Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].ClC1C=CC=C(Cl)C=1NC1C=CC=CC=1C(=O)C(OC)=O>>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([OH:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(=O)c1ccccc1Nc1c(Cl)cccc1Cl
Agent: COC(=O)C(=O)c1ccccc1Nc1c(Cl)cccc1Cl
Product: CCOC(=O)C(O)c1ccccc1Nc1c(Cl)cccc1Cl
Yield: 90.6 %

Procedure:
The same procedures as in the Step 3 of Example 5 were repeated except that 6.8 g of ethyl 2-(2,6-dichloroanilino)-phenylglyoxylate were employed instead of 6.5 g of methyl 2-(2,6-dichloroanilino)phenylglyoxylate, thereby yielding 6.2 g of ethyl 2-(2,6-dichloroanilino)phenylglycolate. m.p. 155°-156° C. Yield: 91% of theoretical amount
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:16]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:28](B(O)O)=[CH:27][CH:26]=[N:25]2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[C:28]([C:2]3[CH:3]=[CH:4][C:5]4[N:9]=[CH:8][N:7]([C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=5)[C:6]=4[CH:16]=3)=[CH:27][CH:26]=[N:25]2)=[CH:22][CH:23]=1
Reactant: Brc1ccc2ncn(-c3ccccc3)c2c1
Reactant: OB(O)c1ccnn1-c1ccc(F)cc1
Product: Fc1ccc(-n2nccc2-c2ccc3ncn(-c4ccccc4)c3c2)cc1

Procedure:
The title compound, off-white solid (39 mg, 30%), MS (ISP) m/z=355.2 [(M+H)+], mp 201° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-phenyl-1H-benzo[d]imidazole (intermediate E) (100 mg, 366 μmol) and 1-(4-fluoro-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate A) (98.0 mg, 476 μmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[CH:11][N:12]=[C:13]([NH:16][C:17](=O)[CH3:18])[CH:14]=3)[CH:9]([CH3:20])[O:8][C:6]=2[CH:7]=1.[H-].[Na+].[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[CH:11][N:12]=[C:13]([N:16]([CH2:29][C:28]4[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=4)[CH2:17][C:18]4[CH:2]=[CH:7][C:6]([O:8][CH3:9])=[CH:5][CH:4]=4)[CH:14]=3)[CH:9]([CH3:20])[O:8][C:6]=2[CH:7]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CC(=O)Nc1cc2c(cn1)C(C)Oc1cc(Cl)ccc1-2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc3c(cn2)C(C)Oc2cc(Cl)ccc2-3)cc1
Reaction time: 0.17 h
Yield: 46.2 %

Procedure:
To a stirred solution of N-(8-chloro-5-methyl-5H-chromeno[3,4-c]pyridin-2-yl)acetamide (250 mg, 0.866 mmol) in DMF (25 mL) was added NaH (62.3 mg, 2.60 mmol) at room temperature and stirred for 10 min. 4-Methoxybenzyl chloride (0.236 mL, 1.732 mmol) was added dropwise and stirred at room temperature overnight. The reaction was quenched with ice and extracted with ethyl acetate (25 mL). The organic layer was separated, washed with water (25 mL), brine (25 mL), dried over sodium sulphate and concentrated under reduced pressure to afford 8-chloro-N,N-bis(4-methoxybenzyl)-5-methyl-5H-chromeno[3,4-c]pyridin-2-amine (200 mg, 0.20 mmol, 24% yield) as a yellow oil. This was taken to the next step without purification. LCMS (ESI) m/e 487.2 [(M±H)+, calcd for C29H28ClN2O3 487.2]; LC/MS retention time (Method C): tR=2.52 min.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.[N:13]1([CH2:18][CH2:19]O)[CH:17]=[CH:16][N:15]=[CH:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOC(C)=O>[N:13]1([CH2:18][CH2:19][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:12])[CH2:7][CH2:8][O:9]3)=[CH:4][CH:3]=2)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: O=C1CCOc2cc(O)ccc21
Reactant: OCCn1ccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1CCOc2cc(OCCn3ccnc3)ccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 29.7 %

