Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:34]([Cl:35])=[CH:33][C:17]3[NH:18][C:19]([O:21][C:22]4[CH:23]=[CH:24][C:25]([CH3:32])=[C:26]([CH:31]=4)[C:27]([O:29][CH3:30])=[O:28])=[N:20][C:16]=3[CH:15]=2)=[CH:10][CH:9]=1.[F:36][C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=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:35][C:34]1[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:41]3[CH:40]=[CH:39][CH:38]=[C:37]([F:36])[CH:42]=3)=[CH:9][CH:10]=2)=[CH:15][C:16]2[N:20]=[C:19]([O:21][C:22]3[CH:23]=[CH:24][C:25]([CH3:32])=[C:26]([CH:31]=3)[C:27]([O:29][CH3:30])=[O:28])[NH:18][C:17]=2[CH:33]=1
Reactant: COC(=O)c1cc(Oc2nc3cc(-c4ccc(Br)cc4)c(Cl)cc3[nH]2)ccc1C
Reactant: OB(O)c1cccc(F)c1
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: C1COCCO1
Product: COC(=O)c1cc(Oc2nc3cc(-c4ccc(-c5cccc(F)c5)cc4)c(Cl)cc3[nH]2)ccc1C

Procedure:
K2CO3 (1 M in water) (0.16 mL, 0.162 mmol) was added to a solution of methyl 5-{[5-(4-bromophenyl)-6-chloro-1H-benzimidazol-2-yl]oxy}-2-methylbenzoate (25.5 mg, 0.054 mmol), 3-fluorophenylboronic acid (9 mg, 0.068 mmol) and Pd(PPh3)4 (6 mg) in dioxane (1 mL). The reaction was microwaved at 150° C. for 8 minutes. Volatiles were removed. The residue was partitioned between EtOAc (50 mL), and water (50 mL). The aqueous phase was extracted with EtOAc (3×40 mL). Combined organics were washed with brine, dried (MgSO4), filtered and concentrated. Purification by HPLC eluting with 10-90% MeCN:water afforded the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[CH:3]=1.[Li]CCCC.FC(F)(F)C[I:21].Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[C:3]=1[I:21]
Reactant: FC(F)(F)CI
Reactant: CC(=O)Nc1ccc(Cl)cc1F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Cl)c(I)c1F
Temperature: -65 °C
Reaction time: 2 h

Procedure:
To a solution of N-(4-chloro-2-fluorophenyl)acetamide prepared above (12.0 g, 64 mmol) in THF (300 mL) at −78° C. is added dropwise n-BuLi (2.0 M in cyclohexane, 64 mL, 128 mmol) keeping the reaction temperature below −60° C. The reaction mixture is stirred between −60 to −70° C. for 2 hours and 1,1,1-trifluoro-2-iodoethane (20.1 g, 96 mmol) is added dropwise at −78° C. The mixture is stirred at this temperature for additional 3 hrs. Then a 1N HCl (200 mL) solution is added slowly at −78° C. The mixture is allowed to warm to room temperature and extracted with EtOAc (200 mL×3). The combined organic layers are washed with water and brine, then dried over MgSO4. The solvent is removed and the residue is stirred in ether and hexanes (1:2, 120 mL) for 1 hour. The solid is filtered to give N-(4-chloro-2-fluoro-3-iodophenyl)acetamide.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12](Cl)=[C:11]([OH:16])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[OH-].[Na+].[Pd]>[CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([OH:16])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c(Cl)c(O)cnn1Cc1ccccc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: O=c1cc(O)cnn1Cc1ccccc1
Yield: 96 %

