Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[Cl:13][C:14]1[CH:28]=[CH:27][C:17]2[O:18][C:19]3[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=3[CH2:21][NH:22][C:16]=2[CH:15]=1>CC(C)=O>[Cl:13][C:14]1[CH:28]=[CH:27][C:17]2[O:18][C:19]3[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=3[CH:21]=[N:22][C:16]=2[CH:15]=1
Reactant: Clc1ccc2c(c1)NCc1ccccc1O2
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CC(C)=O
Product: Clc1ccc2c(c1)N=Cc1ccccc1O2
Reaction time: 168 h

Procedure:
A culture of Hormodendrum cladosporioides NRRL 8132 is grown initially for 14 days on potato dextrose agar slants. The spores and mycelia from a single slant are used to inoculate a 500 ml. seed flask containing 100 ml. of cottonseed meal medium. After further incubation for 7 days at 23 - 25° C. on a rotary shaker at 190 rpm, 25 ml. of the growth is used to inoculate 100 ml. of cottonseed meal medium in a 500 ml. flask. This flask is then incubated at 23 - 25° C. for 24 - 48 hours on the shaker until good growth is evident. A solution of 0.025 part of 8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine in 0.79 part acetone is added and incubation continued for an additional 48 hours. The culture broth is extracted three times with portions of methylene chloride. The methylene chloride extracts are combined, dried over anhydrous sodium sulfate, and stripped to dryness in vacuo. The residue is dissolved in ethyl acetate and chromatographed on silica gel using a 3:97 ethyl acetate-methylene chloride mixture as eluant. Recrystallization of the crude product affords 8-chlorodibenz[b,f][1,4]oxazepine melting at 73 - 73.5° C. and represented by the following structural formula. ##STR4##
Reaction SMILES: C12BC(CCC1)CCC2.[O:10]1CCCC1.[CH3:15][S:16]([CH:19]([C:23]1[C:32]([Cl:33])=[C:31]([Cl:34])[CH:30]=[C:29]2[C:24]=1[N:25]=[C:26]([O:37][CH3:38])[C:27]([O:35][CH3:36])=[N:28]2)[CH2:20][CH:21]=[CH2:22])(=[O:18])=[O:17].C[N+]([O-])(C)C>>[CH3:15][S:16]([CH:19]([C:23]1[C:32]([Cl:33])=[C:31]([Cl:34])[CH:30]=[C:29]2[C:24]=1[N:25]=[C:26]([O:37][CH3:38])[C:27]([O:35][CH3:36])=[N:28]2)[CH2:20][CH2:21][CH2:22][OH:10])(=[O:17])=[O:18]
Reactant: C1CCOC1
Reactant: C=CCC(c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12)S(C)(=O)=O
Agent: B1C2CCCC1CCC2
Agent: C[N+](C)(C)[O-]
Product: COc1nc2cc(Cl)c(Cl)c(C(CCCO)S(C)(=O)=O)c2nc1OC
Reaction time: 20 h
Yield: 57.4 %

Procedure:
A solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran (0.5M, 1.07 ml, 0.537 mmol) was added to a stirred solution of 1-(6,7-dichloro-2,3-dimethyoxyquinoxalin-5-yl)-3-butenyl methyl sulphone (Example 93 (a)) (200 mg, 0.511 mmol) at room temperature under nitrogen. The mixture was stirred for 20 hours and then trimethylamine N-oxide (119 mg, 1.58 mmol) was added in portions. The mixture was stirred at room temperature for 2 hours and then at reflux for 30 minutes, cooled and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with 1:1 hexane:ethyl acetate then neat ethyl acetate) to give 1-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-4-hydroxybutyl methyl sulphone (120 mg, 57%) as a mixture of diastereoisomers (by 1HNMR).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1.[C:35](=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:35])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 89.2 %

Procedure:
A mixture of 0.60 g of methyl [3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetate (compound a-6), 0.13 g of sodium carbonate, and 7.0 ml of ethanol was heated at reflux for 2 hours. After cooling to room temperature, the solvent was distilled out under reduced pressure, and the residue was subjected to silica gel chromatography to give 0.55 g of ethyl [3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetate (compound a-10).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1.O>N1C=CC=CC=1.O1CCCC1>[F:10][C:11]([F:21])([F:22])[C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[O:17])=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: COc1ccccc1N
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccccc1NC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1.7 h
Yield: 98.1 %