Procedure:
Under N2, a solution of 2.0 g (0.012 mol) of 7-hydroxy-4-chromanone (J. Org. Chem., 1994;59:1216) in 25 mL of THF was treated with 1.29 g (0.013 mol) of 2-(1H-1-imidazolyl)-1-ethanol and 3.15 g (0.012 mol) of triphenylphosphine. The solution was cooled in ice and treated over 10 minutes with a solution of 1.89 mL (0.012 mol) of diethyl azodicarboxylate in 5.0 mL of THF. After stirring at room temperature for 3 days, the solution was diluted with EtOAc and washed with saturated NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure left the crude product. Chromatography on silica gel, eluting with a gradient of CHCl3 to CHCl3 /MeOH (96/4) gave the product which was recrystallized from EtOAc/hexane to give 0.92 g (29.7% yield) of a white solid, mp 128-130° C. The structure was confirmed by NMR and mass spectroscopy. MS m/z 259 (M+H+).
Reaction SMILES: [C:1]1(=[O:10])[CH:5]2[CH2:6][CH2:7][CH2:8][CH:4]2[C:3](=[O:9])[O:2]1.COC1C=CC2N=CC=C([C@@H](O)[C@H]3N4C[C@H](C=C)[C@@H](CC4)C3)C=2C=1.[CH3:35][OH:36]>C1(C)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[CH3:35][O:36][C:3]([C@@H:4]1[CH2:8][CH2:7][CH2:6][C@@H:5]1[C:1]([OH:10])=[O:2])=[O:9]
Reactant: CO
Reactant: O=C1OC(=O)C2CCCC12
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Solvent: Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)[C@@H]1CCC[C@@H]1C(=O)O
Temperature: -55 °C
Reaction time: 36 h
Yield: 100 %

Procedure:
(1S,2R)-2-(Methoxycarbonyl)cyclopentanecarboxylic acid was prepared as described in J. Org. Chem. 2000, 65, 6984-6991. Tetrahydro-cyclopenta[c]furan-1,3-dione (5.0 g, 35.7 mmol) was dissolved in a 1:1 mixture of toluene and carbon tetrachloride (720 mL). The mixture was cooled to −55° C. under a nitrogen atmosphere, and then quinine (12.7 g, 39.3 mmol) was added. A solution of methanol (4.33 mL, 107 mmol) in toluene-carbon tetrachloride (1:1, 30 mL) was slowly added via an addition funnel. The suspension was stirred at −55° C. for 36 h, and then allowed to warm to 25° C. The mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (400 mL), washed with 1.0 M aqueous hydrochloric acid solution (2×400 mL) and saturated aqueous brine solution, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to afford the desired product, (1S,2R)-2-(methoxycarbonyl)cyclopentanecarboxylic acid (6.2 g, 35.7 mmol, quantitative), as a clear oil. 1H NMR (400 MHz, CD3OD) δ: 1.67 (1H, m), 1.84 (1H, m), 1.99 (4H, m), 3.08 (2H, m), 3.63 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[N:35][C:34]=1[C:39]1([NH2:42])[CH2:41][CH2:40]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:27])[NH:42][C:39]5([C:34]6[N:35]=[CH:36][CH:37]=[CH:38][N:33]=6)[CH2:41][CH2:40]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: NC1(c2ncccn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncccn5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.2 g, 0.46 mmol, 1 eq), 1-(pyrimidin-2-yl)cyclopropanamine (0.074 g, 0.55 mmol, 1.2 eq), HOBT (0.105 g, 0.77 mmol, 1.7 eq), EDC.HCl (0.0.158 g, 0.82 mmol, 1.8 eq), in DCM at ambient temperature and under nitrogen atmosphere was added diisopropylehtylamine (0.297 g, 2.2 mmol, 5.0 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was further purified by column chromatography (neutral alumina) using 0.5% Methanol/DCM and preparative HPLC. Yield: 0.055 g (45%). 1HNMR (400 MHz, DMSO-d6): δ 1.43-1.44 (m, 2H), 1.59-1.62 (m, 2H), 2.31 (s, 3H), 2.81-2.82 (d, 3H, J=4.56 Hz), 4.01 (s, 3H), 7.17 (s, 1H), 7.26-7.29 (t, 1H, J=4.8 Hz), 7.33-7.36 (dd, 1H, J=8.4, 4 Hz), 7.38-7.43 (t, 2H, J=8.8 Hz), 7.50-7.51 (d, 1H, J=1.6 Hz), 7.72-7.76 (m, 2H), 7.97-8.01 (m, 2H), 8.48-8.49 (d, 1H, J=4.4 Hz), 8.7 (d, 2H, J=4.8 Hz), 8.87 (s, 1H). LCMS: (ES+) m/z=551.2 (M+H) Column-Ascentis Express C18 (5×2.1 mm-2.7 μm) Mphase A: 2% MeCN-98% H2O-10 mM NH4COOH Mphase B: 98% MeCN-2% H2O-10 mM NH4COOH Flow: 1 mL/Min
Reaction SMILES: [Br:1][C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:12]([O:14]CC)=[O:13])[C:8]=2[OH:11])[CH:3]=1.C(O)(=O)C>C(O)C.[OH-].[Na+]>[Br:1][C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:12]([OH:14])=[O:13])[C:8]=2[OH:11])[CH:3]=1
Reactant: CCOC(=O)c1cnc2cc(Br)sc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)c1cnc2cc(Br)sc2c1O
Temperature: 25 °C
Yield: 71.3 %

