Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([O:5][C@H:6]([CH3:30])[CH2:7][N:8]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH2:9][C@@H:10]([NH:12]C(OC(C)(C)C)=O)[CH3:11])(=[O:4])=[O:3].C(O)(C(F)(F)F)=O.ClC(Cl)C>ClCCl>[CH3:1][S:2]([O:5][C@H:6]([CH3:30])[CH2:7][N:8]([CH2:9][C@@H:10]([NH2:12])[CH3:11])[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])(=[O:4])=[O:3]
Reactant: C[C@H](CN(C[C@H](C)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1)OS(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: C[C@H](N)CN(C[C@@H](C)OS(C)(=O)=O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (1R)-2-([(benzyloxy)carbonyl]{(2S)-2-[(tert-butoxycarbonyl)amino]propyl}amino)-1-methylethyl methanesulfonate (2.29 g, 5.15 mmol) in anhydrous dichloromethane (38 mL) was added TFA (38 mL) dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 hour. Reaction was complete as determined by TLC. Most of TFA was azeotropped with dichloroethane. The residue was then diluted with dichloromethane and washed with 2N Na2CO3 (aq.), organic layer was dried over MgSO4. Solvent evaporation afforded (R)-1-(((S)-2-aminopropyl)(benzyloxycarbonyl)amino)propan-2-yl methanesulfonate in quantitative yield (1.8 g) as oil. It was carried to the next step immediately.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:21])[CH2:9][NH:10][C:11](=[O:20])/[CH:12]=[CH:13]/[C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[CH:6][CH:7]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>CN(C)C=O>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:8](=[O:21])[CH2:9][NH:10][C:11](=[O:20])/[CH:12]=[CH:13]/[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(/C=C/c1cccnc1)NCC(O)c1cccc(O)c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(/C=C/c1cccnc1)NCC(=O)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 30.3 %

Procedure:
To a solution of (E)-N-[2-(3-hydroxyphenyl)-2-hydroxyethyl]-3-(3-pyridyl)-2-propenoic acid amide (568 g, 2 mmol) in dimethylformamide (4 ml), pyridinium dichromate (1.28 g, 1.7 eq.) was added under ice-cooling and stirred at room temperature for 10 hours. Then, water (4 ml) was added. Tar materials were filtered out on Celite and water (4 ml) was added to the filtrate and extracted with ethyl acetate. The solvent was distilled out under reduced pressure and the residue was solidified in ethanol to yield the titled compound (171 mg, 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7]([C:22]([OH:24])=O)=[CH:8][CH:9]=1.[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28][NH2:29].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CO.CN(C=O)C>[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28][NH:29][C:22]([C:7]1[CH:6]=[C:5]2[C:10]([S:11](=[O:21])(=[O:20])[NH:12][C:13]3[C:4]2=[CH:3][C:2]([Cl:1])=[C:19]2[C:14]=3[N:15]=[CH:16][CH:17]=[CH:18]2)=[CH:9][CH:8]=1)=[O:24]
Reactant: CN(C)CCN
Reactant: O=C(O)c1ccc2c(c1)-c1cc(Cl)c3cccnc3c1NS2(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)CCNC(=O)c1ccc2c(c1)-c1cc(Cl)c3cccnc3c1NS2(=O)=O
Yield: 51.6 %

Procedure:
In a similar fashion using route 54 general procedure 123, 12-chloro-6,6-dioxo-5,6-dihydro-6λ*6*-thia-4,5-diaza-chrysene-9-carboxylic acid 524 (100 mg, 0.27 mmol), N,N dimethylethylenediamine (0.06 ml, 0.55 mmol), EDC.HCl (80 mg, 0.41 mmol), HOBt (56 mg, 0.41 mmol), TEA (0.12 ml, 0.83 mmol) and DMF (1 ml) gave the title compound (60 mg, 50%) after trituration from MeOH.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][OH:12])[CH:7]=[CH:8][CH:9]=1.I[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][O:12][CH2:11][CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:13])([F:14])[F:1])[CH:5]=1)[CH3:21]
Reactant: CCOC(=O)CI
Reactant: OCCc1cccc(OC(F)(F)F)c1
Agent: [Ag+]
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=S(=O)([O-])C(F)(F)F
Product: CCOC(=O)COCCc1cccc(OC(F)(F)F)c1

