Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH:34]2[CH2:36][CH2:35]2)[C:5]([C:7]2[N:31]([CH2:32][CH3:33])[C:10]3=[N:11][C:12]([NH:19]/[C:20](/SC)=[CH:21]/[C:22](=[O:28])[CH:23]([O:26][CH3:27])[O:24][CH3:25])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH2:37]([N:39]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[NH2:40])[CH3:38]>C(O)(=O)C>[CH:1]1([N:4]([CH:34]2[CH2:36][CH2:35]2)[C:5]([C:7]2[N:31]([CH2:32][CH3:33])[C:10]3=[N:11][C:12]([NH:19]/[C:20](/[NH:40][N:39]([CH2:37][CH3:38])[C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])=[CH:21]/[C:22](=[O:28])[CH:23]([O:26][CH3:27])[O:24][CH3:25])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N/C(=C/C(=O)C(OC)OC)SC)nc21
Reactant: CCN(N)C(=O)OC(C)(C)C
Solvent: CC(=O)O
Product: CCN(N/C(=C\C(=O)C(OC)OC)Nc1nc2c(cc(C(=O)N(C3CC3)C3CC3)n2CC)c2c1ncn2C)C(=O)OC(C)(C)C
Temperature: 35 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of (Z)—N,N-dicyclopropyl-4-(4,4-dimethoxy-1-(methylthio)-3-oxobut-1-enylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 101A, 160 mg, 0.312 mmol) and tert-butyl 1-ethylhydrazinecarboxylate (125 mg, 0.780 mmol) in acetic acid (2 mL) wan stirred at 35° C. overnight. Solvent was evaporated and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 2-8% methanol/dichloromethane). (Z)-tert-Butyl 2-(1-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-4,4-dimethoxy-3-oxobut-1-enyl)-1-ethylhydrazinecarboxylate (195 mg, 0.312 mmol, 100% yield) was obtained as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([N:12]([CH3:14])[CH3:13])=[O:11])=[CH:4][CH:3]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=2[NH:19][N:18]=1>>[CH3:13][N:12]([CH3:14])[C:10](=[O:11])[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:19]2[C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:25]=3[C:17]([C:16]([F:15])([F:27])[F:26])=[N:18]2)=[CH:3][CH:4]=1
Reactant: CN(C)C(=O)CCc1ccc(Br)cc1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Product: CN(C)C(=O)CCc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
The title compound was prepared from 3-(4-bromophenyl)-N,N-dimethylpropanamide and 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole using a similar procedure to that described for Example 1.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C@H:8]2[N:9]3[CH2:11][CH2:12][C:13]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]=4[C@@:7]2([C:22]([O:24][CH3:25])=[O:23])[CH2:6][C@@H:5]([CH2:10]3)[CH:4]=1.ClC1C=CC=C(C(OO)=[O:34])C=1>C(Cl)Cl>[CH3:1][CH2:2][C:3]1[C@H:8]2[N@+:9]3([O-:34])[CH2:11][CH2:12][C:13]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]=4[C@@:7]2([C:22]([O:24][CH3:25])=[O:23])[CH2:6][C@@H:5]([CH2:10]3)[CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCC1=C[C@@H]2CN3CCc4c([nH]c5ccccc45)[C@@](C(=O)OC)(C2)[C@@H]13
Solvent: ClCCl
Product: CCC1=C[C@H]2C[C@]3(C(=O)OC)c4[nH]c5ccccc5c4CC[N@+]([O-])(C2)[C@H]13
Reaction time: 0.25 h

