Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[N:10]2[C:11]3[C:16]([NH:17][C:18](=[O:19])[C:9]2=[CH:8][N:7]=1)=[CH:15][C:14]([C:20](O)=[O:21])=[C:13]([O:23][CH3:24])[CH:12]=3)[CH2:4][CH3:5])[CH3:2].[CH3:25][N:26](C)[CH:27]=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.CNC>O>[CH2:4]([CH:3]([C:6]1[N:10]2[C:11]3[C:16]([NH:17][C:18](=[O:19])[C:9]2=[CH:8][N:7]=1)=[CH:15][C:14]([C:20]([N:26]([CH3:27])[CH3:25])=[O:21])=[C:13]([O:23][CH3:24])[CH:12]=3)[CH2:1][CH3:2])[CH3:5]
Reactant: CN(C)C=O
Reactant: CCC(CC)c1ncc2c(=O)[nH]c3cc(C(=O)O)c(OC)cc3n12
Agent: CNC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Product: CCC(CC)c1ncc2c(=O)[nH]c3cc(C(=O)N(C)C)c(OC)cc3n12
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
1-(1-Ethylpropyl)-8-methoxy-4-oxo-4,5-dihydroimidazo[1,5-a]-quinoxaline-7-carboxylic acid as synthesized in above Example 32, 329 mg, N,N-dimethylformamide 5 mL and 1,1′-carbonyldiimidazole 275 mg were mixed and stirred for an hour at room temperature in nitrogen atmosphere. Dimethylamine hydrochloride 816 mg was added, followed by 5.5 hours' stirring. The reaction mixture was diluted with water, extracted with ethyl acetate and washed with saturated saline. The extract was dried over anhydrous sodium sulfate, and from which the solvent was distilled off. To the residue tert-butyl methyl ether was added, heated under stirring, and the precipitate was recovered by filtration, followed by washing with tert-butyl methyl ether. The product was dried in flowing air (40° C.) to provide 223 mg of the title compound.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:15][N:16]1[C:21](=O)[N:20]([CH3:23])[CH2:19][CH2:18]C1>O>[CH2:19]([N:20]1[CH:23]=[CH:15][N:16]=[C:21]1[O:7][C:6]1[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=1)[CH3:18]
Reactant: CN1CCCN(C)C1=O
Reactant: Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: CCn1ccnc1Oc1ccc(C)cc1
Temperature: 200 °C
Reaction time: 3 h

Procedure:
A mixture of the compound obtained in Example 1-(1) (30.27 g), 4-cresol (17.69 g), Cs2CO3 (53.43 g) and N,N′-dimethylpropyleneurea (DMPU) (136 ml) was stirred at 200° C. for 3 hours. The mixture was cooled to room temperature, diluted with water, and extracted with AcOEt. After washing with brine, the organic layer was dried over MgSO4, filtered and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (neutral OH-type SiO2, hexane/AcOEt=10% to 40%) to give the titled compound (8.54 g, yellow oil).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=O)=[CH:4][C:3]=1[CH3:12].Cl.[C:14](=[NH:19])(OCC)[CH3:15].C(N(CC)CC)C>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[N:19]=[C:14]([CH3:15])[NH:9][N:8]=2)=[CH:4][C:3]=1[CH3:12]
Reactant: CCOC(C)=N
Reactant: Cc1cc(C(=O)NN)ccc1Br
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccc(Br)c(C)c2)n[nH]1
Yield: 59.5 %

