Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([OH:6])=[O:5].[C:14](OC)(OC)(OC)C>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: Cc1cccc([N+](=O)[O-])c1C(=O)O
Reactant: COC(C)(OC)OC
Product: COC(=O)c1c(C)cccc1[N+](=O)[O-]
Temperature: 22.5 °C
Reaction time: 2 h

Procedure:
A mixture of 2-methyl-6-nitrobenzoic acid (300.0 g, 1.66 moles, from Acros Organics, Morris Plains, N.J.) and trimethyl orthoacetate (298.3 g, 2.48 moles, from Aldrich Chemicals, Milwauke, Wis.) was charged into a 3-L 3-necked flask at about 20-25° C. under nitrogen. The reaction mixture was gradually heated and the low-boiling point components generated during the reaction were distilled off to an internal temperature of 95-100° C. After 2 hours, the reaction mixture was cooled to 20-25° C. over 1-2 hours. After heptane (1.50 L, from Aldrich Chemicals) was charged into the reaction mixture over 1.0-1.5 hours, the reaction mixture was seeded with methyl 2-methyl-6-nitrobenzoate (0.5 g) when it became turbid. The suspension was cooled to 0-5° C. over 0.5-1 hour and kept at 0-5° C. for another 1.5-2 hours. The solid was collected by filtration under vacuum, washed with heptane (3x300 mL), and dried to a constant weight in a tray at 30-35° C. under a vacuum at 100-120 torr. The yield of methyl 2-methyl-6-nitrobenzoate was 292.0 g (91%), based on 300.0 g of 2-methyl-6-nitrobenzoic acid. The product was found to have a purity of >99% measured by HPLC based on area percentage, and a water content of <0.1% measured by Karl Fisher titration.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Br[C:10]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:10]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Br
Reactant: Nc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(O)c1cccc([N+](=O)[O-])c1Nc1ccccc1Cl

Procedure:
A mixture of the known compounds 2-chloroaniline (6.3 g., 0.05 mole) and 2-bromo-3-nitrobenzoic acid (12.3 g., 0.05 mole) was refluxed overnight with 11 g. of potassium carbonate and 0.5 g. of copper-bronze in 125 ml. of ethanol. The ethanol was then removed by evaporation and the residue suspended in water. After filtration, the filtrate was acidified. A solid slowly crystallized, providing the compound 2-(2-chloroanilino)-3-nitrobenzoic acid, m.p. 213°-215° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:9]1.C[O:24][C:25](=[O:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][CH2:34]Cl>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:34][CH2:33][O:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[C:25]([OH:36])=[O:24])[CH2:19][CH2:18]2)=[CH:9]1
Reactant: COC(=O)c1ccccc1OCCCl
Reactant: c1ccc2c(c1)c(C1CCNCC1)cn2CCC1OCCO1
Product: O=C(O)c1ccccc1OCCN1CCC(c2cn(CCC3OCCO3)c3ccccc23)CC1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 3 g (0.01 mol) of 1-(2-[1,3]dioxolan-2-yl-ethyl)-3-piperidin-4-yl-1H-indole and 2.8 g (0.013 mol) of 2-(2-chloro-ethoxy)-benzoic acid methyl ester. The crude mixture was purified by flash chromatography over silica gel affording 1.86 g (40% of yield) of 2-(2-{4-[1-(2-[1,3]dioxolan-2-yl-ethyl-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:13])[CH2:9][N:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].O[C:19]1[C:20]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH2:31])=[O:30])[C:21]=2[N:22]=[N:23][N:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:13][C:19]2[C:20]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH2:31])=[O:30])[C:21]=3[N:22]=[N:23][N:24]=2)[CH2:9][N:10]([CH3:11])[CH3:12])=[CH:4][C:3]=1[C:14]([F:15])([F:16])[F:17]
Reactant: CN(C)C[C@@H](N)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: NC(=O)c1cccc2c(O)nnnc12
Product: CN(C)C[C@@H](Nc1nnnc2c(C(N)=O)cccc12)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
Compound 13 was prepared following general synthetic scheme 7 wherein (S)-1-(4-Chloro-3-(trifluoromethyl)phenyl)-N2,N2-dimethylethane-1,2-diamine was reacted with 4-hydroxybenzo[d][1,2,3]triazine-8-carboxamide to give the title compound. LC-MS [439 (M+1)], 1H NMR (400 MHz, DMSO-d6): δ 9.61 (brs, 1H), 9.23 (s, 1H), 9.17 (s, 1H), 8.58 (s, 2H), 8.19 (s, 1H), 8.08 (d, J=8.0 Hz, 2H), 7.92 (s, 1H), 7.78 (d, J=7.2 Hz, 1H), 6.34 (s, 1H), 3.83-3.63 (m, 2H), 2.91 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])[N:8]=1.S(=O)(=O)(O)[OH:22].[OH-].[Na+]>>[F:20][C:2]([F:1])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH2:17])=[O:22])[N:8]=1
Reactant: N#CCCCCn1ccc(NC(N)=NCC(F)(F)F)n1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)CCCCn1ccc(NC(N)=NCC(F)(F)F)n1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
5-[3-(2-[2,2,2-Trifluoroethyl]guanidino)pyrazol-1-yl]valeronitrile (13 g.), was added over 10 minutes to concentrated sulphuric acid (65 ml.) with stirring. The resulting solution was kept at 20° for 18 hours then diluted with ice (300 ml.) and basified to pH 9 with 10.8N sodium hydroxide. The mixture was extracted with EtOAc (3×200 ml.) and the extract was dried (MgSO4) and evaporated in vacuo to an oil which crystallised. The crude material was recrystallised from EtOAc to give 5-[3-(2-[2,2,2-trifluoroethyl]guanidino)pyrazol-1-yl]valeramide, m.p. 130°. The maleic acid salt was prepared in acetone, m.p. 183°-184°.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=1.[NH2:20][C:21]1[C:25]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:24][NH:23][N:22]=1>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:22]3[N:23]=[CH:24][C:25]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)=[C:21]3[N:20]=2)=[CH:5][CH:4]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)cc1
Reactant: Nc1n[nH]cc1-c1ccncc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(-c4ccncc4)c3n2)cc1
Yield: 45.6 %

