Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.CO.C([O:10][C:11]([CH:13]([CH3:35])[CH2:14][CH2:15][N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[C:19]=2[N:18]=[C:17]1[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)=[O:12])C.[OH-].[Li+]>C1(C)C=CC=CC=1.C(O)CCC.O>[C:11]([CH:13]([CH3:35])[CH2:14][CH2:15][N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[C:19]=2[N:18]=[C:17]1[CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)([OH:12])=[O:10]
Reactant: CCOC(=O)C(C)CCn1c(COc2ccc(Cl)cc2)nc2c(C)cccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CCCCO
Solvent: CO
Solvent: O
Product: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.3 %

Procedure:
To a mixture of tetrahydrofuran (42 ml), methanol (14 ml), and water (14 ml), were added 1-[3-(ethoxycarbonyl)butyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (1.3 g, 3.2 mmol) and lithium hydroxide (403 mg, 3 eq.). The resulting mixture was stirred overnight at room temperature and was then concentrated in vacuo to yield a white solid. This residue was taken into 250 ml of a 3:1 butanol:toluene solution. The organic fraction was washed once with 200 ml of water and then dried over magnesium sulfate. The solvents were removed in vacuo to yield 1.22 grams of tan solid, which was further purified by flash chromatography, eluting with a gradient solvent of 19:1 ethyl acetate:methanol to 9:1 ethyl acetate:methanol. The fractions containing the desired material were combined and concentrated under reduced pressure to yield 1.12 grams (94%) of the desired title product as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[C:12]([O:16][C:17](=[O:33])[NH:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][C:26]=2[F:32])[CH2:21][CH2:20]1)([CH3:15])([CH3:14])[CH3:13].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O.CN(C)C=O>[C:12]([O:16][C:17](=[O:33])[NH:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:7](=[O:9])[C:6]3[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[OH:11])=[CH:27][C:26]=2[F:32])[CH2:21][CH2:20]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(N)cc2F)CC1
Reactant: O=C(O)c1cc(Br)ccc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(NC(=O)c3cc(Br)ccc3O)cc2F)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.1 %

Procedure:
A mixture of 5-bromosalicylic acid (326 mg, 1.5 mmol), [1-(4-amino-2-fluorophenyl)piperidin-4-yl]carbamic acid tert-butyl ester (compound of Reference Example 90; 309 mg, 1.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (287 mg, 1.5 mmol), 1-hydroxybenzotriazole (202 mg, 1.5 mmol), triethylamine (210% 1, 1.5 mmol) and N,N-dimethylformamide (5 ml) was stirred at room temperature for 3 hours. Saturated aqueous sodium hydrogen carbonate and water was added to the reaction mixture and the mixture was carried out ultrasound irradiation. The precipitated solid was collected by filtration and washed with water. The solid was suspended in methanol and carried out ultrasound irradiation. The solid was collected by filtration and dried under reduced pressure to give the title compound (224 mg, 47%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:11](=[O:13])[CH:10]=[CH:9][C:8](=[O:14])[C:7]=2[N:6]=[CH:5][CH:4]=1.[F:15][C:16]([F:34])([F:33])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]=[CH:27][CH:28]=[N:29]N(C)C)=[O:18].C(OC(=O)C)(=O)C>CC#N.C1(C)C=CC=CC=1.[Pd]>[CH3:1][O:2][C:3]1[C:12]2[C:11](=[O:13])[C:10]3[C:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[NH:19][C:17](=[O:18])[C:16]([F:33])([F:15])[F:34])=[CH:27][CH:28]=[N:29][C:9]=3[C:8](=[O:14])[C:7]=2[N:6]=[CH:5][CH:4]=1
Reactant: CN(C)N=CC=Cc1ccccc1NC(=O)C(F)(F)F
Reactant: COc1ccnc2c1C(=O)C=CC2=O
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Solvent: CC#N
Product: COc1ccnc2c1C(=O)c1c(-c3ccccc3NC(=O)C(F)(F)F)ccnc1C2=O
Yield: 8.8 %

