Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.[CH2:15]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C:23]1=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[O:29]1CCCC1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:25]1([OH:29])[CH2:26][CH2:27][N:22]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:23][CH2:24]1
Reactant: c1ccc2sccc2c1
Reactant: C1CCOC1
Reactant: O=C1CCCCN1Cc1ccccc1
Agent: [Li]CCCC
Product: OC1(c2cc3ccccc3s2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
Benzothiophene (10 g, 0.07 mol) was dissolved in tetrahydrofuran (150 ml) and cooled to -10° C. (ice/methanol). Butyl lithium (33 ml of 2.5M in hexane, 0.077 mol) was added dropwise and the reaction mixture warmed to room temperature over one hour. Following addition of N-benzyl piperidone (9.16 ml, 0.07 mol) at -40°, the reaction was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and the crude product purified by flash chromatography eluting with 20% and 30% ethyl acetate in petroleum ether to give an orange/red solid. Recrystallisation from ether afforded the title compound as a pale yellow solid (16.87g, 75%); δH (CDCl3), 1.96 (2H, m, NCH2 CH2), 1.99 (1H, s, OH), 2.25 (2H, t of d, J 13.5Hz, J 4.4Hz, NCH2CH2), 2.51 (2H, t of d, J 11.6Hz, J 2.46Hz, NCH2 CH2), 2.76 (2H, m, NCH2CH2), 3.57 (2H, s, NCH2, Ar), 7.30 (8H, m, ArH), 7.70 (1H, d, J 7Hz, ArH), 7.79 (1H, d, J 7.6Hz, ArH). m/z (ES+) 324 (M+1)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=1)([O-])=O.[H][H].ClCCl>[Pd].C(OCC)(=O)C.C(O)(=O)C>[N:17]1([CH2:16][C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:7]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(CN2CCOCC2)cc(-c2ccccc2)c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Nc1cc(CN2CCOCC2)cc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Palladium on carbon (10 wt %, 47.8 mg, 0.045 mmol) was added to a solution of 4-[(5-nitrobiphenyl-3-yl)methyl]morpholine in ethyl acetate (4.1 mL) and acetic acid (0.408 mL). The reaction mixture was fitted with a hydrogen balloon and stirred at room temperature for 3 hours. Dichloromethane was added to the reaction mixture, and then filtered through CELITE and washed with dichloromethane. The organic fractions were washed with saturated aqueous NaHCO3, dried over sodium sulfate, filtered, and concentrated in vacuo to afford 5-(morpholin-4-ylmethyl)biphenyl-3-amine which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.58 (t, J=5.9 Hz, 2H), 7.43 (dd, J=9.5, 5.6 Hz, 2H), 7.35 (t, J=7.3 Hz, 1H), 6.97 (s, 1H), 6.83 (s, 1H), 6.71 (s, 1H), 3.92-3.61 (m, 4H), 3.49 (s, 2H), 2.50 (s, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].I[CH2:23][CH3:24].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:23][CH3:24])[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2
Reactant: CCI
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2cc(Cl)ccc2n1CC
Temperature: 25 °C
Reaction time: 72 h
Yield: 103.6 %

Procedure:
A mixture of ethyl 5-chloro-1H-indole-2-carboxylate (500 mg, 2.17 mmol), potassium carbonate (450 mg, 3.25 mmol), iodoethane (260 μL, 3.25 mmol) and N,N-dimethylformamide (10.8 mL) was stirred at room temperature for 3 days. To the reaction solution was added water, and the mixture was extracted with ethyl acetate twice. The organic layer was combined, washed with water three times, and the organic layer was filtered through diatomaceous earth, followed by silica gel, and then the filtrate was concentrated under reduced pressure to give ethyl 5-chloro-1-ethyl-1H-indole-2-carboxylate (566 mg, 100%) as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[C:4](=O)[C:3]1=O.[CH:13]1([NH2:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[NH2:19].[OH2:21]>C(O)(=O)C>[CH3:1][C:2]1([CH3:12])[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[C:4]2[N:20]=[C:13]3[C:14]([CH2:15][CH2:16][CH2:17][C:18]3=[O:21])=[N:19][C:3]1=2
Reactant: O
Reactant: CC1(C)CCC(C)(C)C(=O)C1=O
Reactant: NC1CCCCC1N
Solvent: CC(=O)O
Product: CC1(C)CCC(C)(C)c2nc3c(nc21)CCCC3=O