Procedure:
To the mixture of 60 g of 2-benzyl-4,5-dichloro-3(2H)-pyridazinone and 38.8 g of potassium hydroxide was added 250 ml of ethanol and 150 ml of water and heated in an oil bath to the refluxing temperature for 10 hours. After reaction the solvent was distilled off under reduced pressure, and to the residual solution was added 200 ml of water and washed twice with chloroform, the water layer was acidified with concentrated hydrochloric acid. The white solid thus separated was filtered off, washed with water and dried to obtain 55 g of 2-benzyl-4-chloro-5-hydroxy-3(2H)-pyridazinone. Subsequently, in aqueous sodium hydroxide solution (NaOH 1.82 g, water 20 ml) were added 5.0 g of 2-benzyl-4-chloro-5-hydroxy-3(2H)-pyridazinone and 200 mg of 5 % Pd/C , then 474 ml of hydrogen gas was absorbed in the solution under normal pressure. After reaction, Pd/C was filtered off and to the solution was added concentrated hydrochloric acid to be acidified. The white solid thus separated was filtered off, washed with water and dried to obtain 4.1 g of 2-benzyl-5-hydroxy-3(2H)-pyridazinone.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7]Br)[CH3:2].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH2:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=1)[CH3:22]>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7][N:23]([CH2:21][CH3:22])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=1)[CH3:2]
Reactant: CCNc1cccc(C)c1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCN(CC)c1cccc(C)c1
Temperature: 95 °C
Reaction time: 17 h

Procedure:
4-Bromobutyric acid ethyl ester (17.1 ml), potassium carbonate (20.5 g), and DMF (80 ml) were added to N-ethyl-m-toluidine (8 g), and the mixture was stirred at 95° C. for 17 hours. The reaction mixture was diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane-ethyl acetate) to give the title compound (14.1 g).
Reaction SMILES: C([C@H](NC(=O)C1C=C(C2C=CC=CC=2)C=C(N2CCCC2=O)C=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)C1C=CC=CC=1.[CH:44]1([CH2:47][O:48][C:49]2[CH:50]=[C:51]([CH:55]=[C:56]([N:58]3[CH2:62][CH2:61][CH2:60][C:59]3=[O:63])[CH:57]=2)[C:52]([OH:54])=O)[CH2:46][CH2:45]1.[CH:64]12[CH2:70][CH:67]([CH2:68][CH2:69]1)[CH2:66][CH:65]2[NH:71][C:72](=[O:87])[C@H:73]([CH3:86])[CH2:74][C@H:75]([OH:85])[C@@H:76]([NH2:84])[CH2:77][C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1>>[CH2:77]([C@H:76]([NH:84][C:52](=[O:54])[C:51]1[CH:55]=[C:56]([N:58]2[CH2:62][CH2:61][CH2:60][C:59]2=[O:63])[CH:57]=[C:49]([O:48][CH2:47][CH:44]2[CH2:45][CH2:46]2)[CH:50]=1)[C@@H:75]([OH:85])[CH2:74][C@H:73]([C:72](=[O:87])[NH:71][CH:65]1[CH2:66][CH:67]2[CH2:70][CH:64]1[CH2:69][CH2:68]2)[CH3:86])[C:78]1[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=1
Reactant: O=C(O)c1cc(OCC2CC2)cc(N2CCCC2=O)c1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Agent: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(-c2ccccc2)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(OCC2CC2)cc(N2CCCC2=O)c1)C(=O)NC1CC2CCC1C2

Procedure:
Prepared in an analogous manner to E6 from 3-cyclopropylmethoxy-5-(2-oxopyrrolidin-1-yl)benzoic acid (D45) and (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (bicyclo[2.2.1]hept-2-yl)amide (D29).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:10])=[C:6]([CH:9]=1)[CH:7]=O.CCCCCCC=CCCC.[F:22][C:23]([F:32])([F:31])/[CH:24]=[CH:25]/[C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN1CCCN(C)C1=O>[I:1][C:2]1[CH:9]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:10][CH:24]([C:23]([F:22])([F:32])[F:31])[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:7]2
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: Nc1ccc(I)cc1C=O
Agent: CCCC=CCCCCCC
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)C1=Cc2cc(I)ccc2NC1C(F)(F)F
Temperature: 60 °C
Yield: 50.3 %

