Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[N+:13]([C:16]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[CH:19][C:17]=1[NH2:18])([O-:15])=[O:14].C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.O>[CH3:7][NH:6][C:5]1[CH:8]=[CH:9][C:2]([C:21]2[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([N+:13]([O-:15])=[O:14])[CH:22]=2)=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: CC1(C)OB(c2ccc(N)c([N+](=O)[O-])c2)OC1(C)C
Reactant: CNc1ccc(Br)cc1[N+](=O)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: O
Solvent: COCCOC
Product: CNc1ccc(-c2ccc(N)c([N+](=O)[O-])c2)cc1[N+](=O)[O-]
Temperature: 130 °C
Yield: 169.4 %

Procedure:
4-Bromo-N-methyl-2-nitroaniline (100 mg, 0.43 mmol), 2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (115 mg, 0.43 mmol), biphenyl-2-yldicyclohexylphosphine (30 mg, 20 mol %) and K3PO4 (275 mg, 1.3 mmol) were suspended in DME-H2O (4:1, 5 mL), the mixture was purged with nitrogen then degassed by sonication. Pd(OAc)2 (5 mg, 5 mol %) was added, and the mixture heated to 130° C. for 10 min under microwave irradiation. The cooled mixture was diluted with EtOAc and H2O. The organics were separated and the aqueous layer extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give the crude product as a dark brown solid (210 mg). The crude material was taken on without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=2)=[C:6]([CH:10]=1)[C:7]([NH:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22])=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1Oc1ccc(F)cn1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2Oc2ccc(F)cn2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-[(5-fluoropyridin-2-yl)oxy]benzoic acid (step 5) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 7.99 (1H, d, J=2.6 Hz), 7.97 (1H, d, J=3.1 Hz), 7.92 (2H, d, J=8.4 Hz), 7.50–7.39 (2H, m), 7.35–7.21 (3H, m), 6.99 (1H, d, J=8.6 Hz), 6.86 (1H, dd, J=8.9, 3.3 Hz), 5.31–5.17 (1H, m), 3.91 (3H, s), 1.42 (3H, d, J=6.9 Hz); MS (ESI) m/z 429 (M+H)+, 427 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1([CH2:13][OH:14])[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.[Br:15][C:16]1[CH:17]=[N:18][C:19](Cl)=[N:20][CH:21]=1.[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[Br:15][C:16]1[CH:17]=[N:18][C:19]([O:14][CH2:13][C:2]2([CH3:1])[O:6][C:5]3=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]3[CH2:3]2)=[N:20][CH:21]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CC1(CO)Cn2cc([N+](=O)[O-])nc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(COc2ncc(Br)cn2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
(2-Methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)-methanol (0.10 g, 0.50 mmol), 5-bromo-2-chloropyrimidine (0.16 g, 0.82 mmol) and NaH (˜30 mg, 60% in mineral oil) were suspended in 2 mL DMF and stirred at r.t. for 2 hours. The resulting mixture was diluted with 150 mL EtOAc, washed with 100 mL NaHCO3 and 100 mL water. The aqueous layer was re-extracted with 100 mL EtOAc. The organic layer was washed with brine and dried over Na2SO4. The concentrated residue was purified by column chromatography (DCM/MeOH, 0 to 3%) to give the title compound (152 mg, 83%) as a white solid. APCI MS m/z 356.6, 358.6 (M+H). 1H NMR (400 MHz, (CD3)2SO) δ 8.77 (s, 2H), 8.14 (s, 1H), 4.61 (s, 2H), 4.41 (d, J=11.1 Hz, 1H), 4.20 (d, J=11.1 Hz, 1H), 1.70 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][C:12]=2[Cl:23])=[N:4][C:5]([Br:8])=[CH:6][CH:7]=1.[CH2:24]([O:26][C:27](OCC)(OCC)OCC)[CH3:25]>C(O)(=O)C>[Br:8][C:5]1[N:4]=[C:3]2[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:13][C:12]=3[Cl:23])[C:27]([O:26][CH2:24][CH3:25])=[N:1][C:2]2=[CH:7][CH:6]=1
Reactant: CCOC(OCC)(OCC)OCC
Reactant: Nc1ccc(Br)nc1NCc1ccc(-c2ccccc2)cc1Cl
Solvent: CC(=O)O
Product: CCOc1nc2ccc(Br)nc2n1Cc1ccc(-c2ccccc2)cc1Cl
Temperature: 70 °C
Reaction time: 7 h
Yield: 2.6 %