Procedure:
To a solution of 20.8 g of o-anisidine in 140 ml of pyridine was added dropwise a solution of 35.2 g of p-trifluoromethyl benzoyl chloride in 30 ml of tetrahydrofuran at 50° to 10° C. After stirring at room temperature for 1.7 hours, the reaction mixture was poured into 1.6 liters of water. The precipitate was collected by filtration, washed with water, and dried to give 48.9 g of 4- trifluoromethyl -2'-methoxybenzanilide.
Reaction SMILES: Cl[CH:2]1[O:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[C:4](=[O:15])[C:3]1([CH3:17])[CH3:16].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>O1CCCC1.CN(C)C=O.CCCCCCC>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][N:5]1[C:4](=[O:15])[C:3]([CH3:17])([CH3:16])[CH:2]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:6]1
Reactant: CC1(C)C(=O)N(Cc2ccccc2Cl)OC1Cl
Reactant: Nc1ccccc1
Solvent: O
Solvent: CCCCCCC
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(Cc2ccccc2Cl)OC1Nc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.5 %

Procedure:
To a stirred solution of 2.6 grams (0.009 mole) of 5-chloro-2-[(2-chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone (Example 23(A)) in 25 ml of tetrahydrofuran was added dropwise to a solution of 1.8 grams (0.019 mole) of aniline in 5 ml of tetrahydrofuran. Upon completion of addition the reaction mixture was heated under reflux for 4 hours; thin layer chromatography of the reaction mixture indicated the presence of starting 5-chloro compound. The reaction mixture was heated under reflux for an additional 60 hours; thin layer chromatography of the mixture again indicated the 5-chloro starting material to be present. The tetrahydrofuran solvent was removed by evaporation under reduced pressure and 0.9 gram (1 equiv.) of aniline in 20 ml of dimethylformamide was added. The solution was heated at 110°-120° for six hours, and was allowed to cool to ambient temperature where it was stirred for 18 hours. The reaction mixture was poured into 100 ml of water and extracted with three 50-ml portions of methylene chloride. The combined extracts were washed with two 50-ml portions of an aqueous solution of 5% hydrochloric acid. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give an oil residue. The residue was subjected to column chromatography on silica gel using 30% ethyl acetate in heptane. The appropriate fractions were combined and concentrated under reduced pressure to give 1.8 grams of 2-[(2-chlorophenyl)methyl]-4,4-dimethyl-5-phenylamino-3-isoxazolidinone; mp 99°-101°.
Reaction SMILES: [C:1]1([C:7]2[C:15]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[CH:17]=3)=[C:10]3[NH:11][CH2:12][CH2:13][CH2:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:32])[CH3:31].O>O1CCCC1>[C:1]1([C:7]2[C:15]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:30](=[O:32])[CH3:31])[CH:17]=3)=[C:10]3[NH:11][CH2:12][CH2:13][CH2:14][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cc(-c2c(-c3ccccc3)nn3c2NCCC3)ccn1
Reactant: CC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(-c2c(-c3ccccc3)nn3c2NCCC3)ccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 12 %

Procedure:
To a solution of 4-(2-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)pyridin-2-amine (29 mg, 0.1 mmol, 1 eq) in 2 mL of tetrahydrofurane is added triethylamine (0.055 mL, 0.4 mmol, 4 eq) and then acetyl chloride (0.024 mL, 0.3 mmol, 3 eq). The mixture is stirred for 4 h at room temperature. Triethylamine (0.055 mL, 0.4 mmol, 4 eq) and acetyl chloride (0.024 mL, 0.3 mmol, 3 eq) are then added. The mixture is stirred overnight at room temperature and then poured into water and extracted with dichloromethane (3×50 mL). The combined organic layers are washed with a saturated solution of NaHCO3, brine, dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude material is purified by column chromatography using silica gel in heptane and ethyl acetate (1:0 to 0:1) as eluent and 4 mg (8%) of N-[4-(2-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)pyridin-2-yl]acetamide are obtained as a light brown oil.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]([CH3:18])/[C:13](=[N:16]/[H])/[NH:14][OH:15])[C:7]([CH3:19])=[CH:6]2)#[N:2].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=O>>[CH3:19][C:7]1[N:8]([CH:12]([C:13]2[N:16]=[C:29]([C:28]3[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=3)[O:15][N:14]=2)[CH3:18])[C:9]2[C:5]([CH:6]=1)=[C:4]([C:20]([F:23])([F:22])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=2
Reactant: [H]/N=C(\NO)C(C)n1c(C)cc2c(C(F)(F)F)c(C#N)ccc21
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1C(C)c1noc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 32B from (1Z)-2-[5-cyano-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxypropanimidamide and 3-(trifluoromethyl)benzoyl chloride: MS (ES) m/z 465 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.[CH2:9]([CH:11]1[O:13][CH2:12]1)Cl>>[CH2:9]([N:1]([CH2:9][CH:11]1[O:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1)[CH:11]1[O:13][CH2:12]1
Reactant: ClCC1CO1
Reactant: Cc1cccc(N)c1
Product: Cc1cccc(N(CC2CO2)CC2CO2)c1
Yield: 100 %

