Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[CH3:21])[NH2:17]>C(O)C>[CH3:13][C:14]1[CH:15]=[C:16]([N:17]2[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]2=[O:11])[CH:18]=[CH:19][C:20]=1[CH3:21]
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: Cc1ccc(N)cc1C
Solvent: CCO
Product: Cc1ccc(N2CCC(C(=O)O)C2=O)cc1C
Yield: 86.3 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g; 1.45 mmol) and 3,4-dimethylaniline (0.540 g; 4.36 mmol) in ethanol (3 mL). 1-(3,4-dimethylphenyl)-2-oxopyrrolidine-3-carboxylic acid 0.292 g (86%) was obtained as a white solid.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[N:10]=[C:11]([C:14]([F:17])([F:16])[Cl:15])[N:12]([OH:13])[C:5]=12)([O-])=O.[NH2:18][C:19]1C=CN=C2N=C(C(F)(F)Cl)N(O)C=12.N([O-])=O.[Na+].[C-]#N.[Na+]>>[C:19]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[N:10]=[C:11]([C:14]([F:17])([F:16])[Cl:15])[N:12]([OH:13])[C:5]=12)#[N:18]
Reactant: O=[N+]([O-])c1ccnc2nc(C(F)(F)Cl)n(O)c12
Reactant: Nc1ccnc2nc(C(F)(F)Cl)n(O)c12
Agent: O=N[O-]
Agent: [C-]#N
Agent: [Na+]
Product: N#Cc1ccnc2nc(C(F)(F)Cl)n(O)c12

Procedure:
7-Chloro-1-hydroxy-2-(difluorochloromethyl)-1H-imidazo-(4,5-b)pyridine is reacted with ammonium hydroxide to obtain 7-amino-1-hydroxy-2-(difluorochloromethyl)-1H-imidazo(4,5-b)pyridine which is oxidized to the corresponding 7-nitro-1-hydroxy-2-(difluorochloromethyl)-1H-imidazo(4,5-b)pyridine. Also, the 7-amino-1-hydroxy-2-(difluorochloromethyl)-1H-imidazo(4,5-b)-pyridine is treated with sodium nitrite and subsequently sodium cyanide to obtain the corresponding 7-cyano-1-hydroxy-2-(difluorochloromethyl)-1H-imidazo(4,5-b)pyridine. On treatment with 70 percent sulphuric acid the corresponding 7-carboxy-1-hydroxy-2-(difluorochloromethyl)-1H-imidazo(4,5-b)pyridine is prepared. On further treatment with SF4 and HF, there is obtained 7-(trifluoromethyl)-1-hydroxy-2-(difluorochloromethyl)-1H-imidazo(4,5-b)pyridine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][C:6]1[CH:19]=[C:9]2[NH:10][C:11](=[O:18])[C:12]3[C:17]([N:8]2[N:7]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3.[F:23][C:24]1[CH:29]=[C:28]([Sn](CCCC)(CCCC)CCCC)[CH:27]=[CH:26][N:25]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:23][C:24]1[CH:29]=[C:28]([C:2]2[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=2)[CH2:5][C:6]2[CH:19]=[C:9]3[NH:10][C:11](=[O:18])[C:12]4[C:17]([N:8]3[N:7]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:27]=[CH:26][N:25]=1
Reactant: O=c1[nH]c2cc(Cc3cccc(Br)c3)nn2c2ccccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(F)c1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc(Cc3cccc(-c4ccnc(F)c4)c3)nn2c2ccccc12

Procedure:
A mixture of Example 61B (0.1 g, 0.282 mmol), 2-fluoro-4-(tributylstannyl)pyridine (0.11 g, 0.285 mmol) triethylamine (0.11 g, 1.1 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.039 g, 0.01 mmol) and tri-o-tolylphosphine (0.007 g, 0.023 mmol) in DMF (2 mL) was heated at 100° C. for 6 hr. The mixture was diluted with EtOAc and washed with sat NaHCO3, H2O and brine, then evaporated. The residue was purified by chromatography on silica gel with 20% to 80% ethylacetate in hexane to provide the desired product. 1H NMR (500 MHz, DMSO-d6) δ ppm 4.10 (s, 2 H) 5.75 (s, 1 H) 7.44-7.53 (m, 4 H) 7.68-7.74 (m, 2 H) 7.83-7.88 (m, 2 H) 8.04 (d, J=8.24 Hz, 1 H) 8.11 (d, J=6.71 Hz, 1 H) 8.30 (d, J=5.49 Hz, 1 H).
Reaction SMILES: B(O)O.Br[C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8].[F:13][C:14]([F:26])([F:25])[O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1>>[F:13][C:14]([F:25])([F:26])[O:15][C:16]1[CH:21]=[C:20]([C:5]2[N:12]=[CH:11][CH:10]=[CH:9][C:6]=2[CH:7]=[O:8])[CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: O=Cc1cccnc1Br
Agent: OBO
Product: O=Cc1cccnc1-c1cccc(OC(F)(F)F)c1