Procedure:
4-Bromo-3-methylbenzoic hydrazide (D30, 3.06 g, 13 mmol), ethyl acetimidate hydrochloride (2.48 g, 20 mmol) and triethylamine (5.6 ml, 40 mmol) were stirred at reflux under Ar for 24 h, and then evaporated to dryness. The residue was chromatographed on silica gel, eluting with dichloromethane/ethanol/ammonia (300:8:1). This gave the title compound (1.95 g, 58%) as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([NH:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH:16]=1)[C:9]([CH3:29])([CH3:28])[CH2:8]2)=[O:4].[OH-].[Na+]>CO.O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH:10]2[C:9]([CH3:28])([CH3:29])[CH2:8][C:7]3[C:12](=[CH:13][CH:14]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=3)[NH:11]2)=[CH:16][C:17]=1[NH:22][C:23](=[O:27])[CH:24]([CH3:25])[CH3:26]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c(NC(=O)C(C)C)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)C(=O)Nc1cc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)ccc1F

Procedure:
A mixture of methyl-2-(4-fluoro-3-isobutyramidophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (183 mg, 0.46 mmol), sodium hydroxide (312 mg, 7.8 mmol) in methanol/water (10 mL/4 mL) was heated to reflux for 1.5 h. LC-MS indicated that the starting material was consumed completely. The solvent was removed in vacuo and the residue was acidified with 2M hydrochloric acid solution to Ph=5. The precipitated white solid was collected by filtration and dissolved in acetone, dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give 2-(4-fluoro-3-isobutyramidophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid, which was purified by recrystallization from dichloromethane/methanol/Hexant to afford 140 mg of off-white crystal. Yield: 79.3%. LC-MS(M+1)=385.
Reaction SMILES: [NH3:1].[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)=[O:3]>C(Cl)Cl>[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:1])(=[O:12])=[O:11])=[CH:6][CH:5]=1)=[O:3]
Reactant: N
Reactant: O=Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of ammonia (0.5 M in 1,4-dioxane, 5 mL) was added to 4-formylbenzenesulfonyl chloride (0.5 g), followed by DCM (10 mL). The reaction mixture was stirred vigorously for 3 h at RT, then concentrated under reduced pressure. The crude residue was purified by flash chromatography to afford 4-formyl-benzenesulfonamide. MS=183.9 [M−H]−.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.C[O-].C([Sn+](CCCC)CCCC)CCC.C([O:29][C:30]([CH3:32])=[CH2:31])(=O)C>C1(C)C=CC=CC=1.[Pd](Cl)Cl.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[O:9]1[C:5]2[CH:4]=[CH:3][C:2]([CH2:31][C:30](=[O:29])[CH3:32])=[CH:10][C:6]=2[CH:7]=[CH:8]1
Reactant: C=C(C)OC(C)=O
Reactant: Brc1ccc2occc2c1
Agent: Cl[Pd]Cl
Agent: CCCC[Sn+](CCCC)CCCC
Agent: C[O-]
Solvent: Cc1ccccc1
Product: CC(=O)Cc1ccc2occc2c1
Temperature: 100 °C
Yield: 103.3 %

Procedure:
A mixture of 1.90 gm (10 mmol) 5-bromobenzofuran, 183 mg (0.6 mmol) tri(o-tolyl)phosphine, 4.3 mL (15 mMol) tributyl tin methoxide, and 1.7 mL (15.4 mMol) isopropenyl acetate in 55 mL toluene was sparged with nitrogen for 15 minutes. To this mixture were then added 54 mg (0.3 mMol) palladium(II) chloride and the mixture was heated to 100° C. for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was filtered through a bed of 100 gm silica gel, eluting with 1 liter of 1:1 hexane:ethyl acetate. Fractions containing crude product were combined and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with a gradient of hexane containing from 0–20% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide about 1.8 gm of the desired compound as an oil which gradually crystallized.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:34][CH3:35])[C:17]4[CH2:22][CH2:21][CH:20]([C:23]5[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:36][CH3:37])[CH:6]=1>C(=O)=O.CO>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:34][CH3:35])[C:17]4[CH2:22][CH2:21][C@H:20]([C:23]5[CH:24]=[CH:25][C:26]([O:29][C:30]([F:32])([F:33])[F:31])=[CH:27][CH:28]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:36][CH3:37])[CH:6]=1
Reactant: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CCC2c1ccc(OC(F)(F)F)cc1
Agent: O=C=O
Solvent: CO
Product: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CC[C@@H]2c1ccc(OC(F)(F)F)cc1