Procedure:
1 mole of N,N-bisglycidyl-m-toluidine was prepared from 4.8 moles of m-toluidine and 2 moles of epichlorohydrin. The excess m-toluidine was required to produce the oxirane ring and was filtered off as the hydrochloride after completion of the reaction.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][CH2:20][OH:21])[C:9](=[O:18])[C:10]1[C:15]([Br:16])=[CH:14][CH:13]=[CH:12][C:11]=1F)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>CN(C)C=O>[CH2:1]([N:8]1[C:9](=[O:18])[C:10]2[C:15]([Br:16])=[CH:14][CH:13]=[CH:12][C:11]=2[O:21][CH2:20][CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1c(F)cccc1Br)N(CCO)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2c(Br)cccc2OCCN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.8 %

Procedure:
To a solution of N-benzyl-6-bromo-2-fluoro-N-(2-hydroxyethyl)benzamide (15.5 g, 44.0 mmol) in N,N-dimethylformamide (200 ml) was added sodium hydride (60%, 2.29 g, 57.2 mmol) under ice-cooling, and the mixture was stirred for 1 hr under ice-cooling. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (4.94 g, 33.8%) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11](OC)=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CO.O>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][OH:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)Cc1cccc([N+](=O)[O-])c1
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(CCO)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
A solution of methyl 2-(3-nitrophenyl)acetate (12 g, 62 mmol) in THF (100 ml) was cooled to 0° C., then MeOH (10 mL) was added slowly, followed by stirring at room temperature overnight. Water was added to terminate the reaction. The aqueous layer was extracted with ethyl acetate 3 times. The combined organic phase was washed with brine, dried over sodium sulfate and concentrated to give 2-(3-nitrophenyl)ethanol (9 g, yield 90%). 1H NMR: 400 MHz CDCl3 δ 8.11-8.07 (m, 2H), 7.59-7.56 (m, 1H), 7.49-7.45 (m, 1H), 3.94-3.91 (m, 2H), 2.99-2.96 (m, 2H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([N:15]2[C:19]([NH2:20])=[CH:18][C:17]([C:21]([CH3:42])([CH3:41])[CH2:22][O:23][Si:24]([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:16]2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.O.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:20][C:19]1[N:15]([C:11]2[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=2)[N:16]=[C:17]([C:21]([CH3:42])([CH3:41])[CH2:22][O:23][Si:24]([C:37]([CH3:40])([CH3:39])[CH3:38])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:18]=1
Reactant: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc(N)n(-c2cccc(OCc3ccccc3)c2)n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc(N)n(-c2cccc(O)c2)n1
Yield: 52 %

Procedure:
A solution of Intermediate 153c (1.21 g, 2.1 mmol) in ethanol (IMS grade, 20 mL) was treated with water (1 mL) and ammonium formate (1.33 g, 21 mmol). The mixture was purged with N2 then 10% Pd/C (0.67 g, 0.63 mmol Pd) was added. The mixture was heated to reflux for 1 h then filtered through celite and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc and water. The phases were separated and the aqueous layer was extracted with EtOAc (×2). The combined organic phase was washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by FCC, using 0-40% EtOAc in cyclohexane, to give the title compound (0.53 g, 41% over 2 steps) as a golden gum. LCMS (Method 3): Rt 4.55 min, m/z 486.5 [MH+].
Reaction SMILES: [BH4-].[Na+].CO.[CH3:5][O:6][C:7](=[O:32])[CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][N:14]1[CH:19](/[CH:20]=[CH:21]/[C:22](=[O:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:18][CH2:17][CH2:16][C:15]1=[O:31]>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:32])[CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][N:14]1[C:15](=[O:31])[CH2:16][CH2:17][CH2:18][CH:19]1/[CH:20]=[CH:21]/[CH:22]([OH:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)CCC/C=C\CN1C(=O)CCCC1/C=C/C(=O)Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCC/C=C\CN1C(=O)CCCC1/C=C/C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 61.8 %