Procedure:
2-(3-(trifluoromethoxy)phenyl)nicotinaldehyde was prepared using the general boronic acid coupling procedure with 2-bromonicotinaldehyde and (3-(trifluoromethoxy)phenyl)boronic acid (101 mg, 144 mg theoretical, 70.1%). LC-MS m/z 268 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][C:17]([O:20][C@@H:21]3[CH:26]4[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]4)[CH2:22]3)=[N:18][CH:19]=2)=[CH:10][C:9]=1[N+:29]([O-:31])=[O:30])(C)(C)C.Cl>CCO>[N:23]12[CH2:28][CH2:27][CH:26]([CH2:25][CH2:24]1)[C@@H:21]([O:20][C:17]1[N:16]=[CH:15][C:14]([C:11]3[CH:12]=[CH:13][C:8]([NH2:7])=[C:9]([N+:29]([O-:31])=[O:30])[CH:10]=3)=[CH:19][N:18]=1)[CH2:22]2
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cnc(O[C@H]3CN4CCC3CC4)nc2)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: Nc1ccc(-c2cnc(O[C@H]3CN4CCC3CC4)nc2)cc1[N+](=O)[O-]

Procedure:
The product of Example 36A (100 mg, 0.23 mmol) was treated with HCl (Aldrich, 4 M in dioxane, 2 mL, 8 mmol) in EtOH (5 mL) at ambient temperature for 1 h. The mixture was concentrated and the title compound was purified by chromatography (SiO2, EtOAc:MeOH (v. 2% NH3.H2O), 50:50, Rf. 0.1) as white solid (50 mg, 64%). 1H NMR (500 MHz, MeOH-D4) δ 1.47-1.64 (m, 1 H), 1.65-1.78 (m, 1 H), 1.78-1.91 (m, 1 H), 1.96-2.16 (m, 1 H), 2.15-2.38 (m, 1 H), 2.73-3.05 (m, 5 H), 3.35-3.47 (m, 1 H), 4.96-5.28 (m, 1 H), 7.10 (d, J=8.8 Hz, 1 H), 7.68 (dd, J=8.8, 2.1 Hz, 1 H), 8.32 (d, J=2.1 Hz, 1 H), 8.79 (s, 2 H) ppm. MS (DCl/NH3): 342 (M+H)+.
Reaction SMILES: Br.[CH3:2][C:3]1[N:4]=[C:5]([NH2:20])[S:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:9]=1.C(N(C(C)C)C(C)C)C.[N:30]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:31]=[O:32].CCOCC>C(Cl)Cl.Cl>[CH2:38]([O:37][C:35](=[O:36])[CH2:34][CH2:33][NH:30][C:31]([NH:20][C:5]1[S:6][C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[CH:9]=2)=[C:3]([CH3:2])[N:4]=1)=[O:32])[CH3:39]
Reactant: CCOC(=O)CCN=C=O
Reactant: Cc1nc(N)sc1-c1ccnc(N2CCOCC2)c1
Agent: Br
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCNC(=O)Nc1nc(C)c(-c2ccnc(N3CCOCC3)c2)s1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a stirred suspension of 4-Methyl-5-(2-morpholin-4-yl-pyridin-4-yl)-thiazol-2-ylamine hydrobromide (13b) (0.04 g, 0.112 mmol) in DCM (3 ml) is added ethyldiisopropylamine (0.039 ml, 0.224 mmol) to afford a solution. The reaction mixture is then treated with ethyl 3-isocyanatopropionate (0.015 ml, 0.112 mmol) and heated whilst stirring to 60° C. for 5 hours in a sealed reaction vessel. The solution is diluted with DCM and hydrochloric acid (30 ml, 1N HCl) and the layers separated. The aqueous is adjusted to pH 8/9 and extracted with ethyl acetate (3×25 ml). The organics are combined and dried (MgSO4), filtered and concentrated in vacuo to yield a clear oil. Trituration with ether yields the titled compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=2[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].O>C(Cl)(Cl)Cl>[CH2:17]([N:1]([CH2:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:4]=1)[C:2]1[C:3]2[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=2[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: Nc1c(-c2ccccc2)sc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: c1ccc(CN(Cc2ccccc2)c2c(-c3ccccc3)sc3ccccc23)cc1
Reaction time: 20 h

