Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]([CH2:11][C:12]([OH:14])=O)[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.C1(C)C(C)=CC=CC=1>O>[CH3:1][C:2]1[S:6][C:5]2[CH:7]([C:8]([OH:10])=[O:9])[CH2:11][C:12](=[O:14])[C:4]=2[CH:3]=1
Reactant: Cc1ccc(C(CC(=O)O)C(=O)O)s1
Solvent: Cc1ccccc1C
Solvent: O
Product: Cc1cc2c(s1)C(C(=O)O)CC2=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 26.5 %

Procedure:
23.5 g of (5-methyl-2-thienyl) succinic acid was added to a mixture of 1.2 kg of polyphosphoric acid and 200 cc of xylene, previously heated to 100° C., and stirred for 3 hours at this temperature. After cooling to 80° C. the reaction mixture was poured in 4 liters of water and extracted with ethyl acetate. The organic phase was washed with water, dried on sodium sulfate then concentrated under reduced pressure. The residue was chromatographed on a silica column (successive eluants: 1/1 hexane-ethyl acetate, then 9/0.9/0.1 methylene chloride-ethanol-acetic acid). 5.7 g (yield: 26%) of 2-methyl-4oxo-5,6-dihydro-4H-cyclopenta[b]thiophene-6-carboxylic acid was obtained which was purified by recrystallization in a hexane-ethyl acetate mixture. Mp=140°-143° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:11]=1[Cl:12])[C:5]([O:7]C)=[O:6].[Li+].[OH-]>C1COCC1.CO.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:11]=1[Cl:12])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Br)c(Cl)c(NC(=O)OC(C)(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(C(=O)O)cc(Br)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
(I5A): A stirred solution of methyl 3-bromo-5-((tert-butoxycarbonyl)amino)-4-chlorobenzoate (1 g, 2.74 mmol, Intermediate 4) in THF (15 mL), MeOH (3.75 mL) and water (3.75 mL) was treated with LiOH (0.263 g, 10.97 mmol). The reaction was stirred at rt for 2 h. The reaction mixture was concentrated and the white residue was suspended in water, then neutralized with AcOH to pH˜6-7. The suspension was stirred for 30 min, then the white solid was collected by filtration and dried in air to yield 3-bromo-5-((tert-butoxycarbonyl)amino)-4-chlorobenzoic acid (0.95 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH2:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35](O)=[O:36])[CH:33]=2)[CH:28]=[CH:27]1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH:25][C:35]([C:32]2[CH:33]=[C:34]3[C:29]([CH:28]=[CH:27][NH:26]3)=[CH:30][CH:31]=2)=[O:36])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CCC(COCC(N)c2ccccc2F)CC1
Product: CC(C)(C)OC(=O)N1CCC(COCC(NC(=O)c2ccc3cc[nH]c3c2)c2ccccc2F)CC1