Procedure:
A mixture of 5-iodo-2-aminobenzaldehyde (24.0 g, 96.7 mmol), diazbicyclo[2.2.2]-undec-7-ene (32.2 g, 212.0 mmol), and ethyl 4,4,4-trifluorocrotonate (35.7 g, 212.0 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (48 mL) was heated at 60° C. for 8 hours. The solution was cooled to room temperature and the solution poured into ethyl acetate-hexanes (1:1, 500 mL). The solution was extracted with 2.5 N aqueous hydrochloric acid (2×200 mL), saturated aqueous ammonium chloride (2×200 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting dark yellow oil was dissolved in hexanes (100 mL) and fine yellow crystals formed upon standing. Vacuum filtration of this suspension yielded ethyl 6-iodo-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate as fine yellow crystals (19.3 g, 50% yield): mp 137-138° C. 1H NMR (CDCl3, 300 MHz) 7.62 (s, 1H), 7.36-7.48 (m, 2H), 6.43 (c, J=8.2 Hz), 5.36 (brs, 1H), 5.11 (q, 1H, J=7.1 Hz), 4.25-4.35 (m, 2H), 1.34 (t, 3H, J=7.0 Hz). ESHRMS m/z 395.9716 (M-H, Calc'd 395.9708).
Reaction SMILES: [Cl:1][C:2](Cl)([Cl:31])[C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH2:18][CH:19](OC)OC)[C:14]([NH:16][CH3:17])=[O:15])=[CH:9][C:8]=1[C:24]([Cl:27])([Cl:26])[Cl:25].[ClH:33]>O>[CH3:17][N:16]1[CH:19]=[CH:18][N:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][C:5]3[CH:28]=[CH:29][CH:30]=[C:3]([C:2]([Cl:31])([Cl:1])[Cl:33])[CH:4]=3)=[C:8]([C:24]([Cl:26])([Cl:27])[Cl:25])[CH:9]=2)[C:14]1=[O:15]
Reactant: CNC(=O)N(CC(OC)OC)c1ccc(Oc2cccc(C(Cl)(Cl)Cl)c2)c(C(Cl)(Cl)Cl)c1
Reactant: Cl
Solvent: O
Product: Cn1ccn(-c2ccc(Oc3cccc(C(Cl)(Cl)Cl)c3)c(C(Cl)(Cl)Cl)c2)c1=O

Procedure:
N-[4-[3-(Trichloromethyl)phenoxy]-3-(trichloromethyl) phenyl]-N-(2,2-dimethoxyethyl)-N'-methylurea (0.02 mole), water (30 ml) and concentrated hydrochloric acid (3 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer and condenser. The mixture is refluxed for a period of about 30 minutes and then cooled and extracted with ethyl acetate. The extract is washed with dilute aqueous sodium bicarbonate, with two portions of water and is then dried. The ethyl acetate is removed by mild warming under reduced pressure to yield the desired product 1-methyl-3[4-[3-(trichloromethyl)phenoxy]-3-(trichloromethyl)phenyl]-4-imidazolin-2-one.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH:22]3[CH2:24][CH2:23]3)=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([NH:34][CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[O:33])=[CH:28][CH:27]=1>>[CH:1]1([CH:7]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:31]=2)[C:9]2[C:10]([CH:22]3[CH2:24][CH2:23]3)=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(-n2cc(C(O)C3CCCCC3)c(C3CC3)n2)cc1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Product: COc1ccc(-n2cc(C(Nc3ccc(C(=O)NCCC(=O)O)cc3)C3CCCCC3)c(C3CC3)n2)cc1
Yield: 5.5 %

Procedure:
Using cyclohexyl[3-cyclopropyl-1-(4-methoxyphenyl)-1H-pyrazol-4-yl]methanol (0.5 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.36 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (43 mg, 5%) was obtained as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH:12]1[C:17]2[CH2:18][NH:19][CH2:20][CH2:21][S:22][C:16]=2[CH:15]=[CH:14][CH:13]=1>>[S:22]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:17]=2[CH2:18][N:19]([C:2]2[N:3]=[C:4]([NH:3][CH2:4][CH2:5][CH2:6][NH2:7])[C:5]3[S:10][CH:9]=[CH:8][C:6]=3[N:7]=2)[CH2:20][CH2:21]1
Reactant: Clc1nc(Cl)c2sccc2n1
Reactant: c1ccc2c(c1)CNCCS2
Product: NCCCNc1nc(N2CCSc3ccccc3C2)nc2ccsc12

