Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.N1C=CC=CC=1.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:17]>C(Cl)Cl>[N+:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][C:16](=[O:17])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=2)=[CH:24][CH:23]=1)([O-:27])=[O:26]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(Cl)cn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cn1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Amino-5-chloropyridine (1.05 g, 8.2 mmol) was suspended in 15 mL dry DCM under Ar, added dry pyridine (0.66 mL, 8.2 mmol), cooled to 0° C. and added 4-nitrophenol chloroformate. A white precipitate forms rapidly. Stirred at ambient temperature for 1 hour, filtered off solid, washed with water and then DCM. A white solid recovered which is consistent with title compound. (2.1 g, 88%) 1H-NMR (D6-DMSO)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:26])[C:5]([C:8](=[N:23][O:24][CH3:25])[CH2:9][NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])=[N:6][CH:7]=1>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([Cl:26])[C:5](/[C:8](=[N:23]\[O:24][CH3:25])/[CH2:9][NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:20])([F:19])[F:21])=[N:6][CH:7]=1
Reactant: CON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Br)cc1Cl
Solvent: CC#N
Product: CO/N=C(/CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Br)cc1Cl
Yield: 44.1 %

Procedure:
143 mg of N-[2-(5-bromo-3-chloropyridin-2-yl)-2-(methoxyimino)ethyl]-2-(trifluoromethyl)benzamide was dissolved in 3 ml of acetonitrile, and the solution was irradiated with light for 12 hours in a quartz cell (manufactured by Fine, 4 clear windows for spectroscopy) using a 100 W high-pressure mercury lamp (manufactured by USHIO INC., lamp: UM-102, power supply: UM-103B-B). After completion of the reaction, the solvent was evaporated under reduced pressure, and the resulting residue was washed with 10 ml of hexane to obtain 63 mg of the desired product as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[CH2:19]([OH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>C(COC)OC>[NH2:1][C:2]1[N:3]=[C:4]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: OCc1ccccc1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCc2ccccc2)nc(N)nc1-c1ccco1
Temperature: 100 °C
Yield: 55.5 %

Procedure:
To a stirred suspension of 300 mg (1.14 mmol) 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile in 9 ml dimethoxyethane were added 0.41 ml (4.0 mmol) benzyl alcohol and 0.25 ml (1.7 mmol) DBU and the mixture heated at 100° C. for 1 hour. The reaction mixture was then concentrated in vacuo. Chromatography (ethyl acetate/hexane 2/1) followed by trituration in ether/hexane afforded 185 mg (56%) 2-amino-4-benzyloxy-6-furan-2-yl-pyrimidine-5-carbonitrile as a white crystalline solid. EI-MS m/e (%): 292 (M+, 40), 91 (C7H7+, 100).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]([CH2:20][CH3:21])([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[C:6]1=[O:22].CCN(CC)CC.[C:30]([N:34]=[C:35]=[O:36])([CH3:33])([CH3:32])[CH3:31]>CN(C=O)C>[C:30]([NH:34][C:35]([NH:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]([CH2:20][CH3:21])([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[C:6]1=[O:22])=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)N=C=O
Reactant: CCC1(c2cccc(OC)c2)CCCCN(CCN)C1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC1(c2cccc(OC)c2)CCCCN(CCNC(=O)NC(C)(C)C)C1=O
Reaction time: 18 h

Procedure:
To a solution of 1-(2-amino-ethyl)-3-ethyl-3-(3-methoxy-phenyl)-azepan-2-one hydrochloride (as described in Example 51, Step C) (0.27 g, 0.826 mmol) in DMF (5.0 mL) was added NEt3 (0.35 mL, 2.48 mmol) and t-butylisocyanate (0.29 mL, 2.48 mmol) and the solution was stirred for 18 hr. The DMF was removed in vacuo, and the residue partitioned between EtOAc and H2O. The organic layer was washed with brine and dried (MgSO4), and the solvents removed in vacuo to obtain the title compound.
Reaction SMILES: C([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[CH3:15])[C:8](/[CH:16]=[CH:17]/[C:18]([O:20]CC)=[O:19])=[CH:7][C:6]=1[CH:23]([CH3:25])[CH3:24])(=O)C.[OH-].[K+].O.Cl>C(O)C>[CH:23]([C:6]1[CH:7]=[C:8](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])[C:9]2[C:14]([C:5]=1[OH:4])=[C:13]([CH3:15])[CH:12]=[CH:11][CH:10]=2)([CH3:25])[CH3:24]
Reactant: CCOC(=O)/C=C/c1cc(C(C)C)c(OC(C)=O)c2c(C)cccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cccc2c(/C=C/C(=O)O)cc(C(C)C)c(O)c12
Temperature: 0 °C
Yield: 47.9 %