Procedure:
A racemic mixture of N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (86 mg, 0.162 mmol from Example 97) was purified using chiral SFC to afford 36.6 mg of peak A (Example 97A) and 31.5 mg of peak B (Example 97B). SFC Method: Chiralpak OJ-H (4.6×250 mm, 5 μM), 30% methanol (0.1% diethylamine) in CO2, 35° C., flow rate 2.0 mL/min for 12 min, absorbance 268 nm, injection 5 μL of 2 mg/mL solution in methanol (multiple stacked injections), tR (peak A)=3.4 min, tR (peak B) 7.5 min. The absolute stereochemistry of individual enantiomers (Examples 97A and 97B) was not determined LC-MS and 1H NMR analytical data for the separated enantiomers was identical to the racemate (Example 97).
Reaction SMILES: [OH:1][N:2]=[C:3]([CH3:18])[C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11](=[O:17])[CH2:10][CH2:9]2)=O.[NH2:19][NH:20][C:21]([NH2:23])=[S:22].CO.O>C(O)(=O)C>[OH:1][N:2]=[C:3]([CH3:18])[C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11](=[O:17])[CH2:10][CH2:9]2)=[N:19][NH:20][C:21]([NH2:23])=[S:22]
Reactant: CC(=NO)C(=O)c1ccc2c(c1)CCC(=O)N2C
Reactant: NNC(N)=S
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CC(=NO)C(=NNC(N)=S)c1ccc2c(c1)CCC(=O)N2C
Yield: 26.2 %

Procedure:
A mixture of 6-(2-hydroxyiminopropionyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline (1 g), thiosemicarbazide (0.48 g), methanol (10 ml), water (5 ml) and acetic acid (0.1 ml) was refluxed for 13 hours with stirring. After cooling, the resulting precipitates were collected by filtration, washed successively with ethanol, water and ethanol, and then dried to give 0.34 g of 6-(2-hydroxyimino-1-thiosemicarbazonopropyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Cl[C:21]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][C:24]([C:30]([F:33])([F:32])[F:31])=[CH:23][C:22]=1[N+:34]([O-:36])=[O:35]>O1CCCC1.COC(C)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][C:21]2[C:22]([N+:34]([O-:36])=[O:35])=[CH:23][C:24]([C:30]([F:33])([F:31])[F:32])=[CH:25][C:26]=2[N+:27]([O-:29])=[O:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2c([N+](=O)[O-])cc(C(F)(F)F)cc2[N+](=O)[O-])C1

Procedure:
(R)-3-Hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (compound 20) is de-protonated with potassium tert-butoxide (KOtBu) in tetrahydrofuran (THF). The resulting anion is reacted 2-chloro-1,3-dinitro-5-trifluoromethylbenzene (compound 2) in tert-butyl methyl ether (MTBE)/THF. When the reaction is complete, the reaction mixture is quenched with water and partitioned with more MTBE. The organic layer is washed with brine and water and concentrated on a rotary evaporator. The solid concentrate is re-dissolved in methanol and re-precipitated with water. The resulting precipitate is filtered and dried to afford (R)-3-(2,6-dinitro-4-trifluoromethylphenoxy)pyrrolidine-1-carboxylic acid tert-butyl ester which can be used in the next step without further purification. This reaction has been carried out at a scale using 4.2 Kg of compound 2.
Reaction SMILES: C[O:2][C:3](=[O:10])[C@@H:4]([NH:6][C:7](=[O:9])[CH3:8])[CH3:5].[Si](C=[N+]=[N-])(C)(C)C>>[C:7]([NH:6][C:4](=[CH2:5])[C:3]([OH:10])=[O:2])(=[O:9])[CH3:8]
Reactant: COC(=O)[C@H](C)NC(C)=O
Agent: C[Si](C)(C)C=[N+]=[N-]
Product: C=C(NC(C)=O)C(=O)O

