Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[N:11]1([CH:17]=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.CN(C=O)C>O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:14]1[CH2:15][CH2:16][N:11]([CH:17]=[O:18])[CH2:12][CH2:13]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: O=CN1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Product: O=CN1CCN(c2ccccc2[N+](=O)[O-])CC1
Temperature: 100 °C
Yield: 33 %

Procedure:
A mixture of 1-chloro-2-nitrobenzene (6.54 g, 41.5 mmol), piperazine-1-carboxaldehyde (4.7 g, 41.5 mmol) and DMF (18 mL) was heated 48 hours at 100° C. The reaction mixture then was cooled, diluted with water and extracted with ethyl acetate (3×). The combined extracts were washed with water, dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with methylene chloride/methanol (98:2) to give 4-(2-nitrophenyl)piperazine-1-carbaldehyde (3.2 g, 13.7 mmol).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=2[O-:14])[CH2:4][CH2:3]1.[C:15]([O:19][C:20]([NH:22][C@@H:23]1[CH2:27][CH2:26][NH:25][CH2:24]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(O)(=O)C.[Na]>CO>[C:15]([O:19][C:20]([NH:22][CH:23]1[CH2:27][CH2:26][N:25]([C@H:2]2[CH2:7][CH2:6][C@H:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=3[O-:14])[CH2:4][CH2:3]2)[CH2:24]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: O=C1CCC(c2cccc[n+]2[O-])CC1
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1CCN([C@H]2CC[C@H](c3cccc[n+]3[O-])CC2)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 17.8 mL of methanol containing 2-(4-oxocyclohexyl)pyridine N-oxide (1.8 g, 9.41 mmol) and 1.75 g (9.41 mmol) of (3R)-(+)-3-(tert-butoxycarbonylamino)-pyrrolidine was added 3.23 mL (56.4 mmol) of glacial acetic acid under an inert atmosphere. The resulting solution was stirred at ambient temperature for 20 minutes, cooled to 0° C., and treated with four equal portions of solid sodium cyanoborohyride (total: 296 mg, 4.71 mmol). The reaction mixture was stirred at 0° C. for 20 minutes more. All volatiles were removed under reduced pressure and the residue was taken up in 200 mL of ethyl acetate. The organic layer was washed with 10% sodium carbonate solution and brine, then dried (sodium sulfate) and concentrated to yield 2.86 g of the crude product as an oil. The desired trans-2-[4-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-cyclohexyl]-pyridine N-oxide was obtained via preparative centrifugal chromatography on silica gel (chloroform-methanol gradient elution). A portion of this material (544 mg, 1.505 mmol) was dissolved in 300 mL ethyl acetate at 0° C., and HCl gas was bubbled through the solution for 10 min. The reaction mixture was allowed to come to room temperature over a 1 hour period. All volatiles were rotoevaporated under reduced pressure to give a white solid. This material was resuspended in 200 mL of ethyl acetate and treated with 10 ml of 10% sodium carbonate solution. After 10 minutes the phases were separated and the organic layer was dried (sodium sulfate). The aqueous layer was concentrated to dryness and the residue was stirred with a chloroform-methanol mixture (4:1, v/v). The suspension was filtered and the filtrate was combined with the ethyl acetate extracts. The combined organic extracts were then concentrated and azeotropically dried with toluene to give 400 mg of the title compound as a tan powder.
Reaction SMILES: [C:1]1([O:11][CH3:12])[C:2](=[CH:4][CH:5]=[C:6]([CH:10]=1)[CH2:7][CH:8]=[CH2:9])[OH:3].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>>[CH2:17]([O:16][C:14](=[O:15])[O:3][C:2]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]=[CH2:9])=[CH:10][C:1]=1[O:11][CH3:12])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C=CCc1ccc(O)c(OC)c1
Reactant: O=C(Cl)OCc1ccccc1
Product: C=CCc1ccc(OC(=O)OCc2ccccc2)c(OC)c1

