Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[C:10]([N+:22]([O-:24])=[O:23])=[C:11]([CH:15](C(O)=O)[C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>S(=O)(=O)(O)O.C(O)(=O)C>[C:1]([C:9]1[C:10]([N+:22]([O-:24])=[O:23])=[C:11]([CH2:15][C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1cccc(C(C(=O)O)C(=O)O)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(O)Cc1cccc(C(=O)c2ccccc2)c1[N+](=O)[O-]
Yield: 47.9 %

Procedure:
A solution of 11.5 g (0.03 mole) of 2-(3-benzoyl-2-nitrophenyl)propanedioic acid in 50 ml of 20% sulfuric acid and 50 ml of acetic acid was heated at reflux under a nitrogen atmosphere overnight. The solution was concentrated and the residue was made basic with 450 ml of 2N potassium bicarbonate. The mixture was extracted twice with diethylether and the aqueous layer was made acidic with 20 ml of conc. sulfuric acid. The solid which precipitated was collected by filtration, washed with water, recrystallized from aqueous isopropanol to yield 4.1 g (48%) of brown solid, m.p. 160°-162° C.
Reaction SMILES: [H-].[Na+].[Br-].[O:4]1[CH2:9][CH2:8][CH2:7][O:6][CH:5]1[CH2:10][CH2:11][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:31][C:32]1[O:36][C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[N:34][C:33]=1[CH2:43][CH2:44][O:45][C:46]1[CH:53]=[CH:52][C:49]([CH:50]=O)=[CH:48][CH:47]=1>CN(C)C=O>[CH3:31][C:32]1[O:36][C:35]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[N:34][C:33]=1[CH2:43][CH2:44][O:45][C:46]1[CH:47]=[CH:48][C:49](/[CH:50]=[CH:11]\[CH2:10][CH:5]2[O:4][CH2:9][CH2:8][CH2:7][O:6]2)=[CH:52][CH:53]=1
Reactant: c1ccc([P+](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(/C=C\CC2OCCCO2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
Sodium hydride (60% in oil, 0.78 g) was added in limited amounts, at room temperature, to a solution of [2-(1,3-dioxan-2-yl)ethyl]triphenylphosphonium bromide (8.9 g) in N,N-dimethylformamide (100 ml). The mixture was stirred for 30 minutes at the same temperature range, to which was added 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzaldehyde (5.0 g). The mixture was stirred for 15 minutes at room temperature, then for 5 hours at 70° C. The reaction mixture was poured into ice-water, which was acidified with 2N HC1,, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4). The residue was purified by means of a silica gel column chromatography. From the fractions eluted with hexane - ethyl acetate (3:1), (Z)-2-[3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]-2-propenyl]-1,3-dioxane (5.1 g, 77%) was obtained as an oily product.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH2:14]([O:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][C@@H:28]([C:42](O)=[O:43])[NH:29][C:30]([C:32]1[N:33]([CH3:41])[C:34]2[C:39]([CH:40]=1)=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>O.C(OCC)(=O)C.CN(C=O)C>[CH2:14]([O:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][C@@H:28]([C:42]([NH:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:43])[NH:29][C:30]([C:32]1[N:33]([CH3:41])[C:34]2[C:39]([CH:40]=1)=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC[C@@H]1N
Reactant: Cn1c(C(=O)N[C@@H](CCCNC(=O)OCc2ccccc2)C(=O)O)cc2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cn1c(C(=O)N[C@@H](CCCNC(=O)OCc2ccccc2)C(=O)N[C@H]2CCC[C@H]2C(=O)OC(C)(C)C)cc2ccccc21
Temperature: 25 °C
Reaction time: 11 h
Yield: 73.5 %