Procedure:
A mixture of 3-amino-6-bromo-2-(N-(2-chloro-4-phenylbenzyl)amino)pyridine (1.85 g), tetraethoxymethane (4.3 g) and acetic acid (18.5 ml) was stirred at room temperature overnight and at 70° C. for 7 hr. The reaction mixture was concentrated to dryness under reduced pressure, and toluene was added, which was followed by concentration under reduced pressure. The residue was dissolved in ethyl acetate and washed twice with saturated aqueous sodium hydrogen carbonate solution and once with saturated brine. The organic layer was dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was applied to silica gel column (n-hexane:ethyl acetate=9:1) to give a single product (55 mg) of 5-bromo-3-(2-chloro-4-phenylbenzyl)-2-ethoxy-3H-imidazo[4,5-b]pyridine and a mixture (977 mg) with a byproduct each as pale-brown amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([C@@](O)([C@@H](O)[C@H](O)[C@H](O)CO)C(N)=O)=[CH:16][CH:15]=1.BrCC(C1C=C([NH:43]C(=O)C)C=CC=1)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH2:43])=[CH:16][CH:15]=1
Reactant: CC(=O)Nc1cccc(C(=O)CBr)c1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc([C@](O)(C(N)=O)[C@@H](O)[C@H](O)[C@H](O)CO)cc2)C1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(N)cc2)C1

Procedure:
Starting from 2,4-dichlorobenzylmethylamine (Example 1, intermediate 1) and N-[3-(2-bromoacetyl)phenyl]acetamide (cf. Example 1, intermediate 2), the aniline derivative 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (cf. Example 1, intermediate 6) was prepared in a similar manner to the synthetic route described in Example 1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:14])[C:11](Cl)=[O:12])=[CH:2]1.[CH:15]1[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:22].N1C=CC=CC=1>C(OCC)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:14])[C:11]([O:21][C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:22])[CH:15]=2)=[O:12])=[CH:2]1
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Reactant: Cc1cccc(O)c1
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1cccc(OC(=O)C(=O)c2c[nH]c3ccccc23)c1
Reaction time: 0.5 h

Procedure:
3-Indolylglyoxylyl chloride (104 g. ) was stirred in diethyl ether (500 ml.) and treated with m-cresol (108 g.) followed by pyridine (79 g.). After stirring for 30 minutes the solid product was collected by filtration, washed with water then with acetonitrile and dried to give m-cresyl 3-indolylglyoxylate as a yellow powder, m.p. 194°-197°. Yield 119 g. (85.5%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].Cl[S:13]([C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([NH:26][C:27](=[O:29])[CH3:28])=[CH:23]2)=[CH:18][CH:17]=1)(=[O:15])=[O:14]>C1COCC1.N1C=CC=CC=1>[C:27]([NH:26][C:22]1[CH:23]=[C:24]2[C:19]([CH:18]=[CH:17][C:16]([S:13]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=3)[C:7]([OH:9])=[O:8])(=[O:15])=[O:14])=[CH:25]2)=[CH:20][CH:21]=1)(=[O:29])[CH3:28]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Reactant: CC(=O)Nc1ccc2ccc(S(=O)(=O)Cl)cc2c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2ccc(S(=O)(=O)Nc3ccc(Cl)c(C(=O)O)c3)cc2c1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To 15 g (0.087 mol) of 5-amino-2-chlorobenzoic acid was dissolved in 450 mL of THF and 15 mL of pyridine. The solution was cooled to 5° C. in an ice-water bath. Then, a solution of 20.8 g (0.074 mol) of compound 131 dissolved in 200 mL of THF was added over a 10 min period. The reaction was kept at 5° C. for 30 min, and then allowed to warm to room temperature. The reaction was allowed to stir for an additional 4 hours. Then, the reaction was filtered to remove some insoluble material and the resulting clear filtrate was reduced to a solid by the removal of the volatiles by rotary evaporation. This solid was extracted with ethyl acetate and 1 N HCl. The ethyl acetate layer was further extracted with 0.5 M NaOH (once) and 0.33 M NaOH (three times). The aqueous layers were combined, acidified with HCl, and back extracted into ethyl acetate. After drying (MgSO4), filtration, and removal of the ethyl acetate by rotary evaporation, the solid residue was dissolved in 2.8 L of 50/50 methanol/water with heating. The solution was allowed to cool to room temperature and a small amount of solid was removed by vacuum filtration and discarded. The clear filtrate was allowed to sit for 48 hours and then was reduced in volume to about 500 mL by rotary evaporation. The solid was collected by vacuum filtration. After drying in vacuo, this provided 17.6 g of compound 132.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[OH:13][C:14]1[CH:26]=[CH:25][C:17]([O:18][CH:19]([CH3:24])[CH:20]=[CH:21][CH2:22][OH:23])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([O:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH:19]([CH3:24])[CH:20]=[CH:21][CH2:22][OH:23])=[CH:25][CH:26]=1)[CH:11]=[N:10]2
Reactant: Clc1ccc2nc(Cl)cnc2c1
Reactant: CC(C=CCO)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C=CCO)Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1
Temperature: 25 °C

