Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([O:27][CH3:28])=[C:19]([CH2:24][CH:25]=O)[CH:20]=[C:21]([F:23])[CH:22]=3)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C(O)(=O)C.C([O-])(=O)C.[Na+].[NH:38]1[CH2:41][CH:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:39]1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([O:27][CH3:28])=[C:19]([CH2:24][CH2:25][N:38]4[CH2:41][CH:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:39]4)[CH:20]=[C:21]([F:23])[CH:22]=3)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: COC(=O)C1CNC1
Reactant: COc1c(CC=O)cc(F)cc1-c1cnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)C1CN(CCc2cc(F)cc(-c3cnc(-c4ccc(OC(C)C)c(Cl)c4)s3)c2OC)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
To a solution of [3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-5-fluoro-2-(methyloxy)phenyl]acetaldehyde (D80) (95 mg), acetic acid (0.044 mL) and sodium acetate (113 mg) in ethanol (20.00 mL) stirred under nitrogen at room temperature was added methyl 3-azetidinecarboxylate (106 mg) in one charge. The reaction mixture was stirred at room temperature for 1 h, then the solvent was evaporated in vacuo. The residue was dissolved in dichloromethane (DCM) (20 mL), sodium triacetoxyborohydride (195 mg) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated brine (30 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo to give the crude product methyl 1-{2-[3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-5-fluoro-2-(methyloxy)phenyl]ethyl}-3-azetidinecarboxylate (D82) (100 mg). The crude product was used for next step without further purification. MS (ES): C26H28ClFN2O4S requires 518. found 519.2 (M+H+).
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[CH:14]=[C:13]([N:15]3[CH:19]=[N:18][C:17]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:16]3)[CH:12]=[CH:11][N:10]=2)=CC=1.C(O)(=O)C>C(O)(C(F)(F)F)=O>[C:21]1([NH:20][C:17]2[N:18]=[CH:19][N:15]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([NH2:8])[CH:14]=3)[N:16]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COc1ccc(CNc2cc(-n3cnc(Nc4ccccc4)n3)ccn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: Nc1cc(-n2cnc(Nc3ccccc3)n2)ccn1
Reaction time: 16 h

Procedure:
[1.5 g, 4.03 mMol] of (4-Methoxy-benzyl)-[4-(3-phenylamino-[1,2,4]triazol-1-yl)-pyridin-2-yl]-amine was dissolved in 25 mL of TFA and stirred at 40 C in a sealed tube for 16 hrs. Then, 10 mL of glacial acetic acid was added and the mixture was stirred at 40 C for an additional 24 hr. The solvent was removed under reduced pressure and the residue triturated with MTBE, The crude material was treated with water and neutralized with 11.4N ammonium hydroxide to pH 9. The resulting solid was isolated via suction filtration and washed with water. This crude product was treated with 0.25N HCl and particulates removed via suction filtration. The filtrates were neutralized with conc. ammonium hydroxide to a pH of 10 and the mixture was extracted with chloroform twice. The organics were combined and washed with water and brine, dried (Na2SO4), and concentrated under reduced pressure. Tan powder collected; 300 mg (33%). 1H NMR 500 MHz (DMSO-d6) ∂ 6.22 (s ex, 2H), 6.88 (m, 2H), 7.09d, 1H), 7.26 (t, 2H), 7.67 (d, 2H), 7.97 (d, 1H), 9.14 (s, 1H), 9.52 (s ex, 1H). LC/MS [M+H+] 253.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13](OCC3C=CC4C(=CC=CC=4)N=3)=[CH:12][CH:11]=2)=[O:9])=[CH:3][CH:2]=1.CON(C)C(=O)C1C=CC([CH2:38][CH2:39][C:40]2[CH:49]=[CH:48][C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:41]=2)=CC=1>>[N:1]1[CH:2]=[CH:3][C:4]([CH2:7][C:8]([C:10]2[CH:11]=[CH:12][C:13]([CH2:38][CH2:39][C:40]3[CH:49]=[CH:48][C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[N:41]=3)=[CH:14][CH:15]=2)=[O:9])=[CH:5][CH:6]=1
