Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][N:9]=1)[CH:5]=O.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[C:3]([F:10])=[C:4](/[CH:5]=[N:23]/[S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH:7]=[CH:8][N:9]=1
Reactant: O=Cc1ccnc(Cl)c1F
Reactant: CC(C)(C)[S@](N)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)[S@@](=O)/N=C/c1ccnc(Cl)c1F
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 91.5 %

Procedure:
To a stirred suspension of 2-chloro-3-fluoroisonicotinaldehyde (0.75 g, 4.70 mmol) and Cs2CO3 (2.297 g, 7.05 mmol) in DCM (20 mL) was added a solution of (R)-2-methylpropane-2-sulfinamide (0.570 g, 4.70 mmol) in DCM (20 mL) dropwise for 10 min. The solution was then stirred for 3.5 h at rt. The reaction mixture was diluted with EtOAc and washed with brine (3×20 mL). The organic solution was dried over MgSO4, filtered, and concentrated in vacuo to give (R,E)-N-((2-chloro-3-fluoropyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (1.13 g, 91%) as a yellow oil which solidified upon standing. MS (ESI) m/z: 263.0 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:5](=[O:19])[O:6][C:7]2[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=[CH:11][C:8]=2[C:9]=1[CH3:10].Cl.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C(O)(C)C.CC(OC)(C)C>[CH3:18][O:17][C:13]1[CH:12]=[CH:11][C:8]2[C:9]([CH3:10])=[C:4]([CH2:3][CH2:2][N:32]3[CH2:31][CH2:30][N:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[O:22][CH3:21])[CH2:34][CH2:33]3)[C:5](=[O:19])[O:6][C:7]=2[C:14]=1[O:15][CH3:16]
Reactant: COc1ccccc1N1CCNCC1
Reactant: COc1ccc2c(C)c(CCCl)c(=O)oc2c1OC
Agent: Cl
Solvent: CC(C)O
Solvent: COC(C)(C)C
Product: COc1ccccc1N1CCN(CCc2c(C)c3ccc(OC)c(OC)c3oc2=O)CC1
Yield: 6 %

