Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:9][C@@H:10]([N:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][N:28]=[C:27](S(C)(=O)=O)[N:26]=2)=[CH:21][C:20]1=[O:35])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[CH3:36][N:37]1[C:41]([NH2:42])=[CH:40][CH:39]=[N:38]1>CN(C=O)C>[Si:2]([O:1][CH2:9][C@@H:10]([N:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH:42][C:41]3[N:37]([CH3:36])[N:38]=[CH:39][CH:40]=3)[N:26]=2)=[CH:21][C:20]1=[O:35])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=1)([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(F)c1)n1ccc(-c2ccnc(S(C)(=O)=O)n2)cc1=O
Reactant: Cn1nccc1N
Solvent: CN(C)C=O
Product: Cn1nccc1Nc1nccc(-c2ccn([C@H](CO[Si](C)(C)C(C)(C)C)c3ccc(Cl)c(F)c3)c(=O)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(S)-1-(2-(tert-Butyldimethylsiloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridine-2(1H)-one (47 mg, 0.087 mmol), 2-methyl pyrazole-3-amine (0.175 mmol, 2.0 equivalents) and anhydrous DMF (3.0 mL) were added to a 25 mL round bottomed flask equipped with a stirring bar. The flask was capped with a rubber septum and flushed with nitrogen. Under a blanket of nitrogen, sodium hydride (8.5 mg, 60% dispersion in mineral oil) was added in one portion. The flask was flushed with nitrogen, capped and stirred at room temperature. The reaction progress was monitored by LCMS, and after 30 minutes, the starting material was consumed. The reaction mixture was quenched by the addition of water (0.5 mL) and ethyl acetate (15 mL). The contents of the round bottomed flask were transferred to a 125 mL separatory funnel, and the reaction flask was rinsed several times with additional ethyl acetate. Crude (S)-1-(2-((tert-butyldimethylsilyl)oxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one was partitioned between ethyl acetate and water (80 mL/30 mL). The ethyl acetate layer was washed once with brine, dried (MgSO4), filtered and concentrated to give crude (S)-1-(2-((tert-butyldimethylsilyl)oxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one. The crude was taken directly into the deprotection step.
Reaction SMILES: [C:1](=[O:3])=[O:2].[CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[O-:14].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>>[OH:14][C:5]1[C:6]([C:1]([OH:3])=[O:2])=[CH:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=1
Reactant: [O-]c1ccc2ccccc2c1
Reactant: O=C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)c1cc2ccccc2cc1O
Temperature: 240 °C
Yield: 69 %

Procedure:
A stainless steel pressure autoclave is charged with 50 parts of kerosene and heated to 240° C. It is then pressurized with 10 bar of carbon dioxide. Over the course of 8 hours, a mixture of 50 parts of sodium β-naphtholate and 32 parts of sodium carbonate are metered in as a suspension in kerosene via a metering pump, part of the kerosene being distilled off, condensed and transferred out of the reaction vessel at reduced pressure. After the usual workup, the 2-hydroxynaphthalene-3-carboxylic acid is obtained in a yield of 69% based on sodium β-naphtholate used. In addition, 20% of unreacted β-naphthol and small amounts of 2-hydroxynaphthalene-6-carboxylic acid and 2-hydroxynaphthalene-3,6-dicarboxylic acid are obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:12]=O)[CH:8]=2)[O:3]1.[CH3:15][C:16]1[C:24]([Cl:25])=[CH:23][CH:22]=[C:21]2[C:17]=1[CH2:18][C:19](=[O:26])[NH:20]2>>[Cl:25][C:24]1[C:16]([CH3:15])=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:26])[C:18]2=[CH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[O:3][C:2]([CH3:14])([CH3:1])[CH2:11][CH2:10]2
Reactant: CC1(C)CCc2cc(C=O)ccc2O1
Reactant: Cc1c(Cl)ccc2c1CC(=O)N2
Product: Cc1c(Cl)ccc2c1C(=Cc1ccc3c(c1)CCC(C)(C)O3)C(=O)N2