Procedure:
A mixture of 2.25 g (10 mmol) of 3-amino-2-phenyl benzo(b)thiophene, 3.8 g (22 mmol) of benzyl bromide, 3.6 g (26 mmol) of K2CO3 and 0.5 g (3.3 mmol) of NAI in 25 ml of absolute CHCl3 is refluxed with stirring for 20 hours. After cooling, it is mixed with water, the organic phase is dried and washed with water. After drying over calcium carbonate and elimination of the solvent, there remains 3-dibenzylamino-2-phenyl-benzo(b)thiophene in the form of a crude oily product which crystallises in ethanol: 2.3 g (57% of theory), colourless crystals, mp 97°-101° (ethanol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([CH2:12][O:13][C:14]2[N:19]=[N:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=2)=[CH:10][O:9][N:8]=1.[CH:23]1([NH2:26])[CH2:25][CH2:24]1>>[CH:23]1([NH:26][C:20]([C:17]2[N:18]=[N:19][C:14]([O:13][CH2:12][C:11]3[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:8][O:9][CH:10]=3)=[CH:15][CH:16]=2)=[O:22])[CH2:25][CH2:24]1
Reactant: O=C(O)c1ccc(OCc2conc2-c2ccccn2)nn1
Reactant: NC1CC1
Product: O=C(NC1CC1)c1ccc(OCc2conc2-c2ccccn2)nn1
Yield: 66 %

Procedure:
As described for example 123 g, 6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (70 mg, 0.24 mmol) was converted, using cyclopropylamine instead of isopropylamine, to the title compound (52 mg, 66%) which was obtained as a white solid. MS: m/e=338.4 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N:19]3[CH2:30][CH2:29][C:22]4[N:23]=[C:24]([S:27][CH3:28])[N:25]=[CH:26][C:21]=4[CH2:20]3)[N:14]=2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH:31]OS([O-])=O.[K+]>C1COCC1.O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N:19]3[CH2:30][CH2:29][C:22]4[N:23]=[C:24]([S:27]([CH3:28])=[O:31])[N:25]=[CH:26][C:21]=4[CH2:20]3)[N:14]=2)=[O:12])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CSc1ncc2c(n1)CCN(c1cccc(C(=O)Nc3ccc(C(C)C)cc3)n1)C2
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1ccc(NC(=O)c2cccc(N3CCc4nc(S(C)=O)ncc4C3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred mixture of N-(4-isopropylphenyl)-6-[2-(methylthio)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]pyridine-2-carboxamide (400 mg, 0.953 mmol) in THF (40 ml) and water (16 ml) was added oxone (potassium peroxomonosulfate, 586 mg, 0.953 mmol). After stirring at room temperature for 3 hours, the reaction mixture was quenched by addition of 10% NaHSO3(aq.) (20 ml) and neutralized with sat'd NaHCO3(aq.) (16 ml). The solution was stirred for 20 minutes before extraction with ethyl acetate (2×60 ml). The combined organic extracts were dried (MgSO4), filtered, and concentrated to give the title compound as a light yellow, amorphous solid which was used without further purification (405 mg, 98%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14](S(C4C=CC=CC=4)(=O)=O)[C:15]([C:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH:18]=4)=[CH:16][C:9]=23)[CH:7]=1.[OH-].[Na+].FC(F)(F)C(O)=O>O1CCOCC1.ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH:18]=4)=[CH:16][C:9]=23)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ccnc2c1cc(C1=CCN(C(=O)OC(C)(C)C)CC1)n2S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCNCC3)cc12
Reaction time: 3 h