Procedure:
To a mixture of tert-butyl (1R,2S)-2-aminocyclopentanecarboxylate (0.21 g), DMF (4.0 ml), and N5-[(benzyloxy)carbonyl]-N2-[(1-methyl-1H-indol-2-yl)carbonyl]-L-ornithine (0.40 g) were added HATU (0.40 g) and diisopropylethylamine (0.27 g) under ice-cooling, followed by stirring at room temperature for 11 hours. To the reaction mixture were added ethyl acetate and water under ice-cooling, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer was combined and washed with a 10% aqueous citric acid solution, a saturated sodium bicarbonate solution, water, and saturated brine in this order. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:THF=5:2→2:1) to obtain tert-butyl (1R,2S)-2-({N5-[(benzyloxy)carbonyl]-N2-[(1-methyl-1H-indol-2-yl)carbonyl]-L-ornithyl}amino)cyclopentanecarboxylate (0.41 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([CH2:22][C:23]([CH3:25])=[CH2:24])[C:3]=1[OH:26].ClC1C=CC=C(C(OO)=[O:35])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([CH2:22][C:23]2([CH3:25])[O:35][CH2:24]2)[C:3]=1[OH:26]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)Cc1c(O)c(Cl)cc(F)c1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(O)c2CC2(C)CO2)c1=O
Temperature: 25 °C
Yield: 88.4 %

Procedure:
In 500 ml of chloroform, 50 g of 1-[4-chloro-6-fluoro-3-hydroxy-2-(2 -methyl-2-propenyl)phenyl]-3-methyl-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-2,6-dione was dissolved, to which 30.0 g of m-chloroperbenzoic acid was added, and the reaction was effected at 60° C. for 4.5 :hours. After completion of the reaction, the reaction mixture was cooled to room temperature and subjected to fractionation with a separatory funnel using chloroform and an aqueous solution of sodium sulfite. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and then water, dried and concentrated. The residue was subjected to recrystallization, which afforded 46 g of 1-[4-chloro-6-fluoro-3-hydroxy-2-(2,3-epoxy-2-methylpropyl)phenyl]-3-methyl-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-2,6-dione.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][C:11]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=O)=S)=[CH:4][CH:3]=1.[NH:26]([C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[NH2:27].C([O-])(=O)C.[Na+]>O1CCOCC1.C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[N:26]([C:28]3[N:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[N:27]=2)=[CH:4][CH:3]=1
Reactant: NNc1ncccn1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NC(=S)c2ccc(F)cc2)CC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)cc3)nn2-c2ncccn2)CC1
Temperature: 80 °C

Procedure:
tert-Butyl 4-{[(4-fluorophenyl)carbonothioyl]-carbamoyl}piperidine-1-carboxylate (0.37 g, 1.01 mmol) was mixed with 2-hydrazinylprimidine (0.13 g, 1.21 mmol) and sodium acetate (0.099 g, 1.21 mmol) in 3 ml of 1,4-dioxane and acetic acid (1:1). After heating at 80° C. for 45 min, the solvents were removed under vacuum. The resulting residue was re-dissolved in dichloromethane and washed with saturated sodium bicarbonate solution and water. The organic layers were concentrated, and the residue was purified by column chromatography using a gradient of 0˜50% ethyl acetate in hexanes. LC-MS (m/z): 369.10 [M−56+H]+, 447.14 [M+Na+H]+. 1HNMR (CDCl3, 500 MHz): δ 8.92 (d, J=4.8 Hz, 2H), 8.25-8.28 (m, 2H), 7.38 (t, J=4.8 Hz, 1H), 7.15 (t, J=8.7 Hz, 2H), 4.24-4.27 (br, 2H), 3.94-4.00 (m, 2H), 2.91-2.96 (br, 2H), 2.00-2.10 (br, 4H), 1.52 (s, 9H).
Reaction SMILES: [CH:1]1([CH2:7][C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:12][C:13]1[C:17]([CH2:18][N:19]2[CH:23]=[C:22]([NH2:24])[CH:21]=[N:20]2)=[C:16]([CH3:25])[O:15][N:14]=1>>[CH:1]1([CH2:7][C:8]([NH:24][C:22]2[CH:21]=[N:20][N:19]([CH2:18][C:17]3[C:13]([CH3:12])=[N:14][O:15][C:16]=3[CH3:25])[CH:23]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: O=C(O)CC1CCCCC1
Agent: Cl
Product: Cc1noc(C)c1Cn1cc(NC(=O)CC2CCCCC2)cn1
Yield: 17 %