Procedure:
(S)-2-Acetylaminopropionic acid methyl ester, conversion>99%, ee>99% (derivatised using TMS-diazomethane and then analysed using the same method developed for the methyl ester).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:15][CH3:16])[C:12]=1[O:13][CH3:14])[C:6]([NH:8][NH2:9])=[O:7].[F:17][C:18]([F:28])([F:27])[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O>>[F:17][C:18]([F:27])([F:28])[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=[N:9][NH:8][C:6](=[O:7])[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:12]([O:13][CH3:14])=[C:11]([O:15][CH3:16])[CH:10]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: COc1cc(C(=O)NN)cc(OC)c1OC
Product: COc1cc(C(=O)NN=Cc2cccc(C(F)(F)F)c2)cc(OC)c1OC

Procedure:
The title compound was prepared from 3,4,5-trimethoxy-benzoic acid hydrazide and 3-trifluoromethyl-benzaldehyde by a procedure similar to Example 22. 1H NMR (DMSO-d6): 11.93 (s, 1H), 8.57 (s, 1H), 8.08 (s, 1H), 8.05 (d, J=8.1 Hz, 1H), 7.82 (d, J=7.5 Hz, 1H), 7.74 (d, J=7.5 Hz, 1H), 7.26 (s, 2H), 3.89 (s, 6H), 3.75 (s, 3H). MS (MH+, MH−): 451, 453.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([OH:21])=O.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[Na+]>CN(C)C=O.O>[C:23]1([NH:22][C:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)=[O:21])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccccn1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1ccccn1
Reaction time: 0.5 h
Yield: 32.3 %

Procedure:
To a solution of carbonyldiimidazole (8.10 g) in dry dimethylformamide (100 mL) under N2 atmosphere, was added the picolinic acid (15.0 g) portionwise, then stirred for 30 minutes. Aniline (10.93 mL) was added rapidly dropwise, then stirred for 18 hours at room temperature. The reaction mixture was poured into water (400 mL), basified with 2.5N NaOH (25 mL) and stirred for 30 minutes while solid precipitated. The solid was collected by vacuum filtration, washed with water, and dried in vacuo. This tan solid was recrystallized from ether/hexane (1/1) to afford 7.69 g (32.3%) of an off-white solid, m. p. 75°-77° C.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[C:5]([CH:9]([C:11]2[CH:20]=[CH:19][C:14]3[NH:15][C:16]([CH3:18])=[N:17][C:13]=3[CH:12]=2)O)[CH:6]=[CH:7][CH:8]=1.S(Cl)([Cl:23])=O>>[ClH:23].[Cl:1][CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([F:2])[CH:4]=1)[C:11]1[CH:20]=[CH:19][C:14]2[NH:15][C:16]([CH3:18])=[N:17][C:13]=2[CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1nc2cc(C(O)c3cccc(F)c3)ccc2[nH]1
Agent: Cl
Product: Cc1nc2cc(C(Cl)c3cccc(F)c3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
(b-1) A mixture of 13 parts of α-(3-fluorophenyl)-2-methyl-1H-benzimidazole-5-methanol monohydrochloride and 81 parts of thionyl chloride was stirred overnight at room temperature. The reaction mixture was concentrated to dry, yielding 12 parts (86.8%) of 5-[chloro(3-fluorophenyl)methyl]-2-methyl-1H-benzimidazole monohydrochloride as a residue (int. 45).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[O:27]=[C:28]1[NH:32][CH:31]([C:33](O)=[O:34])[CH2:30][NH:29]1>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([NH:23][C:33]([CH:31]4[CH2:30][NH:29][C:28](=[O:27])[NH:32]4)=[O:34])[CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: O=C1NCC(C(=O)O)N1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)C5CNC(=O)N5)c4)CC3)cccc2n1
Yield: 51 %

