Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(F)(F)F.P(=O)(O)(O)O.[C:10]1([CH3:17])[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH:18]1[CH2:22][CH2:21][CH2:20][CH:19]=1>CCCCC>[CH:18]1([C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:17])[C:15]=2[OH:16])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: C1=CCCC1
Reactant: Cc1ccccc1O
Agent: FB(F)F
Agent: O=P(O)(O)O
Solvent: CCCCC
Product: Cc1cccc(C2CCCC2)c1O
Temperature: 0 °C
Yield: 29.2 %

Procedure:
170 ml of boron trifluoride/phosphoric acid adduct are added to 1.08 kg (10 moles) of o-cresol in 400 ml of pentane. 680 g (10 moles) of cyclopentene, dissolved in 1 l of pentane, are added dropwise at the reflux temperature in the course of 3 hours. The mixture is stirred for a further hour at the reflux temperature and then poured into ice water. The organic phase is separated off and is extracted with 4 times 600 ml of 10% strength sodium hydroxide solution. The organic phase is dried and evaporated down and the residue is distilled (84°-88° C./0.2 mbar). 515 g of 2-cyclopentyl-6-methylphenol (corresponding to 37% of theory, based on converted cresol) are obtained. 217 g of o-cresol and 282 g of 4-cyclopentyl-2-methylphenol are obtained from the alkaline wash solution after acidification, extraction and distillation.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[N:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=1[CH3:17].C([O:20][C:21](=O)[O:22]CC)C.[Li+].[OH-]>C1COCC1>[CH3:17][C:10]1[CH:11]=[C:12]([CH2:16][C:21]([OH:22])=[O:20])[CH:13]=[C:14]([CH3:15])[N:9]=1
Reactant: Cc1cc(C)nc(C)c1
Reactant: CCOC(=O)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(CC(=O)O)cc(C)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of lithium diisopropylamide (2M in THF/Hept/ethylbenzene, 5 mL) was added a solution of 2,4,6-collidine (1.26 mL) in THF (5 mL). The reaction mixture was stirred at RT for 4 h and added dropwise to a solution of diethylcarbonate (1.38 mL) in THF (5 mL) over 15 min. The resulting mixture was stirred at RT for 20 h. A LiOH solution (1M in water, 28 mL) was added, the mixture was stirred at RT for 2 h and filtered off. The filtrate was evaporated in vacuo. The residue was purified by preparative LC-MS (X) to afford 30 mg of yellow oil as mixture of two regioisomers. LC-MS (E): tR=0.17 min; [M+H]+: 165.97.
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].C(Cl)Cl.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[CH3:20]>CCCCCC>[Br:12][C:13]1[CH:18]=[C:17]([N+:7]([O-:8])=[O:6])[C:16]([F:19])=[CH:15][C:14]=1[CH3:20]
Reactant: Cc1cc(F)ccc1Br
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1cc(F)c([N+](=O)[O-])cc1Br
Temperature: 25 °C
Yield: 52.8 %

Procedure:
To a mixture of nitronium tetrafluoroborate (11.6 g, 87.0 mmol) and CH2Cl2 (60.0 mL) was added 2-bromo-5-fluoro toluene (15.0 g, 10.0 mL, 79.0 mmol) over 5 minutes. After refluxing for 4.5 h, the mixture was cooled to room temperature and poured into ice water (150 mL). The mixture was extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to give 18.3 g of crude product. The crude product was treated with hexane and cooled to −70° C. then the hexane was decanted away from the resulting solid to give the desired product as a semi-solid (9.77 g, 53% yield). The mother liquors were evaporated and purified by column chromatography (silica gel, 2% EtOAc in Hexane) to give 1.0 g of the desired product. 1H NMR (CDCl3) δ 8.26 (d, J=6.9 Hz, 1H), 7.20 (d, J=11.7 Hz, 1H), 2.48 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH3:23])[C:5]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH3:23])[C:5]2[C:10]([C:26]3[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: CNc1nc(Cl)nc2c1c(I)cn2S(=O)(=O)c1ccc(C)cc1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CNc1nc(Cl)nc2c1c(-c1cccnc1)cn2S(=O)(=O)c1ccc(C)cc1
Temperature: 100 °C
Yield: 53.4 %