Procedure:
The title compound was prepared in analogy to Example 1-1 in Scheme 1 by using 2,4-dichlorothieno[3,2-d]pyrimidine and propane-1,3-diamne) and 6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptene. MS obsd. (ESI+) [(M+H)+] 372, 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.71 (d, J=5.3 Hz, 1H), 7.65 (d, J=7.1 Hz, 1H), 7.50 (d, J=7.1 Hz, 1H), 7.17-7.25 (m, 1H), 7.10-7.16 (m, 1H), 7.09 (d, J=5.6 Hz, 1H), 5.01 (s, 2H), 4.35 (br. s., 2H), 3.72 (t, J=6.6 Hz, 2H), 2.92-2.96 (m, 2H), 2.87-2.92 (m, 2H), 1.92-2.01 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>CS(C)=O>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH:13]=[O:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CCN(Cc2ccccc2)C1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=CC1CCN(Cc2ccccc2)C1

Procedure:
(1-Benzylpyrolidin-3-yl)methanol was reacted in the presence of triethylamine and sulfur trioxide-pyridine complex in dimethylsulfoxide to produce 1-benzylpyrrolidine-3-carbaldehyde.
Reaction SMILES: O.[OH-].[Na+].C([O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH2:25][CH3:26])[C:13]3[C:18]([C:19]=2[CH:20]=1)=[CH:17][C:16]([O:21]C(=O)C)=[CH:15][CH:14]=3)(=O)C.Cl>>[CH2:25]([N:12]1[C:13]2[CH:14]=[CH:15][C:16]([OH:21])=[CH:17][C:18]=2[C:19]2[C:11]1=[CH:10][CH:9]=[C:8]([OH:7])[CH:20]=2)[CH3:26]
Reactant: CCn1c2ccc(OC(C)=O)cc2c2cc(OC(C)=O)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCn1c2ccc(O)cc2c2cc(O)ccc21

Procedure:
To 700 ml of water containing 80 g (2.0 mole) of sodium hydroxide was added 85 g (0.27 mole) of N-ethyl-3,6-carbazolediol diacetate. The reaction mixture was heated for one hour then acidified with 3N hydrochloric acid to give the product which was recrystallized from ethanolwater. M.P. 190°-200°C (dec.).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:49][C@@H:50]1[CH2:55][CH2:54][CH2:53][CH2:52][C@@H:51]1[NH2:56]>CN(C)C=O>[NH2:49][C@H:50]1[CH2:55][CH2:54][CH2:53][CH2:52][C@H:51]1[NH:56][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][C:3]=1[S:2][CH3:1]
Reactant: CSc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: N[C@@H]1CCCC[C@@H]1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CSc1cc(C(F)(F)F)ccc1C(=O)N[C@@H]1CCCC[C@@H]1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.9 %

Procedure:
2-Methylsulfanyl-4-trifluoromethyl-benzoic acid (intermediate C, 590 mg, 2.5 mmol) was dissolved in 10 mL dimethylformamide. N,N-Diisopropyl ethyl amine (646 mg, 5 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.05 g, 2.7 mmol) were added. After 5 minutes of stirring at room temperature cis-1,2-diaminocyclohexane (570 mg, 5 mmol) was added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated off. The residue was taken up in 2N sodium carbonate solution and ethyl acetate and was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (dichloromethane/methanol/ammonia 100:0:0->140:10:1) yielded cis-N-(2-amino-cyclohexyl)-2-methylsulfanyl-4-trifluoromethyl-benzamide as a light yellow solid (282 mg, 34%), MS: m/e=3331.1 [(M+H)+].
Reaction SMILES: [Cl:1]C1C(C(F)(F)F)=CC=CC=1C(Cl)=O.[Cl:15][C:16]1[C:24]([Cl:25])=[C:23]([F:26])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19].ClC1C(C(F)(F)F)=CC=CC=1C(O)=O>>[Cl:15][C:16]1[C:24]([Cl:25])=[C:23]([F:26])[CH:22]=[CH:21][C:17]=1[C:18]([Cl:1])=[O:19]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Reactant: O=C(O)c1ccc(F)c(Cl)c1Cl
Agent: O=C(O)c1cccc(C(F)(F)F)c1Cl
Product: O=C(Cl)c1ccc(F)c(Cl)c1Cl