Procedure:
2,2-Dimethyl-6-formylchromane (commercially available) was condensed with 4-methyl-5-chloro-2-oxindole to give 0.3 g of 5-chloro-3-(2,2-dimethyl-chroman-6-ylmethylene)-4-methyl-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:4]([C:9]([O:11]C)=[O:10])=[N:5][CH:6]=[CH:7][N:8]=1.[OH-].[K+]>C(O)C.O>[F:14][C:2]([F:1])([F:13])[C:3]1[C:4]([C:9]([OH:11])=[O:10])=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: COC(=O)c1nccnc1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1nccnc1C(F)(F)F
Yield: 62.6 %

Procedure:
Methyl 3-trifluoromethylpyrazine-2-carboxylate (700 mg, 3.4 mmol) was dissolved in ethanol-water (1:1, 10 ml), followed by adding potassium hydroxide (300 mg) and refluxing under heating for 1 hour. The reaction solution was concentrated under reduced pressure, followed by dilution of residue with water and washing with ethyl acetate. The water layer was acidified with HCl, followed by extracting with ethyl acetate, washing with a saturated brine. The solution was dried over magnesium sulfate, and concentrated under reduced pressure to obtain 409 mg of the desired compound as crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([C:12]([N+:15]([O-:17])=O)=[N:13]O)[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:6]=2[CH:25]=1.[CH3:26][N:27]1[CH2:32][CH2:31]N[CH2:29][CH2:28]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([C:12]([N:13]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)=[N:15][OH:17])[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:6]=2[CH:25]=1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])C(=NO)C1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1
Solvent: C1CCOC1
Product: CN1CCN(C(=NO)C2=Nc3ccc(Cl)cc3C(c3ccccc3F)=NC2)CC1

Procedure:
This compound was obtained by reacting 7-chloro-5-(2-fluorophenyl)-N-hydroxy-α-nitro-3H-1,4-benzodiazepine-2-methanimine with N-methylpiperazine in tetrahydrofuran. The analytical sample was recrystallized from ethanol, mp 198°-200° C.
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[OH:2].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O>CC(CC)=O>[OH:2][C:1]1[C:3]2[O:4][C:1]([CH2:3][CH3:5])([CH3:9])[O:6][C:5]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Oc1cccc(O)c1O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: CCC(C)=O
Product: CCC1(C)Oc2cccc(O)c2O1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of pyrogallol (50 parts) in ethyl methyl ketone (200 parts) was stirred and heated to 50° C, then phosphorus pentoxide was added portionwise at such a rate that the temperature remained about 80° C. After stirring for a further 30 minutes at about 50° C the liquid layer was poured into cold water (1,000 parts) and the crude product isolated by extracting with benzene and evaporating the extracts. Distillation of the crude product gave pure 4-hydroxy-2-ethyl-2-methyl-1,3-benzodioxole (39.5 parts), boiling point 84°-85° C/0.4 mm., melting point 48°-50° C.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])(=O)C>CO>[NH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:12]
Reactant: CC(=O)Nc1ccccc1C(=O)C1CCCCC1
Solvent: CO
Product: Nc1ccccc1C(=O)C1CCCCC1
Temperature: 80 °C
Yield: 91.1 %

Procedure:
A solution of (2-acetamidophenyl) cyclohexyl methanone (0.53 g, 2.16 mmol) in methanol (5 ml) and concentrated hydrochloric add (15 ml) was heated at 80° C. for 1 h. After this time the solution was cooled to ambient temperature and the solvents removed in vacuo. The residue was dissolved in water (10 ml) and basified with 4N sodium hydroxide solution (20 ml). The mixture was then extracted into ethyl acetate (4×20 ml) and the organic layers combined and dried (MgSO4). The solvent was evaporated and the residue chromatographed on silica gel, using petrol:ethyl acetate (2:1), to afford the amine (0.40 g, 91%) as a white solid. mp 73°-75° C. 1H NMR (360 MHz, CDCL3)-- 1.23-2.09 (10H, m), 3.27 (1H, m), 6.29 (2H, brs), 6.64 (2H, m), 7.25 (1H, dt, J=6 and 1 Hz), 7.76 (1H, dd, J -7 and 1 Hz).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8]([NH:10][C:11]3[C:15]([CH3:16])=[CH:14][S:13][CH:12]=3)[NH:9][C:5]=2[CH:4]=1.[Br:19]N1C(=O)CCC1=O>C(O)(=O)C>[ClH:1].[Br:19][C:12]1[S:13][CH:14]=[C:15]([CH3:16])[C:11]=1[NH:10][C:8]1[NH:7][C:6]2[CH:17]=[CH:18][C:3]([F:2])=[CH:4][C:5]=2[N:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cscc1Nc1nc2ccc(F)cc2[nH]1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1csc(Br)c1Nc1nc2cc(F)ccc2[nH]1
Reaction time: 0.17 h