Procedure:
3.5 g (16 mmol) of 4-methoxyquinoline-5,8-dione, 7 g (24 mmol) of 4-(2-trifluoroacetamidophenyl)-1-dimethylamino-1-aza-1,3-butadiene and 15 mL of acetic anhydride in 200 mL of CH3CN are refluxed for 18 hours. After evaporating off the solvent on a rotary evaporator and purifying by filtration through silica (99.5/0.5 CH2Cl2/MeOH), 3 g of adduct are obtained. This compound is dissolved in 150 mL of toluene, 6 g of Pd/C (10%) are added and the reaction medium is refluxed overnight. After filtering off and washing the residue with MeOH and then with CHCl3, the filtrate is concentrated on a rotary evaporator and then purified by flash chromatography on a column of silica (95/5 CH2Cl2/MeOH) to give 0.6 g of the compound in the form of a pale green powder.
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.[Cl:13][C:14]1[CH:15]=[C:16]([C:21]([CH3:39])([CH3:38])[C:22]([N:24]([C@H:26]2[C@H:30]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:29][NH:28][CH2:27]2)[CH3:25])=[O:23])[CH:17]=[C:18]([Cl:20])[CH:19]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:13][C:14]1[CH:15]=[C:16]([C:21]([CH3:39])([CH3:38])[C:22]([N:24]([CH3:25])[CH:26]2[CH:30]([C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[CH2:29][N:28]([C:7]([Cl:10])=[O:6])[CH2:27]2)=[O:23])[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: CN(C(=O)C(C)(C)c1cc(Cl)cc(Cl)c1)[C@@H]1CNC[C@H]1c1ccc(F)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C(=O)C(C)(C)c1cc(Cl)cc(Cl)c1)C1CN(C(=O)Cl)CC1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 196.1 %

Procedure:
To a stirred solution of carbonic acid ditrichloromethyl ester (triphosgene) (12 mg, 0.040 mmol) in CH2Cl2 (3 ml) at −78° C., was added a solution of rac-2-(3,5-dichloro-phenyl)-N-[(3S,4R)-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-N-methyl-isobutyramide (Intermediate VII-5), (41 mg, 0.10 mmol) and pyridine (0.02 ml, 0.22 mmol) in CH2Cl2 (2 ml) over 30 minutes. The temperature was raised to RT, and stirring was continued for 2 hours. The organic phase was washed with H2O, dried over Na2SO4. Purification by flash chromatography (SiO2, EtOAc/Hx 1:1) yielded 37 mg (79%) of the title compound as_colorless oil.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([OH:19])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH2:3][CH2:2]1.[CH3:20][NH:21][C:22]([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:22]([N:21]([CH3:20])[C:17]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[N:8]=1)=[O:19])([CH3:25])([CH3:24])[CH3:23]
Reactant: CNC(C)(C)C
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CCCO2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ccc(C2CC2)c(OCC2CCCO2)n1)C(C)(C)C

