Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24]1.CCN(C(C)C)C(C)C>CC(O)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: O[C@H]1CCNC1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](O)C2)c(Br)c1
Temperature: 140 °C

Procedure:
5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2, 2.37 g, 6.0 mmol) and (S)-pyrrolidin-3-ol (0.627 g, 7.2 mmol) were dissolved in iPrOH (6 mL). DIPEA (2.1 mL, 12 mmol) was added and the RM mixture was heated at 140° C. for 1 h in a MW vial. After cooling to RT, the RM was dissolved in EtOAc, and washed with 0.5 M HCl and brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure until the crystallization began. The mixture was triturated with n-pentane, filtered and dried to afford the title compound as a beige crystalline solid. HPLC (Condition 4) tR=5.51 min, UPLC-MS (Condition 3) tR=1.09 min, m/z=448.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.74-2.03 (m, 2H) 3.55 (d, J=11.34 Hz, 1H) 3.64-3.74 (m, 1H) 3.78-3.89 (m, 2H) 4.33 (br. s, br. s, 1H) 4.97 (d, J=3.13 Hz, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.78-7.90 (m, 2H) 8.32 (d, J=1.56 Hz, 1H) 8.63-8.72 (m, 1H) 10.20 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:10][C@@H:11]1[O:15][C:14]([CH3:17])([CH3:16])[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32](OC(=O)C(F)(F)F)=[CH:31][CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[Cl-].C([Sn](CCCC)(CCCC)[C:56]1[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=1)CCC>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>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:10][C@@H:11]1[O:15][C:14]([CH3:16])([CH3:17])[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:56]2[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=2)=[CH:33][CH:34]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1Cc1ccc(OC(=O)C(F)(F)F)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1Cc1ccc(-c2cccnc2)cc1
Temperature: 100 °C
Yield: 72.3 %

Procedure:
A solution containing the product from Example 23I(0.200 g, 0.283 mmol) in DMF (3 mL) was treated with LiCl (0.120 g, 2.83 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.060 g, 0.085 mmol), and 3-tri-n-butylstannylpyridine (0.200 mL, 0.870 mmol), heated at 100° C. for 16 hours, cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-25% ethyl acetate in dichloromethane to give the title compound (0.130 g, 72% yield).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C1(C)C=CC=CC=1.[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([Cl:23])[C:14]=1[NH:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].C(N(CC)CC)C>>[CH3:29][C:27]([C:26]1[O:31][C:1](=[O:2])[N:24]([C:14]2[C:13]([Cl:12])=[CH:18][C:17]([C:19]([F:20])([F:22])[F:21])=[CH:16][C:15]=2[Cl:23])[N:25]=1)([CH3:28])[CH3:30]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)C(=O)NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(=O)o1
Temperature: 80 °C
Yield: 45.1 %

Procedure:
In 4.6 ml (8.9 mmols) of 20% phosgene-toluene solution, 0.33 g (1 mmol) of N'-(2,6-dichloro-4-trifluoromethylphenyl)-2,2-dimethylpropionhydrazide was heated to reflux for 16 hours (inner temperature of 80° C.). Then, an excess of phosgene and toluene was distilled off. After the residue was dissolved in 5 ml of methylene chloride, 0.65 g (6.4 mmols) of triethylamine was added to the solution and the mixture was heated to reflux for 30 minutes. Next, the mixture was washed with water, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The thus obtained crude product was subjected to silica gel column chromatography to give 0.16 g of 5-(1,1-dimethylethyl)-3-(2,6-dichloro-4-trifluoromethylphenyl)-1,3,4-oxadiazolin-2-one.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]4[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:19]4=3)[C:14]3[C:9]2=[CH:10][C:11]([O:27][CH3:28])=[CH:12][CH:13]=3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>CN(C)C=O>[CH3:26][O:25][C:23]1[CH:22]=[CH:21][C:19]2=[C:20]3[C:15](=[CH:16][CH:17]=[C:18]2[CH:24]=1)[C:14]1[C:9](=[CH:10][C:11]([O:27][CH3:28])=[CH:12][CH:13]=1)[CH:8]3[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[CH:7][CH:6]=1
Reactant: ClCCN1CCCCC1
Reactant: COc1ccc2c(c1)C(c1ccc(O)cc1)c1c-2ccc2cc(OC)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(c1ccc(OCCN3CCCCC3)cc1)c1c-2ccc2cc(OC)ccc12