Procedure:
(5-Fluoro-1H-benzimidazol-2-yl)-(4-methylthiophene-3-yl)amine (300 mg) (example 1) was dissolved in glacial acetic acid (50 ml). At room temperature, N-bromosuccinimide (207 mg) dissolved in glacial acetic acid (10 ml), was slowly added dropwise, with vigorous stirring. After the addition had ended, stirring was continued for another 10 min and the glacial acetic acid was then distilled off under reduced pressure, and the residue was dissolved in ethyl acetate and washed with saturated potassium carbonate solution. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative chromatography and the product-containing fractions were combined, freed from acetonitrile, made basic and extracted three times with ethyl acetate. The organic phases were combined, dried (MgSO4) and filtered. Following removal of the solvent under reduced pressure, water and 2N hydrochloric acid were added to the residue and the mixture was freeze-dried. This gave 245 mg of the desired product.
Reaction SMILES: C(C(NC([C:12]1[CH:36]=[CH:35][CH:34]=[CH:33][C:13]=1[C:14]([N:16]([S:25]SC1C=CC=CC=1)[CH:17]([CH:21]([CH3:24])[CH2:22][CH3:23])[C:18]([OH:20])=[O:19])=[O:15])=O)C(C)CC)(O)=O.BrBr>ClCCl>[CH3:24][CH:21]([CH2:22][CH3:23])[CH:17]([N:16]1[C:14](=[O:15])[C:13]2[CH:33]=[CH:34][CH:35]=[CH:36][C:12]=2[S:25]1)[C:18]([OH:20])=[O:19]
Reactant: CCC(C)C(NC(=O)c1ccccc1C(=O)N(SSc1ccccc1)C(C(=O)O)C(C)CC)C(=O)O
Agent: BrBr
Solvent: ClCCl
Product: CCC(C)C(C(=O)O)n1sc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred, room temperature suspension of 5.3 g (10.0 mmol) of [S-(R*,R*)]-2-[2-[2-(1-carboxy-2-methylbutylcarbamoyl)phenyldisulfanyl benzoylamino]-3-methylpentanoic acid (prepared by the general method of Example 5) in 200 mL of dichloromethane was treated dropwise with 2.4 g (15.0 mmol) of liquid bromine. The reaction mixture was stirred at room temperature for 2 hours, and the solvent was evaporated in vacuo. The residue was triturated with dichloromethane, which was also evaporated in vacuo to remove excess bromine. The residue was partitioned between dichloromethane/5% sodium bicarbonate (200 mL each). The aqueous layer was separated, washed with dichloromethane, and acidified to pH 1.5 with 6.0M hydrochloric acid. After extracting with dichloromethane (2×75 mL), the combined organic layers were washed with water, dried (MgSO4), filtered and evaporated in vacuo to give 4.8 g of the title compound, mp 50°-52° C.
Reaction SMILES: [C:1]([N:4]([CH2:22][C@@H:23]1[O:27][C:26](=[O:28])[N:25]([C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:42][C:41]4[C:37](=[N:38][N:39]([CH3:43])[CH:40]=4)[CH2:36]3)=[C:31]([F:44])[CH:30]=2)[CH2:24]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:21])[CH2:11][N:12](C(OC(C)(C)C)=O)[CH3:13])=[O:6])(=[O:3])[CH3:2].Cl.CCOCC>C(Cl)Cl>[C:1]([N:4]([CH2:22][C@@H:23]1[O:27][C:26](=[O:28])[N:25]([C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:42][C:41]4[C:37](=[N:38][N:39]([CH3:43])[CH:40]=4)[CH2:36]3)=[C:31]([F:44])[CH:30]=2)[CH2:24]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:21])[CH2:11][NH:12][CH3:13])=[O:6])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(N3Cc4cn(C)nc4C3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)CN(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CNCC(=O)OCOC(=O)N(C[C@H]1CN(c2ccc(N3Cc4cn(C)nc4C3)c(F)c2)C(=O)O1)C(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.2 %