Reactant: CON(C)C(=O)c1ccc(CCc2ccc3ccccc3n2)cc1
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Product: O=C(Cc1ccncc1)c1ccc(CCc2ccc3ccccc3n2)cc1

Procedure:
Following the procedure for the preparation of 2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone but substituting N-Methoxy-N-methyl-4-(2-quinolin-2-yl-ethyl)-benzamide provided the title compound. MS: (M+H m/z=353.1).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:9]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][CH:11]2[C:16](=[O:17])OC(C)(C)[O:13][C:12]2=[O:20])[CH:6]=[CH:7][CH:8]=1>C1(C)C=CC=CC=1>[C:24]([O:23][C:22]([N:21]1[C@@H:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:30])([F:1])[F:29])[CH:4]=2)[CH2:10][CH:11]([C:12]([OH:13])=[O:20])[C:16]1=[O:17])=[O:28])([CH3:26])([CH3:27])[CH3:25]
Reactant: CC(C)(C)OC(=O)N[C@H](CC1C(=O)OC(C)(C)OC1=O)c1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C(=O)C(C(=O)O)C[C@@H]1c1cccc(C(F)(F)F)c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
The mixture of tert-butyl (R)-1-[3-(trifluoromethyl)phenyl]-2-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)ethylcarbamate (520 mg, 1.21 mmol) and toluene (15 mL) is stirred at 110° C. for 3 h. Concentration to give (5R)-1-(tert-butoxycarbonyl)-5-[3-(trifluoromethyl)phenyl]-2-oxopyrrolidine-3-carboxylic acid as a colorless oil. This product is used for the next step without further purification. HPLC-MS calculated for C12H10F3NO3 (M-Boc+H+) 274.06, found 274.10.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.C(#N)C.[Cl:22]N1C(=O)CCC1=O>>[Cl:22][C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)=[CH:8]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Solvent: CC#N
Product: C[C@@]1(c2ccc3c(Cl)c(O)ccc3c2)COC(=O)N1
Temperature: 80 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
(R)-4-(6-hydroxynaphthalen-2-yl)-4-methyloxazolidin-2-one (0.5895 g, 0.002423 mol) was suspended in acetonitrile (3.37 mL, 0.0646 mol) in a 40 mL vial equipped with a magnetic stir bar. N-Chlorosuccinimide (0.356 g, 0.00266 mol) was added and the mixture was heated at 80° C. After 2 hours, HPLC analysis showed that the reaction was complete. The mixture was cooled to room temperature and filtered. The residue was washed with acetonitrile, azeotroped with toluene then dried under vacuum and collected to give 590 mg of the title compound (62% yield).
Reaction SMILES: [Br-].[OH:2][CH:3]1[CH2:7][CH2:6][N@@+:5]([CH3:18])([CH2:8][C:9](=[O:17])[NH:10][C:11]2[CH:16]=NC=C[N:12]=2)[CH2:4]1.[Br:19]C[C:21](NC1C=NC=CN=1)=[O:22].BrCC(NC1C=CON=1)=O>>[Br-:19].[OH:2][C@@H:3]1[CH2:7][CH2:6][N+:5]([CH2:8][C:9](=[O:17])[NH:10][C:11]2[CH:16]=[CH:21][O:22][N:12]=2)([CH3:18])[CH2:4]1
Reactant: C[N@@+]1(CC(=O)Nc2cnccn2)CCC(O)C1
Reactant: O=C(CBr)Nc1cnccn1
Agent: O=C(CBr)Nc1ccon1
Agent: [Br-]
Product: C[N+]1(CC(=O)Nc2ccon2)CC[C@@H](O)C1

Procedure:
This compound is prepared by a method that is analogous to that used to prepare (R)-3-hydroxy-1-methyl-1-(pyrazin-2-ylcarbamoylmethyl)-pyrrolidinium bromide (Intermediate B) by replacing 2-Bromo-N-pyrazin-2-yl-acetamide (Intermediate A) with 2-Bromo-N-isoxazol-3-yl-acetamide (Intermediate C).