Procedure:
20.0 g of 3,3,6,6,-tetramethyl-1,2-cyclohexanedione and 20 ml of 1,2-cyclohexanediamine were dissolved in 20 ml of acetic acid. The obtained solution was heated under reflux for 6 hours, cooled by allowing to stand, and poured into water, followed by the extraction with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate, and concentrated in a vacuum. The obtained residue was purified by silica gel chromatography (developer: 5% ethyl acetate/hexane) to give 16.0 g of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:7][O:6][C:5]2([CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[O:4][CH2:3]1.[NH2:15][C:16]1[C:32]([Cl:33])=[CH:31][C:19]([C:20]([NH:22][C@H:23]2[CH2:28][CH2:27][NH:26][CH2:25][C@H:24]2[O:29][CH3:30])=[O:21])=[C:18]([O:34][CH3:35])[CH:17]=1.S1C=CC=C1.[H][H]>CO.[Pt]>[NH2:15][C:16]1[C:32]([Cl:33])=[CH:31][C:19]([C:20]([NH:22][C@H:23]2[CH2:28][CH2:27][N:26]([CH:10]3[CH2:11][CH2:12][C:5]4([O:6][CH2:7][C:2]([CH3:14])([CH3:1])[CH2:3][O:4]4)[CH2:8][CH2:9]3)[CH2:25][C@H:24]2[O:29][CH3:30])=[O:21])=[C:18]([O:34][CH3:35])[CH:17]=1
Reactant: [H][H]
Reactant: CC1(C)COC2(CCC(=O)CC2)OC1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCNC[C@H]1OC
Agent: [Pt]
Solvent: c1ccsc1
Solvent: CO
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(C2CCC3(CC2)OCC(C)(C)CO3)C[C@H]1OC
Yield: 62.6 %

Procedure:
A mixture of 10 parts of 3,3-dimethyl-1,5-dioxaspiro[5.5]undecan-9-one, 9.42 parts of cis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)benzamide, 1 part of a solution of thiophene in methanol 4% and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filterate was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried in vacuo at 60° C., yielding 9.33 parts (62.6%) of cis-4-amino-5-chloro-N-[1-(3,3-dimethyl-1,5-dioxaspiro[5.5]undec-9-yl)-3-methoxy-4-piperidinyl]-2-methoxybenzamide; mp. 187.5° C. (compound 92).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([N:15]([CH2:22][C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[C:25]#[N:26])[CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[S:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Cl-].[NH4+].[N-:33]=[N+:34]=[N-:35].[Na+]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([N:15]([CH2:22][C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[C:25]3[NH:35][N:34]=[N:33][N:26]=3)[CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[S:13][CH:14]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)c1ccc(-c2csc(N(Cc3cccs3)Cc3ccccc3C#N)n2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: CC(C)c1ccc(-c2csc(N(Cc3cccs3)Cc3ccccc3-c3nnn[nH]3)n2)cc1
Yield: 4.1 %

Procedure:
[4-(4-Isopropyl-phenyl)-thiazol-2-yl]-[2-(1H-tetrazol-5-yl)-benzyl]-thiophen-2-ylmethyl-amine (6.0 mg) was prepared following general procedure H from the corresponding nitrile (130 mg, 0.31 mmol), ammonium chloride (3.1 mmol) and sodium azide (3.1 mmol). Purification (Silica gel, methanol/DCM 3:97) provided the product. LCMS m/z: 474 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([OH:12])[CH:8]=[C:7]2[OH:13].[N+:14]([O-])([OH:16])=[O:15]>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([OH:12])[C:8]([N+:14]([O-:16])=[O:15])=[C:7]2[OH:13]
Reactant: Oc1cc(O)c2cccc(Br)c2n1
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1c(O)nc2c(Br)cccc2c1O
Temperature: 100 °C
Yield: 63.9 %