Procedure:
Reaction of 1-(4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (142 mg, 0.5 mmol), prepared from commercially available 4-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (93 mg, 46%). MS (ISP) 409.2 [(M+H)+]; mp 261° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[N+:12]([C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13].C(N(C(C)C)CC)(C)C>CO>[Cl:1][C:2]1[N:3]=[C:4]([O:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=2)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2occc2n1
Reactant: O=[N+]([O-])c1cccc(O)c1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cccc(Oc2nc(Cl)nc3ccoc23)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.7 %

Procedure:
6.4 g (33.9 mmol) of 2,4-dichlorofuro[3,2-d]pyrimidine (see: International Publication Number WO 2008073785 and WO 2008152394) was dissolved in 32 mL of methanol, and 5.7 g (40.6 mmol) of 3-nitrophenol and 12 mL (67.7 mmol) of diisopropylethylamine were added thereto, and stirred for 24 hours at room temperature. Upon the completion of the reaction, the resulting solid was filtered and dried over under a reduced pressure to obtain 6.3 g of the title compound (yield: 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([C:8]2[CH:13]=[C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:11]=[C:10]([N:25]3[C:29](=[O:30])[CH2:28][CH2:27][C:26]3=[O:31])[N:9]=2)[CH:7]=1.[O:33]1CCCC1.[OH-].[Na+].Cl>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([C:8]2[CH:13]=[C:12]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=3)[N:11]=[C:10]([NH:25][C:26](=[O:31])[CH2:27][CH2:28][C:29]([OH:30])=[O:33])[N:9]=2)[CH:7]=1
Reactant: Cc1ccc(Cl)cc1-c1cc(Nc2ccc(C(F)(F)F)cc2)nc(N2C(=O)CCC2=O)n1
Reactant: C1CCOC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(Cl)cc1-c1cc(Nc2ccc(C(F)(F)F)cc2)nc(NC(=O)CCC(=O)O)n1
Reaction time: 1 h

Procedure:
To a stirred solution of 1-[4-(5-chloro-2-methyl-phenyl)-6-(4-trifluoromethyl-phenylamino)-pyrimidin-2-yl]-pyrrolidine-2,5-dione (0.15 g, 0.33 mmol), tetrahydrofuran (15 ml), and water (15 ml), cooled in an ice bath, was added aqueous sodium hydroxide solution (0.25 M, 4.0 ml, 1.0 mmol) dropwise. After stirring for 1 hour, hydrochloric acid (0.25 M, 8.0 ml, 2.0 mmol) was added dropwise. Evaporation of the tetrahydrofuran under reduced pressure and filtration provided the title compound as hydrochloride salt (93% yield). 1H NMR (CD3OD) δ 2.48 (s, 3H, CH3), 2.73-2.76 (m, 2H, CH2), 2.89-2.92 (m, 2H, CH2), 6.81 (s, 1H, Ar), 7.45 (d, 1H, J=8.3 Hz, Ar), 7.54 (dd, 1H, J=8.3 Hz, J=2.2 Hz, Ar), 7.60 (d, 1H, J=2.2 Hz, Ar), 7.76 (d, 2H, J=8.6 Hz, Ar), 8.04 (d, 2H, J=7.9 Hz, Ar).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[CH3:19][CH:20]([C:24]([NH:26][CH2:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=1)=[O:25])[C:21](O)=[O:22]>>[Cl:34][C:32]1[CH:33]=[C:28]([CH:29]=[C:30]([Cl:35])[CH:31]=1)[CH2:27][NH:26][C:24](=[O:25])[CH:20]([CH3:19])[C:21]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:22]
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Reactant: CC(C(=O)O)C(=O)NCc1cc(Cl)cc(Cl)c1
Product: CC(C(=O)NCc1cc(Cl)cc(Cl)c1)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21