Procedure:
Starting Material: Eugenol and benzyl chloroformate.
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:7])[CH2:4][CH2:5][CH3:6].S([O-])([O-])(=O)=S.[Na+].[Na+].I[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[C:17]=1[F:24]>CN(C=O)C.C(N(CC)CC)C.[Cu](I)I>[OH:7][CH:3]([CH2:4][CH2:5][CH3:6])[C:2]#[C:1][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[C:17]=1[F:24]
Reactant: C#CC(O)CCC
Reactant: Fc1ccc(I)c(F)c1F
Agent: I[Cu]I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC(O)C#Cc1ccc(F)c(F)c1F
Temperature: 55 °C
Reaction time: 3 h

Procedure:
In a nitrogen atmosphere, 4-iodo-1,2,3-trifluorobenzene was dissolved into DMF, into which triethylamine, copper iodide (I), and tetrakistriphenylphosphine palladium (0) were added and heated to 55° C. Then, the DMF solution containing 1-hexine-3-ol was added dropwise for 20 minutes, and stirred for 3 hours. After the reaction mixture was poured into a sodium thiosulfate aqueous solution, and stirred for a while, an organic layer was separated, and an aqueous layer was extracted with toluene. After the extract and the organic layer were mixed together, washed using water, 10% hydrochloric acid twice, water, a saturated sodium hydrogen carbonate aqueous solution, and a saturated saline solution in that order, and dried using anhydrous magnesium sulfate, the solvent was evaporated under a reduced pressure. The residue was purified by column chromatography (silica gel, toluene/hexane) to obtain 1-(3-hydroxy-1-hexynyl)-2,3,4-trifluorobenzene.
Reaction SMILES: [Cl:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)/[C:4](=N/S(C2SC=CC=2)(=O)=O)/[CH:3]=1.[C:22]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N:31][S:28]([C:25]2[CH:26]=[CH:27][C:22]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:23][CH:24]=2)(=[O:29])=[O:30])[CH:3]=1
Reactant: O=C1C(Cl)=C/C(=N\S(=O)(=O)c2cccs2)c2ccccc21
Reactant: NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Product: O=C1C(Cl)=CC(=NS(=O)(=O)c2ccc(-c3ccccc3)cc2)c2ccccc21

Procedure:
5.2.31 N-(3-chloro-4-oxonaphthalen-1(4H)-ylidene)biphenyl-4-sulfonamide (12b) was prepared according to the procedure for 12a except using 4-biphenylsulfonamide, which afforded the title compound 154 mg (37.8%) as a yellow solid. When TiCl4.2THF and THF were used instead, the reaction afforded the title compound 586.7 mg (71.9%) as a yellow solid, m.p.: 190-192° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH2:10][O:9][CH2:8][N:7]([S:11]([C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=3[O:21][CH3:22])(=[O:13])=[O:12])[C:6]=2[CH:23]=1.C(N(CC)CC)C.[C:31]([O:34][CH2:35]C)(=[O:33])C>CO>[CH3:35][O:34][C:31]([C:2]1[CH:3]=[CH:4][C:5]2[CH2:10][O:9][CH2:8][N:7]([S:11]([C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=3[O:21][CH3:22])(=[O:13])=[O:12])[C:6]=2[CH:23]=1)=[O:33]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1COCc2ccc(Br)cc21
Reactant: CCOC(C)=O
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)COC2
Yield: 43 %

Procedure:
A solution of 7-bromo-1-(5-chloro-2-methoxy-benzenesulfonyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine (2.00 g, 4.78 mmol), triethylamine (1.21 g, 11.9 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane complex (200 mg, 0.239 mmol) in methanol (30 mL) and ethyl acetate (30 mL) was heated at 130° C. under a carbon monoxide atmosphere (100 bar) for 3 h. The reaction mixture was evaporated and the residue chromatographed (SiO2, heptane-ethyl acetate gradient) to produce 1-(5-chloro-2-methoxybenzenesulfonyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine-7-carboxylic acid methyl ester (825 mg, 43%). Orange solid, MS (ISP)=398.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=O)=[N:6][CH:7]=1.[C:10](=O)([O-])[O-].[K+].[K+].COP(C(=[N+]=[N-])C(=O)C)(=O)OC>CO>[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=1)#[CH:10]
Reactant: O=Cc1ccc(F)cn1
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(F)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.7 %