Procedure:
0.5 g of ethyl (E)-3-(4-acetoxy-3-isopropyl-5-methyl-1-naphthyl)propenoate was dissolved in 50 ml of ethanol, to which a potassium hydroxide aqueous solution (potassium hydroxide 1.6 g/water 10 ml) was added, followed by refluxing for 30 minutes. The solution was cooled to 0° C. and water was added. Dilute hydrochloric acid was added to make the aqueous phase acidic and extracted with ethyl acetate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (40% ethyl acetate/hexane) and the resultant crystals were recrystallized from a mixed solvent of isopropyl ether and ethyl acetate (1:1) and washed with isopropyl ether and hexane (3:7) to obtain 0.19 g of the titled compound as yellow needle.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=1.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([C:37]2[CH:42]=[CH:41][C:40]([Br:43])=[CH:39][CH:38]=2)=[CH:34][CH2:35]O)=[CH:29][CH:28]=1>C1COCC1>[CH3:25][O:24][C:22](=[O:23])[CH2:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:35][CH:34]=[C:33]([C:30]2[CH:29]=[CH:28][C:27]([Br:26])=[CH:32][CH:31]=2)[C:37]2[CH:38]=[CH:39][C:40]([Br:43])=[CH:41][CH:42]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: OCC=C(c1ccc(Br)cc1)c1ccc(Br)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(OCC=C(c2ccc(Br)cc2)c2ccc(Br)cc2)cc1
Reaction time: 1 h
Yield: 62 %

Procedure:
Under a atmosphere of nitrogen, azodicarboxylic dipiperidide (504 mg, 2.0 mmol) was added at 0-5° C. to a stirred solution of tributylphosphine (404 mg, 2.0 mmol), methyl 4-hydroxyphenylacetate (250 mg, 1.5 mmol) and 3,3-bis-(4-bromophenyl)prop-2-en-1-ol (552 mg, 1.5 mmol) in dry THF (10 ml), the mixture stirred for 1 h, filtered and concentrated in vacuo. The crude product was then purified by column chromatography on silica (toluene eluent). The purified product was suspended in petroleum ether, filtered to give 480 mg (62%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@@H:4]([N:16]1[CH2:21][CH2:20][NH:19][C@@H:18]([CH2:22][CH:23]=[CH2:24])[C:17]1=[O:25])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.[C:27]([O:31][C:32]([NH:34][C@H:35]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=1)[C:36](O)=[O:37])=[O:33])([CH3:30])([CH3:29])[CH3:28].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:26])[C@@H:4]([N:16]1[CH2:21][CH2:20][N:19]([C:36](=[O:37])[C@H:35]([NH:34][C:32]([O:31][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:33])[CH2:39][C:40]2[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=2)[C@@H:18]([CH2:22][CH:23]=[CH2:24])[C:17]1=[O:25])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(F)cc1)C(=O)O
Reactant: C=CC[C@@H]1NCCN([C@@H](Cc2ccc3ccccc3c2)C(=O)OC)C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC[C@H]1C(=O)N([C@@H](Cc2ccc3ccccc3c2)C(=O)OC)CCN1C(=O)[C@@H](Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Reaction time: 20 h
Yield: 85 %

Procedure:
To a solution of (S,S)-2-(3-allyl-2-oxo-piperazin-1-yl)-3-naphthalen-2-yl-propionic acid methyl ester, 5, (500 mg, 1.42 mmol) in CH2Cl2 (5.0 mL) are added 2-(R)-tert-butoxycarbonylamino-3-(4-fluorophenyl)propionic acid (473 mg, 1.67 mmol), benzotriazole-1-yl-oxy-tris-pyrrolidinol-phosphonium hexafluorophosphate (PyBOP) (960 mg, 1.85 mmol) and triethylamine (169 mg, 1.67 mmol). The reaction mixture is stirred for 20 h, quenched with 10% NaHCO3 aqueous solution and extracted with EtOAc. The extract is dried over Na2SO4, filtered and concentrated. The residue is purified over silica gel (hexanes/ethyl acetate, 4:1 to 3:2) to afford 0.745 g (85% yield) of the desired product.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH:16]2[C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18][CH2:17]2)[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[OH:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][N:28]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH:16]2[C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18][CH2:17]2)[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([OH:26])=[N:28][CH:29]=2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(CN(CCCCN)C2CCCc3cccnc32)c(C)c1
Reactant: O=C(O)c1ccc(O)nc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cnc(CN(CCCCNC(=O)c2ccc(O)nc2)C2CCCc3cccnc32)c(C)c1
Yield: 19.6 %