Procedure:
Prepared as in Example 4-8 from 2-cyclohexylacetic acid and 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (Example 4-1a). Yield 17%. MS M+H calculated 317.6, found 317.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:15]([CH2:16][O:17][CH3:18])[O:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.C(O)C>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:15]([CH2:16][O:17][CH3:18])[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COCC1OCCN(C(=O)OC(C)(C)C)CC1c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCO
Product: COCC1OCCNCC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 191.8 %

Procedure:
To a solution of tert-butyl (6RS,7SR)-6-(3,4-dichlorophenyl)-7-(methoxymethyl)-1,4-oxazepane-4-carboxylate (147 mg) in ethanol (1.5 ml) was added 14.0 N hydrogen chloride-ethanol solution (1.2 ml), and the mixture was stirred at room temperature for 1 hr. The residue obtained by concentration under reduced pressure was crystallized from ethanol-diisopropyl ether to give the title compound (118 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[O:5][C:6]1[CH:18]=[CH:17][C:9]([C:10]([CH:12]=[CH:13][C:14]([OH:16])=[O:15])=[O:11])=[CH:8][CH:7]=1.[CH3:23][C:24]1C=CC(OC2C=CC(C(C=CC(O)=O)=O)=CC=2)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[O:5][C:6]1[CH:18]=[CH:17][C:9]([C:10]([CH:12]=[CH:13][C:14]([O:16][CH2:23][CH3:24])=[O:15])=[O:11])=[CH:8][CH:7]=1
Reactant: O=C(O)C=CC(=O)c1ccc(Oc2ccc(Cl)c(Cl)c2)cc1
Reactant: Cc1ccc(Oc2ccc(C(=O)C=CC(=O)O)cc2)cc1
Product: CCOC(=O)C=CC(=O)c1ccc(Oc2ccc(Cl)c(Cl)c2)cc1

Procedure:
The procedure in Example 17(1) was followed, except that 6.74 g of 3-[4-(3,4-dichlorophenoxy)benzoyl]acrylic acid were used in place of 3-[4-(4-methylphenoxy)benzoyl]acrylic acid, to give 5.42 g of ethyl 3-[4-(3,4-dichlorophenoxy)-benzoyl]acrylate.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:21])=[C:5]([C:22]([NH:24][C@@H:25]([CH3:28])[CH2:26][OH:27])=[O:23])[C:4]1=[O:29])[CH3:2].[OH-].[Na+:31]>>[CH2:1]([N:3]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[CH:11]=2)[C:6]([O-:21])=[C:5]([C:22]([NH:24][C@@H:25]([CH3:28])[CH2:26][OH:27])=[O:23])[C:4]1=[O:29])[CH3:2].[Na+:31]
Reactant: CCn1c(=O)c(C(=O)N[C@@H](C)CO)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Agent: [Na+]
Agent: [OH-]
Product: CCn1c(=O)c(C(=O)N[C@@H](C)CO)c([O-])c2ncc(Cc3ccc(F)cc3)cc21
Yield: 78 %

Procedure:
In manner similar to that described in example 474, from 1-ethyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[(1S)-2-hydroxy-1-methylethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (757 mg, 1.90 mmol described in example 576) and 1 N sodium hydroxide (1.84 mL) was prepared sodium 1-ethyl-7-[(4-fluorophenyl)methyl]-3-({[(1S)-2-hydroxy-1-methylethyl]amino}carbonyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-4-olate (626 mg, 78% yield) as a white solid. 1H NMR (DMSO-d6) δ 10.43 (d, J=7.2 Hz, 1 H), 8.14 (s, 1 H), 7.59 (s, 1 H), 7.33-7.29 (m, 2 H), 7.12-7.07 (m, 2 H), 4.83 (m, 1 H), 4.10-4.03 (m, 4 H), 3.91 (m, 1 H), 3.40 (m, 1 H), 3.25-3.22 (m, 2 H), 1.07-1.03 (m, 5 H); MS m/z 422 (M+23).
Reaction SMILES: [CH2:1]([OH:6])[C:2]([F:5])([F:4])[F:3].C(N(CC)CC)C.[C:14](Cl)(=[O:16])[CH3:15].O>C(OCC)C>[C:14]([O:6][CH2:1][C:2]([F:5])([F:4])[F:3])(=[O:16])[CH3:15]
Reactant: CC(=O)Cl
Reactant: OCC(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)OCC(F)(F)F
Reaction time: 0.33 h
Yield: 72.9 %