Procedure:
The title compound, MS: m/e=496.2 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and 2-methyl-N-(3,5-dichloro-benzyl)-malonamic acid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[I:12]N1C(=O)CCC1=O>CN(C)C=O.O>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(I)cc(C(=O)O)c1N
Temperature: 60 °C
Yield: 43.5 %

Procedure:
2-Amino-3-methylbenzoic acid (10 g, 66 mmol) was dissolved in 70 mL of N,N-dimethyl-formamide (DMF) and treated with N-iodosuccinimide (16.4 g, 73 mmol). The mixture was heated at 60° C. for 17 hours and allowed to cool to 25° C. The mixture was diluted with water (150 mL and filtered. The air-dried solid was dissolved in ethyl acetate (200 mL) and dried over magnesium sulfate. Evaporation of the solvent provided the title compound of Step A (7.95 g). 1H NMR (CDCl3): δ 7.87 (1H), 7.44 (1H), 2.09 (3H).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:22]([O:24][P:25]([C:30]1[C:31](=[O:45])[NH:32][C:33]2[C:38]([CH:39]=1)=[CH:37][C:36]([S:40]([NH2:43])(=[O:42])=[O:41])=[C:35]([Cl:44])[CH:34]=2)(=[O:29])[O:26][CH2:27][CH3:28])[CH3:23].C1CCN2C(=NCCC2)CC1.Cl>C1COCC1>[CH2:27]([O:26][P:25]([C:30]1[C:31](=[O:45])[NH:32][C:33]2[C:38]([CH:39]=1)=[CH:37][C:36]([S:40]([NH:43][C:1](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:41])=[O:42])=[C:35]([Cl:44])[CH:34]=2)(=[O:29])[O:24][CH2:22][CH3:23])[CH3:28]
Reactant: O=C(O)c1ccccc1
Reactant: CCOP(=O)(OCC)c1cc2cc(S(N)(=O)=O)c(Cl)cc2[nH]c1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1cc2cc(S(=O)(=O)NC(=O)c3ccccc3)c(Cl)cc2[nH]c1=O
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A solution of benzoic acid (111 mg, 0.912 mmol) in 3 ml of anhydrous THF containing 173 mg (1.06 mmol) of carbonyldiimidazole is stirred for 45 minutes at reflux. In parallel, there is prepared a suspension of 300 mg (0.760 mmol) of the compound obtained in Step A in 3 ml of THF, to which there is added 0.125 ml (0.836 mmol) of DBU. Stirring is carried out for 15 minutes at room temperature, and then the benzoic acid solution prepared above is added thereto. The mixture is heated for 3 hours at 60° C. The reaction mixture is cooled in an ice bath and rendered acidic by the addition of 1N HCl. Extraction is carried out with ethyl acetate. The organic phases are combined and washed with a saturated NaCl solution and then dried over MgSO4. After evaporation, the residue is chromatographed over a silica column whilst eluting with a gradient (95/5-90/10) of CH2Cl2/MeOH. The title product is obtained in the form of a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]([O:16][CH2:17][CH3:18])=[O:15])([O-])=O.O1CCCC1>C(O)C.[Pd]>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1cccc2c([N+](=O)[O-])cccc12
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc2c(N)cccc12