Procedure:
In analogy to the procedure described in example 78.1, 2-(3-trifluoromethoxy-phenyl)-ethanol was reacted with ethyl iodoacetate in the presence of silver trifluoromethanesulfonate and 2,6-di-tert-butylpyridin to give [2-(3-trifluoromethoxy-phenyl)-ethoxy]-acetic acid ethyl ester as colorless oil. MS: m/e=293.1 [M+H+].
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([C:13]1[C:14](=[O:23])[O:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)([OH:12])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:48]1[C:49]([C:57]2[CH:58]=[C:59]([NH2:63])[CH:60]=[CH:61][CH:62]=2)=[CH:50][N:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=12>CN(C=O)C>[N:48]1[C:49]([C:57]2[CH:58]=[C:59]([NH:63][C:10]([C:13]3[C:14](=[O:23])[O:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[O:12])[CH:60]=[CH:61][CH:62]=2)=[CH:50][N:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=12
Reactant: O=C(O)c1cc2ccccc2oc1=O
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)c1cc2ccccc2oc1=O
Temperature: 25 °C
Yield: 84.3 %

Procedure:
DIEA (50.4 μL, 0.29 mmol) was added to 3-carboxy-coumarin (50.0 mg, 0.26 mmol) and HATU (110.0 mg, 0.29 mmol) in 1 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (55.0 mg, 0.26 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 83.6 mg of product in 85% yield: LCMS (ESI) m/z 382 (MH+).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]([C:12]2[C:17]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][CH:15]=[CH:14][C:13]=2[OH:24])[CH:9]=[CH:10][CH:11]=1)([O:3][CH2:4][CH3:5])=[O:2].[C:25]12([C:35]3[CH:42]=[CH:41][C:38]([CH2:39]I)=[CH:37][C:36]=3[O:43][CH3:44])[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C(C)C>[C:1]([C:6]1[CH:7]=[C:8]([C:12]2[C:17]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][CH:15]=[CH:14][C:13]=2[O:24][CH2:39][C:38]2[CH:41]=[CH:42][C:35]([C:25]34[CH2:34][CH:29]5[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]5)[CH2:26]3)[CH2:32]4)=[C:36]([O:43][CH3:44])[CH:37]=2)[CH:9]=[CH:10][CH:11]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: COc1cc(CI)ccc1C12CC3CC(CC(C3)C1)C2
Reactant: CCOC(=O)Cc1cccc(O)c1-c1cccc(C(=O)OCC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)Cc1cccc(OCc2ccc(C34CC5CC(CC(C5)C3)C4)c(OC)c2)c1-c1cccc(C(=O)OCC)c1
Yield: 62 %