Procedure:
To a solution of catharanthine (201 mg, 0.60 mmol) in methylene chloride (40 ml) at -15° C. was added a solution of m-chloroperbenzoic acid (111 mg, 0.65 mmol) and the solution stirred for 15 min. To the catharanthine N-oxide thus formed was added a solution of vindoline (270 mg, 0.59 mmol) in methylene chloride. The atmosphere in the reaction flask was then replaced with nitrogen and the remainder of the coupling carried out in this inert atmosphere. Trifluoroacetic anhydride (0.41 ml, 3.01 mmol) was added to the stirred solution maintained at -15° C. After 22 hours this mixture was added to a solution of sodium borohydride in ethanol. After the initial vigorous evolution of gas, water and additional methylene chloride was added to the reaction mixture. The organic phase was separated and the aqueous layer washed with a second portion of methylene chloride. The organic portions were combined and washed with a solution of K2CO3. The organic phase was separated and dried with Na2SO4. The solvent was evaporated in vacuo and the residue dissolved in hot acetone. The solution was cooled and crystals of 3'4'-dehydrovinblastine were isolated. The mother liquors from the crystallization were chromatographed on silica gel plates using methanol-ethyl acetate as the eluting solvent. The combined fractions of 3'4'-dehydrovinblastine, mp 171°-173° obtained from these purifications amounted to 226 mg (0.29 mmol). Calc. for C46H56O8N4 : 792.410. Found: 792.405.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([CH3:18])[C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[C:9]([C:21]#[N:22])[CH:8]=1.Cl>N1C=CC=CC=1>[C:21]([C:9]1[CH:8]=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:12]=[CH:11][C:10]=1[C:13]1[N:17]([CH3:18])[C:16]([C:19]#[N:20])=[CH:15][CH:14]=1)#[N:22]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1C#N
Agent: Cl
Solvent: c1ccncc1
Product: Cn1c(C#N)ccc1-c1ccc(NS(C)(=O)=O)cc1C#N
Temperature: 50 °C
Yield: 26.2 %

Procedure:
A mixture of methanesulfonyl chloride (0.074 mL, 1 mmol) and 5-(4-amino-2-cyanophenyl)-1-methyl-1H-pyrrole-2-carbonitrile (0.166 g, 0.75 mmol) in pyridine (1 mL) was heated to 50° C. for 4 hours. The reaction mixture was acidified with 1N HCl solution and extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane/ethylacetate, 90/10 to 60/40) to afford the title compound (0.059 g, 33%).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH:12][CH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([CH2:20][OH:21])[CH2:16][CH2:15]1>ClCCl>[CH:13]([C@H:14]1[CH2:19][CH2:18][C@H:17]([CH:20]=[O:21])[CH2:16][CH2:15]1)=[O:12]
Reactant: OC[C@H]1CC[C@H](CO)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C[C@H]1CC[C@H](C=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
41.2 g (191 mmol) of pyridinium chlorochromate are added in several portions to a suspension of trans-1,4-bis(hydroxymethyl)cyclohexane (13.8 g, 96 mmol) in 300 ml of dichloromethane. After 1 h 30 min of stirring at room temperature, a further 4 g of pyridinium chlorochromate are added and stirring is continued for 15 min. The reaction medium is filtered through Celite and the filtrate is passed through silica. After evaporation, an oil is obtained, which is used in Stage B without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[SH:15].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>O.[OH-].[Na+]>[CH2:16]([S:15][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])[C:2]=1[Cl:1])[C:6]([OH:8])=[O:7])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(S)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)O)cc(SCc2ccccc2)c1Cl
Reaction time: 18 h

Procedure:
4-Chloro-3-mercapto-5-sulfamylbenzoic acid (0.27 g) is dissolved in water (25 ml) by addition of 1 N sodium hydroxide until pH 8. Benzyl bromide (0.15) is added and the reaction mixture stirred for 18 hours. Addition of 4 N hydrochloric acid until pH 1.5 precipitates a crude material which is collected by filtration, washed with water, and recrystallized from aqueous ethanol to yield 3-benzylthio-4-chloro-5-sulfamylbenzoic acid with a melting point of 241° - 242.5°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][S:16][C:17]3[NH:18][CH:19]=[C:20]([CH2:24]O)[C:21](=[O:23])[N:22]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27].CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:63]1[CH2:67][CH2:66][CH2:65][CH2:64]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][S:16][C:17]3[NH:18][CH:19]=[C:20]([CH2:24][N:63]4[CH2:67][CH2:66][CH2:65][CH2:64]4)[C:21](=[O:23])[N:22]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27]
Reactant: O=c1nc(SCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1CO
Reactant: C1CCNC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=c1nc(SCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1CN1CCCC1
Yield: 13.4 %