Procedure:
Using General Procedure G: To a solution of N1-(3,5-Dimethyl-pyridin-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine (202 mg, 0.60 mmol) in dry DMF (3 mL) was added 6-hydroxy-nicotinic acid (108 mg, 0.78 mmol) followed by EDCI (149 mg, 0.78 mmol), HOBT (106 mg, 0.78 mmol), and DIPEA (0.21 mL, 1.21 mmol). Purification of the crude material by radial chromatography on silica gel (1 mm plate, 10:1:1 CH2Cl2-MeOH—NH4OH) provided 54 mg (20%) of the free base of the title compound as a white foam. Using General Procedure D: Conversion to the HBr salt gave COMPOUND 366 as a white solid. 1H NMR (D2O) δ 1.29-1.42 (m, 2H), 1.49-1.58 (m, 2H), 1.90-2.01 (m, 1H), 2.22-2.35 (m, 2H), 2.54 (s, 3H), 2.56 (s, 3H), 2.57-2.67 (m, 2H), 2.79-2.87 (m, 1H), 3.11-3.15 (m 2H), 3.29-3.40 (m, 2H), 4.33 (d, 1H, J=18.0 Hz), 4.52 (d, 1H, J=18.0 Hz), 4.63 (dd, 1H, J=10.8, 5.7 Hz), 6.82 (d, 1H, J=9.6 Hz), 7.96-8.01 (m, 2H), 8.10 (d, 1H, J=2.1 Hz), 8.23 (s, 1H), 8.46 (d, 1H, J=8.1 Hz), 8.55 (s, 1H), 8.73 (d, 1H, J=5.1 Hz); 13C NMR (D2O) δ 16.89, 17.47, 20.49, 20.74, 25.72, 26.63, 27.82, 39.10, 52.31, 52.90, 62.08, 115.63, 119.37, 125.79, 136.06, 137.16, 137.16, 137.29, 137.49, 139.30, 140.49, 140.88, 147.96, 148.85, 149.33, 151.25, 165.45, 166.46; ES-MS m/z 460 (M+H). Anal. Calcd. For C27H33N5O2.3.0HBr.3.5H2O: C, 42.37; H, 5.66; N, 9.15; Br, 31.32. Found: C, 42.16; H, 5.50; N, 9.26; Br, 31.61.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH2:11][CH:12]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[N:6]2[N:5]=[CH:4][N:3]=1.[Br:23]N1C(C)(C)C(=O)N(Br)C1=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(O)=O>[NH2:1][C:2]1[C:7]2=[C:8]([Br:23])[CH:9]=[C:10]([CH2:11][CH:12]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(Cc2ccc3c(N)ncnn23)C1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC(Cc2cc(Br)c3c(N)ncnn23)C1
Temperature: -20 °C
Reaction time: 3 h
Yield: 192.3 %

Procedure:
To a cooled (−20° C.) solution of tert-butyl 3-[(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)methyl]azetidine-1-carboxylate (325 mg, 1.07 mmol) in DMF (5 mL) and AcOH (1 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (153 mg, 0.54 mmol) in 3 portions over 10 min. The mixture was stirred at −20° C. for 3 h. Aqueous K2CO3 (5%, 20 mL) was added and the mixture was allowed to warm to rt. The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried (Na2SO4) and evaporated to provide 397 mg (97%) of the desired product, which contained minor impurities. ES-MS m/z 382.08 [M+H]+, HPLC RT (min) 3.05.
Reaction SMILES: [CH:1]12[CH2:12][CH2:11][CH:8]([CH:9]=[CH:10]1)[C:7]1[C:2]2=[CH:3][CH:4]=[CH:5][CH:6]=1.C1C[O:16]CC1>>[C@@H:8]12[CH2:11][CH2:12][C@H:1]([CH:10]([OH:16])[CH2:9]1)[C:2]1[C:7]2=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: C1=CC2CCC1c1ccccc12
Product: OC1C[C@H]2CC[C@H]1c1ccccc12
Reaction time: 8 h