Procedure:
A mixture of ethyl 2-bromo-7-hydroxythieno[3,2-b]pyridine-6-carboxylate (1.3 g, 4.3 mmol) [Elliott, R.; O'Hanlon, P. J.; Rodgers, N. B. Tetrahedron, 43(14), 3295 (1987)] in 20 mL of ethanol and 6 mL of 2.5 N sodium hydroxide is heated at reflux for 4 hours. The mixture is poured into ice water and the pH is adjusted to 5-6 by the addition of acetic acid. The mixture is stirred at room temperature and the resulting precipitate is collected by filtration washing with water to provide 840 mg of 2-bromo-7-hydroxythieno[3,2-b]pyridine-6-carboxylic acid. A mixture of 2-bromo-7-hydroxythieno[2,3-b]pyridine-6-carboxylic acid (810 mg, 2.95 mmol) and N,N-carbonyldiimidazole (1.0 g, 6.17 mmol) in 15 mL of N,N′-dimethylformamide is heated at 65° C. for 2 hours. The mixture is poured into 50 mL of ice cold aqueous ammonium hydroxide and stirred for 14 hours. The resultant solids are collected by filtration washing with water to provide 800 mg of 2-bromo-7-hydroxythieno[3,2-b]pyridine-6-carboxamide. A mixture of 2-bromo-7-hydroxythieno[3,2-b]pyridine-6-carboxamide (273 mg, 1.0 mmol) and 3 mL of phosphorous oxychloride is heated at reflux for 1 hour. The solvent is removed in vacuo and the residue is poured into ice water and treated with sodium bicarbonate. The resultant solids are collected by filtration washing with water. The solids are purified by flash column chromatography eluting with chloroform to provide 240 mg of 2-bromo-7-chlorothieno[3,2-b]pyridine-6-carbonitrile as yellow crystals, mp 198-199° C.; 1H NMR (DMSO-d6) δ 8.12 (s, 1H), 9.11 (s, 1H); MS 273.1, 275.1, 277.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:14][N:15]=2)=[O:9])[N:6]=1.[CH2:19](O)[C:20](N)([CH2:23]O)[CH2:21][OH:22].C(OC(C)C)(C)C>C(Cl)Cl.C1(N=C=N)CCCCC1.C(Cl)Cl.CN(C=O)C>[CH:16]([C:13]1[S:12][C:11]([NH:10][C:8](=[O:9])[CH2:7][C:5]2[N:6]=[C:2]([NH:1][C:21](=[O:22])[CH:20]([CH3:23])[CH3:19])[S:3][CH:4]=2)=[N:15][CH:14]=1)([CH3:18])[CH3:17]
Reactant: NC(CO)(CO)CO
Reactant: CC(C)c1cnc(NC(=O)Cc2csc(N)n2)s1
Agent: N=C=NC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Product: CC(C)C(=O)Nc1nc(CC(=O)Nc2ncc(C(C)C)s2)cs1
Temperature: 25 °C
Reaction time: 192 h