Procedure:
The title compound was prepared in a manner analogous to Intermediate 12 substituting 2,3-dichloro-4-fluorobenzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[O:14].[N+:17]([CH3:20])([O-:19])=[O:18]>O>[OH:14][C:7]1([CH2:20][N+:17]([O-:19])=[O:18])[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([O:3][C:2]([F:1])([F:15])[F:16])[CH:5]=2)[NH:9][C:8]1=[O:13]
Reactant: C[N+](=O)[O-]
Reactant: O=C1Nc2ccc(OC(F)(F)F)cc2C1=O
Solvent: O
Product: O=C1Nc2ccc(OC(F)(F)F)cc2C1(O)C[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 0.33 h

Procedure:
5-trifluoromethoxy isatin ((0.115 g) and nitromethane (0.1 ml) were added to water and the reaction mixture was vigorously stirred at a temperature of 30° C. for 20 minutes. The obtained product was extracted with ethyl acetate and the solvent was removed to give pure product.
Reaction SMILES: C(Cl)Cl.[CH2:4]([C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[CH:17]=[CH2:18])C=C>C=CC1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru]Cl.CCCCC>[F:16][C:13]([F:14])([F:15])[C:11]1[CH:12]=[C:7]2[C:8]([CH:17]=[CH:18][CH2:4]2)=[CH:9][CH:10]=1
Reactant: C=CCc1cc(C(F)(F)F)ccc1C=C
Agent: Cl[Ru]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCC
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Product: FC(F)(F)c1ccc2c(c1)CC=C2

Procedure:
Methylene chloride (0.6 L) was added to a 1 L flask containing 2-allyl-4-(trifluoromethyl)-1-vinylbenzene (80.0 g, 0.377 mol). Bis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride (Grubbs catalyst, 1st generation) (3.1 g, 0.0038 mol) was added to the solution and the resulting solution was refluxed overnight (18 h). The solvent was evaporated to give a dark oil, which was passed through a silica gel plug using pentane. After pentane was carefully removed, 57 g (82.8%) of pure product was collected as slight brown oil. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.72 (s, 1H), 7.55 (d, 1H), 7.48 (d, 1H), 6.93 (m, 1H), 6.74 (m, 1H), 3.46 (brs, 1H).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].C(=O)([O-])[O-].[K+].[K+].I[CH:23]([CH3:25])[CH3:24]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH:23]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)([CH3:25])[CH3:24]
Reactant: CC(C)I
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: Cc1ccccc1
Product: CC(C)n1c2ccccc2c2ccccc21
Reaction time: 7 h
Yield: 81.6 %

Procedure:
16 g (95.7 mmol) of carbazole, 38 g (608.2 mmol) of 85% KOH, 21 g (151.9 mmol) of potassium carbonate, 3.2 g (9.4 mmol) of tetra-n-butylammonium hydrogensulfate and 300 ml of toluene were weighed and put in a 1-liter four neck flask, and 25 g (147.1 mmol) of 2-iodopropane was added little by little from a dropping funnel (heat is slightly developed). Subsequently, the reaction was conducted at a temperature of 60° C. to 80° C. for 7 hours. The disappearance of carbazole was confirmed by TLC and gas chromatography. After cooling, the solution was filtered, and the filtrate was washed with water three times. The toluene phase was dried (MgSO4), and concentrated, thus obtaining 21.5 g of a crude product. The crude product was recrystallized from 2-propanol to obtain 16.35 g of a desired product.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:11][O:12][C:13]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)=[O:14].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].O>[CH3:11][O:12][C:13]([C:15]1[CH:16]=[C:17]([C:2]2[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=2)[CH:18]=[CH:19][CH:20]=1)=[O:14]
Reactant: O=C(O)c1cccc(I)c1
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2cccc(C(=O)O)c2)c1
Temperature: 40 °C
Yield: 83.4 %