Procedure:
A 1.8 g portion of the compound of Example 3 was combined with 3.4 g of potassium carbonate, 0.95 g of 1-(2-chloroethyl)piperidine hydrochloride and 20 ml of dimethylformamide, and the reaction was carried out and the product was isolated as described above in Example 6. The chromatography gave 2.05 g of purified product, which was recrystallized from ethyl acetate/isooctane to obtain 1.93 g of highly purified product, m.p. 162°-164° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18]CC)=[O:17])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:21]([F:24])([F:23])[F:22])[N:3]=1.[C:25]1(B(O)O)[CH2:29][CH2:28][CH2:27][CH:26]=1>>[C:25]1([C:2]2[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=3)[CH:5]=[C:4]([C:21]([F:23])([F:24])[F:22])[N:3]=2)[CH2:29][CH2:28][CH2:27][CH:26]=1
Reactant: OB(O)C1=CCCC1
Reactant: CCOC(=O)Cc1ccc(Nc2cc(Cl)nc(C(F)(F)F)c2)cc1
Product: O=C(O)Cc1ccc(Nc2cc(C3=CCCC3)nc(C(F)(F)F)c2)cc1
Yield: 24.1 %

Procedure:
Following General Procedure F, ethyl 2-(4-((2-chloro-6-(trifluoromethyl)pyridin-4-yl)amino)phenyl)acetate (0.115 g, 0.32 mmol) was reacted with cyclopent-1-en-1-ylboronic acid (0.039 g, 0.35 mmol) to afford the title compound (0.028 g, 24%) as a yellow oil. MW=362.35. 1H NMR (CDCl3, 500 MHz) 8.7.35-7.28 (m, 2H), 7.18-7.11 (m, 2H), 7.02-6.95 (m, 1H), 6.89 (s, 1H), 6.69-6.63 (m, 1H), 6.18 (s, 1H), 3.65 (s, 3H), 2.05 (q, J=7.5 Hz, 4H), 1.30-1.22 (m, 2H); APCI MS m/z 363 [M+H]+.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[C:8]([NH2:12])([CH3:11])([CH3:10])[CH3:9]>C(#N)C>[C:8]([NH:12][C:1](=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)N
Reactant: O=C1C=CC(=O)O1
Solvent: CC#N
Product: CC(C)(C)NC(=O)/C=C\C(=O)O
Temperature: -7 °C
Yield: 72.6 %

Procedure:
In a round-bottom flask with a nitrogen atmosphere and containing a mechanical stirrer, a thermometer and an addition funnel, was combined 1,073 grams (10.9 moles) of maleic anhydride (commercially available from Aldrich Chemical, Milwaukee, Wis.) and 6,062 grams of acetonitrile. The mixture was stirred to dissolve the solids and cooled to -7° C. To this was slowly added 800 grams, (10.9 moles) of tert-butylamine (commercially available from Aldrich Chemical, Milwaukee, Wis.) at a rate such that the temperature remained below 0° C. (approximately 2.5 hour addition time). The mixture was stirred at -7° C. for one hour and then overnight at room temperature. The solid was collected by filtration, washed with 500 milliliters acetonitrile and dried to give 1,355 grams of (Z)-4-(tert-butylamino)-4-oxo-2-butenoic acid as a white solid. 13C NMR indicated the product to be 94.62 weight % (Z)-4-(tert-butylamino)-4-oxo-2-butenoic acid, and 5.38 weight % tert-butylamine. This material was used without further purification for the next reaction.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[OH:11].Cl[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][C:14]=1[N+:21]([O-:23])=[O:22]>>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[O:11][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][C:14]=1[N+:21]([O-:23])=[O:22]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [K+]
Agent: [OH-]
Product: O=Cc1ccc(Oc2ccc(Cl)cc2Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.6 %

Procedure:
To powdered potassium hydroxide (9.0 g, 0.12 mol) at 110° C. was added 2,4-dichlorophenol (19.0 g, 0.12 mol) in one portion. The mixture was stirred for 15 min. and a homogenous solution resulted. 4-Chloro-3-nitrobenzaldehyde (20.0 g, 0.11 mol) was added and the thick mixture was stirred at 110° C. for 1 h. After cooling to room temperature, the mixture was partitioned between 2M aqueous sodium hydroxide and ethyl acetate. The organic layer was separated, washed with brine and dried over magnesium sulfate. Evaporation of solvent and recrystallization from ethanol afforded 27.0 g (80%) of the title compound as a pale yellow solid. 1H NMR (CDCl3) δ9.80 (s, 1H), 8.48 (s, 1H), 7.90 (d, 1H), 7.53 (s, 1H), 7.35 (d, 1H), 7.16 (d, 1H), 6.88 (d, 1H). 3-Amino-4-(2,4-dichlorophenoxy)benzaldehyde
Reaction SMILES: ClC[NH:3][CH2:4][Si:5]([CH3:8])([CH3:7])[CH3:6].[CH3:9][C@@H:10](N)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[OH-].[K+]>[C:11]1([CH:10]([C@H:4]([NH2:3])[Si:5]([CH3:8])([CH3:7])[CH3:6])[CH3:9])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C[Si](C)(C)CNCCl
Reactant: C[C@@H](N)c1ccccc1
Agent: [K+]
Agent: [OH-]
Product: CC(c1ccccc1)[C@H](N)[Si](C)(C)C