Procedure:
Phenol 25 (0.656 g., 2.00 mmol, 1 equiv.; from Example 18) is dissolved in 15 mL of methyl isobutyl ketone. 4-[1-Adamantyl]-3-methoxybenzyl iodide (18b) (0.766 g., 2.00 mmol, 1 equiv.) and potassium carbonate (1.00 g., 7.2 mmol, 3.6 equiv.) are added and the mixture is heated to reflux for 5 hours. The solvents are evaporated and the residue is dissolved in methylene chloride. This solution is washed with water and brine, then dried (MgSO4), and concentrated. The crude material is chromatographed on silica gel using 50% CH2Cl2 /hexane to afford 3'-carboethoxy-2-[4-(1-adamantyl)-3-methoxyphenyl]methoxy-[1,1'-biphenyl]-6-acetic acid, ethyl ester (29d) (0.725 g., 1.24 mmol, 62%): 1H NMR (300 MHz, CDCl3) δ 8.06 (dd, J=2, 8 Hz, 1H, ArH), 7.98 (s, 1H, ArH), 7.50-7.47 (m, 2H, ArH), 7.33-6.97 (m, 4H, ArH), 6.69 (dd, J=2, 8 Hz, 1H, ArH), 6.57 (d, J=2 Hz, 1H, ArH), 4.97 (s, 2H, ArCH2O), 4.38 (q, J=7 Hz, 2H, CO2CH2), 4.03 (q, J=7 Hz, 2H, CO2CH2), 3.59 (s, 3H, CH3O), 3.41 (s, 2H, ArCH2CO2), 2.03 (s, 9H, adamantyl), 1.75 (s, 6H, adamantyl), 1.40 (t, J=7 Hz, 3H, CO2CH2CH3), 1.16 J=7 Hz, 3 Hz, CO2CH2CH3); 13C NMR (75 MHz, CDCl3) δ 171.48 (C=O), 166.54 (C=O), 158.84, 156.13, 137.62, 137.33, 135.74, 134.91, 134.21, 131.31, 131.05, 130.44, 128.82, 128.33, 128.14, 126.27, 122.82, 118.09, 111.49, 109.54, 69.75, 60.97, 60.77, 54.82, 40.55, 39.23, 37.13, 36.80, 29.09, 14.38, 14.12.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=[CH:8][C:9]([NH2:11])=[O:10])[C:4]([N+:12]([O-:14])=[O:13])=[N:3]1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[CH2:20]=O>CO>[N:15]1([CH2:20][NH:11][C:9](=[O:10])[CH:8]=[CH:7][C:5]2[C:4]([N+:12]([O-:14])=[O:13])=[N:3][N:2]([CH3:1])[CH:6]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCNC1
Reactant: C=O
Reactant: Cn1cc(C=CC(N)=O)c([N+](=O)[O-])n1
Solvent: CO
Product: Cn1cc(C=CC(=O)NCN2CCCC2)c([N+](=O)[O-])n1
Reaction time: 6 h

Procedure:
1 g. 3-(1-methyl-3-nitro-4-pyrazolyl)-acrylamide (preparation see Example 3) is mixed with 3.5 ml. methanol, 1 ml. pyrrolidine and 0.9 ml. 37% aqueous formaldehyde solution and stirred under reflux for 4 hours. A further 1 ml. pyrrolidine and 0.9 ml. formaldehyde solution are added thereto and the reaction mixture is kept under reflux for a further 3 hours. 1 ml. pyrrolidine and 0.9 ml. formaldehyde are again added thereto and stirring under reflux continued for a further 6 hours. The reaction mixture is then completely evaporated to dryness in a vacuum, the residue is triturated with methanol and the solid material is filtered off with suction. There is thus obtained 0.34 g. 3-(1-methyl-3-nitro-4-pyrazolyl)-acrylic acid N-(pyrrolidinomethyl)-amide; m.p. 180°-183° C. It is soluble in dilute hydrochloric acid. A further 0.35 g. of the same compound is obtained from the mother liquor by evaporation.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8][C:9](=O)[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].Cl.[C:15](O)(=O)C>C(O)C.O>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:15])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: O=c1[nH]c2c(Cl)cccc2o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc2c(Cl)cccc2o1