Procedure:
A modification of the method described in Part D of Example 10 was used to treat 8-bromoquinoline-2,4-diol (10.0 g, 41.6 mmol) with nitric acid (3.6 mL of 11.74 M, 54 mmol). The nitric acid was added at ambient temperature, and then the reaction was heated at 100° C. for one hour, at which time an exotherm occurred. The reaction was allowed to cool to ambient temperature; a precipitate formed and was isolated by filtration and washed with a small volume of water to provide 7.58 g of 8-bromo-3-nitroquinoline-2,4-diol as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.C([Li])CCC.[S:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1>O1CCCC1>[CH3:13][CH:12]([CH3:14])[CH2:11][O:10][C:9](=[O:15])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([C:24]2([OH:27])[CH2:25][CH2:26][S:21][CH2:22][CH2:23]2)=[CH:3][CH:4]=1
Reactant: O=C1CCSCC1
Reactant: CC(C)COC(=O)Nc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)COC(=O)Nc1ccc(C2(O)CCSCC2)cc1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of 2-methylpropyl 4-bromophenylcarbamate (Step 1, 10.0 g, 36.7 mmol) in anhydrous tetrahydrofuran (184 mL) at −78° C. under N2 is treated n-butyllithium (1.6M in hexanes, 48.2 mL, 77.1 mmol) dropwise over 20 mins, and the mixture is stirred at −78° C. for 45 mins. The resulting slurry is then treated with a solution of tetrahydro-2H-thiopyran-4-one (4.48 g, 38.5 mmol) in anhydrous tetrahydrofuran (38 mL) dropwise over 5 mins to give an opaque mixture which is allowed to slowly warm to 0° C. with stirring over approximately 2.5 h. The mixture is then quenched by the slow addition of saturated aqueous ammonium chloride (75 mL), water (75 mL) is added, and the layers are separated. The organic phase is washed with water (50 mL) and saline (50 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the crude product is recrystallized from EtOAc/hexanes to give the title compound, mp 150–151° C.; MS (ESI−) for C16H23NO3S m/z 308 (M−H)−.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[CH2:2].[C:5]([O:9]C)(=[O:8])[CH:6]=[CH2:7].[CH2:11]([C:13](C)=[O:14])[CH3:12]>>[C:5]([OH:9])(=[O:8])[CH:6]=[CH2:7].[Cl:4][CH2:1][C:2]([O:14][CH2:13][CH:11]=[CH2:12])=[O:8]
Reactant: C=CC(=O)OC
Reactant: C=C(Cl)Cl
Reactant: CCC(C)=O
Product: C=CC(=O)O
Product: C=CCOC(=O)CCl

Procedure:
Vinylidene chloride (60.5g) was mixed together with 28.8. of methyl acrylate. 10.6 g of acrylic acid and 11.1 g of allyl monochloroacetate in 100 ml of methyl ethyl ketone to give a 50% by volume solution, the temperature of the methyl ethyl ketone being 40° C. Then as copolymerisation initiator 1.0 g of 2, 2'- azobisisobutyronitrile was added to the monomer solution. The solution was maintained at 40° C until the copolymerisation was complete, which took 6 days.
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]([O:14]C)=[O:13])=[CH:8][C:6]=2[CH:7]=1)#[N:2].C[OH:17]>O>[NH2:2][C:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8][C:6]=2[CH:7]=1)=[O:17]
Reactant: CO
Reactant: COC(=O)c1ccc2oc(C#N)cc2c1
Solvent: O
Product: NC(=O)c1cc2cc(C(=O)O)ccc2o1
Temperature: 0 °C
Reaction time: 6 h
Yield: 97 %

Procedure:
Methyl 2-cyano-1-benzofuran-5-carboxylate (426 mg, 2.0 mmol) is dissolved in MeOH (10 ml). The solution is cooled to 0° C., is treated with LiOH monohydrate (168 mg, 4.0 mmol) in H2O (4 ml), and the reaction is stirred 6 h at RT. The volatiles are removed in vacuo and the residue is dissolved in H2O (10 ml). The pH of the mixture is adjusted to 1.9 with 12N HCl, the white solid is collected, washed with water, and is dried to give 401 mg (97%) of 2-(aminocarbonyl)-1-benzofuran-5-carboxylic acid as an off-white solid. MS (EI) calcd for C10H7NO4: 205.0375, found 205.0369 (M)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-:16].[K+].[O:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:9][CH2:10][C@H:11](/[CH:14]=[CH:20]/[C:19]([O:18][CH2:22][CH3:21])=[O:16])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: C1CCOC1
Reactant: O=CC1CCC(c2ccc(Br)cc2)CC1
Agent: [K+]
Solvent: O
Product: CCOC(=O)/C=C/[C@H]1CC[C@H](c2ccc(Br)cc2)CC1
Reaction time: 8 h