Procedure:
A mixture of Example 87C (400.0 mg, 0.710 mmol) and 20% sodium hydroxide (0.7 mL) solution in dioxane (6 mL) was heated at 90° C. for 6 hours. The mixture was concentrated and the residue was treated with ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate, filtered and concentrated until most of solvent was evaporated. The solids were filtered, washed with ethyl acetate/heptane, and dried under vacuum to afford the protected intermediate. The intermediate was dissolved in dichloromethane (8 mL) and treated with trifluoroacetic acid (0.547 mL, 7.10 mmol) and the mixture was stirred for 3 hours and concentrated. The residue was dissolved in 2.5 mL methanol and treated with 4 mL 1M hydrogen chloride in ether. After stirring for 15 minutes, the mixture was treated with ether. The solids were filtered, washed with ether, and dried under vacuum to afford the title compound as a hydrochloride salt. 1H NMR (400 MHz, CD3OD) δ 2.93-2.83 (m, 2H), 3.50 (t, J=6.1 Hz, 2H), 3.83 (s, 3H), 4.01-3.96 (m, 2H), 6.65-6.59 (m, 1H), 6.74 (s, 1H), 7.38-7.21 (m, 3H), 7.58 (d, J=6.1 Hz, 1H), 8.36 (d, J=6.1 Hz, 1H). MS (ESI+) m/z 324.1 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[N-:14]=[N+]=[N-].[Na+]>C(#N)C.C1COCC1>[NH2:14][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13]
Reactant: OCCCCCCCCCCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: NCCCCCCCCCCCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
11-bromoundecan-1-ol (the compound 31) (15.1 g) was dissolved in 250 ml of acetonitrile, and 15.7 g of sodium azide was added to that, followed by 18-hour reaction caused by refluxing. After cooled down to room temperature, the solid components were removed by filtration. The solvent of the filtrate was distilled away under reduced pressure, to obtain 13.9 g of a transparent, viscous liquid. Of this liquid, 8.34 g was dissolved in 60 ml of THF distilled from calcium hydride in a nitrogen atmosphere, and was cooled in an ice bath. Lithium aluminum hydride (2.53 g) was then dried, and was dissolved in 250 ml of THF. The resultant was dripped, and was then stirred in an ice bath for one hour. After that, 2.5 ml of ion-exchange water, 3.5 ml of 15 wt % aqueous sodium hydride solution, and 7.5 ml of ion-exchange water were added so as to stop reactions. The precipitate generated was removed by filtration, and the solvent of the filtrate was distilled away under reduced pressure. After the filtrate was dried under reduced pressure, the dried filtrate was dissolved in 60 ml of THF, and the same volume of heptane was added to that. The precipitate generated was collected by filtration, to obtain 5.1 g of a white solid 32.
Reaction SMILES: [OH-].[Na+].C([C:10]1[C:11]([N+:33]([O-:35])=[O:34])=[C:12]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][C:24]3C=CC=CC=3)C=2[N+]([O-])=O)[CH:13]=[CH:14][CH:15]=1)C1C=CC=CC=1.C1(S[CH2:43][C:44]#[N:45])C=CC=CC=1.Cl>CS(C)=O>[CH2:17]([O:16][C:12]1[CH:13]=[C:14]([CH2:43][C:44]#[N:45])[CH:15]=[CH:10][C:11]=1[N+:33]([O-:35])=[O:34])[C:22]1[CH:21]=[CH:20][CH:19]=[CH:23][CH:24]=1
Reactant: N#CCSc1ccccc1
Reactant: O=[N+]([O-])c1c(Cc2ccccc2)cccc1Oc1cccc(Cc2ccccc2)c1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: N#CCc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a suspension of NaOH (68.44 g 1.71 mol, Aldrich, 20-40 mesh beads) in 171 mL of DMSO a solution of benzyl-2-nitrophenyl ether (39.23 g, 0.171 mol) and (phenylthio)acetonitrile (25.54 g, 0.171 mol, Lancaster) in 171 mL of DMSO was added dropwise for 10 min and stirred at r.t. for another 25 min. A mixture of 430 g of ice and 430 g of conc. HCl was added. The product precipitated and crystallized. The reaction mixture was cooled down in a refrigerator and filtered. The precipitate was dried on air (hood!) and recrystallized from EtOAc-hexanes. Yield 32.03 g (70%), mp 78-80° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]2[NH:13][CH2:12][CH:11]([CH2:14][CH3:15])[O:10]2)[CH:6]=[CH:7][CH:8]=1.N1C=CC=CC=1.[C:24](Cl)(=[O:28])[CH2:25][CH2:26][CH3:27]>C(Cl)Cl>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]2[N:13]([C:24](=[O:28])[CH2:25][CH2:26][CH3:27])[CH2:12][CH:11]([CH2:14][CH3:15])[O:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCC1CNC(c2cccc(C(F)(F)F)c2)O1
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)N1CC(CC)OC1c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
Four and seven-tenths grams of 2-(m-trifluoromethylphenyl)-5-ethyl-1,3-oxazolidine was combined with 1.6 g of pyridine in 25 ml of methylene chloride and 2.0 g of butyroyl chloride was added dropwise. The mixture was allowed to stir overnight. The mixture was washed with 50 ml of 5% NaOH and 200 ml of water, dried and stripped on the rotary evaporator. Yield was 6.3 g, nD30 1.5015. The structure was confirmed by NMR and infrared spectroscopy.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:12]=[C:13]([N:17]2[CH:21]=[C:20]([C:22]([OH:24])=O)[N:19]=[N:18]2)[CH:14]=[N:15][CH:16]=1.NC1C=NC=C(F)C=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:55][CH2:56][C:57]([N:59]1[CH2:64][CH2:63][CH:62]([O:65][C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=2[Cl:72])[CH2:61][CH2:60]1)=[O:58]>CN(C=O)C.O>[Cl:72][C:67]1[CH:68]=[CH:69][CH:70]=[CH:71][C:66]=1[O:65][CH:62]1[CH2:61][CH2:60][N:59]([C:57](=[O:58])[CH2:56][NH:55][C:22]([C:20]2[N:19]=[N:18][N:17]([C:13]3[CH:14]=[N:15][CH:16]=[C:11]([F:10])[CH:12]=3)[CH:21]=2)=[O:24])[CH2:64][CH2:63]1
Reactant: NCC(=O)N1CCC(Oc2ccccc2Cl)CC1
Reactant: O=C(O)c1cn(-c2cncc(F)c2)nn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1cncc(F)c1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2Cl)CC1)c1cn(-c2cncc(F)c2)nn1
Reaction time: 0.03 h
Yield: 90.74 %