Procedure:
To a mixture of 5-fluoro-2-formylpyridine (1.10 g, 9.0 mmol) in MeOH (38 mL) was added potassium carbonate (2.44 g, 0.018 mol) followed by a solution of (1-diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (2.03 g, 11 mmol) in MeOH (12 mL). The mixture was stirred at room temperature for 90 min, then extracted with diethylether. The organic layers were then washed with sodium hydrogen carbonate solution (1 M) and brine, dried over sodium sulfate, filtered and evaporated at to give the title compound (1.01 g, 78%) as a light brown liquid. MS: m/e=121.0 [M]+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:18]1[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH:23]=1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C.O1CCCC1>[CH3:24][N:21]1[CH2:20][CH2:19][CH:18]([C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[C:9]([OH:8])[CH:10]=3)[NH:14][CH:13]=2)[CH2:23][CH2:22]1
Reactant: [H][H]
Reactant: CN1CC=C(c2c[nH]c3ccc(OCc4ccccc4)cc23)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CN1CCC(c2c[nH]c3ccc(O)cc23)CC1
Yield: 51.1 %

Procedure:
A mixture of 5-benzyloxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (16.4 g, 51.5 mmol) and 5% palladium on carbon (4.0 g) in ethanol (125 mL) and tetrahydrofuran (125 mL) was hydrogenated with an initial hydrogen pressure of 60 psi (413 kPa) at ambient temperature for 16 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was crystallized from methanol and THF to give 6.06 g (51%) of the title compound as white crystals: mp=234-237° C.; MS(m/e): 230 (M+); Calculated for C14H18N2O: Calcd: C, 73.01; H, 7.88; N, 12.16. Found: C, 72.79; H, 8.17; N, 12.33.
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:10])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>C(OCC)(=O)C>[N+:1]([C:4]1[C:5](=[O:10])[N:6]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccnc1O
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Cn1cccc([N+](=O)[O-])c1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
Sodium hydride (1.57 g of a 60% dispersion in mineral oil, 0.039 mole) was washed with hexanes three times (10 mL each) and suspended in dimethylformamide (25 mL). The stirred suspension was cooled in an ice bath, then 3-nitro-2-hydroxypyridine (5.00 g, 0.036 mole) was added in small portions over a 25-minute period. After the addition was complete, the reaction was stirred at 0° C. for 10 minutes, then room temperature for 30 minutes. The reaction mixture was recooled in an ice bath. t-Butyl bromoacetate (5.25 mL, 0.036 mole) was added. The reaction was stirred at 0° C. for 1 hour, then 1.5 hours at room temperature. The reaction mixture was diluted with ethyl acetate (80 mL), and ice (80 g) was added. The aqueous layer was extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with water (4×100 mL), brine (100 mL), and dried over anhydrous sodium sulfate. The solvent was removed, and the resulting residue was chromatographed through silica gel using 10% ethyl acetate/dichloromethane as eluent. The pure fractions were combined, and the solvent was removed under vacuum to afford 6.77 g (75% yield) of the title compound as yellow solid. Rf =0.30 (silica gel, 20% ethyl acetate in dichloromethane).
Reaction SMILES: [CH:1]([Si:4]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[C:7]=1[NH2:13])([CH3:3])[CH3:2].[C:20](OCC)(=O)[CH:21]=[O:22].C1(C)C=CC=CC=1>C(O)C>[CH:17]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:14]([CH3:16])[CH3:15])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:7]=1[N:13]=[CH:20][C:21](=[O:22])[NH:12]2)([CH3:19])[CH3:18]
Reactant: CC(C)[Si](Oc1cccc(N)c1N)(C(C)C)C(C)C
Reactant: CCOC(=O)C=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)[Si](Oc1cccc2[nH]c(=O)cnc12)(C(C)C)C(C)C
Reaction time: 8 h