Procedure:
A mixture of 9.1 g of 4-(4-bromophenyl)cyclohexanecarb-oxaldehyde and 3.8 g of powdered potassium hydroxide in 200 ml of tetrahydrofuran was placed at room temperature in a sulphonation flask while gassing with argon and treated with 9.2 g of triethyl phosphonoacetate within 15 minutes, stirred overnight, taken up in 100 ml of water and extracted three times with 100 ml of methylene chloride each time. The organic phases were washed twice with 100 ml of water each time, dried over magnesium sulphate and concentrated. Low-pressure chromato-graphy of the residue (12 g) on silica gel with hexane/ethyl acetate (vol. 9:1) gave 11.7 g of ethyl (E)-3-[trans-4-(4-bromo-phenyl)cyclohexyl]acrylate as colourless crystals.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:15])[CH:8]=2)[N:3]=1.[NH3:16]>>[NH2:16][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:15])[CH:8]=2)[N:3]=1
Reactant: Cc1ccc2nc(Cl)c([N+](=O)[O-])cc2c1
Reactant: N
Product: Cc1ccc2nc(N)c([N+](=O)[O-])cc2c1
Temperature: 130 °C
Reaction time: 6 h

Procedure:
2.0 g of 2-chloro-6-methyl-3-nitroquinoline (compound C2) is dissolved in 100 ml of ethanolic ammonia solution and stirred at 130° C. for 6 h in an autoclave. After cooling to from temperature, the reaction mixture is concentrated in vacuo and the residue redissolved in 50 ml of ethyl acetate and extracted two times each with 50 ml of halfsaturated aqueous potassium carbonate solution. The organic phase is dried using magnesium sulfate, filtered and evaporated in vacuo. The residue is filtered over silica gel (dichloromethane). 1.5 g of the title compound are obtained as violet solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([S:25]([CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])(=[O:27])=[O:26])[C:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]3[S:22][CH:23]=[CH:24][C:13]=23)=[O:11])=[CH:5][CH:4]=1.O1CCN(CC[N+]#[C-])CC1.O[N:45]1[C:49](=[O:50])[CH2:48][CH2:47][C:46]1=[O:51]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([S:25]([CH2:28][CH2:29][CH2:30][C:31]([O:33][N:45]2[C:49](=[O:50])[CH2:48][CH2:47][C:46]2=[O:51])=[O:32])(=[O:26])=[O:27])[C:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]3[S:22][CH:23]=[CH:24][C:13]=23)=[O:11])=[CH:7][CH:8]=1
Reactant: O=C1CCC(=O)N1O
Reactant: COc1ccc(N(C(=O)c2c3ccccc3nc3sccc23)S(=O)(=O)CCCC(=O)O)cc1
Agent: [C-]#[N+]CCN1CCOCC1
Product: COc1ccc(N(C(=O)c2c3ccccc3nc3sccc23)S(=O)(=O)CCCC(=O)ON2C(=O)CCC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.5 %

Procedure:
A mixture of 66 mg (0.12 mmol) N-(4-Methoxy-phenyl)-N-(carboxypropyl-sulfonyl)-thieno[2,3-b]quinoline-4-carboxamide 17, 25 μl (0.17 mmol) 2-Morpholino-ethyl-isocyanide (MEI) and 21 mg (0.17 mmol) N-Hydroxysuccinimide (HOSu) was stirred overnight at room temperature. The solvent was removed under vacuum and the oily residue was purified by silica gel column chromatography (eluent: methylene chloride/acetone 9:1+0.1% acetic acid). The appropriate fractions were combined and evaporated to yield 75 mg of 18.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O.[IH:21].II.S(=O)(=O)(O)O>CO.C(O)(=O)C>[C:1]1([C:7]2[CH:8]=[C:9]([C:13]3[CH:14]=[CH:15][C:16]([I:21])=[CH:17][CH:18]=3)[CH:10]=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:1]1([C:7]2[CH:8]=[C:9]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:10]=[C:11]([I:21])[CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: I
Reactant: c1ccc(-c2cccc(-c3ccccc3)c2)cc1
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: Ic1cc(-c2ccccc2)cc(-c2ccccc2)c1
Product: Ic1ccc(-c2cccc(-c3ccccc3)c2)cc1
Reaction time: 3 h