Procedure:
To a solution of the 4-chloro-2-benzooxazolinone (0.10 mol) in 200 mL ethanol is added LiOH (0.20 mol) in 100 mL of water. The solution is refluxed for 8 hr and cooled. The solution is neutralized with 1N HCl and extracted with ethyl acetate followed by drying over MgSO4. The solution is concentrated and taken up in 200 mL of toluene and 0.10 mol of acetic acid. The solution is refluxed in a Dean Stark trap for 12 hours, concentrated and purified by flash chromatography.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[N+:10]([O-:12])=[O:11].C([O-])([O-])=O.[K+].[K+].CS(C)=O.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CCOC(C)=O>[F:9][C:4]1[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1c(F)cc(F)cc1N1CCOCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1,3,5-Trifluoro-2-nitro-benzene (5.30 g, 29.9 mmol) and K2CO3 (4.96 g, 35.9 mmol) were mixed in DMSO (40.0 mL, 564 mmol) and morpholine (2.74 mL, 31.4 mmol) was added. The reaction was stirred at rt for 48 h, diluted with EtOAc and washed twice with water. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Title compound isolated as a yellow oil (4.26 g, 58%). LCMS (m/e) 245 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 6.67-6.58 (m, 2H), 3.80 (t, 4H, J=4.2 Hz), 3.06 (t, 4H, J=4.2 Hz), 19F-NMR (CDCl3, 400 MHz) δ −102, −118. Also obtained in this reaction, 4-(3,5-difluoro-4-nitro-phenyl)-morpholine as a yellow solid (2.85 g, 39%). m.p.=112-114° C.; LCMS (m/e) 245 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 6.45-6.37 (m, 2H), 3.86 (t, 4H, J=4.5 Hz), 3.33 (t, 4H, J=4.5 Hz); 19F-NMR (CDCl3, 400 MHz) δ −115.
Reaction SMILES: CS(C)=[O:3].C(Cl)(=O)C(Cl)=O.[F:11][C:12]([F:20])([CH2:15][CH2:16][CH2:17][O:18][CH3:19])[CH2:13][OH:14].C(N(CC)CC)C>ClCCl>[OH2:3].[F:11][C:12]([F:20])([CH2:15][CH2:16][CH2:17][O:18][CH3:19])[CH:13]=[O:14]
Reactant: COCCCC(F)(F)CO
Reactant: CS(C)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCC(F)(F)C=O
Product: O
Temperature: -60 °C
Reaction time: 0.25 h
Yield: 53.4 %

Procedure:
A solution of dry dimethylsulfoxide (3 g, 38 mmoles) in dry dichloromethane (15 ml) is slowly added to a solution of oxalyl chloride (2.4 g, 19 mmoles) in dichloromethane (15 ml), kept under nitrogen and cooled to -60° C. Stirring is continued for 15 min. at -60° C. and followed by addition of 2,2-difluoro-1-hydroxy-5-methoxypentane (2.7 g, 17.5 mmoles) in dichloromethane (15 ml). The reaction mixture is stirred for 11/2 hours at -60° C., triethylamine (8.4 ml, 114 mmoles) in dichloromethane (15 ml) is slowly added, and the cooling bath is removed. The reaction mixture is hydrolyzed with brine and diluted with dichloromethane. The organic phase is then washed successively with 2N HCl containing some sodium chloride, and brine. Usual work-up affords the title compound (1.59 g, 53%) which is used for the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10](Cl)=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[N:7][C:6]=12.[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[C:20]([CH3:25])[CH:19]=1>>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([NH:22][C:21]3[CH:23]=[CH:24][C:18]([F:17])=[CH:19][C:20]=3[CH3:25])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[N:7][C:6]=12
Reactant: Cc1cc(F)ccc1N
Reactant: CCOC(=O)c1cnc2c(Br)cnn2c1Cl
Product: CCOC(=O)c1cnc2c(Br)cnn2c1Nc1ccc(F)cc1C
Yield: 99.9 %

Procedure:
In the same manner as in Example 1, step 4 and using ethyl 3-bromo-7-chloropyrazolo[1,5-a]pyrimidine-6-carboxylate (3.5 g, 11.4 mmol) obtained in Example 22, step 1 and 4-fluoro-2-methylaniline (1.53 mL, 22.8 mmol), the title compound (4.48 g, 99%) was obtained.
Reaction SMILES: BrC1C(=O)[O:4][C:5]2[C:10]([C:11]=1C)=[CH:9][CH:8]=[C:7](O)[CH:6]=2.B(O)(O)O.[C:19]([O-:22])([O-])=O.[Na+].[Na+].[CH3:25][N:26]([CH:28]=[O:29])C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:4][C:5]1[CH:10]=[CH:11][C:25]2[NH:26][C:28](=[O:29])[CH:9]=[CH:8][C:7]=2[C:6]=1[CH:19]=[O:22]
Reactant: Cc1c(Br)c(=O)oc2cc(O)ccc12
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OB(O)O
Agent: [Na+]
Product: O=Cc1c(O)ccc2[nH]c(=O)ccc12
Temperature: 90 °C
Yield: 42 %