Procedure:
To a mixture of 2-chloro-N-methyl-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.175 g, 0.38 mmol), Pd(PPh3)2Cl2 (0.053 g, 0.076 mmol) and pyridine-3-ylboronic acid (0.102 g, 0.83 mmol) in dioxane (2 mL) was added a solution of Na2CO3 (0.12 g, 1.14 mmol) in water (1 mL). After degassing, the mixture was heated at 100° C. for 1.5 h. The mixture was purified by flash column chromatography (Hexane/EtOAc=1:1) to give 2-chloro-N-methyl-5-(pyridin-3-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.084 g).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][CH2:4][CH:5]([NH:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:7]=1[CH3:21].Cl[C:36]1[N:41]=[CH:40][C:39]([CH2:42][CH3:43])=[CH:38][N:37]=1.C(=O)([O-])[O-].[Na+].[Na+].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.O>[CH2:42]([C:39]1[CH:38]=[N:37][C:36]([C:9]2[CH:10]=[CH:11][C:6]([CH:5]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=3)[CH2:4][CH2:3][C:2]([F:33])([F:34])[F:1])=[C:7]([CH3:21])[CH:8]=2)=[N:41][CH:40]=1)[CH3:43]
Reactant: CCc1cnc(Cl)nc1
Reactant: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2C)cc1
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: O
Solvent: COCCOC
Product: CCc1cnc(-c2ccc(C(CCC(F)(F)F)Nc3ccc(C(=O)OC)cc3)c(C)c2)nc1
Temperature: 130 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
A reaction mixture of methyl 4-((4,4,4-trifluoro-1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butyl)amino)benzoate (0.600 g) obtained in Example 10, step A, 2-chloro-5-ethylpyrimidine (0.215 g), tetrakistriphenylphosphinepalladium (0.145 g), sodium carbonate (0.400 g), DME (3 mL) and water (1 ml) was stirred at 130° C. for 1 hr under microwave irradiation under a nitrogen atmosphere. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.507 g).
Reaction SMILES: [N+:1](=[CH2:3])=[N-:2].[CH:4]([C:12](Cl)=[O:13])=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CCOCC.C(Cl)Cl>[N+:1](=[CH:3][C:12]([CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:13])=[N-:2]
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Solvent: CCOCC
Product: [N-]=[N+]=CC(=O)C=Cc1ccccc1
Reaction time: 16 h

Procedure:
To a stirred solution of diazomethane (9.66 g, 0.23 mole) in dry ether (1250 ml.) maintained at 0° to -5°, was added a suspension of the styrene-carbonyl chloride polymer (10.0 g) from Example 7(c) in methylene chloride (50 ml.) over 15 minutes. Stirring was maintained for 5 hours at 0° to -5° and then for 16 hours at room temperature. The reaction mixture was filtered and the polymer washed with ether (2 × 100 ml.) and chloroform (2 × 100 ml.) and dried in vacuo at room temperature to constant weight. The title polymer (10.76 g) was deep yellow in colour and the IR spectrum exhibited absorptions at 2100 (diazo) and 1610 (carbonyl) cm-1. The composition of the polymer was confirmed by microanalysis.
Reaction SMILES: [CH2:1]([C@:4]1([CH2:30][O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:8][C@@H:7]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[C@H:6]([O:18]C(=O)C)[C@@H:5]1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:2]=[CH2:3].N.[CH:40]1[CH:45]=[CH:44][C:43]([O:46][C:47](Cl)=[S:48])=[CH:42][CH:41]=1>CN(C1C=CN=CC=1)C>[CH2:1]([C@:4]1([CH2:30][O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:8][C@@H:7]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[C@H:6]([O:18][C:47]([O:46][C:43]2[CH:44]=[CH:45][CH:40]=[CH:41][CH:42]=2)=[S:48])[C@@H:5]1[O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH:2]=[CH2:3]
Reactant: C=CC[C@]1(COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1
Reactant: S=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccncc1
Agent: N
Product: C=CC[C@]1(COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@H](OC(=S)Oc2ccccc2)[C@@H]1OCc1ccccc1
Reaction time: 8 h
Yield: 70 %