Procedure:
To a solution of isobutyrric acid (49 μl, 0.53 mmol) in CH2Cl2 (1.5 ml), N-cyclohexylcarbodiimide, N'-methyl polystyrene (0.4 g, loading 2 mmol/g, 0.798 mmol), Nhydroxybenzotriazole (0.072 g, 0.53 mmol) and a solution of 2-(2-amino-1,3-thiazol-4-yl)-N-(5-isopropyl-1,3-thiazol-2-yl)acetamide (0.075 g, 0.266 mmol) in CH2Cl2 /DMF (0.4 ml/0.6 ml) were added. The reaction mixture was maintained under stirring at room temperature for about 8 days. After this time, PS-Trisamine (0.44 g, loading 3.62 mmol/g, 1.596 mmol) was added, stirring was continued for about 6 hours and then the mixture was filtered. The resin was washed with CH2Cl2 (1 ml×5), the organic layers were combined and evaporated to dryness to give, after trituration with diisopropyl ether the title compound.
Reaction SMILES: P(OP([O-])=O)([O-])=O.[K+].[C:9]1([C:15]2[CH2:19][C:18]([P:24](=[O:27])([OH:26])[O-:25])([P:20](=[O:23])([OH:22])[OH:21])[O:17][N:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Br[Si](C)(C)C>C(Cl)(Cl)Cl>[C:9]1([C:15]2[CH2:19][C:18]([P:24](=[O:25])([OH:27])[OH:26])([P:20](=[O:21])([OH:22])[OH:23])[O:17][N:16]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=P([O-])(O)C1(P(=O)(O)O)CC(c2ccccc2)=NO1
Agent: C[Si](C)(C)Br
Agent: O=[PH]([O-])O[PH](=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=P(O)(O)C1(P(=O)(O)O)CC(c2ccccc2)=NO1

Procedure:
The diphosphonate, [3-phenyl-5(4H)-isoxazolylidene]bisphosphonic acid tetraethyl ester (III, EXAMPLE 9, 2.10 g) in chloroform (10 ml) is treated with bromotrimethylsilane (4.0 ml) and heated to 50°-60° for 5 hrs. The reaction is concentrated under reduced pressure with heat, taken up in ethyl acetate, extracted with water, and the aqueous fractions are filtered and freeze dried to give (3-phenyl-5(4H)isoxazolylidene)bisphosphonic acid.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][CH2:11][CH:12]([CH2:14][CH2:15][CH2:16][C:17]([CH:20]([CH2:22][OH:23])[OH:21])([OH:19])[CH3:18])[CH3:13])[CH3:8])[CH3:3].[CH3:24][C:25]([CH3:27])=O>C1(C)C(S(O)(=O)=O)=CC=CC=1>[CH3:24][C:25]1([CH3:27])[O:21][CH:20]([C:17]([OH:19])([CH2:16][CH2:15][CH2:14][CH:12]([CH3:13])[CH2:11][CH2:10][CH2:9][CH:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH3:18])[CH2:22][O:23]1
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)(O)C(O)CO
Reactant: CC(C)=O
Agent: Cc1ccccc1S(=O)(=O)O
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)(O)C1COC(C)(C)O1

Procedure:
One g of phytantriol (3.0 mmol) was refluxed using deanstock apparatus for 15 hr in 25 ml of acetone solution with toluene sulfonic acid as catalyst. After the completion of the reaction, the acetone solvent was removed under reduced pressure and the resultant was extracted with chloroform solution. The extract was washed with saturated sodium bicarbonate solution and was again washed with saline to obtain 0.3 g of (2-(2,2-dimethyl-[1,3]dioxolan-4-yl)-6,10,14-trimethyl-pentadecan-2-ol) of which 1- and 2-positions were protected, which is represented by the following formula (IV):
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][C:26]=3[CH3:27])[CH:23]([CH2:28][C:29]([O:31]C)=[O:30])[CH2:22][CH2:21]4)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].O>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][C:26]=3[CH3:27])[CH:23]([CH2:28][C:29]([OH:31])=[O:30])[CH2:22][CH2:21]4)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: COC(=O)CC1CCc2cc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)c(C)cc21
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2c(cc1-c1noc(-c3ccc(OC(C)C)c(C#N)c3)n1)CCC2CC(=O)O
Temperature: 50 °C
Yield: 126.6 %