Procedure:
Sodium borohydride (16 mg, 0.42 mmol), followed by MeOH (0.25 mL), was added to a solution of (Z)-7-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-hept-5-enoic acid methyl ester (16 mg, 0.042 mmol) in CH2Cl2 (0.75 mL) at 0° C. The mixture was allowed to warm to rt. After 2.5 h at rt, the reaction was quenched with aqueous HCl (1.0 M) and extracted with EtOAc (3×15 mL). The combined organic phase was washed with saturated aqueous NaHCO3 (15 mL) and brine (15 mL) then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→50% EtOAc/CH2Cl2, gradient) afforded 10 mg (62%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11]CC)=[O:10])=[CH:4][N:3]=1.[OH-].[Na+].Cl>O>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([OH:11])=[O:10])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc(Cl)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc(Cl)ncc1C(=O)O
Yield: 77.7 %

Procedure:
A solution of ethyl 2-chloro-4-methylpyrimidine-5-carboxylate (1.0 g, 5 mmol), NaOH (0.24 g, 6 mmol) in H2O (30 mL) was stirred at room temperature for 3 h. The solution was acidified with 6N HCl and the resulting solid was filtered and dried to give the title compound (0.67 g 78%), 1H NMR (DMSO-d6) δ 9.01 (s, 1H), 2.75 (s, 3H).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[Cl:13][C:14]1[CH:22]=[C:21]([Cl:23])[C:17]([C:18]([OH:20])=O)=[C:16]([N+:24]([O-:26])=[O:25])[C:15]=1[OH:27].[F:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>C1COCC1.CN(C=O)C>[Cl:13][C:14]1[CH:22]=[C:21]([Cl:23])[C:17]([C:18]([NH:33][C:32]2[CH:34]=[CH:35][C:29]([F:28])=[CH:30][CH:31]=2)=[O:20])=[C:16]([N+:24]([O-:26])=[O:25])[C:15]=1[OH:27]
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)c1c(Cl)cc(Cl)c(O)c1[N+](=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cc1)c1c(Cl)cc(Cl)c(O)c1[N+](=O)[O-]
Reaction time: 0.67 h
Yield: 65.2 %

Procedure:
CDI (2.2 g, 0.013 mol) was added to a stirred solution of 4,6-dichloro-3-hydroxy-2-nitrobenzoic acid (3.0 g, 0.012 mol) in anhydrous THF (30 mL) and DMF (2 mL). After 40 min, 4-fluoroaniline (4 mL, 0.042 mol) was added. The solution was heated under reflux overnight, cooled, and concentrated to a dark brown viscous oil. The oil was purified via SiO2-gel chromatography (dichloromethane/methanol, 19:1-9:1) to yield 4,6-dichloro-N-(4-fluorophenyl)-3-hydroxy-2-nitrobenzamide as a light brown oil (2.7 g, 65%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:13]([OH:15])=[N:12][CH:11]=[N:10][C:9]=2[O:8][C:7]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1)=[O:5])C>[OH-].[Na+]>[OH:15][C:13]1[C:14]2[C:6]([C:4]([OH:5])=[O:3])=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=3)[O:8][C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1c(-c2cccc([N+](=O)[O-])c2)oc2ncnc(O)c12
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1c(-c2cccc([N+](=O)[O-])c2)oc2ncnc(O)c12
Temperature: 25 °C

Procedure:
0.95 g (3.2 mmols) of 4-hydroxy-6-(3-nitrophenyl)furo[2,3-d]pyrimidine-5-carboxylic acid ethyl ester are place in 30 ml of 5% sodium hydroxide solution and heated for 30 min to 100° C. The reaction mixture is filtered whilst hot and the filtrate cooled to RT. Subsequently, the pH value of the solution is adjusted to 1 with conc. hydrochloric acid, whilst cooling. A brown deposit forms, which is filtered off by suction and dried in a HV. m.p.: >300° C. IR: 3448w, 3237m, 3088w, 1752s, 1734s, 1672s, 1531s, 1474m, 1407m, 1381m, 1346s, 1241m, 1211m.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)N)=[CH:4][CH:3]=1.[C:18]([OH:21])(=[O:20])[CH3:19]>C1CCCCC1>[C:10]([N:8]1[C:3]2[CH2:4][CH:19]([C:18]([OH:21])=[O:20])[CH2:6][CH2:7][C:2]=2[C:6]2[C:5]1=[CH:4][CH:3]=[C:2]([Cl:1])[CH:7]=2)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)O
Reactant: NN(C(=O)c1ccccc1)c1ccc(Cl)cc1
Solvent: C1CCCCC1
Product: O=C(O)C1CCc2c(n(C(=O)c3ccccc3)c3ccc(Cl)cc23)C1
Reaction time: 3 h