Procedure:
Using coupling method A, 4-[2-amino-2-(2-fluorophenyl)-ethoxymethyl]piperidine-1-carboxylic acid tert-butyl ester (480 mg, 1.4 mmol) and indole-6-carboxylic acid (242 mg, 1.5 mmol) afforded, after purification (SiO2: 0 to 40% 2 N ammonia/methanol solution in DCM), 355 mg (53%) of the title compound.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].CC(C)([O-])C.[K+].[CH3:15][C:16]1[CH:25]=[CH:24][C:19]([C:20](=[S:23])[CH2:21]Br)=[CH:18][CH:17]=1>CC(O)(C)C.C1C=CC=CC=1>[CH3:15][C:16]1[CH:25]=[CH:24][C:19]([C:20](=[S:23])[CH2:21][CH:2]([C:3]([CH3:5])=[O:4])[C:1]([O:7][CH3:8])=[O:6])=[CH:18][CH:17]=1
Reactant: Cc1ccc(C(=S)CBr)cc1
Reactant: COC(=O)CC(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: c1ccccc1
Product: COC(=O)C(CC(=S)c1ccc(C)cc1)C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
2.28 g (19.7 mmol) of methyl acetoacetate were dissolved in 40 ml of 2-methyl-2-propanol, and 2.21 g (19.7 mmol) of potassium t-butoxide were added to the resulting solution under a nitrogen atmosphere. The mixture was then stirred at room temperature for 1 hour, after which a solution of 4.82 g (19.7 mmol) of 4-methylthiophenacyl bromide in 30 ml of benzene was added dropwise to the resulting mixture. The mixture was then stirred at 60° C. for 3 hours, after which it was cooled. It was then poured into ice-water and extracted with ethyl acetate. The organic extract was washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure. The resulting residue was applied to a silica gel chromatography column and eluted with a 1:4 by volume mixture of ethyl acetate and hexane, to give 4.42 g (yield 80%) of the title compound as a slightly yellow powder.
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[Si:10]([O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Br:9][C:5]1[CH:6]=[C:7]([Cl:8])[C:2]([C:31]2[CH:30]=[CH:29][C:28]([O:27][Si:10]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:33][CH:32]=2)=[N:3][CH:4]=1
Reactant: CC(C)(C)[Si](Oc1ccc(B(O)O)cc1)(c1ccccc1)c1ccccc1
Reactant: Clc1cc(Br)cnc1Br
Product: CC(C)(C)[Si](Oc1ccc(-c2ncc(Br)cc2Cl)cc1)(c1ccccc1)c1ccccc1

Procedure:
5-Bromo-2-(4-tert-butyldiphenylsilyloxyphenyl)-3-chloropyridine is prepared analogously to Example 1 from 2,5-dibromo-3-chloropyridine and 4-tert-butyldiphenylsilyloxybenzeneboronic acid. ##STR29##
Reaction SMILES: [CH:1]([NH:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][N:14]([CH2:32][CH3:33])[CH:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][C:19]([NH:25]C(=O)C(F)(F)F)=[CH:20][CH:21]=3)[CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH:1]([NH:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([CH2:13][N:14]([CH:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][C:19]([NH2:25])=[CH:20][CH:21]=3)[CH2:16]2)[CH2:32][CH3:33])[CH2:11][CH2:12]1)=[O:6])([CH3:2])[CH3:3]
Reactant: CCN(CC1CCN(C(=O)NC(C)C)CC1)C1CCc2ccc(NC(=O)C(F)(F)F)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCN(CC1CCN(C(=O)NC(C)C)CC1)C1CCc2ccc(N)cc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.8 %

Procedure:
To a solution of the 4-({ethyl-[7-(2,2,2-trifluoro-acetylamino)-1,2,3,4-tetrahydro-naphthalen-2-yl]-amino}-methyl)-piperidine-1-carboxylic acid isopropylamide (630 mg, 1.3 mmol) in methanol (20 mL) and water (10 mL) was added potassium carbonate (500 mg) and the reaction was allowed to stir at room temperature for 24 h. The reaction was concentrated in vacuo and partitioned between EtOAc and water. The organic layer was washed with brine, dried (MgSO4) and concentrated to afford 4-{[(7-amino-1,2,3,4-tetrahydro-naphthalen-2-yl)-ethyl-amino]-methyl}-piperidine-1-carboxylic acid isopropylamide as a light brown oil (464 mg).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](OC)=[C:7](OC)C=1)=[O:4].ClCC(C1CC1)=O.CC1C=CC=CC=1C(=O)CCl>>[CH:5]1([C:3]([CH2:2][Cl:1])=[O:4])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COc1ccc(C(=O)CCl)cc1OC
Agent: Cc1ccccc1C(=O)CCl
Agent: O=C(CCl)C1CC1
Product: O=C(CCl)C1CCCC1