Procedure:
The same procedure as E69 from 2-{[(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)methyl]thio}-5-(hydroxymethyl)-4(1H)-pyrimidinone (53 mg, 0.120 mmol), DIAD (0.035 mL, 0.180 mmol), triphenylphosphine (47.1 mg, 0.180 mmol) and pyrrolidine (25.5 mg, 0.359 mmol) in DMF (2 mL), except that the temperature was up to 50° C., to afford the title compound (8 mg, 13.48% yield). LCMS: rt=3.06 min, [M+H+]=496
Reaction SMILES: [F:1][C:2]1[C:3]([C:18]2[NH:22][C:21]([CH3:23])=[C:20]([C:24]([OH:26])=O)[CH:19]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([NH:13][C:14]1([CH3:17])[CH2:16][CH2:15]1)=[N:5]2.CC[N:29](C(C)C)C(C)C.N>CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[C:3]([C:18]2[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH2:29])=[O:26])[CH:19]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([NH:13][C:14]1([CH3:17])[CH2:15][CH2:16]1)=[N:5]2
Reactant: Cc1nc2ccc(F)c(-c3cc(C(=O)O)c(C)[nH]3)c2nc1NC1(C)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: N
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc2ccc(F)c(-c3cc(C(N)=O)c(C)[nH]3)c2nc1NC1(C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-(6-fluoro-2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-2-methyl-1H-pyrrole-3-carboxylic acid (417c) (0.119 g, 0.336 mmol), 0-(˜7-azabenzotriazol-1-yl)-n,′n,′n,′n′-tetramethyluronium-hexafluorophosphate (GenScript Corporation, 0.160 g, 0.420 mmol), DIPEA (0.146 mL, 0.839 mmol), in DMF (1.679 mL) was stirred at RT for 5 min before addition of ammonia (2.0 M solution in MeOH, Sigma Aldrich, 0.336 mL, 0.672 mmol). The resulting mixture was stirred at RT overnight. Reaction mixture was diluted with DCM and washed with water and brine to remove DMF. Purification by Biotage (0-100% EtOAc/hexanes then 30-100% EtOAc:EtOH(3:1)/hexanes) produced desired product. The residue was diluted with DCM and re-washed two times with alternating water and brine washes to remove DMF and provide 5-(6-fluoro-2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-2-methyl-1H-pyrrole-3-carboxamide (0.031 g, 0.88 mmol, 26% yield). 1H NMR (300 MHz, MeOH) δ ppm 0.84-0.94 (m, 4H) 1.56 (s, 3H) 2.38 (s, 3H) 2.55 (s, 3H) 7.01-7.17 (m, 2H) 7.25-7.35 (m, 1H) 7.37-7.47 (m, 1H) 12.84-13.00 (m, 1H). m/z (ESI, +ve) 354.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[CH:4][N+:3]=1[O-].C(OC(=O)C)(=[O:14])C>>[OH:14][CH2:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Cc1c2c(cc[n+]1[O-])OCO2
Reactant: CC(=O)OC(C)=O
Product: OCc1nccc2c1OCO2
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
2-Methyl-3,4-methylenedioxypyridine-N-oxide (120 mg, 0.78 mmol) was dissolved in acetic anhydride (10 ml) and the solution was heated at 110° C. for 15 min, whereupon the mixture was concentrated under reduced pressure. The residue was dissolved in methanol (20 ml) and sodium hydroxide (3 drops, 6M) was added. After 30 min at ambient temperature the mixture was neutralised with acetic acid (pH 6) and concentrated under reduced pressure. The residue was chromatographed on silica (hexane/ethyl acetate, 1:1). Yield: 90 mg (75%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH3:28]>CC(C)=O>[CH2:25]([O:1][C:2]1[CH:3]=[C:4]([CH:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCBr
Reactant: CC(C)(C)OC(=O)C(CN)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCOc1cccc(C(CN)C(=O)OC(C)(C)C)c1