Procedure:
A mixture of 1.99 g (10 mmol) of 2,6-dichloroquinoxaline, 2.13 g (11 mmol) of 4-(4-hydroxyphenoxy)-2-penten-1-ol, 1.73 g (12.5 mmol) of powdered, anhydrous potassium carbonate and 50 ml of dry acetonitrile was warmed at reflux under nitrogen for a period of 3 hours. The mixture was cooled to room temperature, and the solid filtered off and washed well with ether. The filtrates were combined and evaporated to dryness, and the residue partitioned between ether and 2 percent aqueous sodium hydroxide. The aqueous layer was separated and extracted again with ether. The combined organic layers were washed with water, dried over MgSO4 and evaporated to dryness. The residual solid was purified by preparative scale HPLC, eluting with 7:3 hexane:ethyl acetate, to give a solid which was recrystallized from toluene. This gave 2.60 g (73%) of the desired pentenol as pale yellow crystals, having a melting point (m.p.) of 124°-126° C. (Compound C).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C:9](=[O:11])[CH2:8][C@H:7]1[C:12]([OH:14])=O)=[O:5])[CH3:2].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C:9](=[O:11])[CH2:8][C@H:7]1[C:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(=O)C[C@H]1C(=O)O
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CC(=O)C[C@H]1C(=O)N1CCOCC1
Reaction time: 4 h

Procedure:
To a mixture of (1R,2R)-4-oxo-cyclopentane-1,2-dicarboxylic acid monoethyl ester (10.0 mmol) in tetrahydrofuran (25 ml) was subsequently added morpholine (11 mmol) triethylamine (70 mmol), 1-hydroxybenzotriazole hydrate (20 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 20 mmol) and stirring was continued at 22° C. for 4 h. The mixture was partitioned between ethyl acetate and 1N aqueous HCl, the organic layer was washed with saturated aqueous Na2CO3, dried and evaporated to give the title compound as pale brown oil. MS: 270.3 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)[C:13]([F:24])=[CH:12][N:11]=1>>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14]2[C:13]([F:24])=[CH:12][N:11]=[C:10]([NH:5][C:4]3[CH:6]=[CH:7][CH:8]=[C:2]([OH:1])[CH:3]=3)[N:15]=2)=[N:18][CH:19]=1
Reactant: Fc1cnc(Cl)nc1Nc1ccc(Cl)cn1
Reactant: Nc1cccc(O)c1
Product: Oc1cccc(Nc2ncc(F)c(Nc3ccc(Cl)cn3)n2)c1

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 3-hydroxyaniline with 2-chloro-N4-(5-chloropyridin-2-yl)-5-fluoro-4-pyrimidineamine gave N4-(5-chloropyridin-2-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.80 (bs, 1H), 9.77 (bs, 1H), 8.45 (bd, 1H), 8.26 (d, 1H, J=3.9 Hz), 8.15 (d, 1H, J=8.7 Hz), 7.85 (dd, 1H, J=2.4 and 8.7 Hz), 7.06 (m, 3H), 6.43 (bd, 1H, J=7.2 Hz); LCMS: purity: 97%; MS (m/e): 332 (MH+).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([C:22]3[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=3[F:29])[C:4]=2[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[N:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=2)[C:41]([OH:43])=[O:42])O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:13]([N:12]([CH2:15][CH3:16])[CH2:11][CH2:10][CH2:9][NH:8][C:6]1[N:7]=[C:2]([C:38]2[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=2)[C:41]([OH:43])=[O:42])[C:3]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([C:22]3[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=3[F:29])[C:4]=2[N:5]=1)[CH3:14]
Reactant: CCN(CC)CCCNc1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CC1(C)OB(c2cccc(C(=O)O)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 150 °C
Yield: 184 %