Procedure:
Compound 8 (5.0 g, 9.6 mmol) was treated with 27% methanolic ammonia solution overnight. After evaporation of the solvent the crude was coevaporated thrice with dry pyridine and dissolved in the same. To this pre-cooled solution was added DMAP (1.17 g, 9.6 mmol) and then dropwise was added phenyl chlorothionoformate (1.6 mL, 11.53 mmol) and reaction stirred overnight. Reaction was quenched with saturated solution of NaHCO3 and extracted with dichloromethane. The organic layer was dried over MgSO4, concentrated and chromatographed over silica gel (10-30% ethyl acetate in cyclohexane, v/v) to give 10 as yellowish foam (4.1 g, 6.72 mmol, 70%). Rf=0.60 (30% ethyl acetate in cyclohexane, v/v). 1H NMR (600 MHz) δ: 8.58 (1H, s, N—H), 7.48 (1H, s, H6), 7.19 (15H, m), 6.44 (1H, d, JH1′,H2′=6.1 Hz, H1′), 5.97 (1H, app t, J=5.8 Hz, H2′), 5.83 (1H, m, H7′), 5.09 (2H, m, H8′-H8″), 4.77 (1H, d, Jgem=11.2 Hz, CH2Bn), 4.55 (3H, m, CH2Bn, H3′), 3.71 (1H, d, JH5′,H5″=10.3 Hz, H5″), 3.48 (1H, d, JH5′,H5″10.3 Hz, H5′), 2.66 (1H, dd, JH6,H6=14.6 Hz, JH6,H7=8.1 Hz, H6″), 2.35 (1H, dd, JH6,H6=14.6 Hz, JH6,H7=8.1 Hz, H6′), 1.51 (3H, CH3, thymine); 13C NMR (125.7 MHz) δ: 194.4 (>C═S), 163.4 (C4), 150.3 (C2), 137.1, 137.2 (aromatic), 135.6 (C6), 132.4 (C7′), 121.6, 126.7, 127.3, 127.6, 127.8, 128.0, 128.1, 128.4, 128.6, 129.3, 129.5 (aromatic), 118.8 (C8′), 111.5 (C5′), 87.1 (C4′), 85.1 (C2′), 82.9 (C1′), 77.8 (C3′), 74.9 (C—CH2Bn), 73.7 (C5′), 73.7 (C—CH2Bn), 37.3 (C6′), 11.9 (CH3, thymine); MALDI-TOF m/z [M+H]+ found 615.16 calcd 615.21.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])/[N:7]=[C:8](/[C:12]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:13]=1[F:19])\[CH:9]([F:11])[F:10])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([Mg]Cl)[CH:22]=[CH2:23]>C1COCC1>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]([C:12]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:13]=1[F:19])([CH:9]([F:10])[F:11])[CH2:23][CH:22]=[CH2:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC[Mg]Cl
Reactant: CC(C)(C)OC(=O)/N=C(/c1cc(Br)ccc1F)C(F)F
Solvent: C1CCOC1
Product: C=CCC(NC(=O)OC(C)(C)C)(c1cc(Br)ccc1F)C(F)F