Procedure:
A three-necked flask was charged with 250 g of m-terphenyl (ALDRICH), 50 g of hydroiodic acid dihydrate, 75 g of iodine, 750 ml of acetic acid, and 25 ml of concentrated sulfuric acid, and reaction was allowed to proceed at 70° C. for 3 hours. The product was poured into 5 L of methanol and the mixture was stirred for 1 hour and filtrated. The obtained crystals were purified by column chromatography, and recrystallized from acetonitrile to give 64 g of 3′-phenyl-4-iodobiphenyl (Intermediate 4) and 17 g of 3-phenyl-5-iodobiphenyl in the form of white powder. FD-MS and H-NMR analysis identified the powder as Intermediate 4.
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[Br:16][C:17]1[CH:18]=[C:19]([O:26][CH3:27])[CH:20]=[C:21]2[C:25]=1[NH:24][CH2:23][CH2:22]2>>[Br:16][C:17]1[CH:18]=[C:19]([O:26][CH3:27])[CH:20]=[C:21]2[C:25]=1[N:24]([C:2]1[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1)[CH2:23][CH2:22]2
Reactant: COc1cc(Br)c2c(c1)CCN2
Reactant: CCC(CC)n1cc(Cl)nc(Cl)c1=O
Agent: Cl
Product: CCC(CC)n1cc(Cl)nc(N2CCc3cc(OC)cc(Br)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-(1-ethylpropyl)-2(1H)-pyrazinone and 7-bromo-5-methoxyindoline hydrochloride as the starting materials. mp 130–132° C.; 1H NMR (300 MHz, CDCl3): δ 6.92 (d, J=2.6 Hz, 1 H), 6.78 (d, J=2.2 Hz, 1 H), 6.73 (s, 1 H), 4.81 (brs, 1 H), 4.35 (t, J=7.7 Hz, 2 H), 3.78 (s, 3 H), 3.11 (t, J=7.7 Hz, 2 H), 1.87–1.73 (m, 2 H), 1.70–1.60 (m, 2 H), 0.89 (s, 6 H); HRMS (ESI) calcd for C18H22N3O2BrCl (M+H)+: 426.0584; found m/z 426.0606.
Reaction SMILES: CC1(C)[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])O1.[C:11]1([CH2:17][C:18](Cl)=O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CO[CH:23](OC)[N:24](C)C.CO>ClCCl>[O:5]=[C:4]1[C:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:18][NH:24][CH:23]=[C:6]1[C:7]([OH:9])=[O:8]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COC(OC)N(C)C
Solvent: ClCCl
Solvent: CO
Product: O=C(O)c1c[nH]cc(-c2ccccc2)c1=O
Temperature: 65 °C
Reaction time: 3.5 h
Yield: 44.6 %

Procedure:
To a solution of Meldrum's acid (1.0 g, 7.0 mmol) and dry TEA (5 mL, 35.6 mmol) in dry dichloromethane (15 mL) was added phenylacetyl chloride (0.95 mL, 7.13 mmol) dropwise at ice bath temperature. The reaction mixture was allowed to back to RT, stirred for 3.5 h. Crude adduct of Meldrum's acid and acetyl chloride was washed by 3N hydrochloric acid and concentrated. To the residue was added ethanol (20 mL); the reaction mixture was heated to reflux for 3 h. Resultant residue was made to react to N,N-dimethylformamide dimethyl acetal (1.5 mL, 11.2 mmol) in xylenes (15 mL) at 120° C. for 4 hrs with removal of methanol and concentrated in vacuo. The residue was cyclized by ammonium acetate (1.15 g) in methanol (20 mL) at reflux for 4 hrs. Crude ethyl ester was saponificated by 10% sodium hydroxide solution (10 mL) in methanol (20 mL). Reaction mixture was heated at 65° C. for 2.5 hours. Solid precipitated during acidic workup by 3N hydrochloric acid was collected by filter, washed by methanol (small amount), water and diethyl ether, dried to give the title compound D125 (671.2 mg, 21% over four steps). 1H-NMR (400 MHz, DMSO-d6): 13.16 (brs, 1H, NH), 8.60 (d, J=1.6 Hz, 1H, pyridone-H), 8.23 (d, J=1.6 Hz, 1H, pyridone-H), 7.65 (d, J=8 Hz, 2H, ArH), 7.50-7.41 (m, 3H, ArH).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]3[C:17]4[CH2:28][CH2:27][NH:26][C:20]5([CH2:25][CH2:24]C[O:22][CH2:21]5)[C:18]=4[O:19][C:13]=3[CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.F[C:30]1C=C(S)C=CC=1.IC1C=CC2C3CCNC4(CCOC4C)C=3OC=2C=1>>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]3[C:17]4[CH2:28][CH2:27][NH:26][C:20]5([CH2:25][CH2:24][O:22][CH:21]5[CH3:30])[C:18]=4[O:19][C:13]=3[CH:12]=2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1cccc(F)c1)c1ccc2c3c(oc2c1)C1(CCCOC1)NCC3
Reactant: Fc1cccc(S)c1
Agent: CC1OCCC12NCCc1c2oc2cc(I)ccc12
Product: CC1OCCC12NCCc1c2oc2cc(S(=O)(=O)c3cccc(F)c3)ccc12