Procedure:
Chloromethyl(trimethylsilyl)methylamine (25 g, 0.166 mol) was treated under reflux with (R)-(+)-α-methylbenzylamine (78.5 mL, 0.61 mol) for 6 h. After cooling 100 mL of 15% KOH was added. The resulting solution was stirred before extracting twice with diethyl ether. The organics were combined and washed with brine and dried (K2CO3). The solvent was removed in vacuo and the residue was distilled at 0.001 mm Hg to give the title compound as a clear oil between 38°-45° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[CH:10]([C:12]1[N:13]=[CH:14][N:15](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:16]=1)O)[CH3:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl.O1CCCC1.C(OCC)(=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[CH2:10][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1)[CH3:2]
Reactant: CCc1cccc(C)c1C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC[SiH](CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCc1cccc(C)c1Cc1c[nH]cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.3 %

Procedure:
This compound was prepared using methodology described in J. Chem. Soc., Perkin Trans. 1, 2002, 1061-1066. To a stirred solution of 0.35 g (0.76 mmol) rac-(2-ethyl-6-methyl-phenyl)-(1-trityl-1H-imidazol-4-yl)-methanol in 5 ml dichloromethane were added dropwise 1.22 ml (7.63 mmol) triethylsilane and 0.69 ml (9.16 mmol) trifluoroacetic acid. The reaction mixture was stirred at room temperature for 16 hours, and then diluted with a 1:1 mixture of tetrahydrofuran and ethyl acetate. The mixture was washed sequentially with 2 N aqueous sodium hydroxide solution and saturated brine and then the organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, methanol/dichloromethane gradient) to afford 40 mg (26%) of the title compound as a yellow crystalline solid. MS (ISP): 201.3 ([M+H]+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:27])[O:13][C:14](=O)[C:15]=2[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[CH:3]1.[NH3:28]>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:27])[NH:28][C:14](=[O:13])[C:15]=2[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[CH:3]1
Reactant: N
Reactant: Cn1cc(C2=C(c3cccc4ccccc34)C(=O)OC2=O)c2ccccc21
Solvent: CN(C)C=O
Product: Cn1cc(C2=C(c3cccc4ccccc34)C(=O)NC2=O)c2ccccc21
Temperature: 130 °C

Procedure:
56 mg of 3-(1-methyl-3-indolyl)-4-(1-naphthyl)furan-2,5-dione were treated with 5 ml of DMF and 5 ml of 33% aqueous ammonia and the mixture was heated at 130° C. for 5 hours. The formed precipitate was filtered off, washed with water and dried to give 53 mg of 3-(1-methyl-3-indolyl)-4-(1-naphthyl)-1H-pyrrole-2,5-dione, m.p. 258°-260° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([NH:12][C@@H:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[N:3]=1.[F:19][C:20]1[CH:41]=[CH:40][C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:19][C:20]1[CH:41]=[CH:40][C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:2]3[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([NH:12][C@@H:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[N:3]=3)=[CH:27][CH:26]=2)=[CH:22][CH:21]=1
Reactant: CC1(C)OB(c2ccc(Oc3ccc(F)cc3)cc2)OC1(C)C
Reactant: COC(=O)c1cc(N[C@@H](C)C(=O)OC)nc(Cl)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1cc(N[C@@H](C)C(=O)OC)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Temperature: 100 °C
Yield: 1.9 %

