Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]=[C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])[N:9]=2)[CH2:4]1.C1COCC1.C(N(CC)CC)C.Cl[C:39]([O:41][CH2:42][CH:43]([CH3:45])[CH3:44])=[O:40]>C(Cl)Cl>[OH:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:10]1[N:9]=[C:8]([N:5]2[CH2:6][CH2:7][C@@H:3]([CH2:2][NH:1][C:39](=[O:40])[O:41][CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:4]2)[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[N:11]=1
Reactant: CC(C)COC(=O)Cl
Reactant: Cc1ccc2c(N3CC[C@@H](CN)C3)nc(-c3ccccc3O)nc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc2c(N3CC[C@@H](CNC(=O)OCC(C)C)C3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Yield: 70.2 %

Procedure:
A mixture of 2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (200 mg, 0.6 mmol), THF (6.0 mL), and CH2Cl2 was stirred under an N2 atmosphere. Triethylamine (0.166 mL, 1.2 mmol) was added, and the reaction was cooled in an ice bath. To this was added 1 M isobutyl chloroformate solution (78 μL in 600 μL THF, 0.6 mmol). After allowing the reaction mixture to warm to room temperature, CH2Cl2 was added, and the organic solution washed twice with water, then dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using 0-20% EtOAc in CH2Cl2/hexanes (1:1) gave isobutyl ((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate (183 mg, 70%). LC/MS: m/z 435.5 (M+H)+ at 2.63 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). LC/MS: m/z 435 (M+H)+ at 2.63 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.43 (dd, J=8.2, 1.8 Hz, 1H), 8.22 (d, J=8.7 Hz, 1H), 7.58 (s, 1H), 7.42-7.31 (m, 3H), 6.93-6.89 (m, 2H), 4.17-3.91 (m, 3H), 3.80-3.69 (m, 3H), 3.34-3.30 (m, 1H), 3.21-3.07 (m, 2H), 2.49 (s, 3H), 2.16-2.08 (m, 1H), 1.88-1.74 (m, 2H), 0.88 (d, J=6.7 Hz, 6H) ppm.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=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]>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:11]([CH3:10])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: CNc1ccccc1
Reactant: N#Cc1ccc(Cl)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CN(c1ccccc1)c1ccc(C#N)cc1
Reaction time: 12 h
Yield: 91.7 %

Procedure:
The above general procedure was followed using 4-chlorobenzonitrile (137 mg, 1.00 mmol) and N-methylaniline (107 mg, 1.00 mmol) with 1 mol % Pd(dba)2 and 0.8 mol % tri-t-butylphosphine in 1.0 mL of toluene. After 12 hours, the reaction mixture was adsorbed onto silica gel and chromatographed with 10% ethyl acetate/hexanes to give 191 mg (92%) of N-(4-cyanophenyl)-N-methylaniline.
Reaction SMILES: C1(S[C:8]([C@H:15]2[NH:18][C:17](=[O:19])[C@@H:16]2[C@H:20]([O:22][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[CH3:21])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:9])C=CC=CC=1.ClC1C=CC=C(C(OO)=O)C=1>ClCCl.C1(C)C=CC=CC=1>[CH2:13]([O:12][C:10]([C:8]([C@H:15]1[NH:18][C:17](=[O:19])[C@@H:16]1[C@H:20]([O:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])[CH3:21])=[CH2:9])=[O:11])[CH3:14]
Reactant: CCOC(=O)C(C)(Sc1ccccc1)[C@H]1NC(=O)[C@@H]1[C@@H](C)OC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C=C(C(=O)OCC)[C@H]1NC(=O)[C@@H]1[C@@H](C)OC(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
A solution of (3S,4S)-4-(1-phenylthio-1-ethoxycarbonylethyl)- 3-(1-(R)-p-nitrobenzyloxycarbonyloxyethyl)-2-azetidinone (2.0 g) in dry dichloromethane (50 ml) was treated with m-chloroperbenzoic acid (0.69 g) for 3 hours while ice-cooling. The reaction mixture was washed successively with a saturated sodium bicarbonate solution and brine, and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave an oily residue which was dissolved in toluene (18 ml). The toluene solution was stirred under reflux for 1 hour and concentrated in vacuo. An oily residue was purified by silica gel chromatography to yield (3S,4S)-4-(1-ethoxycarbonylethenyl)-3-(1-(R)-p-nitrobenzyloxycarbonyloxyethyl)-2-azetidinone.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7](=[O:34])[C@H:8]([CH2:31][CH2:32][CH3:33])[NH:9][C@@H:10]([C:15]2[CH:20]=[CH:19][C:18](C3C=CC(S(C)(=O)=O)=CC=3)=[CH:17][CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH2:5][CH2:4]1)#[N:2].[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1B(O)O.BrC1C=CC([C@H](N[C@H](C(NC2(C#N)CC2)=O)CCC)C(F)(F)F)=CC=1>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:1]([C:3]1([NH:6][C:7](=[O:34])[C@@H:8]([NH:9][C@@H:10]([C:15]2[CH:20]=[CH:19][C:18]([C:37]3[CH:38]=[CH:39][C:40]([F:42])=[CH:41][C:36]=3[F:35])=[CH:17][CH:16]=2)[C:11]([F:12])([F:14])[F:13])[CH2:31][CH2:32][CH3:33])[CH2:5][CH2:4]1)#[N:2]
Reactant: CCC[C@H](N[C@@H](c1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Reactant: OB(O)c1ccc(F)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CCC[C@H](N[C@@H](c1ccc(Br)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Product: CCC[C@H](N[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1