Procedure:
A solution of (b) (80.7 g) in ethanol (1 liter) was treated with a 50% solution of ethyl glyoxalate in toluene (60 ml, 294 mmol) and heated to reflux for 2 hours. The mixture was left at room temperature overnight and filtered affording 5-triisopropylsilanyloxy-1H-quinoxalin-2-one. The filtrate was evaporated and the residue chromatographed eluting with a 0-3% gradient of methanol in dichloromethane affording 8-triisopropylsilanyloxy-1H-quinoxalin-2-one as a white solid (14.9 g).
Reaction SMILES: OS(O)(=O)=O.[CH3:6][N:7]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([C:15]([OH:17])=[O:16])=[N:8]1.[CH3:18]O>>[CH3:6][N:7]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([C:15]([O:17][CH3:18])=[O:16])=[N:8]1
Reactant: CO
Reactant: Cn1cc([N+](=O)[O-])c(C(=O)O)n1
Agent: O=S(=O)(O)O
Product: COC(=O)c1nn(C)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Concentrated H2SO4 (0.4 ml) was added to 1-methyl-4-nitropyrazole-3-carboxylic acid (2.02 g) in MeOH (40 ml) and the mixture heated to reflux for 4 hours. After cooling to room temperature, the reaction was concentrated in vacuo. The crude material was dissolved in EtOAc (60 ml) then washed with water (10 ml) and brine (10 ml). The organic layer was dried, filtered and concentrated to give methyl 1-methyl-4-nitropyrazole-3-carboxylate, 1.96 g.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([CH:7]([NH:10][C:11]1[C:12]([N+:25]([O-:27])=[O:26])=[CH:13][C:14]([CH2:21][CH:22]=[N:23]O)=[C:15]([CH3:20])[C:16]=1[N+:17]([O-:19])=[O:18])[CH2:8][CH3:9])[CH3:6]>O1CCCC1>[CH2:5]([CH:7]([NH:10][C:11]1[C:12]([N+:25]([O-:27])=[O:26])=[CH:13][C:14]([CH2:21][C:22]#[N:23])=[C:15]([CH3:20])[C:16]=1[N+:17]([O-:19])=[O:18])[CH2:8][CH3:9])[CH3:6]
Reactant: CCC(CC)Nc1c([N+](=O)[O-])cc(CC=NO)c(C)c1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCC(CC)Nc1c([N+](=O)[O-])cc(CC#N)c(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
A solution of thionyl chloride (25.0 ml) in tetrahydrofuran (THF; 100 ml) is added at <20° C. to a solution of {5-[(1-ethylpropyl)amino]-4,6-dinitro-o-tolyl}acetaldehyde oxime (12.0 g; 0.037 mol) in THF (160 ml). The reaction mixture is stirred overnight at room temperature, filtered, and the filtrate concentrated in vacuo to leave an oil which crystallizes, when seeded, to afford the title product (9.8 g), an orange solid. A sample is purified for analysis, melting point 59°-60° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C@@H:7]([OH:21])[C@@H:8]2[N:12]([CH3:13])[C:11](=[O:14])[CH2:10][C@@H:9]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[F:29].C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>COCCOC.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:22][C:23]1[CH:24]=[C:25]([C:2]2[S:6][C:5]([C@@H:7]([OH:21])[C@@H:8]3[N:12]([CH3:13])[C:11](=[O:14])[CH2:10][C@@H:9]3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:4][CH:3]=2)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)c1ccc(Br)s1
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: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)c1ccc(-c2ccc(F)c(Cl)c2)s1
Temperature: 25 °C
Yield: 68.9 %