Procedure:
In a manner similar to that described above, 2-(chloroacethyl)furan, 2-(chloroacethyl)thiophene, 4-(chloroacetyl)-1,2-dimethoxybenzene, chloroacetyl-cyclopropane, and o-methylphenacyl chloride were prepared.
Reaction SMILES: C([O:4][CH2:5][C@H:6]1[O:15][C@@H:14]2[C@@H:9]([S:10][C:11]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:12]=3[N:13]2[CH3:16])[C@@H:8]([O:22]C(=O)C)[C@@H:7]1[O:26]C(=O)C)(=O)C.N>CO>[Cl:21][C:18]1[CH:19]=[CH:20][C:11]2[S:10][C@H:9]3[C@@H:8]([OH:22])[C@H:7]([OH:26])[C@@H:6]([CH2:5][OH:4])[O:15][C@H:14]3[N:13]([CH3:16])[C:12]=2[CH:17]=1
Reactant: CC(=O)OC[C@H]1O[C@@H]2[C@@H](Sc3ccc(Cl)cc3N2C)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Solvent: CO
Product: CN1c2cc(Cl)ccc2S[C@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]21
Reaction time: 24 h
Yield: 55.9 %

Procedure:
The suspension of 1.50 g of the compound (1) obtained in Example 1 in 50 ml of methanol saturated with ammonia was allowed to stand at 4° C. for 24 hours. The reaction solution was concentrated under reduced pressure. To the resulting residue water was added, and the precipitated product was filtered and washed with water, and ether successively. The resulting crude product was recrystallized with 2-propanol to obtain 600 mg (yield: 55.9%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH2:7][CH2:6]2.[N:15]1[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[C:7](=[CH:21][C:18]1[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=1)[CH2:6]2
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Reactant: O=Cc1ccncc1
Product: COc1cc2c(cc1OC)C(=O)C(=Cc1ccncc1)C2

Procedure:
Additionally, it is disclosed in Example 2, 4 and 6 of JP-A 8-225527 (1996) (EP-711,756-A1, U.S. Pat. No. 5,606,064) that reaction of 5,6-dimethoxy-1-indanone with pyridin-4-aldehyde afforded 5,6-dimethoxy-2-(pyridin-4-yl)methyleneindan-1-one (Example 2), followed by reaction with benzyl bromide afforded 1-benzyl-4-(5,6-dimethoxyindan-1-on-2-ylidene)methylpiridinium bromide (Example 4), then reduction in the presence of platinum oxide afforded Donepezil (Example 6). According to this method, yield for Donepezil through Example 2, 4 and 6 was 58.5% (87%×83%×81%).
Reaction SMILES: [F:1][CH:2]([F:8])[CH2:3][NH:4][CH2:5][CH:6]=[CH2:7].C(N(CC)C(C)C)(C)C.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25]Cl)=[CH:21][N:20]=1>>[Cl:18][C:19]1[N:20]=[CH:21][C:22]([CH2:25][N:4]([CH2:3][CH:2]([F:8])[F:1])[CH2:5][CH:6]=[CH2:7])=[CH:23][CH:24]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: C=CCNCC(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C=CCN(Cc1ccc(Cl)nc1)CC(F)F
Temperature: 70 °C
Yield: 100.7 %

Procedure:
An amount of 16.46 g (0.135 mol) of N-(2,2-difluoroethyl)prop-2-en-1-amine is placed in 31.9 g (0.244 mol) of N,N-diisopropylethylamine and 20 g (0.122 mol) of 2-chloro-5-(chloromethyl)pyridine are introduced at 70° C. The mixture is heated at 70° C. for 16 hours and the excess N,N-diisopropylethylamine is subsequently distilled off. The residue is treated with 100 ml of water and extracted twice with 50 ml of dichloromethane. After drying the combined organic phases over magnesium sulphate, they are filtered through a layer of silica gel and the solvent is removed under vacuum. An amount of 30.3 g (98% content) of N-[(6-chloropyridin-3-yl)methyl]-N-(2,2-difluoroethyl)prop-2-en-1-amine is obtained (corresponds to 97.9% yield).
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH3:26])[C:12]2[CH:13]=[C:14]([CH:23]([CH3:25])[CH3:24])[C:15]3[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=3[CH:22]=2)=[CH:7][CH:6]=1)C.[OH-].[K+]>C(O)C>[CH3:26][N:11]([C:12]1[CH:13]=[C:14]([CH:23]([CH3:25])[CH3:24])[C:15]2[O:19][CH2:18][C:17]([CH3:20])([CH3:21])[C:16]=2[CH:22]=1)[C:8]1[CH:7]=[CH:6][C:5]([C:4]([OH:27])=[O:3])=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1ccc(N(C)c2cc(C(C)C)c3c(c2)C(C)(C)CO3)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1cc(N(C)c2ccc(C(=O)O)cc2)cc2c1OCC2(C)C
Yield: 80 %