Procedure:
The title compound was prepared in 51% yield according to the general procedure for the preparation of the amides (Method C) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 2-oxo-4-imidazolidinecarboxylic acid.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:38]1[CH:43]=[CH:42][N:41]=[CH:40][N:39]=1)[S:7]([C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[C:24]([N+:34]([O-])=O)=[N:25][N:26](C3CCCCO3)[CH:27]=2)=[CH:12][C:11]=1[F:37])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.ClCCl>CO>[NH2:34][C:24]1[C:23]([C@H:19]2[CH2:20][CH2:21][CH2:22][C@@H:18]2[O:17][C:13]2[C:14]([CH3:16])=[CH:15][C:10]([S:7]([NH:6][C:38]3[CH:43]=[CH:42][N:41]=[CH:40][N:39]=3)(=[O:9])=[O:8])=[C:11]([F:37])[CH:12]=2)=[CH:27][NH:26][N:25]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C)c(O[C@H]3CCC[C@@H]3c3cn(C4CCCCO4)nc3[N+](=O)[O-])cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)c(F)cc1O[C@H]1CCC[C@@H]1c1c[nH]nc1N
Yield: 81.2 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 22c by using the N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-4-({(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclopentyl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide (101 mg, 0.185 mmol) prepared in Example 85c, triethylsilane (0.10 mL), trifluoroacetic acid (0.5 mL), dichloromethane (2.0 mL) and methanol (1.0 mL), to yield the title compound (65 mg, 76%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10])[C:5]#[N:6].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:19][CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[C:8]([CH3:11])[C:9]=1[O:10][CH2:19][CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]
Reactant: CC(C)(C)OC(=O)CCCBr
Reactant: Cc1cc(C#N)cc(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C#N)cc(Cl)c1OCCCC(=O)OC(C)(C)C
Temperature: 65 °C
Reaction time: 72 h
Yield: 30.3 %

Procedure:
A mixture of 3-chloro-4-hydroxy-5-methyl-benzonitrile (1.15 g, 6.87 mmol) and Cs2CO3 (13.43 g, 41.2 mmol) in DMF (45 mL) is stirred at rt for 30 min before tert.-butyl 4-bromobutanoate (1.55 g, 6.95 mmol) is added. The orange suspension is stirred at 65° C. for 72 h. Another portion of tert.-butyl 4-bromobutanoate (1.55 g, 6.95 mmol) is added and stirring is continued at 65° C. for 24 h. The mixture is dilued with water (150 mL) and extracted three times with DCM (3×50 mL) and EA (3×50 mL). The org. extracts are combined, dried over MgSO4, filtered and concentrated. The crude product is purified by MPLC on silica gel eluting with heptane:EA:methanol to give tert-butyl 4-(2-chloro-4-cyano-6-methylphenoxy)butanoate (645 mg) as a colourless oil; LC-MS: tR=1.01 min, [M+H]+=no mass detectable; 1H NMR (D6-DMSO): δ 7.94 (d, J=1.7 Hz, 1H), 7.75 (d, J=1.3 Hz, 1H), 3.95 (t, J=6.3 Hz, 2H), 2.46 (t, J=7.2 Hz, 2H), 2.30 (s, 3H), 1.98 (quint, J=6.6 Hz, 2H), 1.41 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.C1C(=O)N([Br:17])C(=O)C1.[OH-].[Na+]>S(=O)(=O)(O)O.O>[Br:17][C:5]1[C:6]([O:8][CH3:9])=[CH:7][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: COc1ccnc(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(Cl)ncc1Br
Temperature: 25 °C