Procedure:
Compound 1 (15 g, 46 mmol), the boric acid (8.7 g, 50.6 mmol), Pd(PPh3)4 (1.88 g, 2.3 mmol), Na2CO3 (12.1 g, 115 mmol) were added to DMF (250 mL). The reaction mixture was degassed with N2 for three times, and then heated to 90° C. for 16 h. After cooled to RT, the solvent was concentrated, the residue was dissolved in sat Na2CO3 (150 mL). The aqueous was washed with DCM (100 mL×4), and then acidified by con.HCl to pH to ˜4. The result precipitate was collected by filtration, triturated with hot EA (50 mL), afforded compound 2 (6.5 g, 42%) as yellow solid. 1HNMR (DMSO-d6, 400 MHz): δ 10.55 (s, 1H), 7.71 (d, J=4.0 Hz, 1H), 7.24 (s, 1H), 7.19 (d, J=4.0 Hz, 1H), 6.86 (s, 1H), 3.88 (s, 3H), 2.45 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[CH:13]3)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[O:31][CH3:32]>>[CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[C:13]3[CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=2[O:31][CH3:32])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: O=C(NCC1CCCC1)c1ccc2[nH]ccc2c1
Product: COC(=O)c1ccc(Cc2c[nH]c3ccc(C(=O)NCC4CCCC4)cc23)c(OC)c1
Yield: 33 %

Procedure:
The starting indole (C) was prepared according to the procedure of Example 1, starting with 5-(N-cyclopentylmethylcarbamoyl)indole (A) and methyl 4-bromomethyl-3-methoxybenzoate (B) to yield methyl 4-[5-(N-cyclopentylmethylcarbamoyl)indol-3-ylmethyl]-3-methoxybenzoate (C) (1.14 g, 33%) as a tan foam; partial NMR (80 MHz, CDCl3): 3.45(dd, 2H, CH2N), 3.93(s, 3H, OCH3), 3.95(s, 3H, OCH3), 4.17(s, 2H, ArCH2), 6.17(t, 1H, NHCO), 7.01(d, 1H, H2 -indole), 7.16(d, 1H), 8.04(br s, 1H, H4 -indole), 8.45(br s, 1H, NH).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-:9].[Na+].O.[CH2:12]=O>C(O)(=O)C>[OH:1][C:2]1[C:3]([CH3:8])=[N:4][C:5]([CH2:12][OH:9])=[CH:6][CH:7]=1
Reactant: Cc1ncccc1O
Reactant: C=O
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc(CO)ccc1O
Reaction time: 2 h

Procedure:
A mixture of 27.2 g. (0.25 mol) of 3-hydroxy-2-methylpyridine, 100 ml. of 10% sodium hydroxide in 75 ml. of water and 22.5 ml. (0.25 mol) of 40% formalin (aqueous methanolic formaldehyde solution) is refluxed for two hours. An additional amount of 40% formalin (22.5 ml.) is added and the reflux is continued for two hours. The mixture is acidified with acetic acid and the resulting precipitate is filtered and washed with acetone. The filtrate is evaporated to dryness and the residue is repeatedly extracted with hot acetone. The extract is dried, treated with charcoal and evaporated to give crude 3-hydroxy-6-hydroxymethyl-2-methylpyridine as a solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:33]([N:35]=[C:36]=[O:37])[CH3:34].C(=O)(O)[O-].[Na+]>ClCCl.C(OC(C)C)(C)C>[CH2:33]([NH:35][C:36]([N:15]1[CH2:16][CH2:17][C:12]([S:9]([C:6]2[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=2)(=[O:10])=[O:11])([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[CH2:13][CH2:14]1)=[O:37])[CH3:34]
Reactant: CCN=C=O
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1(c2cc(F)ccc2F)CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)N1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
The 4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)piperidine hydrochloride (80 mg, 0.20 mmol) obtained in Example 260 and triethylamine (0.092 ml, 0.66 mmol) were dissolved in dichloromethane (4 ml), followed by the addition of ethyl isocyanate (0.027 ml, 0.34 mmol) at room temperature. After stirring at room temperature for 6 hours, a saturated aqueous solution of sodium bicarbonate (0.5 ml) was added. The residue obtained by concentrating the reaction mixture under reduced pressure was subjected to flash silica gel chromatography, and the fraction obtained from the dichloromethane:methanol=50:1 eluate was concentrated under reduced pressure to give a white solid. The resulting solid was washed with diisopropyl ether, whereby the title compound (74 mg, 0.17 mmol, 85%) was obtained as a white powder.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[CH2:25][OH:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].[Cl:27][C:28]1[CH:33]=[CH:32][C:31](O)=[CH:30][N:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C>ClCCl.O1CCCC1>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[Cl:24])(=[O:15])=[O:16])[CH2:11][C@H:10]2[CH2:25][O:26][C:31]2[CH:30]=[N:29][C:28]([Cl:27])=[CH:33][CH:32]=2)=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: Oc1ccc(Cl)nc1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2CO)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2COc2ccc(Cl)nc2)CC1
Reaction time: 8 h
Yield: 38.4 %