Procedure:
A solution of 15.8 g of tricyclo[6.2.2.02,7]dodeca-2,4,6,9-tetraene in 42 mL of THF was added to 82 mL of 1M BH3 in THF at 0° C. The reaction mixture was stirred overnight while the temperature reached rt. The reaction was quenched by addition of 40 mL of 0.3N NaOH solution followed by 134 mL of a 35% H2O2 solution. The mixture was extracted with Et2O, washed with H2O, dried over MgSO4 and concentrated in vacuo to obtain 17.7 g of the desired compound as yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([F:15])([F:14])[F:13])=[CH:4][N:3]=1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.Cl>>[F:9][C:8]([F:11])([F:10])[C:6]1[C:5]([C:12]([F:15])([F:14])[F:13])=[CH:4][N:3]=[C:2]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:7]=1
Reactant: FC(F)(F)c1cnc(Cl)cc1C(F)(F)F
Reactant: C1CNCCN1
Agent: Cl
Product: FC(F)(F)c1cnc(N2CCNCC2)cc1C(F)(F)F
Yield: 65.2 %

Procedure:
Working as described in Example 1, but starting with 10 g (0.04 mol) of 2-chloro-4,5-bis(trifluoromethyl)pyridine and 10.3 g (0.12 mol) of piperazine, the base having a boiling point B.p. 0.04 of 100-102° C. was obtained, and then, after conversion to the hydrochloride, 7.8 g of the title compound .
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C:12]1[C:13](Cl)=[N:14][C:15]([Cl:19])=[C:16]([F:18])[CH:17]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>CC(N(C)C)=O>[CH2:1]([O:8][N:9]1[C:10](=[O:11])[C:12]2[CH:17]=[C:16]([F:18])[C:15]([Cl:19])=[N:14][C:13]=2[N:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=2)[C:31]1=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NOCc1ccccc1)c1cc(F)c(Cl)nc1Cl
Reactant: Cc1ccc(N=C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(Cl)nc32)cc1
Yield: 73.2 %

Procedure:
Using the General Method 5, the reaction of N-benzyloxy-2,6-dichloro-5-fluoro-3-pyridinecarboxamide (Example M-2, 2.00 g, 6.34 mmol) and 60% NaH in oil (300 mg, 7.52 mmol) with 4-methylphenyl isocyanate (1.20 mL, 9.51 mmol) in DMA afforded crude product. Recrystallization from chloroform provided 1.91 g of the title compound as a solid, mp 218-219° C.
Reaction SMILES: [C:1]([C:3]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)([CH2:9][CH2:10][C:11]([OH:13])=O)[CH2:4][CH2:5][C:6]([OH:8])=[O:7])#[N:2].Cl[C:22]1C=CC(C(C#N)(CCC(O)=O)CCC(O)=O)=CC=1.O1CCCC1.CC(C)([O-])C.[K+]>C(O)(=O)C>[C:6]([CH:5]1[CH2:4][C:3]([C:1]#[N:2])([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH2:9][CH2:10][C:11]1=[O:13])([O:8][CH3:22])=[O:7]
Reactant: N#CC(CCC(=O)O)(CCC(=O)O)c1ccc(Cl)cc1
Reactant: Cc1ccc(C(C#N)(CCC(=O)O)CCC(=O)O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C1CC(C#N)(c2ccc(C)cc2)CCC1=O
Yield: 99 %

Procedure:
Following the procedure of Example 1, Part B, but substituting 42.44 gm. (0.14 mole) of the dimethyl ester of 4-cyano-4-(p-tolyl)pimelic acid (prepared in Part A, above) for the dimethyl ester of 4-(p-chlorophenyl)-4-cyanopimelic acid and using 900 ml. of the tetrahydrofuran, 31.5 gm. (0.28 mole) of the potassium tert-butoxide, and 225 ml. of the 2.5 N aqueous acetic acid instead of the 700 ml., the 24.4 gm. (0.218 mole), and the 175 ml., respectively, there is prepared 39.3 gm. (99% yield) of 2-carbomethoxy-4-cyano-4-(p-tolyl)cyclohexanone as a gum.
Reaction SMILES: [BrH:1].C([O:4][C:5](=O)[CH2:6][N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=[NH:13])C>C(O)C>[BrH:1].[N:13]1[C:5](=[O:4])[CH2:6][N:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=12
Reactant: CCOC(=O)Cn1ccccc1=N
Agent: Br
Solvent: CCO
Product: O=C1CN2C=CC=CC2=N1
Temperature: 25 °C