Procedure:
In analogy to the procedure described in Example 47 b), 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid was reacted with N,2-dimethylpropan-2-amine (CAN 94896-77-2) in the presence of TBTU and DIEA to give the title compound as colorless oil; MS (EI): m/e=333.5 [MH+].
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([CH:8]([C:18]([NH:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[N:26][CH:25]=[CH:24]3)=[O:19])[CH2:9][NH:10]C(=O)OC(C)(C)C)=[CH:5][CH:4]=1.[ClH:31].O1CCOCC1>C(Cl)Cl>[ClH:31].[ClH:31].[NH2:10][CH2:9][CH:8]([C:6]1[S:7][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=1)[C:18]([NH:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[N:26][CH:25]=[CH:24]2)=[O:19]
Reactant: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(CO)s1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(CO)s1
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 2-(5-(hydroxymethyl)thiophen-2-yl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (E238) in CH2Cl2 was added 4 N HCl-dioxane and the solution was stirred for 4 h. The solvents were evaporated to give 3-amino-2-(5-(hydroxymethyl)thiophen-2-yl)-N-(isoquinolin-6-yl)propanamide dihydrochloride (E239).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([C:20]([O:22]C)=[O:21])[C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1>CO.O>[CH3:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([C:20]([OH:22])=[O:21])[C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:19])[F:17])=[CH:12][CH:11]=1
Reactant: COC(=O)c1cccc(C)c1-c1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cccc(C(=O)O)c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
6N Sodium hydroxide (260 mL) is added slowly at room temperature to a solution of 183 g of methyl 6-methyl-4′-trifluoromethyl-biphenyl-2-carboxylate in 1200 mL of methanol. The reaction mixture is heated under gentle reflux for 2.5 hours, cooled to room temperature and diluted with 300 mL of water. The reaction mixture is evaporated under reduced pressure (110-120 mbar/40° C.) to a suspension of about 750 mL which is filtered through the filter agent Celite® 521, and the filter cake is washed sequentially with 250 mL of water and 250 mL of heptane. The organic layer is separated and the aqueous layer is washed with 250 mL of heptane. The aqueous layer is acidified with 500 mL of 4N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract is washed with water and filtered through the filter agent Celite® 521. The ethyl acetate solution (ca. 1000 mL) is evaporated under reduced pressure (110-120 mbar/40° C.) to a volume of 600 mL to which is added heptane (3125 mL). The suspension is then heated to reflux until a clear solution is obtained, the solution is cooled to 0° C. and the resulting solid is filtered off to yield 6-methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[S:8][C:9]=1[CH2:10][N:11]1[C:15]2=[N:16][CH:17]=[C:18]([OH:20])[CH:19]=[C:14]2[CH:13]=[CH:12]1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].C([O:41][C:42](=[O:45])[CH2:43]Br)(C)(C)C.C(OCC)(=O)C>CN(C)C=O>[CH2:1]([C:5]1[N:6]=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:23][CH:22]=2)[S:8][C:9]=1[CH2:10][N:11]1[C:15]2=[N:16][CH:17]=[C:18]([O:20][CH2:43][C:42]([OH:45])=[O:41])[CH:19]=[C:14]2[CH:13]=[CH:12]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1Cn1ccc2cc(O)cnc21
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1Cn1ccc2cc(OCC(=O)O)cnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
200 mg 1-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-1H-pyrrolo[2,3-b]pyridin-5-ol were dissolved in 20 ml dimethylformamide and 300 mg cesium carbonate and 180 mg tert.-butylbromoacetate were added. The reaction mixture was stirred at room temperature for one hour then 100 ml ethyl acetate were added and the mixture was washed five times with portions of 20 ml of water The organic layer was dried over MgSO4 and the solvent removed under reduced pressure. The residue was dissolved in 10 ml dichloromethane and 4 ml trifluoroacetic acid were added. The reaction mixture was stirred at room temperature for three hours then 100 ml toluene were added and the solvents removed under reduced pressure. The residue was purified by RP-HPLC to provide 155 mg {1-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-acetic acid as lyophilisate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[O:38]1[CH2:42][CH2:41][O:40][CH:39]1[CH2:43][NH:44][CH3:45]>>[O:38]1[CH2:42][CH2:41][O:40][CH:39]1[CH2:43][N:44]([CH3:45])[C:21]1[N:20]=[C:19]([O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:29]=[C:30]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[CH:31]=[C:2]([F:1])[CH:3]=3)=[CH:9][CH:10]=2)[CH:24]=[CH:23][N:22]=1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: CNCC1OCCO1
Product: CN(CC1OCCO1)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and [1,3]dioxolan-2-ylmethyl-methylamine according to conditions described in general procedure C. Mp: 111-112° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.75-3.96 (m, 8 H), 3.27 (m, 4 H), 3.80 (m, 4H), 4.75-5.0 (m, 2 H), 6.27 (d, J=5.1Hz, 1 H), 7.05 (d, J=12.5 Hz, 1 H), 7.28 (d, J=8.8 Hz, 1 H), 7.42-7.62 (m, 5 H), 7.84 (d, J=7.7 Hz, 1 H), 7.99-8.01 (m, 1 H), 8.28 (d, J=5.5 Hz, 1 H), 10.47 (s, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][NH2:24]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:24][CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=1[F:20])=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: NCc1ccccc1F
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCc1ccccc1F
Yield: 92 %

Procedure:
The compound prepared in Example 3 was reacted with 2-fluoro-benzylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 92%).
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9](Br)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[CH3:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](B(O)O)=[CH:22][CH:21]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([C:2]2[C:15]3[C:16]4=[C:17]5[C:12](=[CH:13][CH:14]=3)[CH:11]=[CH:10][C:9]([C:2]3[C:15]6[C:16](=[CH:17][CH:12]=[CH:13][CH:14]=6)[C:5]([CH3:6])=[CH:4][CH:3]=3)=[C:8]5[CH:7]=[CH:6][C:5]4=[CH:4][CH:3]=2)=[CH:22][CH:21]=1
Reactant: Brc1ccc2ccc3c(Br)ccc4ccc1c2c43
Reactant: Cc1ccc(B(O)O)c2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2ccc3ccc4c(-c5ccc(C)c6ccccc56)ccc5ccc2c3c54)c2ccccc12
Temperature: 130 °C
Reaction time: 9 h
Yield: 126.8 %