Procedure:
To a solution of 2-chloro-4-methoxypyridine (10.0 g, 69.7 mmol) in 50 mL of sulfuric acid at 0° C. was added NBS. The reaction mixture was allowed to stir and warm up to room temperature for 2 hours and then heated at 60° C. for 5 hours. Then it was cooled to room temperature and neutralized with 1 N NaOH (pH ˜7), diluted with water (50 mL) and the aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layers were washed with water (2×50 mL), saturated NaHCO3, brine, dried over Mg2SO4 and concentrated to provide an oil, which was chromatographed. On elution with 0-25% EtOAc/hexanes, the final product was obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:7])=[N:4][NH:5][CH:6]=1.[H-].[Na+].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C)C=O>[CH2:10]([N:5]1[CH:6]=[C:2]([Br:1])[C:3]([CH3:7])=[N:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1n[nH]cc1Br
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn(Cc2ccccc2)cc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Into a 500-mL 3-neck round-bottom flask, was placed a solution of 4-bromo-3-methyl-1H-pyrazole (20.0 g, 124 mmol) in N,N-dimethylformamide (100 mL). The system was purged with nitrogen, then the solution was cooled to 0° C. Sodium hydride (60% dispersion in mineral oil, 10.0 g, 250 mmol) was carefully added portion-wise and then the resulting mixture was stirred for 30 min at room temperature. The mixture was cooled to 0° C., then benzyl bromide (22.1 mL, 186 mmol) was added drop-wise and the resulting mixture was stirred overnight at room temperature. The mixture was carefully quenched by drop-wise addition of water (40 mL), then the mixture was extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with brine (4×100 mL), dried (Na2SO4), filleted and concentrated under reduced pressure to obtain the title compound as a yellow oil (24.9 g, 80%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH3:26])[N:16]=[C:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[CH2:19]([C:17]1[CH:18]=[C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:15]([CH3:26])[N:16]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cn1nc(Cc2ccccc2)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(Cc2ccccc2)cc1C1CCNCC1
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
4-(5-Benzyl-2-methyl-2H-pyrazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.032 g) was dissolved in a 25% v/v solution of trifluoroacetic acid in DCM (7 mL) and stirred for 30 minutes. The solvents were then evaporated under reduced pressure to give a clear oil which was purified by column chromatography on SCX-2 stationary phase using a gradient of DCM up to 50% 7N NH3 in MeOH in DCM as eluent. Evaporation of solvent under reduced pressure gave the title compound as a clear oil (0.018 g); NMR(CDCl3): 1.50-1.60 (qd, 2H), 1.85 (br d, 2H), 2.64 (tt, 1H), 2.66-2.76 (qd, 2H), 3.17 (br d, 2H), 3.76 (s, 3H), 3.91 (s, 2H), 5.76 (s, 1H), 7.16-7.20 (m, 1H), 7.24-7.30 (m 4H); MS: 256 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:21][CH:20]=2)=[C:10]([CH:14]=1)[C:11](O)=[O:12])=[O:5])[CH3:2].[NH:37]1[CH2:40][CH:39]([C:41]([O:43][CH3:44])=[O:42])[CH2:38]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:23][CH:24]=2)=[C:10]([CH:14]=1)[C:11]([N:37]1[CH2:40][CH:39]([C:41]([O:43][CH3:44])=[O:42])[CH2:38]1)=[O:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(OCCCc2ccc(OCCCCOc3ccccc3)cc2)c(C(=O)O)c1
Reactant: COC(=O)C1CNC1
Product: CCOC(=O)c1ccc(OCCCc2ccc(OCCCCOc3ccccc3)cc2)c(C(=O)N2CC(C(=O)OC)C2)c1

Procedure:
The compound is prepared in analogy to the process described in Example 6 from 5-(ethoxycarbonyl)-2-{3-[4-(4-phenoxybutoxy)phenyl]propoxy}benzoic acid and methyl 3-azetidinecarboxylate [CAS No. 343238-58-4]. The crude product is immediately reacted further without purification.