Procedure:
A stirred mixture of 2.0 g. of N1 -p-chlorophenyl-N1 -benzoylhydrazine, 1.1 g. of cyclohexanone-3-carboxylic acid, 5 ml. of glacial acetic acid and 7 ml. of cyclohexane were heated under an atmosphere of nitrogen. After 3 hours of stirring at reflux, the reaction mixture was concentrated under reduced pressure and 10 ml. of ethanol was added to the residue. After standing overnight in the refrigerator, the insoluble portion was removed by filtration, washed with a small amount of cold ethanol and dried, yielding 0.4 g. of product, m.p. 196°-197° . Following a recrystallization from ethanol, 0.2 g. of 9-benzoyl-6-chloro-1,2,3,4-tetrahydrocarbazole-2-carboxylic acid was obtained, m.p. 207°-208°.
Reaction SMILES: [I:1]I.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([CH3:16])=[C:14]([C:17]([O:19][CH3:20])=[O:18])[N:13]([CH3:21])[N:12]=2)=[CH:7][CH:6]=1>CCO.S([O-])([O-])(=O)=O.[Ag+2]>[I:1][C:10]1[CH:9]=[C:8]([C:11]2[C:15]([CH3:16])=[C:14]([C:17]([O:19][CH3:20])=[O:18])[N:13]([CH3:21])[N:12]=2)[CH:7]=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: II
Reactant: COC(=O)c1c(C)c(-c2ccc(OC)cc2)nn1C
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: COC(=O)c1c(C)c(-c2ccc(OC)c(I)c2)nn1C
Reaction time: 8 h

Procedure:
Silver sulfate (261 mg, 0.837 mmol) and iodine (212 mg, 0.837 mmol) were added successively to a solution of methyl 3-(4-methoxyphenyl)-1,4-dimethyl-1H-pyrazole-5-carboxylate (217.8 mg, 0.837 mmol) in EtOH (8.4 mL) at 25° C. and the reaction was stirred vigorously overnight. The reaction mixture was filtered through a plug of Celite®. The filtrate was diluted with EtOAc (80 mL) and washed with satd Na2SO3 (30 mL). The organic layer was washed with brine (2×30 mL), dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Biotage Horizon, 25M, Si, ˜20 mL/min, 100% hexanes for 144 mL, gradient to 20% EtOAc in hexanes over 1125 mL) to afford methyl 3-(3-iodo-4-methoxyphenyl)-1,4-dimethyl-1H-pyrazole-5-carboxylate, as a colorless solid. Rf=0.31 (20% EtOAc/hexanes). LCMS calc.=387.02. found=386.91 (M+H)+. 1H NMR (600 MHz, CDCl3): δ 7.99 (d, J=2.1 Hz, 1H); 7.48 (dd, J=8.5, 2.2 Hz, 1H); 6.82 (d, J=8.5 Hz, 1H); 4.12 (s, 3H); 3.89 (s, 3H); 3.86 (s, 3H); 2.31 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].I[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH3:39].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:25][S:22]([NH:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[CH:12]=[CH:11][C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[C:2]([NH:1][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH3:39])[CH:14]=2)=[CH:16][CH:17]=1)(=[O:24])=[O:23]
Reactant: Cc1ccccc1I
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccc(NS(C)(=O)=O)cc2)cc1N
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccccc1Nc1cc(-c2ccc(NS(C)(=O)=O)cc2)ccc1C(=O)OC(C)(C)C
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To toluene 3.0 mL suspension of tert-butyl 2-amino-4-(4-(methanesulfonamido)phenyl)benzoate 0.12 g and cesium carbonate 0.27 g were added 2-iodotoluene 0.084 mL, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 7.9 mg, tris(dibenzylideneacetone)dipalladium(0) 3.0 mg and palladium acetate 1.5 mg at room temperature, and it was stirred at 110° C. for 24 hours. 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 7.9 mg, tris(dibenzylideneacetone)dipalladium(0) 3.0 mg and palladium acetate 1.5 mg were added to it, and it was stirred at 110° C. for 21 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added to it, and insoluble matter was filtrated. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=2:1] to give tert-butyl 4-(4-(methanesulfonamido)phenyl)-2-(2-methylanilino)benzoate.