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[C:14]([CH3:21])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[C:11](Cl)[CH:10]=1)C1C=CC=CC=1.[CH3:23][C:24]1[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=1.OC1C2C(=C(C)C(OC)=CC=2)N=C(N2C=CC(C(C)C)=N2)C=1>>[OH:8][C:9]1[C:18]2[C:13](=[C:14]([CH3:21])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[C:11]([N:25]2[C:24]([CH3:23])=[CH:28][C:27]([CH3:29])=[N:26]2)[CH:10]=1
Reactant: Cc1cc(C)[nH]n1
Reactant: COc1ccc2c(OCc3ccccc3)cc(Cl)nc2c1C
Agent: COc1ccc2c(O)cc(-n3ccc(C(C)C)n3)nc2c1C
Product: COc1ccc2c(O)cc(-n3nc(C)cc3C)nc2c1C

Procedure:
The title compound was prepared from 4-benzyloxy-2-chloro-7-methoxy-8-methyl-quinoline (63) and 3,5-dimethylpyrazole following the procedure reported for the preparation of 4-hydroxy-2-(3-isopropylpyrazol-1-yl)-7-methoxy-8-methylquinoline (64): m/z=284 (M+H)+.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].C(N)CC.[CH2:10]([P:12](OC)(=[O:15])[O:13][CH3:14])[CH3:11]>>[CH3:14][O:13][P:12]([CH2:10][CH3:11])([CH2:3][CH2:2][C:1]([NH2:5])=[O:4])=[O:15]
Reactant: CCP(=O)(OC)OC
Reactant: C=CC(N)=O
Solvent: CCCN
Product: CCP(=O)(CCC(N)=O)OC
Temperature: 50 °C
Reaction time: 5 h
Yield: 92.3 %

Procedure:
71 g of acrylamide and 120 g of n-propylamine are mixed at room temperature under nitrogen and the mixture is heated to 50° C. 122 g of dimethyl ethanephosphonate are added dropwise to the reaction solution in the course of 30 minutes. The reaction mixture is then stirred for 5 hours at reflux temperature and the solvent (low-boiling solvent such as excess propylamine+N-methyl-N-propylamine) is removed by vacuum distillation. The crude product is obtained in a yield of 175 g with a 94.4% purity, which corresponds to a theoretical yield of 92.3%.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[NH:10][CH2:11][CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:15](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CN=C1.C(O)C>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:14])[NH:10][CH2:11][CH2:12][O:13][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCO)OCc1ccccc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(C)[Si](OCCNC(=O)OCc1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Subsequently, to a solution of (2-hydroxyethyl)carbamic acid benzyl ester (5.37 g, 27.5 mmol) in dimethylformamide (160 ml) were added t-butyldiphenylsilyl chloride (8.6 ml, 33.0 mmol) and imidazole (2.3 g, 33.8 mmol) in an ice bath, and the mixture was stirred at room temperature overnight. After checking the completion of the reaction, ethanol was added thereto and the reaction mixture was stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (5:1) as the eluant to afford [2-(t-butyldiphenylsilyloxy)ethyl]carbamic acid benzyl ester (11.93 g, yield 100%) as a colorless and transparent syrup.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([C@:13]([NH:20][S@@](C(C)(C)C)=O)([CH3:19])[C:14]([F:18])([F:17])[CH2:15][OH:16])[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.Cl>CO>[NH2:20][C@@:13]([C:11]1[CH:10]=[N:9][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH:12]=1)([CH3:19])[C:14]([F:17])([F:18])[CH2:15][OH:16]
Reactant: CC(C)(C)[S@@](=O)N[C@](C)(c1cnn(-c2cccc(Br)c2)c1)C(F)(F)CO
Agent: Cl
Solvent: CO
Product: C[C@@](N)(c1cnn(-c2cccc(Br)c2)c1)C(F)(F)CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