Procedure:
A solution of ethyl 5-nitro-1-naphthoate (3.304 g, 13.47 mmol) in ethanol (10 ml)-tetrahydrofuran (20 ml) was hydrogenated under normal temperature and normal pressure using 10% palladium/carbon (containing water by 50%) (0.5 g) as a catalyst until the starting material disappeared. The catalyst was filtered off and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1−3/1) to give the objective substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[Cl:31][C:32]1[CH:33]=[C:34]([NH2:38])[CH:35]=[CH:36][CH:37]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:38][C:34]1[CH:35]=[CH:36][CH:37]=[C:32]([Cl:31])[CH:33]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccccc1
Reactant: Nc1cccc(Cl)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Nc1cccc(Cl)c1)c1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Solid 5-bromo-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 5, method B; 200 mg, 0.65 mmol) was added to a stirred suspension of CDI (106 mg, 0.65 mmol) in THF (6 ml) under nitrogen at 20° C. The reaction mixture was stirred at room temperature for 10 min. 3-Chlorobenzenamine (83 mg, 0.65 mmol) was then added dropwise. After refluxing for 14 h, the reaction mixture was concentrated to obtain crude product. The crude product was purified by silica gel chromatography eluting with hexane:ethyl acetate (10:1) to yield the title compound. 110 mg.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[C:14](=[O:15])[CH2:13][CH2:12][C@H:11]1[CH:16]=[CH:17][CH:18]([OH:26])[CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.[OH-].[Na+].Cl>CO.CCOCC>[CH:20]1([CH2:19][CH:18]([OH:26])[CH:17]=[CH:16][C@@H:11]2[CH2:12][CH2:13][C:14](=[O:15])[C@H:10]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:27])=[O:2])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)CCCCCC[C@@H]1C(=O)CC[C@H]1C=CC(O)CC1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: O=C(O)CCCCCC[C@@H]1C(=O)CC[C@H]1C=CC(O)CC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of trans-2-(4-cyclohexyl-3-hydroxy-1-butenyl)-5-oxocyclopentaneheptanoic acid methyl ester, Isomer A (11.56 g), described in Example 10, in 53 ml of methanol is added 10% NaOH (18.3 ml). The mixture is stirred at room temperature for 2 hr then rendered acidic with 10% HCl and diluted with ether. The ether solution is washed with water, dried and evaporated to yield Isomer A of the title compound, νmaxCHCl3 1730, 1710 cm-1.
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:3]1.O[CH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]1>>[F:19][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:12]=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=2)[C:8]([O:10][CH2:21][CH2:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:9])[CH2:3]1
Reactant: O=C(O)[C@](O)(c1ccc(Br)cc1)[C@@H]1CCC(F)(F)C1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Product: O=C(OCCC1CCNCC1)[C@](O)(c1ccc(Br)cc1)[C@@H]1CCC(F)(F)C1

Procedure:
Using (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)acetic acid and t-butyl 4-(2-hydroxyethyl)tetrahydro-pyridine-1(2H)-carboxylate, the title compound was prepared by a method similar to steps 2 and 3 of Referential Example 12.
Reaction SMILES: [CH3:1][CH:2]([OH:17])[C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.O>[Pd].CO>[CH3:1][CH:2]([OH:17])[C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: CC(O)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CC(O)c1ccc(-c2ccc(N)cc2)o1
Yield: 70.9 %

Procedure:
A mixture of 79 g (0.34 mole) of the compound of Example I, 1 tsp. of 5% Pd/C, 50% H2O, and 500 ml of methanol was shaken under hydrogen pressure with the theoretical amount of H2 being absorbed. The catalyst was removed by filtration, and the filtrate was taken to near dryness on a Calab evaporator. The resulting solid was filtered and air-dried to yield 49 g (71%) of title compound. An analytical sample was prepared by recrystallizing a sample twice from ethanol/charcoal, m.p. 100°-104°.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][O:11][C:12](=[O:20])[CH2:13]/[CH:14]=[CH:15]/[CH2:16][C:17](O)=[O:18]>>[C:1]1([CH2:7][CH2:8][NH:9][C:17]([CH2:16]/[CH:15]=[CH:14]/[CH2:13][C:12]([O:11][CH3:10])=[O:20])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCc1ccccc1
Reactant: COC(=O)C/C=C/CC(=O)O
Product: COC(=O)C/C=C/CC(=O)NCCc1ccccc1

Procedure:
The sub-title compound was prepared from benzeneethanamine and E-hex-3-enedioic acid monomethyl ester using the procedure of Example 6(a) mp 69°-70°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[O:11][CH2:12][C:13]#[N:14])[C:5]([Cl:19])=[CH:4][N:3]=1.[CH2:20]([N:22]1[CH2:28][CH2:27][C:26]2[CH:29]=[C:30]([NH2:33])[CH:31]=[CH:32][C:25]=2[CH2:24][CH2:23]1)[CH3:21]>>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[O:11][CH2:12][C:13]#[N:14])=[N:7][C:2]([NH:33][C:30]2[CH:31]=[CH:32][C:25]3[CH2:24][CH2:23][N:22]([CH2:20][CH3:21])[CH2:28][CH2:27][C:26]=3[CH:29]=2)=[N:3][CH:4]=1
Reactant: CCN1CCc2ccc(N)cc2CC1
Reactant: N#CCOc1ccccc1Nc1nc(Cl)ncc1Cl
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4OCC#N)n3)cc2CC1