Procedure:
To a mixture of the (S)-methyl 2-chloro-6-((1-methoxy-1-oxopropan-2-yl)amino)pyrimidine-4-carboxylate (4.826 g, 17.63 mmol) in dioxane (100 mL) was added 2-(4-(4-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.651 g, 21.17 mmol), 2M aqueous Na2CO3 (17.6 mL, 35.2 mmol) and PdCl2(dppf) (0.727 g, 0.89 mmol). The flask was flushed with argon, sealed, and heated on a 100° C. oil bath for 30 minutes. The flask ruptured. As much of the reaction mixture as possible was partitioned between methanol and hexanes. The hexanes were removed and the methanol layer was washed a second time. The methanol fraction was evaporated in vacuo and chromatographed over silica gel with 20-60% EtOAc in hexanes. The product fractions were isolated and evaporated in vacuo and chromatographed a second time over silica gel with 10-50% EtOAc in hexanes. The product fractions were evaporated in vacuo and the resulting solid triturated with 2 mL MeOH, filtered, rinsed once with 1 mL MeOH, and dried under vacuum at 40° C. to give (S)-methyl 2-(4-(4-fluorophenoxy)phenyl)-6-((1-methoxy-1-oxopropan-2-yl)amino)pyrimidine-4-carboxylate as a yellow powder (0.140 g, 0.329 mmol, 2% yield). 1H NMR (400 MHz, DMSO-d6): 8.34-8.25 (3H, m), 7.31-7.24 (2H, m), 7.19-7.14 (2H, m), 7.10 (1H, s), 7.06 (2H, d, J=8.8 Hz), 4.60-4.52 (1H, m), 3.89 (3H, s), 3.64 (3H, s), 1.45 (3H, d, J=7.2 Hz). LC/MS: m/z=426.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([O:10]C)=O)=[CH:4][CH:3]=1.[NH3:12]>CO>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:12])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Cl)nn1
Reactant: N
Solvent: CO
Product: NC(=O)c1ccc(Cl)nn1
Temperature: 0 °C
Yield: 99 %

Procedure:
Dissolve methyl 6-chloropyridazine-3-carboxylate (0.498 g, 2.89 mmol) in methanol (28 mL). Cool the solution to 0° C. with an acetone/dry ice bath. Bubble ammonia into the reaction mixture, then allow it to warm to 0° C. over 1 hour before concentrating to give the title compound (0.451 g, 99%): TOF MS ES+ 157.0 (M)+, HRMS calcd for C5H4N3OCl 157.0043 (M)+, found 157.0010, time 4.45 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.1 TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 10-20% over 5 min then 20-95% over 18], tR=5.2 min, 100% purity.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])=[O:10])=[CH:5][CH:4]=1.C[S-].[Na+]>CN(C)C=O>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:18])([F:19])[F:20])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2ccccc2C(F)(F)F)cc1
Agent: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(O)cc1)c1ccccc1C(F)(F)F
Yield: 78.8 %