Procedure:
A mixed solution of 2 g of 1,6-dibromopyrene, 2 g of 4-methyl-1-naphthaleneboronic acid, 2.9 g of tripotassium phosphate, 0.59 g of tetrabutylammonium bromide, 40 mg of palladium acetate and 100 ml of dimethylformamide was heated and stirred under a nitrogen gas stream at 130° C. for 9 hours. The solution was cooled to room temperature and 500 ml of water was poured into the solution, followed by extraction with 200 ml of dichloromethane. The organic layer was washed twice with 100 ml of water, dried over magnesium sulfate and then concentrated by evaporation. The resulting concentrate was recrystallized from toluene and then vacuum-dried at 70° C. to obtain 1.7 g of 1,6-di(4-methylnaphthalen-1-yl)pyrene as an opaque white powder.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9]1.Cl.[NH2:16][CH:17]([CH2:23][SH:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C>[CH:8]1([C:12]([NH:16][CH:17]([CH2:23][SH:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:14])[CH2:9][CH2:10][CH2:11]1
Reactant: CCOC(=O)C(N)CS
Reactant: O=C(O)C1CCC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C(CS)NC(=O)C1CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (15 mL) was added to a suspension of cyclobutanecarboxylic acid (2.57 mL) and ethyl 2-amino-3-mercaptopropanoate hydrochloride (5 g) in DMF (40 mL). The resulting mixture was cooled in an ice bath and a solution of T3P (1.57M in THF, 20.6 mL) was added dropwise. The resulting mixture was allowed to warm to RT and stirred overnight. The reaction was quenched with saturated sodium bicarbonate solution (50 mL) and the layers separated. The aqueous phase was extracted with DCM (2×100 mL). The combined organic solutions were washed with brine (100 mL), dried over sodium sulphate, filtered and evaporated. The resulting white solid was purified by silica gel chromatography eluting with 4:1 to 1:1 isohexane:ethyl acetate gradient. The fractions containing product were combined and evaporated to give the subtitled compound as a clear oil. Yield 3.20 g.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[C:11]([Br:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][S-:18].[Na+].C(OCC)C.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([S:18][CH3:17])[CH:12]=[C:11]([Br:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[S-]
Reactant: Brc1cc(Br)cc(OCc2ccccc2)c1
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cc(Br)cc(OCc2ccccc2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 42.4 %

Procedure:
To a solution of 1-benzyloxy-3,5-dibromo-benzene (9.6 g, 28.1 mmol) in dry DMF (55 mL) was added sodium thiomethoxide (1.97 g, 28.1 mmol). The reaction mixture was then stirred at 100° C. for 1 h. After cooling to room temperature, the reaction mixture was poured into a mixture of diethyl ether (50 mL) and water (20 mL) along with intense stirring. The organic layer was separated and washed with water and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica using hexanes-acetone (5:0.2) as eluent to afford 3.68 g (42%) of title compound as an yellow oil. 1H NMR (CDCl3, 300 MHz): δ 7.41-7.26 (m, 5H); 6.96 (s, 1H); 6.90 (s, 1H); 6.80 (s, 1H); 5.05 (s, 2H); 2.46 (s, 3H).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12]1(=[O:19])[NH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>[Cu]I.CCOC(C)=O.O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([N:18]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]2=[O:19])=[CH:3][CH:4]=1
Reactant: O=C1CCCCCN1
Reactant: COC(=O)c1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N2CCCCCC2=O)cc1
Yield: 51.8 %

Procedure:
A mixture of methyl 4-iodobenzoate (5.24 g, 20.0 mmol), caprolactam (2.26 g, 20.0 mmol), K2CO3 (3.58 g, mmol), CuI (1.53 g, mmol), and 1,10-phenantroline (1.45 g, 35 mmol, 3.3 eq) was heated at 120–125° C. for 15 h. To the cooled mixture was added EtOAc/H2O. The organic layer was washed with H2O and brine, dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (hexanes:EtOAc=1:1 to 0:1) to give pure 4-(2-oxo-azepan-1-yl)-benzoic acid methyl ester as a white solid (2.56 g, yield: 51.8%). 1H NMR (DMSO-d6) δ 8.01 (d, J=8.6 Hz, 2H), 7.31 (d, J=8.6 Hz, 2H), 3.87 (s, 3H), 3.76 (m, 2H), 2.68 (m, 2H), 1.79 (m, 4H) ppm. LC-MS (ESI) 248.28 (M+H), tR=2.69 min (10–90% MeOH in H2O with 10 mM NH4OAc in a 4-min run).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=O)=[CH:4][CH:3]=1.[CH3:13][C:14]#[N:15]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:8])[CH2:13][C:14]#[N:15])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: CC#N
Product: N#CCC(=O)c1ccc(F)cc1
Yield: 86 %