Procedure:
To a solution of 9 (50 mg, 0.08 mmol) in CH2Cl2 (2 mL) under nitrogen was added 1N HCl in Et2O (2.0 mL, 2.0 mmol). The reaction mixture was stirred at rt for 2 h, concentrated in vacuo, and purified directly by HPLC (C-18 column, 30-80% gradient elution, MeCN:H2O with 0.1% TFA). Fractions containing product were lyophilized to give 15 mg (36%) of the title compound as the trifluoroacetate salt. 1H NMR (400 MHz, DMSO-d6): δ 9.07 (br s, 1H), 7.54 (s, 1H), 7.43 (dd, 1H), 7.16 (dd, 1H), 6.87 (dd, 1H), 5.96-5.92 (m, 2H), 4.80-4.74 (m, 1H), 4.48-4.46 (m, 4H), 4.15-4.09 (m, 4H), 3.91 (dd, 1H), 3.85 (s, 3H), 3.76 (dd, 1H), 2.62 (s, 3H), 2.47 (s, 3H). MS 519 (M+1)+
Reaction SMILES: [CH2:1]([Sn:5](Cl)(Cl)[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].CO.O.[F-:15].[F-:16].[NH4+].[NH4+]>>[CH2:1]([Sn:5]([F:16])([F:15])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: [F-]
Reactant: CCCC[Sn](Cl)(Cl)CCCC
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CCCC[Sn](F)(F)CCCC

Procedure:
Advantageously, dibutyl tin chloride and an ammonium difluoride are reacted to form a dibutyl tin difluoride precipitate. Dibutyl tin dichloride (DBTCl) is solubilized in an alcohol, preferably methanol, in a first reaction vessel. In a second such vessel, ammonium difluoride (NH4F, HF) is dissolved in a solvent which is preferably water. The contents of one reaction vessel are poured into the other and, on contact of the two solutions, a dibutyl tin difluoride precipitate is formed. The mixture is stirred to enhance the contact between the two solutions and to maximize the yield of precipitate. The resulting precipitate is recovered, drained, washed with water, washed with a solvent such as acetone to eliminate any remaining water and dried.
Reaction SMILES: [CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Br:24]Br.O>ClCCl>[Br:24][C:19]1[CH:18]=[C:17]([C:14]2[N:15]=[CH:16][C:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:12][N:13]=2)[CH:22]=[CH:21][C:20]=1[OH:23]
Reactant: CCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: BrBr
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCc1cnc(-c2ccc(O)c(Br)c2)nc1
Reaction time: 2 h
Yield: 76.6 %

Procedure:
A solution of 5 g of 4-(5-decyl-2-pyrimidinyl)phenol in 50 ml of dichloromethane was treated at 0° C. while gassing with argon with a solution of 2.6 g of bromine in 50 ml of dichloromethane. The reaction mixture was stirred for a further 2 hours and then treated with water. The organic phase was separated and the aqueous phase was back-extracted three times with 50 ml of dichloromethane each time. The combined organic phases were washed with water, sodium hydrogen carbonate solution and again with water, dried over magnesium sulfate, filtered and subsequently concentrated. The residue was purified by chromatography on silica gel with toluene/ethyl acetate (vol. 4:1). Recrystallization from hexane gave 4.8 g of 2-bromo-4-(5-decyl-2-pyrimidinyl)phenol.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:24])=[CH:5][C:6]([Cl:23])=[C:7]([C:9]2[NH:10][C:11](=[O:22])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=3)[N:13]=2)[CH:8]=1.[C:25](Cl)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>C1COCC1>[Cl:23][C:6]1[C:7]([C:9]2[NH:10][C:11](=[O:22])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=3)[N:13]=2)=[CH:8][C:3]([CH2:2][NH:1][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[C:4]([F:24])[CH:5]=1
Reactant: NCc1cc(-c2nn(-c3ccc(F)c(Cl)c3)c(=O)[nH]2)c(Cl)cc1F
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1cc(-c2nn(-c3ccc(F)c(Cl)c3)c(=O)[nH]2)c(Cl)cc1F