Procedure:
3-Iodobenzoic acid (1.0 g, 4.03 mmol, 1 equiv.), 3-(methoxycarbonyl)phenylboronic acid (0.73 g, 4.03 mmol, 1 equiv.), and Pd(OAc)2 (27 mg, 0.12 mmol, 0.03 equiv.) were mixed in DMF (10 mL) at RT with stirring, followed by the addition of 1.5M cesium carbonate (8.06 mL, 1.16 mmol, 3 equiv.). The mixture was heated at 40° C. for 4 hours. At the conclusion of this period, the reaction was worked up by adding water and adjusting the pH to 3 with 1N HCl. The aqueous mixture was extracted (3×) with EtOAc/THF. The organic layers were rinsed (3×) with water. The organic layer was dried over sodium sulfate and concentrated to give an off-white solid. The solid was stirred in hexanes (10 mL), filtered and dried under high vacuum to give 3′-(methoxycarbonyl)biphenyl-3-carboxylic acid (860 mg, 3.36 mmol, 83% yield) as a white solid. MS (ESI+)=257.23 (M+H)+.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[C:6](=[O:11])[NH:7][CH:8]=[CH:9][CH:10]=1.[C:12]([C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1)#[N:13]>C1COCC1>[C:12]([C:14]1[CH:22]=[CH:21][C:17]([C:18]([O:3][CH2:4][C:5]2[C:6](=[O:11])[NH:7][CH:8]=[CH:9][CH:10]=2)=[O:19])=[CH:16][CH:15]=1)#[N:13]
Reactant: O=c1[nH]cccc1CO
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccc(C(=O)OCc2ccc[nH]c2=O)cc1
Reaction time: 0.5 h
Yield: 28.54 %

Procedure:
In Example 3, 0.0723 g of 60% NaH was dispersed in mineral oil (0.64 mmol) and was suspended in 50 mL of THF in a 100 mL RBF under the presence of argon gas. Then, 0.2026 g (1.62 mmol) of 3-(hydroxymethyl)pyridine-2(1H)-one was slowly added into the solution. This solution was stirred for 30 min with gentle heating before 0.2661 g (1.61 mmol) of 4-cyanobenzoyl chloride was added. The reaction was stirred with gentle heating for 48 hours. The reaction was quenched with 20 mL of and was washed with ethyl acetate (4×20 mL) and the organic layers combined. The organic layer was washed with brine (3×20 mL) before being dried of MgSO4. The solvent was evaporated in vacuo to produce a white solid. The product was purified with silica gel column chromatography using 10% methanol in dichloromethane as eluent. The yield of the reaction was 0.1175 g (28.54% yield). MP: 200-203° C. IR (cm−1): 3406.04 (m, broad), υ (O—H), 3113.07 (m, broad), υ (N—H), 1728.71 (m), υ (C═O), 1617.96 (s), υ (C═C aromatic). 1H NMR (DMSO-d6, 500 MHz) δ: 5.17 (s, 2H), 6.23 (t, J=6.6 Hz, 1H), 7.42 (dd, J=4.5, 2.0 Hz, 1H), 7.63 (dd, J=4.7, 1.1 Hz, 1H), 8.02 (d, J=4.8, 2H), 8.10 (d, J=4.7, 2H), 11.80 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[C:3]=1[CH3:23].Br[CH2:25][C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:29][O:28][C:26](=[O:27])[CH2:25][O:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[C:3]=1[CH3:23]
Reactant: COC(=O)CBr
Reactant: Cc1c(O)c([N+](=O)[O-])cc2c1CCN(C(=O)OC(C)(C)C)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1c([N+](=O)[O-])cc2c(c1C)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 55 °C
Reaction time: 13 h

Procedure:
To a solution of 828 mg of t-butyl 7-hydroxy-6-methyl-8-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate in 25 ml of DMF were added 0.268 ml of methyl bromoacetate and 390 mg of potassium carbonate, followed by stirring at 55° C. for 13 hours. The reaction mixture was allowed to cool, and water added, followed by extraction with EtOAc twice. The combined organic layer was washed with saturated brine, the organic layer was dried over anhydrous sodium sulfate and then filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 1.076 g of t-butyl 7-(2-methoxy-2-oxoethoxy)-6-methyl-8-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate as a yellowish white solid.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)=[CH:6][C:5]=1[OH:28].Br[CH:31]([CH3:33])[CH3:32]>>[F:29][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)=[CH:6][C:5]=1[O:28][CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)Br
Reactant: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Product: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(OC(C)C)c2)n1

Procedure:
Using the compound obtained in Example 347 and 2-bromopropane, white powdery N-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide was obtained following the procedure of Example 348.