Procedure:
Following general procedure I and using 4-[methyl-(3,3-dimethyl-7-isopropyl-2,3-dihydro-benzofuran-5-yl)-amino]-benzoic acid ethyl ester (Compound 23, 0.03 g, 0.081 mmol) and 2 mL of 5M potassium hydroxide solution in 10 mL of ethanol, the title compound (0.022 g, 79%) was obtained as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.90 (d, 2H, J=9.0 Hz), 6.85 (d, 1H, J=2.2 Hz), 6.78 (d, 1H, J=2.2 Hz), 6.63 (d, 2H, J=9.0 Hz), 4.27 (s, 2H), 3.33 (s, 3H), 3.09 (heptet, 1H, J=6.8 Hz), 1.33 (s, 6H), 1.23 (d, 6H, J=6.8 Hz).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[O:11][CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1)(=[O:3])[CH3:2].C(OCC)(=O)C.Cl>C(OCC)(=O)C>[ClH:19].[Cl:20][C:15]1[CH:14]=[C:13]([CH:12]2[O:11][CH2:10][CH2:9][NH:8][CH2:7][CH:6]2[CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: CC(=O)NCC1CN(C(=O)OC(C)(C)C)CCOC1c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)NCC1CNCCOC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 136.8 %

Procedure:
To a solution of tert-butyl (6RS,7RS)-6-[(acetylamino)methyl]-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (176 mg) in ethyl acetate (0.5 mL) was added 4 N hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 2 hr. The crystals obtained by concentration under reduced pressure were recrystallized from ethanol-water to give the title compound (102 mg).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:32])[C:10]([O:12][CH2:13][C@@H:14]1[C:18]([OH:20])([CH3:19])[C@:17]([F:22])([CH3:21])[CH:16]([N:23]2[CH:28]=[C:27]([CH3:29])[C:26](=[O:30])[NH:25][C:24]2=[O:31])[O:15]1)=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O.O.C(=O)(O)[O-].[Na+]>ClCCl>[NH2:8][CH:9]([CH3:32])[C:10]([O:12][CH2:13][C@@H:14]1[C:18]([OH:20])([CH3:19])[C@:17]([F:22])([CH3:21])[CH:16]([N:23]2[CH:28]=[C:27]([CH3:29])[C:26](=[O:30])[NH:25][C:24]2=[O:31])[O:15]1)=[O:11]
Reactant: Cc1cn(C2O[C@H](COC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(C)(O)[C@@]2(C)F)c(=O)[nH]c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: Cc1cn(C2O[C@H](COC(=O)C(C)N)C(C)(O)[C@@]2(C)F)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 556.6 %

Procedure:
To a stirred solution of (2S)-((2R,4R)-4-fluoro-3-hydroxy-3,4-dimethyl-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methyl 2-(tert-butoxycarbonylamino)propanoate (Example 47, about 0.005 g, 0.01 mmol) in dichloromethane was added trifluoroacetic acid (about 0.01 ml, 0.10 mmol) at about 0° C. and stirred at room temperature for about 1 hour. Completion of the reaction monitored by thin-layer chromatography and water added to the reaction mixture. The aqueous layer was added to saturated sodium bicarbonate and extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulphate, Concentrated under reduced pressure to afford (0.02 g) crude compound. ES Mass: [M+1] 360 (100%).
Reaction SMILES: Br[C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:4]([C:13]([O:15][CH3:16])=[O:14])[C:3]=1[CH3:17].[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])(O)=O.[Na+]>C(COC)OC.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>[CH3:17][C:3]1[C:4]([C:13]([O:15][CH3:16])=[O:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:6][C:2]=1[C:21]1[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1c(-c2ccccc2)[nH]c(Br)c1C
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1c(-c2ccccc2)[nH]c(-c2ccncc2)c1C
Yield: 45.5 %