A solution of (R)-2-methyl-propane-2-sulfinic acid {(R)-1-[1-(3-bromo-phenyl)-1H-pyrazol-4-yl]-2,2-difluoro-3-hydroxy-1-methyl-propyl}-amide (590 mg, 1.2 mmol) in methanol (5 ml) was treated at 0° C. with hydrochloric acid (4N in dioxane, 2.6 ml, 10.2 mmol), and the reaction mixture was stirred at 25° C. for 2 hours. For the workup, the solution was concentrated at reduced pressure, and the resultant residue was diluted with water (10 ml). The aqueous layer was treated with a saturated solution of sodium hydrogencarbonate to a pH of about 8, then extracted with ethyl acetate (4×10 ml). The combined organic layers were washed with brine (15 ml), dried over sodium sulphate, and evaporated at reduced pressure. The crude material thus obtained was purified by column chromatography on silica gel using a gradient of hexane/ethyl acetate=85:15 to 80:20 as the eluent to give the (R)-3-amino-3-[1-(3-bromo-phenyl)-1H-pyrazol-4-yl]-2,2-difluoro-butan-1-ol (400 mg, 96% yield) as a light yellow solid which was used in the next step without further purification. MS (ISP): m/z=346.5 [M+H]+.
Reaction SMILES: [C:1]([NH:20][CH:21]1[CH:28]2[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:30][C:22]1([OH:31])[CH2:23]3)[CH2:27]2)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[C:41]1[CH:48]=[CH:47][C:44]([CH2:45]Br)=[CH:43][CH:42]=1>C1COCC1>[C:1]([NH:20][CH:21]1[CH:28]2[CH2:27][CH:26]3[CH2:25][CH:24]([CH2:23][C:22]1([O:31][CH2:45][C:44]1[CH:47]=[CH:48][C:41]([C:33]4[O:32][C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[N:34]=4)=[CH:42][CH:43]=1)[CH2:30]3)[CH2:29]2)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccc(-c2nc3ccccc3o2)cc1
Reactant: OC12CC3CC(CC(C3)C1NC(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Solvent: C1CCOC1
Product: c1ccc(C(NC2C3CC4CC(C3)CC2(OCc2ccc(-c3nc5ccccc5o3)cc2)C4)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.08 h

Procedure:
To KH (35%; 0.43 g; 0.0038 mole) in THF (10 ml) under N2 and cooled in ice is added N-trityl-1-hydroxytricyclo[3.3.1.13,7 ]decan-2-amine (1.3 g; 0.0032 mole) and this mixture is stirred in an ice bath for 5 minutes and then at room temperature for an hour. To this mixture is added 4-(benzoxazol-2-yl)benzyl bromide all at once and an immediate yellow suspension develops. The reaction is stirred at room temperature for 4 hours, filtered and the filtrate stripped to dryness to give a solid residue. The components are separated on HPLC, eluting with 8% ethyl acetate/hexane to obtain N-trityl-1-[4-(benzoxazol-2-yl)benzyloxy]tricyclo[3.3.1.13,7 ]decan-2-amine (m.p. 208°-210° C.) which is used directly in step C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([Cl:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:11][C:12]1[CH:13]=[C:14]([C:18]23[CH2:26][CH:22]([NH:23][CH:24]2[CH3:25])[CH2:21][CH2:20][CH2:19]3)[CH:15]=[CH:16][CH:17]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.N>O1CCCC1.C(Cl)Cl.C(N(CC)CC)C>[ClH:10].[OH:11][C:12]1[CH:13]=[C:14]([C:18]23[CH2:26][CH:22]([N:23]([CH2:8][CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:24]2[CH3:25])[CH2:21][CH2:20][CH2:19]3)[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC1NC2CCCC1(c1cccc(O)c1)C2
Agent: Cl
Agent: N
Agent: [Al+3]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC1N(CCc2ccccc2)C2CCCC1(c1cccc(O)c1)C2
Temperature: 25 °C
Reaction time: 20 h
Yield: 15.6 %

Procedure:
0.62 g of phenylacetyl chloride is added dropwise under ice-cooling to a mixture of 0.35 g of 1-(3-hydroxyphenyl)7-methyl-6-azabicyclo[3,2,1]octane, 1 ml of triethylamine and 7 ml of methylenedichloride. The mixture is stirred at room temperature for 20 hours. Then, the mixture is concentrated under reduced pressure. Water is added to the residue, and the aqueous mixture is extracted with benzene. The benzene extract is washed with diluted hydrochloric acid, water, aqueous sodium bicarbonate and water, successively. The benzene extract is dried and evaporated to remove solvent. The residue thus obtained is dissolved in 12 ml of tetrahydrofuran. 0.6 g of lithium aluminium hydride is added to the tetrahydrofuran solution, and said solution is refluxed for 1.5 hours. After cooling, diluted hydrochloric acid is added to the reaction solution to decompose lithium aluminium hydride. Then, the reaction solution is made alkaline with aqueous ammonia and extracted with chloroform. The chloroform extract is washed with water, dried and then evaporated to remove solvent. The residue is dissolved in 5 ml of chloroform. The chloroform solution is poured onto a column of 20 g of silica gel. Then, the column is eluted with a mixture of 300 ml of chloroform and 50 ml of methanol, and the effluent is evaporated to remove solvent. Methanolic hydrogen chloride is added to the residue in ether, and the crystalline precipitate is collected by filtration. The precipitate is recrystallized from acetone. 0.09 g of 1-(3-hydroxyphenyl)-6-phenethyl- 7-methyl-6-azabicyclo[3,2,1]octane hydrochloride is obtained. M.p. 231°-233°C.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([CH:7]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:8](O)=[O:9])=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH3:29][O:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[N:34][CH:33]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O>[CH3:29][O:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:8](=[O:9])[CH:7]([C:4]2[CH:3]=[CH:2][C:1]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:6][CH:5]=2)[CH2:11][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)=[N:34][CH:33]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(-c2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(-c3ccccc3)cc2)nc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 17.8 %

Procedure:
A slurry of 2-biphenyl-4-yl-3-cyclopentylpropionic acid (prepared in Example 21, 1.25 g 4.25 mmol) in methylene chloride (10 mL) was treated with dry N,N-dimethylformamide (5 drops). The reaction mixture was cooled to 0° C. and then treated dropwise with oxalyl chloride (1.85 mL, 21.23 mmol). The reaction mixture was allowed to stir at 0° C. for 30 min and then allowed to warm to 25° C. where it was stirred for 2 h. The reaction mixture was concentrated in vacuo to provide an orange semi-solid residue. This residue was treated with a small amount of methylene chloride and was slowly added to a cooled (0° C.) solution of 6-aminonicotinic acid methyl ester (776 mg, 5.10 mmol) and triethylamine (1.19 mL, 8.50 mmol) in methylene chloride (10 mL). The resulting reaction mixture was stirred at 0° C. and allowed to warm to 25° C. The reaction mixture was stirred at 25° C. for 15 h. The reaction mixture was then concentrated in vacuo to remove methylene chloride. The resulting residue was partitioned between water and ethyl acetate, and the layers were separated. The aqueous layer was further extracted with ethyl acetate (1×100 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) afforded 6-(2-biphenyl-4-yl-3-cyclopentyl-propionylamino)-nicotinic acid methyl ester (325 mg, 18%) as a white solid: mp 63-65° C.; EI-HRMS m/e calcd for C27H28N2O3 (M+) 428.2099, found 428.2100.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:21](/B(O)O)=[CH:22]\[CH2:23][CH2:24][CH3:25].[ClH:29]>CCOCC>[ClH:29].[O:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][CH2:12][NH:11][C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2](/[CH:21]=[CH:22]/[CH2:23][CH2:24][CH3:25])=[CH:3][N:4]=3)[N:7]=2)[CH2:16][CH2:17]1