Procedure:
To a solution in acetone (240 ml), of 2-(3-hydroxyphenyl)-(tert-butoxycarbonyl)ethylamine obtained in Step 1, K2CO3 (19.8 g) and 1-bromobutane (15 ml) were added. The suspension was refluxed for 3 days and the solvent was evaporated under reduced pressure. The residue was dissolved in H2O (200 ml) and extracted with CH2Cl2 (2×200 ml). The solvent was eliminated under reduced pressure and the residue was purified by flash chromatography (petroleum ether/EtOAc 85:15) affording 1 (11.3 g, 81% over 3 steps) of the title compound as colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[NH2:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.O>CO>[OH:20][C:16]1[CH:15]=[C:14]([NH:13][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: Nc1cccc(O)c1
Solvent: CO
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(Nc2cccc(O)c2)n1
Yield: 97.7 %

Procedure:
A mixture of 188.6 g (1 mole) of 2-chloro-6-methoxy-3-nitropyridine and 262 g (2.4 mole) of m-aminophenol is heated in 500 ml of methanol gradually up to the reflux. After 2 hours of heating time, the mixture is cooled down, 1000 ml of water are stirred in, the crystals formed are filtered off by suction and are thoroughly washed with water. The compound is obtained in the form of orange colored crystals with a melting point of 156°-8° C. and in a yield of 97.7% of theory.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[C@H:5]([OH:9])[C:6]([OH:8])=O.Cl.[NH2:15][C@H:16]([C:18]([NH:20][N:21]1[C:27](=[O:28])[CH:26]([CH2:29][CH2:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:25]2[CH:39]=[CH:40][CH:41]=[CH:42][C:24]=2[C:23]2[CH:43]=[CH:44][CH:45]=[CH:46][C:22]1=2)=[O:19])[CH3:17]>>[F:13][C:11]1[CH:10]=[C:4]([CH:3]=[C:2]([F:1])[CH:12]=1)[C@H:5]([OH:9])[C:6]([NH:15][C@H:16]([C:18]([NH:20][N:21]1[C:27](=[O:28])[CH:26]([CH2:29][CH2:30][CH2:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:25]2[CH:39]=[CH:40][CH:41]=[CH:42][C:24]=2[C:23]2[CH:43]=[CH:44][CH:45]=[CH:46][C:22]1=2)=[O:19])[CH3:17])=[O:8]
Reactant: O=C(O)[C@@H](O)c1cc(F)cc(F)c1
Reactant: C[C@H](N)C(=O)NN1C(=O)C(CCCCc2ccccc2)c2ccccc2-c2ccccc21
Agent: Cl
Product: C[C@H](NC(=O)[C@@H](O)c1cc(F)cc(F)c1)C(=O)NN1C(=O)C(CCCCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Following General Procedure D and using (S)-3,5-difluoromandelic acid (Example L) and 5-(L-alaninyl)-amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-S), the title compound was prepared. The product was purified by chromatography (silica, 1-2% MeOH/CHCl3).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Br:23]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:23])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCCOc1nc(N)c2ncn(Cc3ccccc3)c2n1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 64 %

Procedure:
6-Amino-9-benzyl-2-butoxypurine (120 mg, 0.404 mmol) and bromine (0.5 ml) were dissolved in 50 ml of methylene chloride and the solution was stirred at room temperature for 5 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated and dried on sodium sulfate and evaporated in vacuo to dryness. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (97 mg, yield 64%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.[N:10]1([CH2:15][C:16]2[CH:17]=[CH:18][C:19](Br)=[N:20][CH:21]=2)[CH:14]=[CH:13][N:12]=[CH:11]1>>[N:10]1([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[N:20][CH:21]=2)[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Reactant: OB(O)c1ccncc1
Product: c1cc(-c2ccc(Cn3ccnc3)cn2)ccn1