Procedure:
DIPEA (195 mg, 1.66 mmol) was added to a stirred solution of 1-(5-fluoro-pyridin-3-yl)-1H-[1,2,3]triazole-4-carboxylic acid (70 mg, 0.33 mmol) (prepared by the method used for the synthesis of Intermediate 64, starting from 3-amino-5-fluoropyridine) in DMF (5 mL) followed by HOBt (55 mg, 0.41 mmol) and EDCI (177 mg, 0.92 mmol). After 2 minutes of stirring, 2-amino-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (prepared according to Step 1 and 5 of the General Scheme) (124 mg, 0.4 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. Cold water was then added and the solid was collected to afford 147 mg (90.74% Yield) of 1-(5-fluoro-pyridin-3-yl)-1H-[1,2,3]triazole-4-carboxylic acid {2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 441 (M+1), 98.31%. 1H NMR (300 MHz, DMSO-d6): δ 9.5 (s, 1H), 9.24 (d, 1H), 8.76 (d, 1H), 8.56 (t, 1H), 8.46 (d, 1H), 7.74 (d, 1H), 7.48 (d, 1H), 7.36 (q, 2H), 7.02 (t, 1H), 4.8 (m, 1H), 4.4 (d, 2H), 3.8 (t, 2H), 3.6 (t, 2H), 2.1 (d, 2H), 1.8 (d, 2H).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH:5]([NH:17][C:18]([N:20]1[CH:28]=[C:26]([CH3:27])[C:24](=[O:25])[NH:23][C:21]1=[O:22])=[O:19])[CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])C.Cl>C(O)C.[OH-].[Na+]>[N:20]1([C:18]([NH:17][CH:5]([CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:4]([OH:29])=[O:3])=[O:19])[CH:28]=[C:26]([CH3:27])[C:24](=[O:25])[NH:23][C:21]1=[O:22]
Reactant: CCOC(=O)C(CCCNC(=O)OC(C)(C)C)NC(=O)n1cc(C)c(=O)[nH]c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cn(C(=O)NC(CCCNC(=O)OC(C)(C)C)C(=O)O)c(=O)[nH]c1=O
Reaction time: 12 h