Procedure:
The title compound was prepared from [2-(2,5-dichloropyrimidin-4-ylamino)-phenoxy]acetonitrile and 3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine in an analogous manner to Example 927 (microwave: 120° C., 2 hours) to afford a white solid (17 mg, 22%). Mp: 153-6° C. LCMS (m/e) 449 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.46 (d, J=9 Hz, 1H), 8.10 (s, 1H), 7.63 (s, 1H), 7.35 (s, 1H), 7.23 (d. J=8 Hz, 1H), 7.15 (m, 2H), 7.06 (m, 2H), 6.94 (s, 1H), 4.90 (s, 2H), 2.92 (m, 4H), 2.71-2.55 (m, 6H), 1.14 (t. J=7 Hz, 3H).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:21][C@H:22]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:23][N:24]4C(=O)C5C(=CC=CC=5)C4=O)=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.NN>C(O)C>[NH2:24][CH2:23][C@H:22]([NH:21][C:19]([C:15]1[N:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:10]2=[N:17][C:16]=1[CH3:18])=[O:20])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@@H](CN1C(=O)c2ccccc2C1=O)c1ccccc1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@@H](CN)c1ccccc1
Temperature: 85 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a suspension of 300 mg of 8-(cyclohexylmethoxy)-N-[(1R)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-phenylethyl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide in 6 ml of ethanol was added 0.13 ml of hydrazine monohydrate, followed by stirring at 85° C. for 1 hour. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 200 mg of N-[(1R)-2-amino-1-phenylethyl]-8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([C@H:8]1[CH2:13][CH2:12][C@H:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]3[CH:21]=[C:22]([F:26])[CH:23]=[CH:24][CH:25]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)[CH2:6][CH3:7].[C:27](Cl)(=[O:29])[CH3:28].Cl>[N+](C1C=CC=CC=1)([O-])=O.C1(C)C=CC=CC=1>[C:27]([C:23]1[CH:24]=[CH:25][C:20]([C@H:17]2[CH2:18][CH2:19][C@H:14]([C@H:11]3[CH2:10][CH2:9][C@H:8]([CH2:5][CH2:6][CH3:7])[CH2:13][CH2:12]3)[CH2:15][CH2:16]2)=[CH:21][C:22]=1[F:26])(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3cccc(F)c3)CC2)CC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O=[N+]([O-])c1ccccc1
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(C(C)=O)c(F)c3)CC2)CC1
Temperature: 0 °C

Procedure:
Successively, anhydrous aluminum chloride (30.8 g, 0.23 mol) was dissolved in nitrobenzene (150 ml), followed by adding to the solution, the total quantity of the above compound 3-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]fluorobenzene (38.7 g) at room temperature, dissolving the mixture together with stirring, adding acetyl chloride (27.3 g, 0.348 mol) over 15 minutes, reacting the mixture on heating at a reaction temperature of 35°-40° C. for 2 hours, adding the reaction solution after completion of the reaction to a mixture of 6N hydrochloric acid (50 ml) with ice water (500 g) to subject them to decomposition reaction, adding toluene (500 ml) to extract the resulting oily layer, washing the extract solution with an aqueous solution of sodium hydrogen carbonate, further washing it with water until the washing water became neutral, distilling off toluene and nitrobenzene and recrystallizing the residue from ethyl acetate to obtain 2-acetyl-5-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]fluorobenzene (a compound of the formula (VII) wherein R1 =C3H7 and R"=CH3) (23.8 g). This product exhibited liquid crystal phases and had a crystal-nematic phase transition point (C-N point) of 90.5° C. and a nematic phase-isotropic liquid phase transition point (N-I point) of 204.7° C. (iii) Successively, the compound 2-acetyl-5-[trans-4-(trans-4-propylcyclohexyl) cyclohexyl]fluorobenzene (23.8 g) was added to diethylene glycol (100 ml), followed by agitating the mixture, adding hydrazine hydrate (17.9 g) and potassium hydroxide (20.1 g), gradually raising the temperature with stirring to react the mixture at 180° C. for 3 hours, allowing the resulting material to cool down to room temperature, adding water (500 ml), extracting the deposited crystals with toluene (100 ml), washing the extract solution with water, drying it over anhydrous sodium sulfate, distilling off toluene and recrystallizing from ethyl acetate to obtain 2-ethyl-5-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]fluorobenzene (15.2 g).