Procedure:
Process A; starting materials: 3-(2-chloroethyl)-7,8-dimethoxy-4-methyl-2H-1-benzopyran-2-one (Example 32) and 1-(2-methoxyphenyl)piperazine hydrochloride; yield 6%; m.p. 146°-148° C. (from isopropanol/TBME).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:3].[OH:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]([C@@H:26]2[CH2:30][C@H:29]([S:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[CH2:28][N:27]2[C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][C:48]([N+:51]([O-:53])=[O:52])=[CH:47][CH:46]=2)=[O:42])=[O:25])[CH2:20][CH2:19]1>CN(C)C1C=CN=CC=1.C(Cl)Cl.C(OCC)(=O)C>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][O:4][C:2]([O:15][CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][N:21]([C:24]([C@@H:26]3[CH2:30][C@H:29]([S:31][CH2:32][C:33]4[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=4)[CH2:28][N:27]3[C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][C:48]([N+:51]([O-:53])=[O:52])=[CH:47][CH:46]=3)=[O:42])=[O:25])[CH2:22][CH2:23]2)=[O:3])=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(CCO)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(CCOC(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
5.86 g of 4-dimethylaminopyridine and a solution of 10.35 g of p-nitrobenzyl chloroformate in 40 ml of anhydrous methylene chloride were added to a solution of 22.35 g of (2S,4S)-2-[4-(2-hydroxyethyl)-1-piperazinylcarbonyl]-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (prepared as described in Preparation 7) in 160 ml of anhydrous methylene chloride, and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was diluted with 300 ml of ethyl acetate and washed with 100 ml of water, with 100 ml of a saturated aqueous solution of sodium hydrogencarbonate and with 100 ml of a saturated aqueous solution of sodium chloride, in that order. The solvents were removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel. Those fractions eluted with ethyl acetate were collected and concentrated by evaporation under reduced pressure, to give 26.35 g of the title compound as a colorless powder.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[CH:14]=[CH:13][S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](O)(=[O:20])[C:17]([CH3:19])=[CH2:18]>ClCCl>[CH3:18][CH:17]1[CH2:19][C:14]2[C:15]3[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][CH:9]=[CH:10][C:11]=3[S:12][C:13]=2[C:16]1=[O:20]
Reactant: C=C(C)C(=O)O
Reactant: c1ccc(-c2cccc3sccc23)cc1
Solvent: ClCCl
Product: CC1Cc2c(sc3cccc(-c4ccccc4)c23)C1=O
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A solution of 76.2 g of 4-phenylbenzo[b]thiophene (0.36 mol) and 37.5 ml of methacrylic acid (0.44 mol) in 50 ml of dichloromethane was added dropwise to 1000 g of super-PPA heated to 80° C. and stirred at 80° C. for 5 hours. The dark red mixture was added to 1000 g of crushed ice and stirred until the polyphosphoric acid had completely dissolved. The aqueous phase was extracted twice with 400 ml each time of a dichloromethane/hexane solvent mixture (30/70 parts by volume). The GC-MS. of the organic phase showed only starting product and no trace of the desired product.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:17][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cccnc1F
Reactant: NCc1ccc(F)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cccnc1NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-fluoro-3-nitropyridine (2.5 g, 17.6 mmol), 4-fluorobenzyl-amine (4.40 g, 35.2 mmol), and N,N-diisopropyl-N-ethylamine (4.55 g, 35.2 mmol) in anhydrous acetonitrile (30 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum, and the residue partitioned between water and ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 15% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the 2-(4-fluorobenzylamino)-3-nitropyridine intermediate as yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([C:23]([CH2:27][CH3:28])([OH:26])[CH2:24][CH3:25])[CH2:18]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29][NH2:30]>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C@@H:17]([OH:21])[CH2:18][C@@H:19]([C:23]([CH2:27][CH3:28])([OH:26])[CH2:24][CH3:25])[C:20]([NH:30][CH3:29])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(O)(CC)[C@@H]1C[C@@H]([C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)OC1=O
Reactant: CN
Solvent: CO
Product: CCC(O)(CC)[C@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(=O)NC
Reaction time: 8 h
Yield: 96 %

Procedure:
A solution of 361 mg (0.91 mmoles) of (3S, 5S)-5-[(1S)-1-(N-t-butoxycarbonylamino)-2-cyclohexylethyl]-3-(1-ethyl-1-hydroxypropyl)dihydrofuran-2(3H)-one (prepared as described in Preparation 21) in 10 ml of methanol was saturated with gaseous methylamine by passing the gas through the solution whilst ice-cooling, and then the flask containing the reaction mixture was stoppered tightly and allowed to stand at room temperature overnight. The reaction mixture was then concentrated by evaporation under reduced pressure, and the residue was purified by medium pressure silica gel column chromatography (using a 20:1 by volume mixture of methylene chloride and methanol as eluent), followed by recrystallization from hexane, to give 372 mg (yield 96%) of the title compound as white crystals, melting at 152°-155° C.
Reaction SMILES: [CH3:1][S:2]([O:5][C@H:6]1[C@H:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)[CH2:9]O[CH2:7]1)(=[O:4])=[O:3].Br[C:20]1C=CC(O[C@@H]2CCC[C@H]2O)=CC=1>>[CH3:1][S:2]([O:5][C@@H:6]1[CH2:7][CH2:20][CH2:9][C@H:10]1[O:11][C:12]1[CH:13]=[CH:14][C:15]([Br:18])=[CH:16][CH:17]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)O[C@@H]1COC[C@H]1Oc1ccc(Br)cc1
Reactant: O[C@@H]1CCC[C@H]1Oc1ccc(Br)cc1
Product: CS(=O)(=O)O[C@@H]1CCC[C@H]1Oc1ccc(Br)cc1