Procedure:
The product from Example 11, 15, is dissolved in ethanol (500 mL) and to this added 2M sodium hydroxide (50 mL) and the reaction stirred for 12 hours. The reaction is neutralized with 2M HCl solution (50 mL) and evaporated to a small volume. This residue is diluted with water (250 mL) and extracted with dichloromethane (4×100 mL), dried, filtered, and evaporated to give a solid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([F:31])=[CH:29][C:25]([C:26]([OH:28])=O)=[C:24]([F:32])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[CH3:76][N:77]([CH3:82])[CH2:78][CH2:79][CH2:80][NH2:81]>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([F:31])=[CH:29][C:25]([C:26]([NH:81][CH2:80][CH2:79][CH2:78][N:77]([CH3:82])[CH3:76])=[O:28])=[C:24]([F:32])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)O)cc3F)ncc21
Reactant: CN(C)CCCN
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CCCNC(=O)c1cc(F)c(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)cc1F
Reaction time: 0.17 h
Yield: 80 %

Procedure:
To a mixture of 0.0606 g (0.134 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2,5-difluoro-benzoic acid (I-232) and 4 mL of dimethylformamide was added 0.0292 g (0.216 mmole) of 1-hydroxybenzotriazole, 0.0784 g (0.207 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.1083 g (0.804 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0202 g (0.198 mmole) of 3-(dimethylamino)-propylamine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0576 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-dimethylamino-propyl)-2,5-difluoro-benzamide (I-237) as a white solid.
Reaction SMILES: Cl[CH:2]1[C:8](=[O:9])[CH:7]2[CH2:10][CH2:11][C:4]([O:12][CH3:13])([CH:5]=[CH:6]2)[C:3]1=[O:14]>C(O)(=O)C.[Zn]>[CH3:13][O:12][C:4]12[CH2:11][CH2:10][CH:7]([CH:6]=[CH:5]1)[C:8](=[O:9])[CH2:2][C:3]2=[O:14]
Reactant: COC12C=CC(CC1)C(=O)C(Cl)C2=O
Agent: [Zn]
Solvent: CC(=O)O
Product: COC12C=CC(CC1)C(=O)CC2=O
Temperature: 95 °C

Procedure:
Zinc dust (1.53 g, 0.0233 mol) is added in one portion to a solution of 3-chloro-1-methoxybicyclo[3.2.2]non-6-en-2,4-dione, prepared in Step 1b, in glacial acetic acid (20 ml) and the mixture is heated to 95° C. for 1¾ hours. The mixture is cooled to room temperature, filtered through diatomaceous earth and the filtrate is concentrated under reduced pressure. The residue is partitioned between ethyl acetate and water, and the aqueous phase is extracted with ethyl acetate. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure. Purification by column chromatography on silica gel, and further purification by preparative reverse-phase HPLC, gives 1-methoxybicyclo[3.2.2]non-6-en-2,4-dione.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:7][C:8]([CH3:28])=[C:9]([C:24]([O:26][CH3:27])=[O:25])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[CH2:29]([O:36][C:37]([NH:39][C@H:40]([C:46]([O:48][CH3:49])=[O:47])[CH2:41][CH2:42][C:43](O)=[O:44])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>ClCCl.C(N(CC)CC)C>[CH2:29]([O:36][C:37]([NH:39][C@H:40]([C:46]([O:48][CH3:49])=[O:47])[CH2:41][CH2:42][C:43]([NH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:7][C:8]([CH3:28])=[C:9]([C:24]([O:26][CH3:27])=[O:25])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:44])=[O:38])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reactant: COC(=O)[C@H](CCC(=O)O)NC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1=C(COCCNC(=O)CC[C@H](NC(=O)OCc2ccccc2)C(=O)OC)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Yield: 74 %

Procedure:
A mixture of 2-[2-aminoethoxymethyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (1.61 g), ("amlodipine"), (S)-4-benzyloxycarbonylamino-4-methoxycarbonylbutanoic acid (1.28 g) [see G. H. L. Nefkens and J. F. Nivard, Rec. Trav. Chim. Pays Bas, 199, 83, 1964], 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.83 g), 1-hydroxybenzotriazole (0.59 g) and triethylamine (0.44 g) in dichloromethane (25 ml) were reacted together as described in Example 5 part (a) to give the title compound (2.0 g) as an essentially pure solid foam which was used directly in Example 1 and Preparation 2 without further purification.