Procedure:
To a solution of [1-(5-bromo-2-fluoro-phenyl)-2,2-difluoro-eth-(Z)-ylidene]-carbamic acid tert-butyl ester (9.61 g, 27.3 mmol) in 114 ml THF at −75° was added dropwise allylmagnesium chloride solution 2 mol/L in THF (15.0 ml, 30 mmol). The reaction temperature was not allowed to exceed −60° C. After 10 minutes the reaction was quenched with 10% aqueous NH4Cl and extracted with TBME. The organic phase was washed with brine, dried with Na2SO4 and evaporated. The crude product was chromatographed on silica gel with 1-5% TBME/hexane to give 10.39 g of the title compound.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([C:15]([OH:17])=O)[CH:12]=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:51]1[CH2:56][CH:55]=[C:54]([C:57]2[CH:58]=[C:59]([CH:62]=[CH:63][CH:64]=2)[C:60]#[N:61])[CH2:53][CH2:52]1>CN(C)C=O>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([C:15]([N:51]3[CH2:52][CH:53]=[C:54]([C:57]4[CH:58]=[C:59]([CH:62]=[CH:63][CH:64]=4)[C:60]#[N:61])[CH2:55][CH2:56]3)=[O:17])[CH:12]=[N:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1cccc(C2=CCNCC2)c1
Reactant: O=C(O)c1cncc(C#Cc2ccccc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccc(C2=CCN(C(=O)c3cncc(C#Cc4ccccc4)c3)CC2)c1
Reaction time: 0.25 h
Yield: 31.1 %

Procedure:
A solution of 5-phenylethynyl-pyridine-3-carboxylic acid (0.46 g, 2.1 mmol) in anhydrous dimethylformamide (7 ml) is treated with HATU (0.78 g, 2.1 mmol) and diisopropylethylamine (0.98 ml, 5.6 mmol). The reaction mixture is stirred 15 mins. at ambient temperature before being treated with a solution of 3-(1,2,3,6-tetrahydropyridin-4-yl)-benzonitrile (1.9 mmol) in dimethylformamide (6 ml). The reaction mixture is stirred at ambient temperature 3 hours, concentrated under vacuum and the residue partitioned between ethyl acetate (200 ml) and saturated aqueous sodium bicarbonate ((45 ml). The organic layer is dried (magnesium sulfate), concentrated under vacuum and the residue chromatographed on silica gel (dichloromethane/methanol 39:1) to give 3-[1-(5-phenylethynyl-pyridine-3-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-benzonitrile as a yellow oil (0.23 g). This material is dissolved in methanol (15 ml), cooled to 0° C. and saturated with hydrogen chloride gas. The reaction vessel is sealed and allowed to stand at 0° C. for 18 hours. The reaction mixture is concentrated to dryness under vacuum, redissolved in methanol (15 ml) and cooled to 0° C. The solution is saturated with ammonia gas and the vessel sealed before being allowed to stand at 0° C. for 48 hours. The reaction mixture is concentrated to dryness under vacuum and the residue chromatographed on silica gel (dichloromethane/methanol 9:1) to give the title compound as a yellow amorphous solid (0.2 g). 1H NMR (DMSO, 500 MHz) δ8.85 (s, 1H), 8.67 (s, 1H), 8.10 (s, 1H), 7.85 (s, 1H), 7.80 (m, 1H), 7.75 (m, 1H), 7.60 (m, 3H), 7.48 (m, 3H), 6.38 (m, 1H), 4.38 (br m, 1H), 4.19 (br m, 1H), 3.90 (br m, 1H), 3.60 (br m, 1H), 2.63 (br m, 2H). EI MS M++H: 407.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1B(O)O>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:20]3[CH:19]=[CH:18][C:17]([F:16])=[CH:22][C:21]=3[F:23])[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1ccc(F)cc1F

Procedure:
The title compound, MS: m/e=330.4 (M+H+), was prepared in accordance with the general method of example 7 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2,4-difluorobenzene boronic acid.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[O:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[N:19]([CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH:31](Br)[C:32]([O:34][CH3:35])=[O:33])=[CH:26][CH:25]=1)[CH3:20]>CN(C)C=O.O>[O:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[N:19]([CH2:21][CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:30][CH:31]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:32]([O:34][CH3:35])=[O:33])=[CH:28][CH:29]=1)[CH3:20]
Reactant: COC(=O)C(Br)Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)Sc1ccccc1
Temperature: 25 °C