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 5-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-2-(3-chloro-4-fluorophenyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-86, 0.300 g), pivaloyl chloride (0.3 mL), TEA (2.0 mL), dry THF (10 mL) to afford 0.083 g of the desired product. 1H NMR (300 MHz, DMSO): δ 1.13 (s, 9H), 4.30 (d, J=6.4 Hz, 2H), 7.53-7.66 (s, 3H), 7.91-8.15 (s, 3H), 12.67 (s, 1H); MS (adz): 455.19 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([C:17]4[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=4)[C:11]=3[C:10](=[O:23])[N:9]2CC2C=CC(OC)=CC=2)=[CH:4][CH:3]=1>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([C:17]4[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=4)[C:11]=3[C:10](=[O:23])[NH:9]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2C(=O)c3c(c(C)nn3-c3ccnn3C)C2c2ccc(Cl)cc2)cc1
Solvent: CCOC(C)=O
Product: Cc1nn(-c2ccnn2C)c2c1C(c1ccc(Cl)cc1)NC2=O

Procedure:
The title compound was prepared in analogy to the procedure described in Step 85.6 using 4-(4-chlorophenyl)-5-(4-methoxybenzyl)-3-methyl-1-(1-methyl-1H-pyrazol-5-yl)-4,5-dihydropyrrolo-[3,4-c]pyrazol-6(1H)-one (Step 114.1). tR: 4.14 min (HPLC 1); tR: 0.92 min (LC-MS 2); ESI-MS: 328 [M+H]+ (LC-MS 2); ESI-MS: 326 [M−H]− (LC-MS 2); Rf=0.61 (EtOAc).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:21][CH3:22])=[C:6]([CH:8]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[C:11](=[O:17])[C:10]([CH3:19])([CH3:18])[C:9]2=[O:20])[CH:7]=1.[F-].[Cs+].[Cl:25][C:26]1[N:31]=[C:30]([CH3:32])[C:29](B(O)O)=[CH:28][CH:27]=1>ClCCl.O>[Cl:25][C:26]1[N:31]=[C:30]([CH3:32])[C:29]([C:2]2[CH:3]=[CH:4][C:5]([CH2:21][CH3:22])=[C:6]([CH:8]3[C:13](=[O:14])[C:12]([CH3:15])([CH3:16])[C:11](=[O:17])[C:10]([CH3:19])([CH3:18])[C:9]3=[O:20])[CH:7]=2)=[CH:28][CH:27]=1
Reactant: CCc1ccc(Br)cc1C1C(=O)C(C)(C)C(=O)C(C)(C)C1=O
Reactant: Cc1nc(Cl)ccc1B(O)O
Agent: [Cs+]
Agent: [F-]
Solvent: ClCCl
Solvent: O
Product: CCc1ccc(-c2ccc(Cl)nc2C)cc1C1C(=O)C(C)(C)C(=O)C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
A mixture of 6-(5-bromo-2-ethylphenyl)-2,2,4,4-tetramethylcyclohexane-1,3,5-trione (0.19 g, 0.5 mmol), cesium fluoride (0.24 g, 1.6 mmol), 6-chloro-2-methylpyridin-3-ylboronic acid (0.13 g, 0.8 mmol) and degassed 1,2-dimethoxyethane (1.7 ml) is stirred under nitrogen at room temperature for 30 minutes. [1,1′-Bis-(diphenylphosphino)ferrocene]dichloro-palladium(II) (0.034 g, 0.042 mmol) is added and the mixture is stirred at room temperature for 10 minutes and then heated at 80° C. overnight. After cooling to room temperature the reaction mixture is diluted with dichloromethane (5 ml) and water and filtered through diatomaceous earth. The filtrate is acidified with 2M aqueous hydrochloric acid, and the organic phase is separated, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is dissolved in N,N-dimethylformamide (approximately 1 ml) and purified by preparative reverse phase HPLC to afford 6-[5-(6-chloro-2-methylpyridin-3-yl)-2-ethylphenyl]-2,2,4,4-tetramethylcyclohexane-1,3,5-trione as a pale brown solid (75.3 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH2:9][O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[N+:12]([O-])([OH:14])=[O:13]>C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3]1[C:11]2[O:10][CH2:9][O:8][C:7]=2[CH:6]=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: COc1cccc2c1OCO2
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: COc1cc([N+](=O)[O-])cc2c1OCO2
Temperature: 25 °C
Yield: 46 %