Procedure:
The title compound of Step 2 was prepared according to the general procedure for the synthesis of trans-4-(4-bromophenoxy)tetrahydrofuran-3-yl methanesulfonate in Example 2, except that trans-2-(4-bromophenoxy)cyclopentanol was used in place of trans-4-(4-bromophenoxy)tetrahydrofuran-3-ol, and the reaction mixture was quenched by addition of saturated aqueous ammonium chloride solution. The organic layer was then washed with saturated aqueous ammonium chloride solution, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo to provide product as a brown oil. Yield: 3.86 g, 11.5 mmol, 98%. 1H NMR (400 MHz, CDCl3) δ 1.79-2.00 (m, 4H), 2.14-2.26 (m, 2H), 3.03 (s, 3H), 4.78 (m, 1H), 5.07 (m, 1H), 6.82 (d, J=9.0 Hz, 2H), 7.39 (d, J=9.1 Hz, 2H).
Reaction SMILES: [CH3:1][S:2]([CH3:4])=[O:3].CN(P(N(C)C)(N(C)C)=O)C.[Li]CCCC.Br[CH2:22][C:23]1[C:24]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[N:25][C:26]2[C:31]([C:32]=1[C:33]([NH:35][C@H:36]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:37][CH3:38])=[O:34])=[CH:30][CH:29]=[CH:28][CH:27]=2>C1COCC1>[CH3:1][S:2]([CH2:4][CH2:22][C:23]1[C:24]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[N:25][C:26]2[C:31]([C:32]=1[C:33]([NH:35][C@H:36]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH2:37][CH3:38])=[O:34])=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:3]
Reactant: CS(C)=O
Reactant: CC[C@H](NC(=O)c1c(CBr)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC[C@H](NC(=O)c1c(CCS(C)=O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
A solution of DMSO (0.075 mL, 1.05 mmol) and HMPA (0.38 mL, 2.2 mmol) in anhydrous THF (3 mL) was prepared under N2 and cooled to −78° C. To this was added a solution of n-BuLi (0.71 mL, 1.6 M in hexanes, 1.13 mmol), the reaction allowed to stir for 10 min., then 3-(bromomethyl)-2-phenyl-N-[(1S)-1-phenylpropyl]quinoline-4-carboxamide (8) (200 mg, 0.44 mmol) was added as a solution in anhydrous THF (1 mL). The reaction was allowed to stir 10 min., additional anhydrous THF (1 mL) added, and reaction allowed stirring another 10 min. The cooling bath was then removed, saturated aqueous NH4CI (1 mL), H2O (1 mL), and Et2O (1 mL) added, the layers shaken together, and then separated. The organics were then dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc/CH2Cl2) to give the desired product (170 mg, 85% yield) as a solid. 1H NMR (300 MHz, CDCl3, 52° C.) δ 8.10 (d, J=8.0 Hz, 1H), 7.86-7.61 (m, 2H), 7.55-7.25 (m, 12H), 5.29-5.16 (m, 1H), 3.44-3.07 (m, 2H), 2.73-2.37 (m, 2H), 2.27-2.15 (m, 3H), 2.15-1.86 (m, 2H), 1.02 (t, J=7.4 Hz, 3H); LCMS: m/z 457 (MH+). HRMS m/z 457.1927, calcd. 457.1950.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:15](=[O:16])[N:14]([CH2:22][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1COc2ccccc2NC1=O
Reactant: O=C(CCl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1COc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Reaction time: 15 h
Yield: 62.1 %

Procedure:
In 150 ml of N,N-dimethylformamide is dissolved 12.3 g of 3(S)-tert-butoxycarbonylamino-2,3,4,5-tetrahydro-1,5-benzoxazepine-4-one, and 8.7 g of benzyl chloroacetate, 8.7 g of anhydrous potassium carbonate and 1 g of potassium iodide are added to the solution. After stirring for 15 hours, the mixture is poured in ice-cooled water. The deposited material is collected by filtration, washed with water and recrystallized from ethyl acetate-hexane to give 11.7 g of benzyl 3(S)-tert-butoxycarbonylamino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate as colorless prisms, melting at 122°-124° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=2)=[C:7]([Cl:24])[C:6]=1[CH3:25])(=[O:3])[CH3:2].[C:26](Cl)(=[O:30])[CH:27]([CH3:29])[CH3:28]>>[C:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])=[C:15]([C:20]([F:21])([F:23])[F:22])[CH:14]=2)=[C:7]([Cl:24])[C:6]=1[CH3:25])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(Cl)c(Oc2ccc(N)c(C(F)(F)F)c2)c(Cl)c1C
Reactant: CC(C)C(=O)Cl
Product: CC(=O)Oc1cc(Cl)c(Oc2ccc(NC(=O)C(C)C)c(C(F)(F)F)c2)c(Cl)c1C
Yield: 84.9 %

