford product as a yellow oil (792.3 mg, 32% yield). Rf=0.75 MS (ES+): m/z=287 LC retention time: 1.81 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].Br[CH2:15][CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:18][CH2:17][CH2:16][CH2:15][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: ClCCCBr
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OC)c(OCCCCl)c1
Temperature: 82.5 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
In a 100 mL volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 10.2 g (54.9 mmol) of methyl 3-hydroxy-4-methoxybenzoate (purity: 98 wt. %), 11.5 g (71.4 mmol) of 3-bromo-1-chloropropane (purity: 98 wt. %), 8.5 g (60.4 mmol) of potassium carbonate (purity: 98 wt. %), and 30 mL of acetone. The resulting mixture was refluxed under stirring at 80-85° C. for 8 hours in an argon gas atmosphere. After the reaction was complete, the reaction mixture was filtered. To the concentrate was added n-heptane, to precipitate a crystalline product. The crystalline product was collected and dried under reduced pressure, to give 13.7 g (isolated yield: 95.8%, purity: 99% in terms of area percentage by high performance liquid chromatography) of methyl 3-(3-chloropropoxy)-4-methoxybenzoate as a white crystalline product.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8]CC)=O)=[CH:2]1.[NH2:11][C:12]1[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=1[CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[CH3:22]>>[CH3:22][N:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[CH2:15][CH2:14][C:13]1[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=1[NH:11][C:6]([C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)=[O:8]
Reactant: CN1CCCCC1CCc1ccccc1N
Reactant: CCOC(=O)c1ccoc1
Product: CN1CCCCC1CCc1ccccc1NC(=O)c1ccoc1

Procedure:
Reaction of ethyl furan-3-carboxylate prepared by the method of Boyd et al, Synthesis, 545, (Oct. 1971) with 2-(2-aminophenethyl)-1-methylpiperidine according to the procedure of Example 115 provides 2'-[2-(1-methyl-2-piperidyl)ethyl]-3-furancarboxanilide, m.p. 114.5°-115.5° C. (corr.), from isopropyl ether and then ethyl acetate.