Procedure:
The title compound was synthesized in similar manner to that described for N1-(1-cyanocyclopropyl)-N2-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-norvalinamide via Suzuki cross-coupling between 2,4-difluorophenylboronic acid and N2-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N1-(1-cyanocyclopropyl)-L-norvalinamide in the presence of [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), dichloromethane complex.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][CH:6]([CH2:10][CH3:11])[C:7](Cl)=[O:8].[C:12]1([S:18][CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)(Cl)Cl>[CH3:5][CH:6]([CH2:10][CH3:11])[C:7]([C:15]1[CH:16]=[CH:17][C:12]([S:18][CH3:19])=[CH:13][CH:14]=1)=[O:8]
Reactant: CSc1ccccc1
Reactant: CCC(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CCC(C)C(=O)c1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 500 mL RBF equipped with a mechanical stirrer was charged with AlCl3 (35.4 g) and CHCl3 (300 mL) and cooled in an ice bath. Then 2-methylbutanoyl chloride (31.4 g) was added over 0.5 h to the ice-cold suspension. Keeping the internal temperature <10° C., thioanisole (31.2 mL) was added dropwise over 1 h. After completion of addition, the resulting mixture was stirred at r.t. for 2 h. The resulting suspension was poured onto an ice-water mixture and stirred until decoloraton. The organic layer was separated, washed with water, dried over Na2SO4 and concentrated to dryness. The resulting white solid was swished in hexane and collected by filtration to give the title compound as a white solid. 1H NMR(CD3COCD3): δ0.88 (3H, t), 1.12 (3H, d), 1.47 (1H, m), 1.78 (1H, m), 2.57 (3H, s), 3.49 (1H, m), 7.37 (2H, d), 7.93 (2H, d).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH:9]([F:16])([F:15])[C:10]([CH:12]([F:14])[F:13])=[O:11]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:10]([OH:11])([CH:9]([F:16])[F:15])[CH:12]([F:14])[F:13])=[CH:4][C:3]=1[OH:8]
Reactant: O=C(C(F)F)C(F)F
Reactant: Nc1ccccc1O
Solvent: Cc1ccccc1
Product: Nc1ccc(C(O)(C(F)F)C(F)F)cc1O

Procedure:
A mixture of 2-amino-hydroxybenzene, toluene and sym-tetrafluoroacetone can be heated in a Hastelloy® bomb. The solvent can be removed by evaporation and the residual material can be purified by chromatography on silica gel to give 4-amino[2,2-difluoro-1-hydroxy-1-(difluoromethyl)ethyl]-3-hydroxybenzene.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][C:4]=2[CH:3]=[N:2]1.Cl[C:18]1[N:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=1.CC(C1C=C(C(C)C)C(C2C(P(C(C)(C)C)C(C)(C)C)=CC=CC=2)=C(C(C)C)C=1)C.CC([O-])(C)C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:24][C:21]1[N:20]=[N:19][C:18]([N:2]2[CH:3]=[C:4]3[CH2:5][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][CH2:8][C:9]3=[N:1]2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]ncc2C1
Reactant: Cc1ccc(Cl)nn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1ccc(-n2cc3c(n2)CCN(C(=O)OC(C)(C)C)C3)nn1
Temperature: 120 °C