Procedure:
Methyl[3,5-dichloro-4-(4-amino-3-trifluoromethylphenoxy)phenyl] acetate (70 mg) was coupled with isobutyryl chloride (30 mg), using the method described in Example 1(h). After purification on column (silica gel, ethyl acetate/petrolium ether, 1:9), 70 mg (84%) of methyl(3,5-dichloro-4-[4-isobutyramido-3-trifluoromethylphenoxy]phenyl) acetate was obtained, which was hydrolysed using the method described in Example 1(i). This gave 50 mg (74%) of 3,5-dichloro-4-(4-isobutyramido-3-trifluoromethylphenoxy)phenylacetic acid, m/z 450.
Reaction SMILES: [CH3:1][NH:2][NH2:3].O[CH:5]=[CH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])=O>CO.O>[CH3:1][N:2]1[CH:5]=[CH:6][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=[N:3]1
Reactant: O=C(C=CO)c1ccccc1O
Reactant: CNN
Solvent: CO
Solvent: O
Product: Cn1ccc(-c2ccccc2O)n1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Methyl hydrazine (23.2 mmol, 1.23 ml) is added to a solution of 2-(3-hydroxy-2-propen-1-on-1yl)phenol (J. Am. Chem. Soc., 72:3396, 1950), 15.4 mmol, 2.54 g) in methanol (7 ml) and the mixture is heated at 100° C. for one hour. After cooling, the reaction mixture is diluted with water (100 ml) and stirred for one hour. The precipitate is collected via filtration and purified on silica gel (30% ethyl acetate/hexane) to give 811 mg of 2-(1-methylpyrazol-3-yl)phenol.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2.[Cl:17][C:18]1[CH:19]=[C:20]([SH:25])[CH:21]=[CH:22][C:23]=1[Cl:24]>>[Cl:17][C:18]1[CH:19]=[C:20]([S:25][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]3)[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: O=C1CCc2cc(OCCCBr)ccc2N1
Reactant: Sc1ccc(Cl)c(Cl)c1
Product: O=C1CCc2cc(OCCCSc3ccc(Cl)c(Cl)c3)ccc2N1

Procedure:
Prepared analogous to Example 122 from 6-(3-bromopropoxy)-3,4-dihydro-carbostyril (m.p. 111°-118° C.) and 3,4-dichloro-thiophenol.
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:9]=[CH:8][NH:7][N:6]=1)[CH2:2][CH3:3].[CH2:10]([N:12]([CH2:16][CH3:17])[C:13](Cl)=[O:14])[CH3:11].O1CCCC1>C(N(CC)CC)C>[CH2:10]([N:12]([CH2:16][CH3:17])[C:13]([N:7]1[CH:8]=[N:9][C:5]([S:4][CH2:1][CH2:2][CH3:3])=[N:6]1)=[O:14])[CH3:11]
Reactant: CCCSc1nc[nH]n1
Reactant: CCN(CC)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCSc1ncn(C(=O)N(CC)CC)n1

Procedure:
A mixture of 7.2 g. 3-propylthio-1,2,4-triazole, 6.8 g. diethylcarbamoyl chloride, 35 ml. dry tetrahydrofuran and 9 ml. dry triethylamine was refluxed under anhydrous conditions for 72 hours. The reaction mixture was worked up as described in Example 1 to produce a residual oil. This oil was distilled under reduced pressure to give 1-diethylcarbamoyl-3-propylthio-1,2,4-triazole, b.p. 118° - 121°C./0.2 mm. (89.9% 1-isomer by GLC assay). Elemental analysis satisfactory.
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([CH2:8][S:9][CH2:10][CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[CH:5][CH:4]=1)=[O:2].[CH2:23](O)[CH2:24][OH:25]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:2]1[CH2:23][CH2:24][O:25][CH:1]1[C:3]1[O:7][C:6]([CH2:8][S:9][CH2:10][CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(CSCCN2C(=O)c3ccccc3C2=O)o1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCSCc1ccc(C2OCCO2)o1
Reaction time: 6 h
Yield: 79 %