Procedure:
A solution of 9 g (34.4 mmol) of (2-imino-2H-pyridin-1-yl)-acetic acid ethyl ester hydrobromide salt in 200 mL of ethanol is heated at reflux for 18 h. The reaction mixture is then cooled to room temperature and the precipitate is collected. The isolated solid is washed with ethanol to give the desired compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:40])[C:18]([C:24]3[CH:39]=[CH:38][C:27]4[N:28](CC=C)[C:29](=[O:34])[N:30](CC=C)[C:26]=4[CH:25]=3)([OH:23])[C:19]([F:22])([F:21])[F:20])=[C:13]([Cl:41])[CH:12]=2)=[CH:7][C:6]=1[F:42])=[O:4].Cl.[Li+].[OH-]>C(O)CC>[Cl:41][C:13]1[CH:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[C:6]([F:42])[CH:7]=2)[CH:16]=[CH:15][C:14]=1[CH:17]([CH3:40])[C:18]([OH:23])([C:24]1[CH:39]=[CH:38][C:27]2[NH:28][C:29](=[O:34])[NH:30][C:26]=2[CH:25]=1)[C:19]([F:22])([F:20])[F:21]
Reactant: C=CCn1c(=O)n(CC=C)c2cc(C(O)(C(C)c3ccc(-c4ccc(C(=O)OC)c(F)c4)cc3Cl)C(F)(F)F)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCCO
Product: CC(c1ccc(-c2ccc(C(=O)O)c(F)c2)cc1Cl)C(O)(c1ccc2[nH]c(=O)[nH]c2c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.9 %

Procedure:
A mixture of RhCl3 trihydrate (2.5 mg) and 3′-chloro-4′-[2-(1,3-diallyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-3-fluoro-biphenyl-4-carboxylic acid methyl ester (57 mg) in n-PrOH (2 ml) was heated for 2 h to 100° C. in a sealed tube. 25% aqueous HCl (1 ml) was added and heating continued for 2 h at 100° C. The mixture was alkalized by addition of LiOH and stirred for 30 min at room temperature. Volatile solvents were evaporated and the residue dissolved in 1N aqueous NaOH (10 ml). The aqueous phase was washed with ether, acidified with 25% aqueous HCl and then extracted with EtOAc. The combined org. phases were dried over Na2SO4 and then concentrated to an oil. The residue was purified by prep. HPLC (C18-column, solvent gradient 20-98% CH3CN in 0.1% HCOOH[aq]) to give the title compound (12 mg) as a white solid. MS (m/e)=509.3 [M+H+].
Reaction SMILES: C[N:2]1[C:15]2[C:6](=[CH:7][CH:8]=[C:9]3[C:14]=2[N:13]=[CH:12][CH:11]=[CH:10]3)[CH:5]=[CH:4][C:3]1=O.P(Cl)(Cl)([Cl:19])=O.P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:19][C:3]1[CH:4]=[CH:5][C:6]2[C:15](=[C:14]3[C:9](=[CH:8][CH:7]=2)[CH:10]=[CH:11][CH:12]=[N:13]3)[N:2]=1
Reactant: Cn1c(=O)ccc2ccc3cccnc3c21
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: Clc1ccc2ccc3cccnc3c2n1
Yield: 75 %

Procedure:
Under a stream of argon, to compound (2) (8 g; 38 mmol), phosphorus oxychloride (72 mL) and phosphorus pentachloride (9.8 g; 47.6 mmol) were added in an ice bath. The resulting reaction mixture was stirred and refluxed for 8 hours, and excess phosphorus oxychloride was removed under reduced pressure. To the resulting reaction concentrate, ice water and concentrated aqueous ammonia were added and the resulting mixture was made alkaline to precipitate crude crystals. The crude crystals were separated by filtration and washed with water, and then dried under reduced pressure to give 6.1 g (yield: 75%) of the title compound (3).
Reaction SMILES: CN1[C:7]([CH3:8])=[CH:6][C:5](=O)[CH:4]=[C:3]1[CH3:10].[C:11](Cl)([Cl:13])=[O:12]>>[CH2:3]([CH:4]([CH2:5][CH2:6][CH2:7][CH3:8])[C:11]([Cl:13])=[O:12])[CH3:10]
Reactant: O=C(Cl)Cl
Reactant: Cc1cc(=O)cc(C)n1C
Product: CCCCC(CC)C(=O)Cl
Yield: 89 %