Procedure:
A mixture of tert-butyl 1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (3.72 g, 16.67 mmol), 3-chloro-6-methylpyridazine (3.2 g, 24.92 mmol), Pd2(dba)3 (760 mg, 0.83 mmol), tBuXPhos (705 mg, 1.66 mmol) and tBuONa (1.99 g, 20.77 mmol) in toluene (90 mL) is degassed by argon and heated at 120° C. in a sealed tube overnight. EtOAc (200 mL) and water (250 mL) are added and the layers are separated. The organic layer is washed with water (200 mL) and then brine (200 mL), dried and evaporated. Purification of the residue by flash column with hexane/EtOAc (2:1) gives a white solid that is a mixture of two regioisomers. Recrystallization of the solid from hexane/EtOAc (1:1) gives the title compound as white needles. MS (M+1): 316.2.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]3[S:15][CH:16]=[CH:17][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>ClCCl>[S:15]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:23](=[O:24])[C:22]4[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=4[CH3:20])=[CH:19][CH:18]=3)=[O:7])[C:9]=2[CH:17]=[CH:16]1
Reactant: Nc1ccc(C(=O)N2CCCCc3sccc32)cc1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3sccc32)cc1

Procedure:
As described for Example 1, 4-(4-aminobenzoyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine (0.001 ml) is reacted with 2-methylbenzoyl chloride in dichloromethane to give the product. Crystallization from ethyl acetate-hexane gives crystals, m.p. 181°-182° C.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5](Cl)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N1C=CC=CC=1>O>[C:5]([NH:4][CH2:3][CH2:1][OH:2])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: NCCO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: OCCNC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A mixture of ethanolamine, trityl chloride and pyridine was refluxed for 15h. Water was added slowly to the cooled reaction and the precipitate collected by filtration. The crude product recrystallized from a 1:1 mixture of ethanol and water.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Br:9]Br.O.S(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([Br:9])[CH:5]=[CH:4][C:3]=1[OH:8]
Reactant: BrBr
Reactant: Oc1ccccc1F
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(Br)cc1F
Reaction time: 2 h
Yield: 90.3 %

Procedure:
To a stirred solution of 2-fluorophenol (22.4 g, 0.2 mole) in methylene chloride (250 ml) which was cooled to ~3° C. in an ice bath, was added, all at once, bromine (31.97 g, 0.2 mole). The resulting solution was stirred at ice bath temperature for two hours and then at room temperature for 1 hour. The mixture was poured into water (600 ml) containing excess sodium bisulfite. The organic phase was separated and the aqueous phase was washed with additional methylene chloride (200 ml). The combined organic extracts were washed with saturated sodium bicarbonate, dried (MgSO4) and the solvent evaporated to give the desired 2-fluoro-4-bromophenol as a colorless oil (34.5 g, 90%). The NMR (CDCl3) was consistent with the assigned structure. The gc of this material showed that it contained only a trace of the 2,6-isomer. This material was used directly in the following step without additional purification.
Reaction SMILES: [Li]CCCC.[Si]([CH:10]=[N+:11]=[N-:12])(C)(C)C.[O:13]=[C:14]1[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:17]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:16][CH2:15]1>C1COCC1>[C:22]([O:21][C:19]([NH:18][C@@H:17]([CH2:16][CH2:15][C:14](=[O:13])[CH:10]=[N+:11]=[N-:12])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:20])([CH3:23])([CH3:25])[CH3:24]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CCOC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](CCC(=O)C=[N+]=[N-])NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
n-BuLi was added dropwise to a solution of TMSCHN2 (690 mL, 1.38 mol) in dry THF (3 L) (600 mL, 1.5 mol) at −78° C., and the mixture was stirred at −78° C. for 30 minutes. The mixture was then transferred to a solution of (S)-1-tert-butyl 2-ethyl 5-oxopyrrolidine-1,2-dicarboxylate (300 g, 1.17 mol) in dry THF (3 L) via cannula, and the mixture was stirred at −78° C. for 30 minutes. The reaction mixture was then quenched with sat. NH4Cl solution, and extracted with DCM three times. The combined organic layer was concentrated in vacuum and the crude product was purified by silica gel column chromatography (3:1 petroleum ether:EtOAc) to afford (S)-ethyl 2-((tert-butoxycarbonyl)amino)-6-diazo-5-oxohexanoate (262 g, 75%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:16][CH2:17][CH2:18][CH2:19][Cl:20]>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:8])[N:4]([CH2:16][CH2:17][CH2:18][CH2:19][Cl:20])[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]cccc1Br
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1c(Br)cccn1CCCCCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
To a solution of 3-bromo-2(1H)-pyridinone (commercial source: Alfa Aesar) (5 g, 28.7 mmol) in DMF (130 ml) was added K2CO3 (4.8 g, 34.5 mmol). The reaction mixture was stirred at room temperature for 1 hour, then 1-bromo-4-chlorobutane (3.3 ml, 28.7 mmol) was added and the reaction mixture was stirred for 18 hours at room temperature. DMF was evaporated, water was added to the crude and the organic layers were extracted with DCM. The organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with a gradient of methanol in DCM (from 0 to 5%) to afford the title compound (4.82 g, 63%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[N:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30]CC3C=CC=CC=3)=[CH:26][CH:25]=2)[C:21](=[O:23])[CH3:22])=[CH:5][CH:4]=1.Cl>CCO.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[N:20]([C:24]2[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=2)[C:21](=[O:23])[CH3:22])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2N(C(C)=O)c2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(-c2sc3cc(OC)ccc3c2N(C(C)=O)c2ccc(O)cc2)cc1
Reaction time: 4 h
Yield: 66 %