Procedure:
A mixture of methyl 5-bromo-4-methyl-2-phenylpyrrole-3-carboxylate (82 mg, 0.278 mmol), 4-pyridylboronic acid (68 mg, 0.556 mmol), PdCl2(PPh3)2 (20 mg, 0.0278 mmol), and saturated aqueous NaHCO3 (0.3 mL) in dimethoxyethane (1.5 mL) was refluxed for 16 hours. The mixture was extracted with CH2Cl2 (10 mL×3), the combined organic layer dried over Na2SO4, and concentrated ini vacito. The residue was purified by PTLC (1 mm) with acetone-hexane (1:2) to afford the title compound (37 mg, 46% yield).
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([O:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:4]#[C:5][CH3:6].O>ClCCl>[CH2:3]([O:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:2][CH3:1])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:4]#[C:5][CH3:6]
Reactant: CN
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: O
Product: CC#CCOc1ccc(S(=O)(=O)NC)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 92 %

Procedure:
To 22.5 mL (0.045 mol) of a 2M solution of methylamine in dichloromethane, cooled to 0° C., was added a solution of 3.67 g (0.015 mol) of 4-but-2-ynyloxy-benzenesulfonyl chloride in 45 mL of dichloromethane. The reaction was allowed to warm to room temperature and stirred for 48 h. The resulting solution was poured into water and extracted with dichloromethane. The combined organics were washed with 2N citric acid solution, water and brine, dried over Na2SO4, filtered through Magnesol® and concentrated in vacuo to provide 3.23 g (92%) of the N-methyl sulfonamide as a white solid; m.p.78-80° C.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)#[CH:2].Br[C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1.CCN(C(C)C)C(C)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>[O:14]1[CH2:15][CH2:16][N:11]([C:10]2[C:5]3[N:6]([C:17]([CH:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]4)=[C:3]([C:1]#[C:2][C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:33]=4)[N:4]=3)[N:7]=[CH:8][CH:9]=2)[CH2:12][CH2:13]1
Reactant: C#Cc1nc2c(N3CCOCC3)ccnn2c1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Brc1ccc2ccccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of compound 41d (1.4 g, 3.4 mmol) in DMF (5 mL) was treated with 2-bromoquinoline (2.0 g, 9.6 mol), Pd(PPh3)2Cl2 (240 mg, 0.34 mmol), Cut (30 mg, 0.16 mmol) and DIPEA (4.4 g, 34.11 mmol) under N2. The reaction mixture was stirred at rt overnight, and concentrated in vacuo. The residue obtained was purified by flash column chromatography on silica gel (EtOAc:petroleum ether (1:2)) to obtain compound 41e as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C31H34N6O3: 539.3 (M+H). found: 539.4.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.[Cl:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Cl:28])[C:12]=1[NH:13][C:14]1[C:23]2[C:18](=[C:19]([OH:26])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[O:17][C:16](=[O:27])[CH:15]=1>>[Br:1][CH2:2][CH2:3][CH2:4][O:26][C:19]1[C:20]([O:24][CH3:25])=[CH:21][CH:22]=[C:23]2[C:18]=1[O:17][C:16](=[O:27])[CH:15]=[C:14]2[NH:13][C:12]1[C:11]([Cl:28])=[CH:10][N:9]=[CH:8][C:7]=1[Cl:6]
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Reactant: BrCCCBr
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCBr

Procedure:
The title compound was prepared from 1,3-dibromopropane and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedure outlined in Example 25. 1H NMR (400 MHz, DMSO-d6): δ 9.53 (s, 1H), 8.81 (s, 2H), 7.96 (d, 1H), 7.22 (d, 1H), 4.65 (s, 1H), 4.11 (t, 2H), 3.93 (s, 3H), 3.77 (t, 2H), 2.18 (m, 2H); MS (ESI): 472.7.
Reaction SMILES: [Br-].[Al+3].[Br-].[Br-].[CH3:5][C:6]12[CH2:19][C:10]1([C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12])[N:9]1[C:20](=[O:31])[CH:21]([NH:22][C:23](=[O:30])[CH2:24][N:25]3[CH:29]=[N:28][N:27]=[N:26]3)[C@H:8]1[S:7]2>ClCCl>[CH3:5][CH:6]1[CH:19]=[C:10]([C:11]([O:13][CH2:14][C:15]([Cl:17])([Cl:18])[Cl:16])=[O:12])[N:9]2[C:20](=[O:31])[CH:21]([NH:22][C:23](=[O:30])[CH2:24][N:25]3[CH:29]=[N:28][N:27]=[N:26]3)[C@H:8]2[S:7]1
Reactant: CC12CC1(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)Cn3cnnn3)[C@H]1S2
Agent: [Al+3]
Agent: [Br-]
Solvent: ClCCl
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cn3cnnn3)[C@H]2S1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.2 %

Procedure:
A solution of aluminum bromide (0.4 g.) in dried dichloromethane (5 ml.) was dropwise added under ice-cooling to a suspension of 2,2,2-trichloroethyl 2-methyl-2,3-methylene-6-{2-(1H-tetrazol-1-yl)acetamido}penam-3-carboxylate (0.46 g.) in dried dichloromethane (10 ml.). After stirring for 4 hours at room temperature, the reaction mixture was washed in turn with 2% hydrochloric acid three times, a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution and then dried over magnesium sulfate. After drying, the solvent was distilled off and the residue was crystallized from ethanol to give 2,2,2-trichloroethyl 2-methyl-7-{2-(1H-tetrazol-1-yl)acetamido}-3-cephem-4-caboxylate (0.24 g.), mp 168° to 170° C.
Reaction SMILES: Cl[C:2]1[C:11]([C@@H:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH3:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:25])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Sn](CCCC)(CCCC)CCCC)[N:28]=1>O1CCOCC1.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>[Cl:25][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([CH3:26])[N:28]=1)[C:11]([C@@H:12]([N:14]1[C:15](=[O:24])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]1=[O:23])[CH3:13])=[CH:10]2
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(C)n1
Reactant: C[C@@H](c1cc2cccc(Cl)c2nc1Cl)N1C(=O)c2ccccc2C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1cccc(-c2nc3c(Cl)cccc3cc2[C@H](C)N2C(=O)c3ccccc3C2=O)n1
Temperature: 100 °C

Procedure:
A stirred mixture of (S)-2-(1-(2,8-dichloroquinolin-3-yl)ethyl)isoindoline-1,3-dione (254.3 mg, 0.685 mmol) and tetrakis(triphenylphosphine)palladium (79.16 mg, 68.50 μmol), 2-methyl-6-(tributylstannyl)pyridine (523.6 mg, 1.37 mmol) in dioxane (degassed) was heated at 100° C. for 28 h, complete by LC-MS solvent removed and chromatographed: 89:9:1 (DCM/MeOH,NH4OH)gradient. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.78 (1H, s), 8.15 (1H, dd, J=8.3, 1.3 Hz), 7.98 (1H, dd, J=7.5, 1.3 Hz), 7.73-7.78 (2H, m), 7.58-7.69 (4H, m), 7.36 (1H, d, J=7.6 Hz), 7.16 (1H, d, J=7.6 Hz), 6.11-6.19 (1H, m), 2.33 (3H, s), 1.82 (3H, d, J=7.0 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[CH:32]1([CH2:38][N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:30])[F:31])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:42]4[CH2:43][CH2:44][N:39]([CH2:38][CH:32]5[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]5)[CH2:40][CH2:41]4)=[O:23])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: C1CCC(CN2CCNCC2)CC1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCN(CC2CCCCC2)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(cyclohexylmethyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=611.96 (M+H+); retention time=0.65 minutes.