Procedure:
Synthesized using 4-pyridylboronic acid (123 mg, 1.00 mmol) and 1a (95 mg, 0.4 mmol) according to Method C. Yellow solid. Yield: 73 mg, 77%. 1H NMR (500 MHz, CDCl3): δH (ppm): 5.22 (s, 2H), 6.94 (t, J=1.3 Hz, 1H), 7.14 (brs, 1H), 7.54 (dd, J=2.5, 8.2 Hz, 1H), 7.60 (s, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.88 (dd, J=1.6, 4.1 Hz, 2H), 8.64 (dd, J=0.6, 2.5 Hz, 1H), 8.73 (dd, J=1.6, 4.4 Hz, 2H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.3, 119.3, 121.2, 130.8, 132.3, 136.2, 137.6, 149.1, 150.8, 155.1; MS (ESI): m/z=237.02 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[CH:17][C:16](/[C:19](/[CH3:23])=[CH:20]/[CH2:21][OH:22])=[CH:15][CH:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:26]([O:28][C@@H:29]([CH2:35][C:36]1[CH:41]=[CH:40][C:39](O)=[CH:38][CH:37]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:27]>>[F:1][C:2]([F:24])([F:25])[C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[CH:15][C:16](/[C:19](/[CH3:23])=[CH:20]/[CH2:21][O:22][C:39]3[CH:38]=[CH:37][C:36]([CH2:35][C@H:29]([O:28][CH2:26][CH3:27])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:41][CH:40]=3)=[CH:17][CH:18]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: C/C(=C\CO)c1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc2)cc1)OCC
Yield: 81.3 %

Procedure:
The title compound (656 mg, 81%) was prepared as a colourless oil from (E)-3-(3′,5′-bis-trifluoromethyl-biphenyl-4-yl)-but-2-en-1-ol (500 mg, 1.39 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (348 mg, 1.46 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH:9]([CH3:11])[CH3:10].[F:13][C:14]1[CH:27]=[CH:26][C:17]([C:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=O)=[CH:16][CH:15]=1.OS(O)(=O)=O.[NH4+].[OH-]>CC(O)=O.O.CCCCCC.CCOC(C)=O>[F:13][C:14]1[CH:27]=[CH:26][C:17]([C:18]2[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:8]([CH:9]([CH3:11])[CH3:10])[C:3]3[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=3)[N:1]=2)=[CH:16][CH:15]=1
Reactant: CC(C)C(=O)c1ccccc1N
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(F)cc2)nc2ccccc2c1C(C)C
Temperature: 25 °C

Procedure:
A mixture of 1-(2-aminophenyl)-2-methyl-1-propanone (5.526 gm, 33.9 mmol), ethyl p-fluorobenzoylacetate (7.12 gm, 33.9 mmol) and concentrated H2SO4 (0.34 ml) in glacial HOAc (34 ml) was refluxed for 22 hours. The reaction mixture was cooled to room temperature and poured into an ice-cold solution of concentrated NH4OH (48 ml) in H2O (120 ml). The resulting mixture was extracted twice with Et2O and the combined Et2O layers were washed with H2O and brine, then dried (Na2SO4), filtered and stripped to yield a cloudy brown oil. Flash chromatography (Merck SiO2, 10% EtOAc in hexane) afforded impure 2-(4-fluorophenyl)-4-(1-methylethyl)-3-quinoline-carboxylic acid, ethyl ester as an oil. Most of the volatile impurities were distilled off under an oil pump vacuum (bath temp. 85° C.), leaving a yellow oil (5.096 gm) which was 77% by weight 2-(4-fluorophenyl)-4-(1-methylethyl)-3-quinolinecarboxylic acid, ethyl ester (34% effective yield).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[CH:5][C:3]=1[NH2:4].[Cu][C:11]#[N:12].C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([C:11]#[N:12])=[CH:8][C:2]=1[F:1]
Reactant: N#C[Cu]
Reactant: Nc1ccc(I)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(N)c(F)c1
Reaction time: 0.08 h
Yield: 67 %