Procedure:
2-(4-Methoxyphenyl)-3-[N-(4-benzyloxyphenyl)acetamido]-6-methoxy-benzo[b]thiophene (2.43 g, 4.77 mmol) was dissolved in 50 mL of 1:1 EtOH/EtOAc containing 5% con. HCl. To this solution was added 1.0 g of 5% Pd/C. The resulting mixture was hydrogenated at 40 psi for 4 h. The mixture was then filtered through Celite to remove the catalyst. The filtrate was concentrated in vacuo to a semi-solid. Chromatograhy (SiO2, CHl3) provided 1.32 g (83%) of 2-(4-methoxyphenyl)-3-[N-(4-hydroxyphenyl)acetamido]-6-methoxy-benzo[b]thiophene as an amber foam. 1H NMR (DMSO-d6) δ (doubling due to amide rotamers) 9.53 and 9.36 (s, 1H), 7.62-6.51 (m, 11 H), 3.78 and 3.58 (s, 6H), 2.01 and 1.76 (s, 3H). FD mass spec: 419. Anal. Calcd. for C24H21NO4S.0.19 CHCl3 : C, 65.71; H, 4.83; N, 3.17. Found: C, 65.80; H, 4.70; N, 3.01.
Reaction SMILES: C[N:2](C)[C:3]([C:5]1[CH:32]=[CH:31][C:8]2[N:9](CCC(C)C)[C:10]([CH2:12][N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[N:15]([CH:22]([CH3:24])[CH3:23])[C:14]3=[O:25])=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[NH4+]>>[CH:22]([N:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:13]([CH2:12][C:10]2[N:11]([CH2:7][CH2:6][CH:5]([CH3:32])[CH3:3])[C:7]3[CH:6]=[C:5]([C:3]([NH2:2])=[O:4])[CH:32]=[CH:31][C:8]=3[N:9]=2)[C:14]1=[O:25])([CH3:23])[CH3:24]
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(C(=O)N(C)C)ccc21
Agent: [NH4+]
Agent: [OH-]
Product: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2ccc(C(N)=O)cc21

Procedure:
2-(3-Isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-3-(3-methyl-butyl)-3H-benzoimidazole-5-carboxylic acid amide was prepared by the same procedure as 2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5-carboxylic acid dimethylamide, except using ammonium hydroxide.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[O-:12].[K+].Cl[CH2:15][C:16]([C:18]1[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[C:21]([OH:27])=[C:20]([CH:28]([CH3:30])[CH3:29])[CH:19]=1)=[O:17].C(N(CC)CC)C.Cl>O.CN(C)C=O>[OH:27][C:21]1[C:22]([CH:24]([CH3:26])[CH3:25])=[CH:23][C:18]([C:16](=[O:17])[CH2:15][O:12][N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])=[CH:19][C:20]=1[CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)c1cc(C(=O)CCl)cc(C(C)C)c1O
Reactant: O=C1c2ccccc2C(=O)N1[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)c1cc(C(=O)CON2C(=O)c3ccccc3C2=O)cc(C(C)C)c1O
Yield: 44 %

Procedure:
A mixture of 3.03 g (15 mmol) of potassium 1,3-dioxo-1,3-dihydro-isoindol-2-olate [prepared according to P. Consonni, D Favara, A. Omodei-Salé, G. Bartolini, A. Ricci, J. Chem. Soc., Perkin Trans. 2, 1983, 967-973], 3.82 g (15 mmol) of 2-chloro-1-(4-hydroxy-3,5-di-iso-propyl-phenyl)-ethanone, 2.3 ml of triethylamine and 100 ml of dimethylformamide is stirred at room temperature and under nitrogen atmosphere for 1.5 hours. Then the mixture is poured onto 500 ml of water containing 9 ml of 2N HCl and is extracted with ethyl acetate. The collected organic phases are washed with water, dried and evaporated. The resulting crude product is recrystallized from ethyl acetate and hexane to give 2.52 g of compound 114, m.p. 136-139°.
Reaction SMILES: Cl[CH2:2][C:3]([NH:6][C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[CH3:16])=[O:8])([CH3:5])[CH3:4].[H-].[Na+].CO>C1COCC1.C(Cl)(Cl)Cl>[CH3:2][C:3]1([CH3:5])[CH2:4][N:9]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2[CH3:16])[C:7](=[O:8])[NH:6]1
Reactant: Cc1ccncc1NC(=O)NC(C)(C)CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccncc1N1CC(C)(C)NC1=O
Reaction time: 2 h
Yield: 93.9 %