Procedure:
Prepared as described for 7-[(3-fluorophenyl)sulfonyl]-3,4,5′,6′-tetrahydro-2H,4′H-spiro[1-benzofuro[2,3-c]pyridine-1,3′-pyran] (Example 22) starting from 3-fluorobenzenethiol and 7-iodo-2′-methyl-3,4,4′,5′-tetrahydro-2H-spiro[1-benzofuro[2,3-c]pyridine-1,3′-furan].
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]#[CH:14])(OC(C)(C)C)=O.[CH2:15]([O:17][C:18]([C:20]1[C:24]([CH3:25])=[C:23](/[CH:26]=[C:27]2\[C:28](=[O:38])[NH:29][C:30]3[C:35]\2=[C:34](I)[C:33]([F:37])=[CH:32][CH:31]=3)[NH:22][CH:21]=1)=[O:19])[CH3:16]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.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.[Cu]I>[CH2:15]([O:17][C:18]([C:20]1[C:24]([CH3:25])=[C:23](/[CH:26]=[C:27]2\[C:28](=[O:38])[NH:29][C:30]3[C:35]\2=[C:34]([C:14]#[C:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[C:33]([F:37])=[CH:32][CH:31]=3)[NH:22][CH:21]=1)=[O:19])[CH3:16]
Reactant: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: CCOC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(I)c32)c1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(C#C[C@@H]4CCCN4)c32)c1C
Reaction time: 2 h

Procedure:
Using Method C above, (S)-N-Boc-2-Ethynyl-pyrrolidine (106 mg, 0.55 mmol) (Example 87B) was coupled with (Z)-5-(5-fluoro-4-iodo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (80 mg, 0.18 mmol) (Example 116B) using (Ph3P)4Pd (21 mg, 0.02 mmol) and a catalylic amount of CuI in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4, concentrated and the residue was chromatographed on a silica gel column with a 0-40% EtOAc in hexanes gradient. The resulting intermediate was dissolved in 5 mL of a 50% trifluoroacetic acid in CH2Cl2 solution that contained 0.5 mL of H2O at 0° C. and stirred for 2 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with ammonium hydroxide. The organic layer was dried over Na2SO4 and concentrated. (S)-(Z)-5-[[5-Fluoro-2-oxo-4-[(pyrrolidin-2-yl)ethynyl]-1,2-dihydro-indol-3-ylidene]methyl]-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester was obtained after silica gel column chromatography with a 0-100% EtOAc in hexanes-30% THF in EtOAc gradient and precipitation out of THF with excess of hexanes. (Yield 21 mg, 28%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:11]=[C:12]([NH:17][C:18](=[O:20])[CH3:19])[CH:13]=[CH:14][C:15]=1[OH:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([O:16][C:15]2[CH:14]=[CH:13][C:12]([NH:17][C:18](=[O:20])[CH3:19])=[CH:11][C:10]=2[F:9])[CH:7]=1
Reactant: CC(=O)Nc1ccc(O)c(F)c1
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Oc2cc(Cl)ncn2)c(F)c1
Temperature: 70 °C
Yield: 71 %

Procedure:
A mixture of 4,6-dichloropyrimidine (1.50 g, 10.0 mmol), N-(3-fluoro-4-hydroxyphenyl)acetamide (1.70 g, 10.0 mmol), K2CO3 (1.8 g, 13.0 mmol), and DMF (15 mL) was heated at 70° C. for 1.5 h. The mixture was concentrated to half its original volume and cooled in an ice bath. The mixture was treated with H2O (100 mL) to precipitate the product which was collected by vacuum filtration. The product was washed with H2O and vacuum dried on the funnel overnight to give the title compound (2.0 g, 71%) as a gray solid. 1H NMR (DMSO-d6) δ 10.26 (s, 1H), 8.67 (s, 1H), 7.78 (dd, 1H, J=12.6, 2.0 Hz), 7.56 (s, 1H), 7.37-7.30 (m, 2H), 2.08 (s, 3H); MS (ESI+) m/z 282.10 (M+H)+.