Procedure:
85 g (0.85 mol) of trifluoroethanol and 80 ml of diethyl ether were poured to a four-neck flask of 2 liter, and further 129 g (1.27 mmol/1.49 eq) of triethylamine was added thereto. Then, the resultant mixture was ice-cooled and stirred while dropping a solution diluting 100 g (1.27 mol/1.49 eq) of acetyl chloride with 80 ml of diethyl ether by dropping funnel. While dropping, the temperature of the resultant reacted solution was kept between 27 to 35° C. The period of time for dropping was 20 minutes. After that, the resultant mixed solution was stirred for 1.5 hours at room temperature and 350 ml of water was added, then, the reaction was completed. Subsequently, an organic phase was separated by the separatory funnel and dried using magnesium sulfate. Thereafter, purification by distilling was conducted to obtain 88 g of 2,2,2-trifluoroethyl acetate (CH3COOCH2CF3) of which yield was 72.9%.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C1C(=O)N([Br:19])C(=O)C1>CC(N=NC(C#N)(C)C)(C#N)C.C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nccc2ccccc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1nccc2ccccc12
Yield: 17.6 %

Procedure:
To 1-methylisoquinoline (0.99 g, 6.91 mmol), NBS (1.35 g, 1.1 eq) and AIBN (10 mg, catalytic amount) was added CCl4 (15 mL), which was then refluxed for 2 h. The suspended particles were removed by filtration, and washed with CCl4. The organic layers were combined, concentrated under reduced pressure, and separated by column chromatography (30%, ethyl acetate/hexane) to give the title compound (270 mg, Yield: 18%) as a violet solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O[Li].O>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1ccc(CNc2nccc(NCCc3ccc(OC)c(OC)c3)n2)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CCNc2ccnc(NCc3ccc(C(=O)O)cc3)n2)cc1OC
Reaction time: 24 h
Yield: 92.5 %

Procedure:
To a stirred solution of compound 8 (670 mg, 1.59 mmol) in THF (15 mL) at room temperature was added a solution of LiOH.H2O (166 mg, 3.97 mmol) in water (5 mL). After 24 h, the reaction mixture was concentrated, diluted with water and acidified with 2N HCl (pH at 5-6). A precipitate formed, which was separated by filtration, rinsed with water and dried to afford the title compound 9 (600 mg, 1.47 mmol, 93% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ(ppm): AB system (δA=7.87, δB=7.41, J=8.2 Hz, 4H), 7.68-7.58 (m, 1H), 7.12-6.56 (m, 5H), 5.75 (d, J=5.5 Hz, 1H), 4.53 (d, J=6.3 Hz, 2H), 3.74 and 3.72 (2s, 6H), 3.48-3.30 (m, 2H), 2.80-2.60 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH:26]([CH3:28])[O:25][CH:24]([CH3:29])[CH2:23]2)[C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:33][N:34]1[CH:38]=[N:37][CH:36]=[N:35]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:9]#[N:10])([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:23][CH:24]([CH3:29])[O:25][CH:26]([CH3:28])[CH2:27]2)[CH2:33][N:34]2[CH:38]=[N:37][CH:36]=[N:35]2)=[CH:4][CH:3]=1
Reactant: ClCn1cncn1
Reactant: CC1CN(CCCCCCCCCCCC(C#N)c2ccc(Cl)cc2)CC(C)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CN(CCCCCCCCCCCC(C#N)(Cn2cncn2)c2ccc(Cl)cc2)CC(C)O1