Procedure:
Using general method L, ethyl 4-fluorobenzoate (119 g, 0.71 mol) and MeCN (75 mL) were combined to afford 3-(4-fluorophenyl)-3-oxopropionitrile (100 g, 86% yield). 1H NMR (300 MHz, CDCl3): δ 7.98-7.94 (m, 2H), 7.22 (d, J=6.6 Hz, 2H), 4.07 (s, 2H).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH3:9][C:10]1([CH3:19])[CH2:15][CH2:14][CH2:13][C:12]([CH3:17])([CH3:16])[C:11]1=O>O.CO>[CH3:9][C:10]1([CH3:19])[CH2:15][CH2:14][CH2:13][C:12]([CH3:17])([CH3:16])[C:11]1=[N:2][OH:3]
Reactant: NO
Reactant: CC1(C)CCCC(C)(C)C1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1(C)CCCC(C)(C)C1=NO
Temperature: 25 °C
Yield: 32.2 %

Procedure:
A solution of 2.3 g of hydroxylamine hydrochloride and 3.6 g of sodium acetate in 20 ml of water is added at RT to a solution of 3.4 g of 2,2,6,6-tetramethylcyclohexanone in 20 ml of MeOH and the reaction mixture is then refluxed for 48 hours. After cooling to RT, the precipitate formed is filtered off, washed with water and dried under vacuum to give 1.2 g of the expected product.
Reaction SMILES: [CH3:1][C:2]1([SH:15])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Li+].[CH3:17][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[CH3:1][C:2]1([S:15][CH3:17])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CC1(S)CCN(C(=O)OC(C)(C)C)CC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CSC1(C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Yield: 96.8 %

Procedure:
To a solution of tert-butyl 4-methyl-4-sulfanyl-piperidine-1-carboxylate (380 mg, 1.642 mmol) in THF (5 mL) cooled to −78° C. was added LiHMDS (1.724 mL of 1 M, 1.724 mmol) and the solution stirred for 10 mins before MeI (256.3 mg, 0.1124 mL, 1.806 mmol) was added and the solution allowed to warm to 0° C. over approximately 1 h. The reaction was then quenched carefully by the addition of saturated ammonium chloride and extracted into EtOAc. The aqueous was further extracted with EtOAc and the combined organics were washed with brine, dried (MgSO4) and concentrated to give a yellow oil (390 mg, 96%).
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CCCCCC.CCOC(C)=O>[OH:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)CCCC#CCO
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)CCC/C=C\CO

Procedure:
Lindlar catalyst (palladium on calcium carbonate, poisoned with lead; 60 mg) was added to a solution of alkyne 38 (1.26 g, 8.07 mmol) in 2:1 hexane/EtOAc at 0° C. Hydrogen was bubbled through the reaction mixture until TLC analysis indicated the disappearance of 38 (2-3 h). The mixture was filtered and concentrated to yield 39 was a colorless liquid (1.277 g, 100%): IR (neat) 3410 (br), 3015 (w), 2940 (s), 2860, 1740 (s), 1435,, 1365, 1245, 1205, 1155, 1025, 1000 cm-1 ; 1H NMR (CDCl3) δ 5.66 (ddt, J1 =10.9 Hz, J2 -6.8 Hz, J3 =1.4 Hz, 1H), 5.44 (dtt, J1 =10.9 Hz, J2 =7.5 Hz, J3 =1.3 Hz, 1H), 4.15 (dd, J1 =6.7 Hz, J2 =1.1 Hz, 2H), 3.66 (s, 3H), 2.32 (t, J=7.3 Hz, 2H), 2.12 (dq, J1 =7.5 Hz, J2 =1.1 Hz, 2H), 1.99 (br, 1H), 1.71 (p, J=7.3 Hz, 2H9. A minor amount (ca. 3%) of methyl trans-7-hydroxy-5-heptenoate could be seen in the 1H NMR spectrum at δ 4.09. The longer the reaction proceeded beyond completion, the greater the amount of this product was produced.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9](C#N)[C:10]([C:12]2[CH:13]=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=2)=[O:11])=[CH:5][CH:4]=1.Cl.N>C(O)(=O)C>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=2)=[O:11])=[CH:7][CH:8]=1
Reactant: CSc1ccc(C(C#N)C(=O)c2ccc(C)nc2)cc1
Agent: Cl
Agent: N
Solvent: CC(=O)O
Product: CSc1ccc(CC(=O)c2ccc(C)nc2)cc1

Procedure:
A mixture of 8.0 g (28 mmol) of 3-[2-(4-(methylthio)phenyl)-2-cyanoacetyl](6-methyl)pyridine, 20 ml of acetic acid and 60 ml of concentrated hydrochloric acid was heated at 95° C. to 100° C. for 1.5 h. The orange solution was cooled and adjusted to pH 10 using concentrated ammonia solution. The resulting yellow-beige suspension was filtered and the residue was washed with water and dried. This gave 5.35 g (74%) of the title product in the form of a yellow solid.