Procedure:
To a solution of methyl (5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-6-methyl indan-1-yl)acetate (23.0 mg, 0.053 mmol, from Step H) in THF (2 mL) and H2O (0.7 mL) lithium hydroxide monohydrate (4.0 mg, 0.107 mmol) was added. The reaction mixture was heated to 50° C. for 3 hr, cooled to ambient temperature and partitioned between EtOAc and 5% citric acid. The organic layer was washed with H2O, brine, dried over MgSO4, filtered and concentrated in vacuo. Purification of the residue by flash chromatography (2% CH3OH/CH2Cl2/0.2% HCO2H) on SiO2 afforded 28.0 mg of the title compound as a white film: 1H NMR (500 MHz, DMSO-d6) δ 1.34 (d, 6H, J=5.9 Hz), 1.60-1.74 (m, 1H), 2.25-2.39 (m, 2H), 2.55 (s, 3H), 2.64-2.92 (m, 3H), 3.42-3.47 (m, 1H), 4.85-5.05 (m, 1H), 7.32 (s, 1H), 7.56 (d, 1H, J=9.4 Hz), 7.86 (s, 1H), 8.38 (d, 1H, J=9.6 Hz), 8.51 (s, 1H); HPLC A: rt=3.84 min, m/z=418.5 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1.[CH3:22]N(C)C=O.[H-].[Na+].CI>C(OCC)(=O)C.O1CCCC1>[CH3:22][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1
Reactant: CN(C)C=O
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2C)CC1
Reaction time: 1 h

Procedure:
Combine (1H-benzimidazol-2-yl)(1-ethoxycarbonyl-piperidin-4-yl)amine (1.44 g, 5.0 mmol) and dimethylformamide (3 mL) and tetrahydrofuran (25 mL). Add sodium hydride (0.34 g, 60% in oil, 8.5 mmol). After 1 hour, add methyl iodide (1 mL). After 18 hours, evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give (1-methyl-1H-benzimidazol-2-yl)(1-ethoxycarbonylpiperidin-4-yl)amine: Rf=0.25 (silica gel, ethyl acetate).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[F:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16](/[CH:21]=[CH:22]/[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)=[N:17][NH:18]2)=[CH:14][C:13]=1[C:30]#[N:31].[Cl-].[NH4+]>O1CCCC1.C(OC(=O)C)C>[F:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16](/[CH:21]=[CH:22]/[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)=[N:17][NH:18]2)=[CH:14][C:13]=1[CH2:30][NH2:31]
Reactant: N#Cc1cc2c(/C=C/c3cccc(F)c3)n[nH]c2cc1F
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NCc1cc2c(/C=C/c3cccc(F)c3)n[nH]c2cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
To a suspension of 5 mg of lithium aluminum hydride in 1 mL of tetrahydrofuran was added 13 mg of aluminum chloride (III), followed by 9 mg of 6-fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carbonitrile obtained by Example 100, and stirred at room temperature overnight. After adding saturated aqueous ammonium chloride, the reaction solution was added with 15 mL of ethylacetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate (twice) and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified and separated by silica gel column chromatography (methanol:chloroform=1:9), to afford 3 mg of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1([CH2:20][CH3:21])[CH2:8][CH2:7][CH2:6][CH2:5][N:4]2[C:9](=[O:19])[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][N:14]=3)[N:12]=[C:3]12.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30](O)=[O:31])[CH:25]=1.COC1N=CC=CC=1C(O)=O>>[CH2:20]([C:2]1([NH:1][C:30]([C:26]2[CH:25]=[C:24]([O:23][CH3:22])[CH:29]=[CH:28][N:27]=2)=[O:31])[CH2:8][CH2:7][CH2:6][CH2:5][N:4]2[C:9](=[O:19])[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][N:14]=3)[N:12]=[C:3]12)[CH3:21]
Reactant: COc1ccnc(C(=O)O)c1
Reactant: CCC1(N)CCCCn2c1nc(-c1ccncn1)cc2=O
Agent: COc1ncccc1C(=O)O
Product: CCC1(NC(=O)c2cc(OC)ccn2)CCCCn2c1nc(-c1ccncn1)cc2=O
Yield: 31 %