Procedure:
To the compound 4-chloro-2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)pyrido[2,3-d]pyrimidin-7(8H)-one (210.5 mg, 0.50 mmol) in dioxane (15 mL) and water (5 mL) were added 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (125 mg, 0.75 mol), potassium carbonate (210 mg, 1.20 mmol) and tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol). The mixture was heated with microwave at 150° C. for 15 min. The mixture was concentrated, then mixed with DMSO (0.75 mL) and water (0.25 mL). Separation by HPLC afforded the title compound (467 mg, 32%). LC-MS m/z 508 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[S:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.[CH2:38](P(=O)(OCC)OCC)[P:39](=[O:46])([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42].CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[S:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:38]/[P:39](=[O:46])([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])=[CH:11][N:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(N2CCCCC2)sc1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(N3CCCCC3)sc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 58.3 %

Procedure:
To a mixture of 3-[(3-methoxy-4-{[5-methyl-2-(piperidin-1-yl)-1,3-thiazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.15 g), tetraethyl methylenediphosphonate (0.09 g) and N,N-dimethylformamide (5 mL) was added sodium hydride (60% in oil, 0.015 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-{3-[(3-methoxy-4-{[5-methyl-2-(piperidin-1-yl)-1,3-thiazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate as colorless crystals (0.11 g, yield 58%) from a fraction eluted with ethyl acetate-hexane (4:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 95-96° C.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH2:34][CH2:35]CS([O-])(=O)=O)[CH2:19][CH2:18][N:17]([C:20](=[O:33])[C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)[CH2:16]2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[C:42]1([C:48]2([C:54]([NH2:56])=[O:55])[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2([CH2:34][CH2:35][N:51]3[CH2:50][CH2:49][C:48]([C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)([C:54]([NH2:56])=[O:55])[CH2:53][CH2:52]3)[CH2:19][CH2:18][N:17]([C:20](=[O:33])[C:21]3[CH:22]=[C:23]([O:31][CH3:32])[C:24]([O:29][CH3:30])=[C:25]([O:27][CH3:28])[CH:26]=3)[CH2:16]2)=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)C2)cc(OC)c1OC
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-[4-(tert-butyldimethylsilyloxy)-phenyl]-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (8 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (12 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34](O)=[O:35])=[O:30])[CH:11]=1)=[O:9].FC(F)(F)C1C=C(C=CC=1)CNC(C1C=CN=C(C2C=C(N3CCCCC3)C=CC=2NC(=O)C2C=CC=C(C(N(CCC(NCCOC)=O)C)=O)C=2)C=1)=O.[C:99]([N:102]1[CH2:107][CH2:106][NH:105][CH2:104][CH2:103]1)(=[O:101])[CH3:100]>>[C:99]([N:102]1[CH2:107][CH2:106][N:105]([C:34]([C:33]2[CH:32]=[C:31]([CH:39]=[CH:38][CH:37]=2)[C:29]([NH:28][C:17]2[CH:18]=[CH:19][C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:21][C:16]=2[C:12]2[CH:11]=[C:10]([CH:15]=[CH:14][N:13]=2)[C:8]([NH:7][CH2:6][C:5]2[CH:40]=[CH:41][CH:42]=[C:3]([C:2]([F:1])([F:44])[F:43])[CH:4]=2)=[O:9])=[O:30])=[O:35])[CH2:104][CH2:103]1)(=[O:101])[CH3:100]
Reactant: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: CC(=O)N1CCNCC1
Agent: COCCNC(=O)CCN(C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Product: CC(=O)N1CCN(C(=O)c2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1