Procedure:
2-Trifluoromethylphenyl 4-methoxyphenyl ketone (1.402 g) obtained in Example 144 was dissolved in N,N-dimethylformamide (15 ml), sodium thiomethoxide (877 mg) was added, and the admixture was refluxed with heat for 4 hours under argon. The reaction mixture was treated in the same manner as described in Example 33 to obtain 1.050 g of the title compound (yield: 79%).
Reaction SMILES: [C:1]([C:3]1[CH2:4][N:5]([CH3:9])[CH2:6][CH2:7][CH:8]=1)#[N:2].[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CC=CC=1>O1CCOCC1>[CH3:9][N:5]1[CH2:6][CH2:7][CH:8]([S:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]([C:1]#[N:2])[CH2:4]1
Reactant: CN1CCC=C(C#N)C1
Reactant: Sc1ccccc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CN1CCC(Sc2ccccc2)C(C#N)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-cyano-1-methyl-1,2,5,6-tetrahydropyridine (6.1 g 0.05 m.) thiophenol (5.50 g., 0.05 m.) and pyridine (1 ml.) was stirred at room temperature for 1 hour, diluted with dioxan (7 ml.) and heated at 110° with stirring for 24 hours. The solvent was removed in vacuo and the residual brown oil diluted with benzene (100 ml.) washed with N/1 hydrochloric acid (3 × 25 ml.) and the combined washings made basic, with 2N sodium hydroxide and extracted into benzene (3 × 25 ml). The combined extracts were washed with saturated brine, dried (MgSO4) and evaporated to give a residual solid. Recrystallisation from benzene - 60°/80° petroleum ether gave the title compound as colourless plates (8 g., 75%) m.p. 114°C. Found: C, 67.42; H, 6.97; N, 11.99. C13H16N2S requires: C, 67.21; H, 6.94; N, 12.06%.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][CH2:10][O:11][C:12]([CH:14](P(OCC)(OCC)=O)[CH3:15])=[O:13].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]([CH:39]=O)=[CH:31]2)[CH:25]=1>O1CCCC1>[CH2:10]([O:11][C:12]([C:14]([CH3:15])=[CH:39][C:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:30]([C:26]2[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=2)[CH:31]=1)=[O:13])[CH3:9]
Reactant: O=Cc1cn(-c2cccnc2)c2ccccc12
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)=Cc1cn(-c2cccnc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of lithium diisopropylamide (from 1.4 ml of diisopropylamine and 6.3 ml of 1.6M n-butyllithium in hexane) in 25 ml of dry tetrahydrofuran under nitrogen is cooled to -70° and 2.14 ml of triethyl 2-phosphonopropionate is added dropwise. The reaction mixture is stirred for 20 minutes at -70° and 2.0 g of N-(3-pyridyl)indole-3-carboxaldehyde is added. The reaction is allowed to warm to room temperature for 14 hours. The solvent is evaporated and the residue is partitioned between 20 ml of half saturated ammonium chloride solution and 30 ml of methylene chloride. The organic phase is separated, dried over sodium sulfate and evaporated to a solid which is recrystallized from methanol to yield 3-[2-(ethoxycarbonyl)prop-1-enyl]-N-(3-pyridyl)indole, m.p. 97°-99°.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:6](=[O:7])[CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:16])=[O:15])=[CH:10][CH:9]=2)[O:3]1.FC(F)(F)C(O[I:23](C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.II>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:17])[C:6](=[O:7])[C:5]([I:23])=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:16])=[O:15])=[CH:10][CH:9]=2)[O:3]1
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Reactant: CS(=O)c1ccc(C2=CC(=O)C(C)(C)O2)cc1
Agent: II
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)c1ccc(C2=C(I)C(=O)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
To a stirred solution of 6 g of 2,2-dimethyl-5-{4-(methylsulfinyl)phenyl}-3(2H)-furanone in 200 ml carbon tetrachloride and 100 ml chloroform, were added 5.15 g of [bis(trifluoroacetoxy)iodo]benzene (BTI) and 6.5 g of iodine. The reaction solution was stirred at room temperature. After 4 hours, the reaction was quenched by adding saturated aqueous sodium thiosulfate until the characteristic color of iodine disappeared. The quenched solution was extracted with water and dichloromethane (100 ml×3). The organic layer was concentrated in vacuo and the resulting crude product was recrystallized from hexane/ethylacetate to yield 4.5 g of 2,2-dimethyl-4-iodo-5-{4-(methylsulfinyl)phenyl}-3(2H)-furanone. NMR: δ1.53 (s, 6H), 2.79 (s, 3H), 7.81 (d, J=8.1 Hz, 2H), 8.38 (d, J=8.1 Hz, 2H). IR (cm−1): 2975, 2929, 1699, 1595, 1404, 1319, 1150, 969, 766, 552.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](O)=[O:18].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:17](=[O:18])[C:16]3[CH:20]=[CH:21][CH:22]=[C:14]([CH3:13])[CH:15]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1cccc(C(=O)O)c1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cccc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)c1
Reaction time: 0.17 h
Yield: 55.3 %

Procedure:
5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.250 g, 1.09 mmol), 3-methylbenzoic acid (311 mg, 2.28 mmol), BOP-Cl (581 mg, 2.28 mmol), and triethylamine (0.757 mL, 5.43 mmol) in DCM (5 mL) were stirred at room temperature for 30 minutes. 3M LiOH (3 mL) was then added. The reaction was stirred for an additional 10 minutes and then poured into water. The mixture was then filtered, washed with DCM, washed with 10:1 DCM:MeOH and dried to give N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylbenzamide (210 mg, 55.5% yield) as a solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].[N+:9]([O-])([OH:11])=[O:10]>C(OC(=O)C)(=O)C.C(O)(=O)C>[N+:9]([C:4]1[CH:3]=[C:2]([C:6]([OH:8])=[O:7])[S:1][CH:5]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cccs1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)c1cc([N+](=O)[O-])cs1

Procedure:
2-Thiophenecarboxylic acid (6.4 g, 50 mM) was suspended in acetic anhydride (15 ml) and fuming nitric acid (16 ml) in glacial acetic acid (25 ml) added slowly over 1 hour with stirring, while keeping the temperature of the reaction mixture below 30° C. The reaction mixture was stirred at ambient temperature for 2 hours. The product was purified by subjecting to chromatography (470 ml) on HP20SS resin using methanol/(water+1% acetic acid): 0/100→50/50 as eluant. The pure title compound was obtained (1.3 g) together with a mixture of 4- and 5- nitrothiophene-2-carboxylic acid (4.4 g).