Procedure:
A mixture of N-[2-[(5-formyl-2-furanylmethyl)thio]ethyl ]-1H-isoindole-1,3-(2H)-dione (15 g), p-toluenesulphonic acid (0.12 g) and 1,2-ethanediol (6.2 g) in benzene (160 ml) was refluxed under Dean-Starke conditions. After 6 hours, the solution was washed with a solution of sodium carbonate (1.2 g) in water (25 ml), dried (Na2CO3), decolourised (charcoal) and evaporated in vacuo. The semi-solid residue was suspended in ether (200 ml) and filtered off to give the title compound (13.5 g), m.p. 83°-85°.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]=[CH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:14][C:13]=2[C:25]=1[C:26]([CH3:29])([CH3:28])[CH3:27])C1C=CC=CC=1>[Pd].C(O)(=O)C>[C:26]([C:25]1[C:13]2[CH:14]=[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:16][C:12]=2[CH:11]=[CH:10][C:9]=1[OH:8])([CH3:29])([CH3:28])[CH3:27]
Reactant: CCCCCCC=Cc1cc2c(C(C)(C)C)c(OCc3ccccc3)ccc2o1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCCCCCCc1cc2c(C(C)(C)C)c(O)ccc2o1
Reaction time: 36 h
Yield: 68.4 %

Procedure:
10% Palladium on carbon (1.1 g) was added to a solution of 5-benzoxy-4-tert-butyl-2-(1-octenyl)benzofuran (1.1 g, 2.9 mmol) in acetic acid (50 ml), and the mixture was stirred for 36 h under a hydrogen atmosphere. After filtering off the Pd on carbon, the solvent was distilled off with an evaporator. The concentrate was purified by silica gel chromatography (chloroform) to afford 4-tert-butyl-5-hydroxy-2-octylbenzofuran [600 mg (yield, 69%)] a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[CH2:3][C:4]([NH:6][C:7]1[C:15]([C:16]2C=N[CH:19]=[CH:20][CH:21]=2)=[C:10]2[N:11]=[CH:12][CH:13]=[CH:14][N:9]2[N:8]=1)=[O:5].[Cl:24][C:25]1[CH:30]=CC(/C=C/B(O)O)=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:30]=[CH:19][C:20](/[CH:21]=[CH:16]/[C:15]2[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:1])([CH3:22])[CH3:23])=[N:8][N:9]3[CH:14]=[CH:13][CH:12]=[N:11][C:10]=23)=[CH:27][CH:26]=1
Reactant: CC(C)(C)CC(=O)Nc1nn2cccnc2c1-c1cccnc1
Reactant: OB(O)/C=C/c1ccc(Cl)cc1
Product: CC(C)(C)CC(=O)Nc1nn2cccnc2c1/C=C/c1ccc(Cl)cc1