Procedure:
4-Methoxy-benzo[1,3]dioxole (2.03 g, 13.34 mmole) was dissolved in acetic anhydride (20 mL) and cooled in an ice bath while stirring. Nitric acid (1.5 mL) was added dropwise with an addition funnel over 30 minutes. The ice bath was removed and the mixture was stirred overnight allowing the reaction to heat up to room temperature. The mixture was poured into ice water and the product crashed out and was filtered and washed with water. The precipitate was dried under vacuum in a dessicator yielding (1.21 g, 46% yield) of 4-methoxy-6-nitro-benzo[1,3]dioxole. NMR-DMSO-d6: 7.63 (s, 1H), 7.52 (s, 1H), 6.25 (s, 2H), 3.95 (s, 3H)
Reaction SMILES: O1C2=CC=CC2=CC=C1[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]1[C:16](=[O:21])[C:17]([F:20])([F:19])[F:18].[C:22]([O:25][CH2:26][CH3:27])(=O)[CH3:23]>[Pd].CO>[O:25]1[C:26]2[CH:27]=[CH:12][CH:13]=[CH:14][C:15]=2[CH2:23][CH:22]1[CH:14]1[CH2:15][CH2:10][N:11]([C:16](=[O:21])[C:17]([F:18])([F:20])[F:19])[CH2:12][CH2:13]1
Reactant: CCOC(C)=O
Reactant: O=C(N1CCCCC1c1ccc2cccc-2o1)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: O=C(N1CCC(C2Cc3ccccc3O2)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 1-(4-benzofuran-2-yl-piperidin-1-yl)-2,2,2-trifluoro-ethanone (11.50 g), 10% palladium on carbon (1.15 g), ethyl acetate (135 mL) and methanol (15 mL) is shaken under hydrogen atmosphere (3.5 bar) at room temperature for 24 h. The catalyst is then separated by filtration and the filtrate is concentrated to give an oil that is submitted to the next reaction without further purification. Yield: 11.12 g (crude); LC (method 2): tR=1.34 min.
Reaction SMILES: [O:1]1[CH:9]2[CH:2]1[CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8]2.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.O>C(Cl)Cl>[CH2:10]([NH:17][C@@H:2]1[CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][C@H:9]1[OH:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C1=CCCC2OC2CC1
Reactant: NCc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: ClCCl
Solvent: O
Product: O[C@@H]1CCC=CCC[C@H]1NCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83 %

Procedure:
To a stirred solution of 5,6-epoxycyclooctene III (10.0 g, 0.081 mol) in dry CH2Cl2 (100 ml) kept under nitrogen atmosphere, benzylamine (10.35 g, 0.097 mol) and Ytterbium(III) trifluoromethanesulfonate (4.96 g, 0.008 mol) were added and the mixture was stirred for 24 hrs at room temperature. Extractive work-up of the reaction mixture with water and CH2Cl2 gave the title product as a white solid (yield 83%). m.p.: 70-71° C., b.p:140° C./1 mm Hg. 1H NMR (CDCl3): δ 7.59-7.56 (m, 2H, ArH), 7.38-7.35 (m, 3H, ArH), 5.64-5.44 (m, 2H, CH=CH), 5.42-5.00 (bs, D2O exchangeable, OH) 4.07 (AB syst, 2H, J=12.57 Hz, PhCH2), 3.75-3.65 (m, 1H, CHOH), 3.00-3.15 (m, 1H, CHNH--), 2.35-2.02 (m, 6H), 1.95-1.42 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1.C(N=C=NCCCN(C)C)C.[CH3:30][S:31]([NH2:34])(=[O:33])=[O:32]>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH:34][S:31]([CH3:30])(=[O:33])=[O:32])=[O:15])=[CH:12][CH:11]=1
Reactant: COc1ccccc1Sc1ccc(C(=O)O)cc1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COc1ccccc1Sc1ccc(C(=O)NS(C)(=O)=O)cc1
Reaction time: 1 h
Yield: 30.9 %

Procedure:
4-(2-methoxyphenylthio)benzoic acid (126 mg, 0.48 mmol), 4-dimethylaminopyridine (12.2 mg, 0.10 mmol) and 1-ethyl-3-(dimethylaminopropyl)carbodiimide (195 mg, 0.97 mmol) were dissolved in anhydrous N,N-dimethylformamide (4 mL) and stirred for 60 minutes. To this solution was added methanesulphonamide (70 mg, 0.72 mmol) and the reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched by the addition of water (10 mL) and the mixture extracted with ethyl acetate (3×10 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 50 mg of a crude oil which was purified by preparative HPLC title compound.