Procedure:
Thiophenol (0.92 mL) was added slowly to an ice-cooled, stirred suspension of sodium hydride (60% dispersion in oil, 0.38 g) in dry N,N-dimethylformamide (60 mL). The mixture was allowed to warm to room temperature over 30 minutes prior to the addition of a solution of methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-bromopropanoate (3.85 g) in N,N-dimethylformamide (40 mL) and the mixture was then heated at 80° C. for 72 hrs, cooled and diluted with water (1 L). The mixture was extracted with ethyl acetate (3×250 mL) and the combined organic solutions washed with water (3×1 L) and brine (1 L), dried (MgSO4) and evaporated. The residue was chromatographed on silica gel using a gradient of 1% methanol to 2% methanol in dichloromethane as eluent to afford the title compound, mp 78°-9° C. (dichloromethane-hexane).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10](Br)[CH:11]=2)[CH:6]=1.[CH3:29][S:30]([O-:32])=[O:31].[Na+].N1CCC[C@H]1C(O)=O.CS(C)=O>O.[Cu]I>[CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:30]([CH3:29])(=[O:32])=[O:31])[CH:11]=2)[CH:6]=1
Reactant: CS(=O)[O-]
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)OC)cc3ccc(Br)cc23)cc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)OC)cc3ccc(S(C)(=O)=O)cc23)cc1
Temperature: 115 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
A mixture of [6-bromo-4-(4-ethanesulfonyl-phenoxy)-naphthalen-2-yl]-acetic acid methyl ester (32 mg, 0.07 mmol, methyl ester of example 15-1), sodium methanesulfinate (10 mg, 0.09 mmol), L-proline (4 mg, 0.028 mmol), copper(I) iodide (3 mg, 0.014 mmol) and dimethyl sulfoxide (0.3 mL) was stirred at 115° C. overnight under an argon atmosphere. The resulting mixture was diluted with water (5 mL), and extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (30% ethyl acetate in petroleum ether) to give [4-(4-ethanesulfonyl-phenoxy)-6-methanesulfonyl-naphthalen-2-yl]-acetic acid methyl ester (11 mg) as a yellow solid.
Reaction SMILES: C(OC([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([C:19]1[NH:20][C:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:22]2[C:27]=1[CH:26]=[CH:25][C:24]([Cl:28])=[CH:23]2)=[O:18])=O)C1C=CC=CC=1.Br.C(OCC)C>C(O)(=O)C>[CH3:11][NH:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([C:19]1[NH:20][C:21]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:22]2[C:27]=1[CH:26]=[CH:25][C:24]([Cl:28])=[CH:23]2)=[O:18]
Reactant: O=C(CNCCCNC(=O)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CNCCCNC(=O)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12
Reaction time: 2 h