Procedure:
This time, 10 mmols of N-methyl-2,6-dimethyl-4-pyridone were used and 117 g of phosgene were introduced in the course of 2 and a half hours. A yield of 89% of 2-ethylhexanoyl chloride was obtained, after distillation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]([F:23])[F:22])[C:17]([OH:19])=O)[C:10](=[O:24])[CH:9]=2)[CH:7]=1.[NH2:27][C:28]1[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=1.CC(C)N=C=NC(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]([F:23])[F:22])[C:17]([NH:27][C:28]3[CH:29]=[CH:30][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:37][CH:38]=3)=[O:19])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COc1cn(C(CC(F)F)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC(=O)C(CC(F)F)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1
Reaction time: 0.58 h

Procedure:
97.0 mg (253 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4-difluorobutanoic acid (racemate), 42.0 mg (253 μmol) of ethyl 4-aminobenzoate, 36.0 mg (253 μmol) of Oxima and 39.0 μl (253 μmol) of DIC in 2.5 ml of dimethylformamide were reacted according to General Method 5B. The crude product was purified by preparative HPLC [column: Chromatorex C18, 10 μm, 125×30 mm, mobile phase: acetonitrile/0.05% formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3 min 90% acetonitrile)]. Yield: 81.7 mg (60% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.Cl.[NH2:41][CH2:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46]>O1CCCC1>[CH2:48]([O:47][C:45](=[O:46])[CH2:44][CH2:43][CH2:42][NH:41][C:18](=[O:20])[CH2:17][N:16]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH3:49]
Reactant: O=C(O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Reactant: CCOC(=O)CCCN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCNC(=O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Yield: 16.9 %

Procedure:
A solution of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (8.0 g, 0.028 mole), 1,1'-carbonyldiimidazole (4.5 g, 0.028 mole), and anhydrous tetrahydrofuran (100 ml) was stirred at room temperature with a stream of nitrogen bubbling through it for 3 hours. The nitrogen flow was stopped and triethylamine (6.3 g, 0.062 mole) and ethyl 4-aminobutyrate hydrochloride (5.2 g, 0.031 mole) were added all at once. The reaction mixture was stirred under nitrogen over the weekend. The tetrahydrofuran was evaporated and the solid residue triturated in water (100 ml) and filtered off to give 4.7 g (42%) of cake. A 2.3-g portion of the filter cake was recrystallized from isopropyl ether-ethanol to give 1.9 g of white solid, mp 127°-129° C.
Reaction SMILES: [OH:1][C:2]([CH3:17])([CH3:16])[CH2:3][NH:4][C:5]([C:7]1[C:11]([N+:12]([O-])=O)=[CH:10][N:9]([CH3:15])[N:8]=1)=[O:6]>C(O)C.[Pd]>[NH2:12][C:11]1[C:7]([C:5]([NH:4][CH2:3][C:2]([OH:1])([CH3:16])[CH3:17])=[O:6])=[N:8][N:9]([CH3:15])[CH:10]=1
Reactant: Cn1cc([N+](=O)[O-])c(C(=O)NCC(C)(C)O)n1
Agent: [Pd]
Solvent: CCO
Product: Cn1cc(N)c(C(=O)NCC(C)(C)O)n1
Reaction time: 16 h
Yield: 99.5 %

Procedure:
To a solution of N-(2-hydroxy-2-methylpropyl)-1-methyl-4-nitro-1H-pyrazole-3-carboxamide (391 mg, 1.61 mmol) in ethanol was added under an argon atmosphere Pd/C 10% (40 mg, 0.04 mmol) at ambient temperature. The mixture was stirred at that temperature under a hydrogen atmosphere for 16 hours. The catalyst was filtered off and washed with ethanol. The filtrate was concentrated in vacuo to give the title compound as waxy solid (340 mg, 99% yield) which was used without any further purification.