Procedure:
1-(2-Chloro-1,1-dimethyl-ethyl)-3-(4-methyl-pyridin-3-yl)-urea (I-200d: 1 g, 4.149 mmol) in dry THF (5 mL) was added dropwise to a stirred mixture of NaH (298 mg, 6.208 mmol) in dry THF (10 mL) under argon atmosphere over a period of 10 minutes at 0° C. The resulting reaction mixture was stirred for 2 hrs. The reaction was monitored by TLC (5% MeOH in CHCl3). The reaction mixture was partitioned between water and ethylacetate. The organic layer was dried over Na2SO4 and concentrated to afford 800 mg of the product (94.33% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-])=[C:6]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH:5]=1)([O-:3])=[O:2].P(Cl)(OCC)OCC.[OH-].[Na+]>C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(-n2cncn2)c1
Agent: CCOP(Cl)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccnc(-n2cncn2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.4 %

Procedure:
To a solution of 4-nitro-2-(1H-1,2,4-triazol-1-yl)pyridine 1-oxide (0.643 g, 3.10 mmol) in CHCl3 (30 mL) at 0° C. was added diethyl chlorophosphite (1.35 mL, 9.31 mmol). The reaction mixture was allowed to stir at rt for 72 h. Additional diethyl chlorophosphite (1.35 mL, 9.31 nmmol) was added and the reaction mixture was heated at 80° C. for 18 h. The reaction mixture was cooled to 0° C., basified by the addition of 1N NaOH solution and extracted with DCM. The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography. The product was triturated with hexane to provide 4-nitro-2-(1H-1,2,4triazol-1-yl)pyridine (0.192 g, 32.3%). LCMS: (FA) ES+ 192.3.
Reaction SMILES: [CH2:1]([N:7]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[CH:24][CH:23]=1)[C:8]1[CH:20]=[CH:19][C:11]2[O:12]C(C)(C)[O:14][C:15](=[O:16])[C:10]=2[CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[Na+]>CO>[CH2:1]([N:7]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]#[C:29][C:30]2[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)=[CH:26][CH:27]=1)[C:8]1[CH:20]=[CH:19][C:11]([OH:12])=[C:10]([CH:9]=1)[C:15]([OH:16])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN(Cc1ccc(C#Cc2ccc(OC)cc2)cc1)c1ccc2c(c1)C(=O)OC(C)(C)O2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(OC)cc2)cc1)c1ccc(O)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.4 %

Procedure:
To a solution of 6-(hexyl{4-[(4-methoxyphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one (520 mg; 1.05 mmol) in MeOH (20 mL) was added an aqueous solution of NaOH (1.05 mL, 5N). The reaction mixture was stirred at rt for 1 h. The yellow precipitate obtained was filtrated and washed with cola water. It was suspended again in MeOH (20 mL) and aqueous solution of NaOH (2 mL, 5N) and heated at 70° C. overnight. The reaction mixture was poured into an aqueous solution of HCl (1N) and extracted with Et2O. The combined organic layers were washed with brine, dried over magnesium sulfate, filtrated and concentrated. Purification by preparative HPLC using a X-Terra column followed by a recrystallisation in MeOH gave 55 mg (12%) the title compound as a brown powder. HPLC, Rt: 4.24 min purity: 95.0%). LC/MS, M+(ESI): 458.3, M−(ESI): 456.1 1H NMR (CDCl3) δ: 12.70 (brs, 1H), 10.20 (brs, 1H), 7.46 (d, J=5.3 Hz, 2H), 7.44 (d, J=4.5 Hz, 2H), 7.23 (d, J=7.3 Hz, 2H), 6.98 (m, 4H), 6.78 (d, J=9.0 Hz, 1H), 4.46 (s, 2H), 3.78 (s, 3H), 3.31 (m, 2H), 1.51 (m, 2H), 1.25 (m, 6H), 0.84 (m, 3H).