Procedure:
To a cold mixture (ice bath) of (1R,2R,4S)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-hydroxymethyl-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (example 155, 28.5 mg), 2-chloro-5-hydroxypyridine (19 mg) and triphenyl phosphine (28 mg) in dichloromethane (1 mL) was added a solution of di-tert-butyl-azodicarboxylate (25 mg) in tetrahydrofuran (1 mL). The reaction mixture was stirred overnight then adsorbed unto silica and was purified by flash chromatography on silica gel with a gradient of cyclohexane:ethyl acetate (4:1 to 1:1 v/v) as eluant to afford the title compound (14 mg, 36%) as a colorless solid. MS (EI): 512.0 (M+H)+.
Reaction SMILES: [C:1]([N:9]1[CH:14]=[CH:13][CH:12]([CH2:15][C:16]2[N:20]([CH3:21])[C:19]3[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=3[N:17]=2)[CH:11]=[CH:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[C:1]([N:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]2[N:20]([CH3:21])[C:19]3[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=3[N:17]=2)=[CH:13][CH2:14]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(CC2C=CN(C(=O)c3ccccc3)C=C2)nc2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cn1c(CC2=CCN(C(=O)c3ccccc3)C=C2)nc2ccccc21
Yield: 58.5 %

Procedure:
A mixture of 16 parts of 1-benzoyl-1,4-dihydro-4-[(1-methyl-1H-benzimidazol-2-yl)methyl]pyridine and 160 parts of methanol was hydrogenated at normal pressure and at 50° C. with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97.5:2.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The oily residue was crystallized from 14 parts of 1,1'-oxybisethane. The product was filtered off and dried, yielding 7.8 parts (58.5%) of 1-benzoyl-4-[(1-methyl-1H-benzimidazol-2-yl)methyl]pyridine; mp. 159.3° C. (32).
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:7]2[N:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:6]12)=[O:4].CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.[CH2:45]([N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CCOCC>[ClH:1].[ClH:1].[C:46]1([CH2:45][N:52]2[CH2:53][CH2:54][N:55]([CH2:2][C:3]([N:5]3[CH2:10][CH:9]=[C:8]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=4)[N:7]4[N:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:6]34)=[O:4])[CH2:56][CH2:57]2)[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: CCOC(=O)c1cnn2c1N(C(=O)CCl)CC=C2c1cccc(C(F)(F)F)c1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: CCOCC
Product: CCOC(=O)c1cnn2c1N(C(=O)CN1CCN(Cc3ccccc3)CC1)CC=C2c1cccc(C(F)(F)F)c1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
A mixture of 2.065 g of 4-(chloroacetyl)4,5-dihydro-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]-pyrimidine-3-carboxylic acid, ethyl ester, 535 mg of [1,8-bis(dimethylamino)naphthalene, N,N,N',N'-tetramethyl-1,8-naphthalenediamine], 2.88 g of N-benzylpiperazine and 100 ml of dry ether was stirred at room temperature overnight and then filtered. The filtrate was evaporated, the residue dissolved in 300 ml of ether and 1 ml of concentrated hydrochloric acid in 50 ml of water was added. The solid was collected, giving 845 mg of the desired product, mp 228°-230° C.