Procedure:
This compound was prepared from 3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)-benzoic acid 4.1e using the procedure described for the preparation of N1-(2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)-N3-(3-(2-methoxyethylamino)-3-oxopropyl)-N3-methylisophthalamide 4.2. N-Acetylpiperazine was used as the amine component in this coupling. 1H-NMR (400 MHz, DMSO-d6, ppm): δ 12.48 (s, 1H), 9.57 (m, 1H), 8.93 (d, J=5.2 Hz, 1H), 8.39 (d, J=11.2 Hz, 2H), 7.99˜7.46 (m, 11H), 4.63 (d, J=6.0 Hz, 2H), 3.55˜3.42 (m, 12H), 2.21 (s, 3H), 1.79 (s, 4H), 1.62 (s, 2H). MS (ES, m/z): 713 [M+H]+.
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[CH3:22][O:23][C:24]([C:26]1[CH:34]=[CH:33][C:29]([CH2:30][CH2:31]Br)=[CH:28][CH:27]=1)=[O:25].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:31][CH2:30][C:29]2[CH:33]=[CH:34][C:26]([C:24]([O:23][CH3:22])=[O:25])=[CH:27][CH:28]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Reactant: COC(=O)c1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc(CCN2CCC(C(C(N)=O)(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.6 g--see Preparation 8), 4-methoxycarbonylphenethyl bromide (0.53 g--see Preparation 15), anhydrous potassium carbonate (0.5 g) and acetonitrile (20 ml) was heated under reflux for 1.5 hours. On cooling to room temperature, water (60 ml) was added and the resulting mixture extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (2% up to 6%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless foam, yield, 0.44 g.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=1.[2H]C(Cl)(Cl)Cl.[2H]C([2H])([2H])O[2H]>>[NH2:40][C:37]1[CH:38]=[CH:39][C:34]([CH2:33][CH2:32][NH:31][C:25]2[N:24]=[C:23]([C:19]3[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=3)[CH2:16][N:11]([CH2:10][CH2:9][CH2:8][NH2:7])[S:12]([CH3:15])(=[O:13])=[O:14])[CH:28]=[CH:27][N:26]=2)=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Reactant: NCCc1ccc(N)cc1
Agent: [2H]C(Cl)(Cl)Cl
Agent: [2H]OC([2H])([2H])[2H]
Product: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc(N)cc3)n2)c1

Procedure:
Intermediate 4 from above was coupled with 4-(2-Amino-ethyl)-phenylamine following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 455. CDCl3-CD3OD, shifts relative to the solvent peak at 7.24 ppm) δ 8.1 (m, 2H) 7.9 (d, 1H) 7.5 (d, 1H) 7.4 (m, 1H) 7.2 (m, 3H) 7.1 (d, 2H) 4.4 (s, 2H) 3.7 (m, 2H) 3.2 (m, 4H) 2.9 (m, 2H) 2.8 (s, 3H) 2.6 (m, 2H) 1.6 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=3)[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:19][CH2:20][C:21]1([OH:29])[CH2:26][CH2:25][CH2:24][C:23]([CH3:28])([CH3:27])[CH2:22]1.C(#N)C.C(=O)(O)[O-].[Na+]>>[CH3:27][C:23]1([CH3:28])[CH2:24][CH2:25][CH2:26][C:21]([CH2:20][NH:19][C:2]2[C:3]3[CH2:11][N:10]([C:12]4[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=4)[CH2:9][CH2:8][C:4]=3[N:5]=[CH:6][N:7]=2)([OH:29])[CH2:22]1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)nc1
Reactant: CC1(C)CCCC(O)(CN)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(N2CCc3ncnc(NCC4(O)CCCC(C)(C)C4)c3C2)nc1
Temperature: 25 °C

Procedure:
4-chloro-5,6,7,8-tetrahydro-6-(5-methylpyridin-2-yl)pyrido[4,3-d]pyrimidine (0.030 g, 0.00012 mol) and 1-aminomethyl-3,3-dimethyl-cyclohexanol (0.022 g, 0.00014 mol) in acetonitrile (3 mL, 0.06 mol) was heated via microwave in a sealed tube at 180° C. for a total of 2 hours and five minutes. The reaction mixture was cooled to room temperature and poured into saturated sodium bicarbonate. The mixture was extracted with equal amounts of ethyl acetate and the organic layer was dried over magnesium sulfate. The residue was purified by flash chromatography over silica gel methanol/dichloromethane (0-10%) to yield the title compound.