Procedure:
To a solution of (±)-(4R*,5R*)-5-[(1S*)(5-bromo(2-thienyl))hydroxymethyl]-1-methyl-4-phenylpyrrolidin-2-one (300 mg, 0.82 mmol) in 1,2-dimethoxyethane (2.8 mL) was added 3-chloro-4-fluorobenzeneboronic acid (85.9 mg, 1.07 mmol), followed by a 1M Na2CO3 solution (2.2 mL). A catalytic amount of Pd(PPh3)4 was added and the reaction mixture was heated at the reflux temperature for 3 h, then allowed to cool to room temperature and poured onto a mixture of ice and CH2Cl2. The resulting mixture was extracted with CH2Cl2, dried (MgSO4) and concentrated under reduced pressure. The crude product was triturated (Et2O/ cyclohexane) to give (±)-(4R*,5R*)-5-{(1S*)[5-(3-chloro-4-fluorophenyl)(2-thienyl)]hydroxymethyl}-1-methyl-4-phenylpyrrolidin-2-one (235 mg, 69%): mp 194° C.; TLC (EtOAc) Rf 0.47
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:3]=12.[Br:14]N1C(=O)CCC1=O.O>C(O)(=O)C>[Br:14][C:7]1[C:2]([Cl:1])=[C:3]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][NH:8][C:4]2=[N:5][CH:6]=1
Reactant: O=[N+]([O-])c1c[nH]c2nccc(Cl)c12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1c[nH]c2ncc(Br)c(Cl)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.2 %

Procedure:
Into a suspension of 4-chloro-3-nitro-1H-pyrrolo[2,3-b]pyridine (50.0 g) in acetic acid (300 mL) were added N-bromosuccinimide (NBS, 70.9 g, 1.60 equiv) in small portions at 25° C. The reaction mixture was stirred at 25° C. for 18 h. Water (3.0 mL) was added slowly over 30 min to get a light yellow slurry. The resulting solid was collected by filtration and washed with a 2:2:1 (v/v/v) mixture of saturated sodium sulfite solution, water, and methanol, followed by water and a 1:1 (v/v) mixture of methanol and water. The cake was dried in a vacuum at 50° C. oven overnight to give the 44.9 g (65% yield) of 5-bromo-4-chloro-3-nitro-1H-pyrrolo[2,3-b]pyridine as an light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 13.7 (s, 1H), 8.93 (s, 1H), 8.66 (s, 1H). 13C NMR (75 MHz, DMSO-d6) δ 146.9, 146.4, 133.9, 133.2, 127.0, 116.7, 111.3. HRMS calcd. For C7H2BrC1N3O2 [M-H]−: 273.9024, found 273.9031.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.I[C:11]1[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=1>>[CH3:18][C:13]1[CH:12]=[C:11]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[N:2]2)[CH:16]=[C:15]([CH3:17])[CH:14]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: c1ccc2[nH]ncc2c1
Product: Cc1cc(C)cc(-n2ncc3ccccc32)c1
Yield: 96 %

Procedure:
Using general procedure A, indazole (148 mg, 1.25 mmol) was coupled with 5-iodo-m-xylene (150 μL, 1.04 mmol). The crude product was purified by flash chromatography on silica gel (2×15 cm; hexane-ethyl acetate 10:1; 10 mL fractions). Fractions 4-10 provided 222 mg (96% yield) of the product as a pale yellow oil. 1H NMR (300 MHz, CDCl3): δ 8.20 (d, J=1.0 Hz, 1H), 7.83-7.74 (m, 2H), 7.46-7.40 (m, 1H), 7.36 (s, 2H), 7.25-7.19 (m, 1H), 7.01 (s, 1H), 2.43 (s, 6H).
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].P(=O)(O)(O)O.[F:14]F>>[F:14][C:7]1[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][CH:8]=1
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: FF
Agent: O=P(O)(O)O
Product: O=c1[nH]cc(F)c(=O)[nH]1