Reactant: Brc1cnc2ccc(NCCCN3CCOCC3)nn12
Reactant: CCC/C=C/B(O)O
Agent: Cl
Solvent: CCOCC
Product: CCC/C=C/c1cnc2ccc(NCCCN3CCOCC3)nn12
Yield: 55 %

Procedure:
Prepared from the product of step A (example 16) and (E)-1-penteneboronic acid according to general procedure 2. The free base was converted to the HCl salt with 2N HCl in Et2O to provide the title compound (58 mg, 55%) as a brown solid; 1H NMR (500 MHz, CD3OD) δ 7.65 (d, J=9.7 Hz, 1H), 7.56 (s, 1H), 6.77-6.63 (m, 3H), 3.91-3.89 (m, 4H), 3.54 (t, J=6.4 Hz, 2H), 3.24-3.21 (m, 6H), 2.27 (q, J=6.8 Hz, 2H), 2.20-2.14 (m, 2H), 1.58-1.51 (m, 2H), 0.98 (t, J=7.4 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ 155.6, 136.8, 134.2, 129.2, 126.4, 124.8, 116.4, 115.0, 65.4, 57.0, 53.5, 39.8, 36.8, 24.4, 23.7, 14.1; HPLC tR=9.3 min (Synergi), 97.3%; ES-MS: (M+H)=330 m/z.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Reactant: O=C(Cl)c1ccccc1
Product: Cn1c(C#N)ccc1-c1ccc(NC(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for acylation of 5-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile using benzoyl chloride (64 μL, 0.55 mmol) to provide N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]benzamide (0.035 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1.O[CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][C:21]1=[O:25].S(=O)(=O)(O)O.N>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]3[C:17]=2[CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][C:21]2=[O:25])=[CH:6][CH:7]=1
Reactant: Cc1ccc2nc(-c3ccc(Cl)cc3)cn2c1
Reactant: O=C1CCCN1CO
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1ccc2nc(-c3ccc(Cl)cc3)c(CN3CCCC3=O)n2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
An intimate mixture is prepared of 4.8 g (0.02 mol) of 2-(4-chlorophenyl)-6-methylimidazo[1,2-a]pyridine and 2.53 g (0.022 mol) of N-hydroxymethyl-2-pyrrolidinone, and this is then introduced into 20 ml of concentrated sulphuric acid. The solution is stirred for one day at room temperature, then poured into 800 ml of water, and 55 ml of ammonia solution are added. The lactam is extracted with methylene chloride, the organic phase is washed, dried and evaporated, and the residue is purified by chromatography, eluting with a 70:30 ethyl acetate, toluene mixture. The white solid obtained melts at 186°-187.5° C.
Reaction SMILES: [CH:1](/[C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18]C(=O)OCCC)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[CH:2]\[CH2:3][CH2:4][CH3:5].[OH-].[K+]>C(O)COCCO.O>[CH:1](/[C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[CH2:10][CH2:11]1)=[CH:2]\[CH2:3][CH2:4][CH3:5]
Reactant: CCC/C=C/[C@H]1CC[C@H](c2ccc(NC(=O)OCCC)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: CCC/C=C/[C@H]1CC[C@H](c2ccc(N)cc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 118 mg of propyl p-[trans-4-(trans-1-pentenyl)cyclohexyl]phenylcarbamate and 12.5 ml of a 10% solution of potassium hydroxide in diethylene glycol/water (vol. 4:1) was boiled at 120° C. for 1 hour, then cooled to room temperature and partitioned between 70 ml of diethyl ether and 70 ml of water. The aqueous phase was back-extracted twice with 70 ml of diethyl ether each time. The organic phases were washed twice with 50 ml of water each time, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the brown, crystalline residue (150 mg) on 35 g of silica gel with ethyl acetate/petroleum ether (vol. 15:85) gave 76.6 mg (88%) of p-[trans-4-(trans-1-pentenyl)cyclohexyl]aniline as slightly yellowish crystals; purity 97%; Rf-value 0.24 (ethyl acetate/petroleum ether, vol. 1:5).