Procedure:
This compound (350 mg.) was prepared using the procedure described in Example 2b except using 500 mg. (1.25 mmoles) of 2-(4-chlorophenyl)-13-(2,6-dimethyl-4-morpholinyl)tridecanonitrile, 60 mg (1.35 mmoles) of sodium hydride, 150 mg. (1.25 mmoles) of 1-(chloromethyl)-1,2,4-triazole, and 15 ml. of DMF and was isolated as an amber oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:39])[NH:15][CH2:16][C:17]([C:20]2[O:21][C:22]([C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([OH:32])[CH:26]=3)[CH:24]=2)([CH3:19])[CH3:18])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[CH:24]=[C:20]([C:17]([CH3:18])([CH3:19])[CH2:16][NH:15][C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[O:39])[O:21][C:22]=2[C:33]2[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=2)=[CH:26][C:27]=1[OH:32]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NCC(C)(C)c2cc(-c3ccc(Cl)c(O)c3)c(-c3ccncc3)o2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CNC(=O)C1CCNCC1)c1cc(-c2ccc(Cl)c(O)c2)c(-c2ccncc2)o1
Reaction time: 2 h
Yield: 92.8 %

Procedure:
A solution of the product of Example 12 Step 1 (110 mg, 0.19 mmol) in dichloromethane (5 ml) was treated with trifluoroacetic acid (1 ml). After stirring for 2 h, the mixture was concentrated, re-dissolved in dichloromethane and washed with saturated aqueous sodium hydrogen carbonate solution. The organic solution was dried and concentrated in vacuo to yield the title compound (80 mg, 93%); MS (ES+) m/e 454, 456 [M+H]+.
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C.[CH2:30]([O:37][C:38]([N:40]1[CH2:47][C@@H:46]([OH:48])[CH2:45][C@H:41]1[C:42](O)=[O:43])=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C=O>[CH2:30]([O:37][C:38]([N:40]1[CH2:47][C@@H:46]([OH:48])[CH2:45][C@H:41]1[C:42]([NH:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:43])=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(O)[C@@H]1C[C@H](O)CN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)N
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)[C@@H]1C[C@H](O)CN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 24.7 %

Procedure:
4.56 g (16.58 mmol) of diphenylphosphoryl azide, 1.50 g (20.55 mmol) of t-butylamine and 2.78 g (27.80 mmol) of triethylamine were successively added, whilst ice-cooling, to a solution of 3.68 g (13.90 mmol) of (4S)-1-benzyloxycarbonyl-4-hydroxy-L-proline in 30 ml of dimethylformamide, and the mixture was stirred for 5 hours. At the end of this time, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic extract was washed with a 10% w/v aqueous solution of citric acid, with a 10% w/v aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which the resulting mixture was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was recrystallized from a mixture of methylene chloride and diethyl ether, to give 1.10 g of the title compound as colorless crystals, melting at 129°-130° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[C:18]([O:22][C:23](=[O:32])[NH:24][CH:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1)([CH3:21])([CH3:20])[CH3:19]>ClCCl.CN(C)C=O>[C:18]([O:22][C:23](=[O:32])[NH:24][CH:25]1[CH2:26][CH2:27][CH:28]([NH:31][C:4]([C:3]2[C:2]([Cl:1])=[N:10][CH:9]=[C:8]([F:11])[CH:7]=2)=[O:6])[CH2:29][CH2:30]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: O=C(O)c1cc(F)cnc1Cl
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(F)cnc2Cl)CC1
Reaction time: 4 h
Yield: 39.5 %