Procedure:
The process comprises reacting uracil in an aqueous phosphoric acid solution with elemental fluorine and heating the resultant reaction solution to form 5-fluorouracil.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH:18]1[CH2:20][CH2:19]1.Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].[H-].[Na+]>CN(C=O)C>[CH3:32][O:31][C:29](=[O:30])[CH2:28][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([CH:18]1[CH2:20][CH2:19]1)[N:8]2[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Oc1cccc2c1cc(C1CC1)n2Cc1ccccc1-c1ccccc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1cc(C1CC1)n2Cc1ccccc1-c1ccccc1
Yield: 58.5 %

Procedure:
1-([1,1'-Biphenyl]-2-ylmethyl)-2-cyclopropyl-4-hydroxy-1H-indole (367 mg, 1.1 mmol) was alkylated by treating with 0.1 mL (1.1 mmol) of methyl bromoacetate and 43 mg(1.1 mmol) of 60% NaH/mineral oil in DMF as described in Example 1, Part E. The product was purified by chromatography over silica gel eluting with 20% EtOAc/hexane to give 265 mg(59% yield) of [[1-([1,1'-biphenyl]-2-ylmethyl)-2-cyclopropyl-1H-indol-4-yl]oxy]acetic acid methyl ester.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:22]=4[O:23][CH:24]([CH3:30])[C:25]([O:27]CC)=[O:26])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[OH-].[Na+]>CO>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:22]=4[O:23][CH:24]([CH3:30])[C:25]([OH:27])=[O:26])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(C)Oc1c(COc2ccc3oc(-c4nc(C(C)(C)C)cs4)cc3c2)cccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc(COc2ccc3oc(-c4nc(C(C)(C)C)cs4)cc3c2)c1OC(C)C(=O)O
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To a solution of ethyl 2-{2-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yloxy]methyl}-6-methoxyphenoxy}propionate (2.30 g) in a mixed solvent of tetrahydrofuran (30 ml)and methanol (15 ml) was added 1N sodium hydroxide solution (6.8 ml) at room temperature. The solution was stirred for two hours and concentrated under reduced pressure. The residue was diluted with water and acidified with 1N hydrochloric acid and was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate to give 2-{2-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yloxy]methyl}-6-methoxyphenoxy}propionic acid (2.17 g) as an amorphous solid.
Reaction SMILES: [Br-].[C:2]1([C:8]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11][O:10][C:9]2=[N+:13]([CH3:15])[CH3:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:29]2[N:30]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=3)[C:31]3[C:36]([N:37]=2)=[CH:35][N:34]=[CH:33][N:32]=3)[CH2:24][CH2:23]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C(=O)C>O>[CH3:14][N:13]([CH3:15])[C:9](=[O:10])[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:12][CH2:11][N:22]1[CH2:23][CH2:24][CH:25]([NH:28][C:29]2[N:30]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=3)[C:31]3[C:36]([N:37]=2)=[CH:35][N:34]=[CH:33][N:32]=3)[CH2:26][CH2:27]1
Reactant: C[N+](C)=C1OCCC1(c1ccccc1)c1ccccc1
Reactant: c1ccc(Cn2c(NC3CCNCC3)nc3cncnc32)nc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(C)C(=O)C(CCN1CCC(Nc2nc3cncnc3n2Cc2ccccn2)CC1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
A mixture of 3.46 parts of N-(dihydro-3,3-diphenyl-2(3H)-furanylidene)-N-methylmethanaminium bromide, 3.1 parts of N-(4-piperidinyl)-9-(2-pyridinylmethyl)-9H-purin-8-amine, 1.5 parts of sodium carbonate and 45 parts of N,N-dimethylacetamide was stirred overnight at 80° C. after cooling, the reaction mixture was poured into water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 4.1 parts (71%) of N,N-dimethyl-α,α-diphenyl-4-[[9-(2-pyridinylmethyl)-9H-purin-8-yl]amino]-1-piperidinebutanamide; mp. 191.6° C. (compound 122).