Procedure:
By analogy with the method described in example 13 (step 13.5), using (+/−) 10-amino-1 0-ethyl-2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-a]azepin-4-one and 4-methoxy-pyridine-2-carboxylic acid in place of (+)10-amino-10-methyl-2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-a]azepin-4-one and 2-methoxy nicotinic acid, 37 mg (31%) of the compound was obtained as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[C:12]([CH2:13][CH2:14]O)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].C(N(C(C)C)CC)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.Cl.[CH3:43][C:44]1[CH:45]=[C:46]([CH:58]=[CH:59][CH:60]=1)[CH2:47][C:48]1([C:54]([O:56][CH3:57])=[O:55])[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1>ClCCl>[C:1]([C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[C:12]([CH2:13][CH2:14][N:51]3[CH2:52][CH2:53][C:48]([CH2:47][C:46]4[CH:58]=[CH:59][CH:60]=[C:44]([CH3:43])[CH:45]=4)([C:54]([O:56][CH3:57])=[O:55])[CH2:49][CH2:50]3)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)C1(Cc2cccc(C)c2)CCNCC1
Reactant: N#Cc1ccc(Cn2cncc2CCO)cc1
Agent: Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(Cc2cccc(C)c2)CCN(CCc2cncn2Cc2ccc(C#N)cc2)CC1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a cold (-78° C.) solution of 3-(4-cyanobenzyl)-3H-imidazol-4-ylethyl alcohol (184 mg, 0.81 mmol) and diisopropylethylamine (155 μL, 0.89 mmol) in dichloromethane (3.8 mL), trifluoromethanesulfonic anhydride (143 μL, 0.85 mmol) was added. The resulting mixture was stirred at -78° C. for 20 min., and was treated with a solution of methyl 4-(3-methylbenzyl)piperidine-4-carboxylate hydrochloride salt (276 mg, 0.97 mmol; Example 61, Step B) and diisopropylethylamine (186 μL, 1.07 mmol) in dichloromethane (1 mL). The reaction mixture was stirred at -78° C. for one h., and at room temp. for two h. The resultant solution was concentrated under vacuum, and the residue was partitioned between dichloromethane and aqueous sodium bicarbonate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was subjected to high pressure liquid column chromatography on C-18 reverse phase stationary phase. Collection and lyophilization of appropriate fractions provided the title compound as white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[Li]CCCC.[F:15][C:16]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:17]=1[CH:18]=[O:19]>CC(OC)(C)C>[F:15][C:16]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:17]=1[CH:18]([C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)[OH:19]
Reactant: O=Cc1ccc(F)cc1F
Reactant: COc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Product: COc1ccc(C(O)c2ccc(F)cc2F)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-bromo-2-methoxypyridine 1 (2.10 g, 10.6 mmol) in anhydrous TBME (20 ml) at −32° C. under argon atmosphere was added n-BuLi solution (5.8 ml of 2 M solution in cyclohexane, 11.7 mmol) drop wise over 15 min under argon condition. After stirring for 1 h, 2,4-difluorobenzaldehyde (1.54 g, 10.6 mmol) was added drop wise over 15 min and the reaction mixture was stirred for 30 min under −32° C. under argon atmosphere. Reaction mixture was allowed to warm up to 0° C. and quenched with saturated NH4Cl (20 ml). The phases were separated and the aqueous layer was extracted with TBME (20 ml and 10 ml). All combined organic phases were washed with water (50 ml), and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (hexanes:ethyl acetate, 85:15). Yield 2.28 g (850%). 1H NMR (CDCl3, 500 MHz): δ 8.16 (s, 1H), 7.57-7.52 (m, 2H), 6.93-6.76 (m, 2H), 6.72 (d, 1H, J=9.0 Hz), 6.07 (d, 1H, J=3.5 Hz), 3.92 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ 163.9, 162.4, 159.6, 145.0, 137.2, 131.0, 128.2, 126.5, 111.5, 110.9, 103.9, 67.3, 53.6.