Procedure:
2-Chloro-5-fluoro nicotinic acid (3.00 g, 0.017 mol) (see Preparation 41), was dissolved in dichloromethane (100 ml) and N,N-dimethylformamide (1 drop) was added, followed by oxalyl chloride (3.0 ml, 0.034 mol). The reaction mixture was held at room temperature for 4 hours, after which time the solvent was removed in vacuo. The residue was suspended in dichloromethane (100 ml) and triethylamine (5 ml) added followed by addition of (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (5.40 g, 0.026 mol) (Preparation 42a). The reaction mixture was then held under an atmosphere of nitrogen at room temperature for a further 18 hours. The reaction mixture was then washed with water (100 ml) and the organic phase dried over anhydrous magnesium sulphate. The solvent was removed in vacuo, and the residue triturated with ethyl acetate/pentane: (1:1, by volume, 10 ml) giving {4-[(2-chloro-5-fluoro-pyridine-3-carbonyl)amino]-cyclohexyl}-carbamic acid tert-butyl ester (2.5 g, 80:20 syn:anti) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26](I)[CH:25]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([Br:23])[CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Brc1cccc(I)c1
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc(Br)c2)CC1
Temperature: 80 °C

Procedure:
A stirred mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (prepared as described in Tetrahedron Letters 2000, 3705-3708; 6.52 g, 21.1 mmol), 1-bromo-3-iodobenzene (4.05 mL, 31.8 mmol), bis-(triphenyl-phosphine)-palladium(II) chloride (892 mg, 1.27 mmol), K2CO3 (8.7 g, 63 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (704 mg, 1.27 mmol) in 120 mL dimethylformamide is heated at 80° C. under argon for 14 h. The mixture is cooled to RT, dimethylformamide is removed in vacuo. After addition of brine, the aqueous layer is extracted three times with CH2Cl2. The combined organic extracts are dried (Na2SO4) and evaporated in vacuo. Flash chromatography of the residue (SiO2, hexane/ethyl acetate) affords 4-(3-bromo-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester as a colourless viscous resin: MS 338.2/340.2 [M+H]+; retention time 8.01 min (HPLC, Nucleosil C18; 5→100% CH3CN in H2O within 8 min, then 100% CH3CN for 2 min).
Reaction SMILES: [OH-:1].[Na+].Cl[C:4]1[C:9]([N:10]2[CH2:15][CH2:14][N:13]([CH:16]([CH3:18])[CH3:17])[CH2:12][CH2:11]2)=[N:8][CH:7]=[CH:6][N:5]=1>O.CS(C)=O>[CH:16]([N:13]1[CH2:14][CH2:15][N:10]([C:9]2[C:4](=[O:1])[NH:5][CH:6]=[CH:7][N:8]=2)[CH2:11][CH2:12]1)([CH3:18])[CH3:17]
Reactant: CC(C)N1CCN(c2nccnc2Cl)CC1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)N1CCN(c2ncc[nH]c2=O)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of NaOH (5.4 g, 125 mmol) in a mixture of water/DMSO (1: 1; 15 mL) was added 2-chloro-3-(4-isopropylpiperazin-1-yl)pyrazine (2.66 g, 12 mmol; from Step 1). After being stirred at 80° C. for 2 h, the dark red solution was cooled to room temperature, extracted with EtOAc overnight to give, after drying and solvent removal in vacuo, 2.6 g (70%) of the title compound as a white solid. HPLC purity: 87%. MS m/z 223 (M+H)+. HRMS m/z calcd for C11H18N4O (M)+ 222.1481, found 222.1489.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:14][C:15]#[N:16]>>[N:12]1[CH:11]=[CH:10][CH:9]=[N:8][C:7]=1[N:1]1[CH2:6][CH2:5][N:4]([CH2:14][C:15]#[N:16])[CH2:3][CH2:2]1
Reactant: N#CCBr
Reactant: c1cnc(N2CCNCC2)nc1
Product: N#CCN1CCN(c2ncccn2)CC1

Procedure:
The title compound is synthesized by coupling of 2-piperazin-1-yl-pyrimidine and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a white solid; ES-MS: M+=204.2: 1HNMR(DMSO-d6) 8.35 (d, 2H), 6.60 (t, 1H), 3.80-3.70 (m, 6H), 2.45-2.40 (m, 4H).