Procedure:
9.5 G. of 5-chloro-3-phenylisoindole-1-carboxylic acid {3-[(benzyloxycarbonyl)methylamino]propyl}amide are dissolved in 20 ml. of glacial acetic acid and 30 ml. of a solution of 33% hydrobromic acid in glacial acetic acid are added thereto. The mixture is allowed to stand at room temperature for 2 hours with occasional agitation and it is thereafter poured into 300 ml. of diethyl ether. The separated hydrobromide is removed by filtration under suction, washed with diethyl ether and treated with 200 ml. of 2-N ammonium hydroxide solution. The liberated base is extracted with methylene chloride and the extract washed with water, dried over sodium sulfate and evaporated to dryness. After crystallization of the solid residue from ethanol, there is obtained 5-chloro-3-phenylisoindole-1-carboxylic acid [3-(methylamino)propyl]amide in the form of yellowish crystals having a melting point of 162°-164° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[C:12]([OH:14])=O)=[CH:5][CH:4]=1.[CH3:15][N:16]([CH3:34])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1>>[CH3:15][N:16]([CH3:34])[C:17]1[CH:18]=[CH:19][C:20]([CH2:23][N:24]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:32])[CH3:33])=[CH:27][CH:26]=2)[C:12]([CH:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=3)[CH2:7][CH2:8]2)=[O:14])=[CH:21][CH:22]=1
Reactant: COc1ccc2c(c1)C(C(=O)O)CC2
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Product: COc1ccc2c(c1)C(C(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(C(C)C)cc1)CC2
Yield: 46 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 6-methoxyindan-1-carboxylic acid (0.5 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.7 g) as starting materials, N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-6-methoxyindan-1-carboxamide (0.53 g) was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[NH:5][C:4](=[O:11])[C:3]=1[N+:12]([O-:14])=[O:13].[NH3:15]>CO>[NH2:15][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[NH:5][C:4](=[O:11])[C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CC(C)c1cc(Cl)c([N+](=O)[O-])c(=O)[nH]1
Reactant: N
Solvent: CO
Product: CC(C)c1cc(N)c([N+](=O)[O-])c(=O)[nH]1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of 4-chloro-6-isopropyl-3-nitro-1H-pyridin-2-one (700 mg, 3.23 mmol) in 6-7 μL of 7 N NH3 in MeOH is stirred at 100° C. in a sealed tube for 1.5 h. After cooling, the reaction mixture is concentrated in vacuo. The residue is suspended in H2O, filtered, washed with H2O, and dried, yielding 4-amino-6-isopropyl-3-nitro-1H-pyridin-2-one. 1H NMR (DMSO-d6, 300 MHz) δ 10.96 (br s, 1H), 8.15 (br s, 2H), 5.70 (d, J=0.9 Hz, 1H), 2.58 (sept, J=6.9 Hz, 1H), 1.11 (d, J=6.9 Hz, 6H) ppm.
Reaction SMILES: [Si](C=[N+]=[N-])(C)(C)[CH3:2].[NH2:8][C:9]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([F:21])[C:10]=1[F:22].CO>C1COCC1>[CH3:2][O:14][C:13](=[O:15])[C:12]1[CH:16]=[C:17]([N+:18]([O-:20])=[O:19])[C:9]([NH2:8])=[C:10]([F:22])[C:11]=1[F:21]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Nc1c([N+](=O)[O-])cc(C(=O)O)c(F)c1F
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A 2 M solution of TMS diazomethane in hexanes (6.88 mL, 13.75 mmol) is added to a suspension of 4-amino-2,3-difluoro-5-nitro-benzoic acid 3 (2.00 g, 9.17 mmol) in 25 mL of 4:1 THF:MeOH at 0° C. under nitrogen atmosphere. Upon completion of addition, reaction mixture is warmed to room temperature. After 0.5 hours, excess TMS diazomethane is destroyed by the careful addition of acetic acid. The reaction is then concentrated under reduced pressure and dried in vacuo to give 1.95 g (92%) of pure desired product: MS APCI (−) m/z 231 (M−1) detected.
Reaction SMILES: O[C:2]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:3]=1[NH:4][C:5]([C:7]1[CH:22]=[CH:21][C:10]2[N:11]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:12]([CH3:14])=[N:13][C:9]=2[CH:8]=1)=[O:6].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:14][C:12]1[N:11]([CH:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[C:10]2[CH:21]=[CH:22][C:7]([C:5]3[O:6][C:2]4[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:3]=4[N:4]=3)=[CH:8][C:9]=2[N:13]=1
Reactant: Cc1nc2cc(C(=O)Nc3ccc([N+](=O)[O-])cc3O)ccc2n1C1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nc2cc(-c3nc4ccc([N+](=O)[O-])cc4o3)ccc2n1C1CCOCC1
Reaction time: 4 h
Yield: 77.4 %

Procedure:
5-(2-Hydroxy-4-nitroanilinocarbonyl)-2-methyl-1-(tetrahydropyran-4-yl)benzimidazole (see Working Example 47-1) (195 mg, 0.492 mmol) was added to toluene (20 mL), after which p-toluenesulfonic acid hydrate (280 mg, 1.47 mmol) was added and this was refluxed with stirring for 4 hours. After the solvent was concentrated under reduced pressure, a sodium bicarbonate water (10 mL) was added and this was stirred at room temperature for 1 hour. The precipitated crystals were filtered off, and after being washed with water were dried with heating at reduced pressure to yield the title compound (144 mg, 77.4% yield) as a pale yellow solid.