Procedure:
The product from Example 110B and trans-2-(4-chlorophenyl)vinylboronic acid were processed using the method analogous to that described in Example 110C to afford the title compound. H NMR (400 MHz, CD3OD) δ ppm 8.80 (dd, J=7.0, 1.7 Hz, 1H), 8.60 (dd, J=4.1, 1.6 Hz, 1H), 7.65 (d, J=16.3 Hz, 1H), 7.47-7.50 (m, 2H), 7.31-7.34 (m, 2H), 7.19 (d, J=16.5 Hz, 1H), 7.03 (dd, J=7.0, 4.1 Hz, 1H), 2.41-2.41 (bs, 2H), 1.17 (s, 9H); MS (ESI) m/z 369 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:31]([NH2:32])=[CH:30][C:29]([Cl:33])=[CH:28][C:3]=1[C:4]([O:6][CH2:7][C:8]1([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:5].[C:34](N1C=CN=C1)(N1C=CN=C1)=[O:35].C(OCC)C>O1CCCC1>[Cl:33][C:29]1[CH:28]=[C:3]([C:4]([O:6][CH2:7][C:8]2([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)=[O:5])[C:2]2[NH:1][C:34](=[O:35])[NH:32][C:31]=2[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COC(=O)c2cc(Cl)cc(N)c2N)(c2ccc(F)cc2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COC(=O)c2cc(Cl)cc3[nH]c(=O)[nH]c23)(c2ccc(F)cc2)CC1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-((2,3-diamino-5-chlorobenzoyloxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (714 mg, 1.5 mmol) in tetrahydrofuran (10 mL) at 0° C. was added carbonyldiimidazole (242 mg, 1.5 mmol). The ice bath was removed and stirring continued for 1 h. The reaction was treated with a second portion of carbonyldiimidazole (242 mg, 1.5 mmol) and stirred for 1 h at room temperature. The solution was transferred to a microwave vial and heated at 70° C. for 1 h via microwave. The reaction was poured into diethyl ether, washed with water, then brine, dried over magnesium sulfate, and concentrated. Column chromatography (25%→100 ethyl acetate/n-hexane) gave 0.52 g (69%) as a brown solid. 1H-NMR (CDCl3, 500 MHz) δ 9.69 (bs, 1H), 9.05 (bs, 1H), 7.42 (d, J=1.8 Hz, 1H), 7.38 (dd, J=8.6, 5.2 Hz, 2H), 7.19 (d, J=1.5 Hz, 1H), 7.11 (dd, J=8.6, 8.5 Hz, 2H), 4.32 (s, 2H), 3.81 (m, 2H), 3.09 (m, 2H), 2.24 (m, 2H), 1.89 (m, 2H), 1.44 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 164.6, 162.6, 160.6, 157.4, 155.1, 136.5, 131.1, 128.8 (d, J=7.7 Hz), 126.0, 121.1, 115.7 (d, J=21 Hz), 114.7, 111.8, 79.8, 73.1, 40.6, 39.9, 31.8, 28.6. Mass spec.: 525.87 (MNa)+.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.P(Cl)(Cl)([Cl:9])=O.[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[C:16](O)=[N:17][CH:18]=1.O>C(OCC)(=O)C>[Cl:9][C:16]1[C:15]([N+:20]([O-:22])=[O:21])=[CH:14][C:13]([F:12])=[CH:18][N:17]=1
Reactant: O=[N+]([O-])c1cc(F)cnc1O
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(F)cnc1Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
To a mixture of phosphorus pentachloride (9.41 g, 45.2 mmol) and phosphorus oxychloride (4.2 mL, 45.1 mmol) at 60° C. was added in portions 5-fluro-2-hydroxy-3-nitropyridine (6.5 g, 41.1 mmol). The mixture was stirred in an oil bath at 100° C. under nitrogen overnight, cooled to room temperature and poured into ice/water. After addition of more water and ethyl acetate, the mixture was filtered through Celite® to remove dark insoluble material. The organic phase was washed with brine, filtered again to remove more dark material, dried over MgSO4 and concentrated. The residue was subjected to flash chromatography on silica gel using chlorform as eluant. Fractions containing the title compound were combined and concentrated to provide a yellow oil (3.51 g, 48%) which solidified on standing at 5° C. overnight.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5](=[O:8])[NH:6][N:7]=1.N1C=CC=CC=1.[C:17]1([CH3:26])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5](=[O:8])[N:6]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH3:26])[N:7]=1
Reactant: Cn1c(=O)[nH]nc(Br)c1=O
Reactant: Cc1ccccc1B(O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccccc1-n1nc(Br)c(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
0.5 g (2.43 mmol) of intermediate 2a are placed in the presence of 0.4 mL (4.85 mmol) of pyridine, 0.66 g (4.85 mmol) of o-tolyl boronic acid, 0.66 g (3.64 mmol) of copper acetate in 50 mL of CH2Cl2. The reaction medium is stirred for 24 h at room temperature and then filtered on celite. The filtrate is washed with water, and then with 0.01N hydrochloric acid. After drying on MgSO4, the organic phase is dry concentrated. After washing the obtained residue with diethyl ether, 0.54 g of a white solid corresponding to the compound 41 are isolated (yield 75%)