Procedure:
A 50 ml of two-neck round bottom flask was filled with argon gas, and the solution of 2-fluoro-4-iodoaniline (1 g, 5.219 mmol, 1 equiv.) in DMF was put into the flask. To the solution was added Copper (I) cyanide (453.4 mg, 5.063 mmol, 1.2 equiv.) and heated to reflux for 5 hours. After confirming the completion of the reaction with TLC, saturated sodium bicarbonate solution was added to the solution and stirred for 5 minutes. The resulting solution was extracted with methylenechloride, washed with water and brine, dried over Na2SO4, filtered and evaporated. The obtained liquid was column-chromatographed (n-hexane/ethyl acetate=2/1) to yield a pale yellow solid (461.6 mg).
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:33])/[CH:19]=[C:20](\[C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=2)/[C:21]([F:24])([F:23])[F:22])=[CH:14][C:13]=1[CH3:34]>O1CCCC1>[CH2:1]([S:8][C:20]([C:25]1[CH:26]=[C:27]([Cl:32])[CH:28]=[C:29]([Cl:31])[CH:30]=1)([C:21]([F:22])([F:23])[F:24])[CH2:19][C:18]([C:15]1[CH:16]=[CH:17][C:12]([Br:11])=[C:13]([CH3:34])[CH:14]=1)=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1Br
Reactant: SCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)CC(SCc2ccccc2)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1Br
Temperature: 25 °C
Reaction time: 19 h
Yield: 43 %

Procedure:
Benzylmercaptan (0.18 g) and a solution of sodium hydroxide (0.1 eq) were added to a solution of (E)-1-(4-Bromo-3-methyl-phenyl)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-but-2-en-1-one (0.5 g) in tetrahydrofurane (11.4 mL). The solution was stirred at room temperature for 19 hours then heated at 80° C. for 4 hours. Then, more benzylmercaptan (0.5 mL) was added and the solution was stirred at 80° C. for 16 hours. More sodium hydroxide (20 mg) was added and after 90 minutes, the reaction was quenched by the addition of a saturated solution of sodium chloride, and then extracted with diethyl ether. The collected organic phases were dried over magnesium sulfate, filtered and the filtrate was evaporated under vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate) to give 3-Benzylsulfanyl-1-(4-bromo-3-methyl-phenyl)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-butan-1-one (276 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=1)[C:5]([O:7][CH3:8])=[O:6].[C:20](OCC)(OCC)(OCC)[CH3:21]>C(O)(=O)C>[CH3:20][C:21]1[N:12]([C:13]2[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)[C:11]2[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=2[N:1]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: COC(=O)c1ccc(Nc2cccc(C)c2)c(N)c1
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(c1)nc(C)n2-c1cccc(C)c1
Temperature: 25 °C
Yield: 86.4 %

Procedure:
A mixture of the compound obtained in Step 2 (0.46 g, 1.80 mmol) and triethyl orthoacetate (1.46 g, 9.00 mmol) was dissolved in 3 mL of acetic acid 3 mL, and stirred under reflux for 12 hours. The reacted mixture was cooled to room temperature and concentrated under reduced pressure, and then diluted with 20 mL of ethyl acetate. The resultant material was washed with 30 mL of a saturated aqueous solution of sodium carbonate twice and then 30 mL of water once, sequentially, and then the organic layer was taken, and dehydrated with anhydrous sodium sulfonate and concentrated under reduced pressure, and purified by a column chromatograph, to obtain methyl 2-methyl-1-m-tolyl-1H-benzo[d]imidazole-5-carboxylate as a purple solid (436 mg, 86%).