Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][CH2:14][C:13]=34)[O:6][N:5]=2)[CH2:3][CH2:2]1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]2[CH:11]=[N:10][C:9]([C:7]3[O:6][N:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[N:8]=3)=[C:13]2[CH2:14]1)(=[O:24])[CH3:23]
Reactant: c1ccc2c(c1)NCc1c(-c3nc(C4CC4)no3)ncn1-2
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1Cc2c(-c3nc(C4CC4)no3)ncn2-c2ccccc21

Procedure:
A mixture of 3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-4,5-dihydroimidazo[1,5-a]quinoxaline (XXXIII, EXAMPLE 101, 0.201 g) and acetic anhydride (3 ml) in THY (0.7 ml) is heated at 80° for 45 min. The reaction mixture is then cooled, concentrated, and partitioned between dichloromethane and aqueous sodium bicarbonate. The organic phase is separated and filtered through sodium sulfate and concentrated. The crude product is crystallized from dichloromethane and hexane to give the title compound, which is then recrystallized from ethyl ether/ethyl acetate/hexane. mp 202.0°-202.5°; MS (m/z) at 321; IR (mineral oil) 1674, 1639, 1501, 1358 and 1401 cm-1 ; NMR (CDCl3) 1.15, 2.18, 2.29, 5.32, 7.41.7.62 and 8.15 δ.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH:18]C(=O)OC(C)(C)C)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[NH4+].[OH-]>Cl.CCO.O>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH2:18])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1NC(=O)OC(C)(C)C
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOCc1nc2cnc3ccccc3c2n1N
Yield: 57 %

Procedure:
tert-Butyl N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)carbamate (14.3 g, 41.8 mmol) was dissolved in 150 mL of 2 M HCl in EtOH, and the reaction mixture was heated to reflux for 3 h. The reaction mixture was cooled and concentrated under reduced pressure to give a brown solid. The brown solid was dissolved in 100 mL of H2O and treated with 100 mL of concentrated NH4OH solution. The basic, aqueous solution was then extracted with CH2Cl2 (4×). The combined organic layers were then washed with brine and dried over Na2SO4. The solution was filtered and concentrated under reduced pressure to give a brown foam. The foam was triturated with Et2O (150 mL) and filtered. The filtrate was concentrated to give 2-ethoxymethy-1H-imidazo[4,5-c]quinolin-1-amine (5.77 g) as a tan solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[C:3]=1[NH:10][C:11]#[N:12].[NH:13]1[CH:17]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:15]=[N:14]1.Cl.O1CCOCC1>CCOCC>[CH2:21]([O:20][C:18]([C:16]1[CH:17]=[N:13][N:14]([C:11](=[NH:12])[NH:10][C:3]2[C:4]([Br:9])=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Br:1])[CH:15]=1)=[O:19])[CH3:22]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: N#CNc1c(Br)cc(F)cc1Br
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCOC(=O)c1cnn(C(=N)Nc2c(Br)cc(F)cc2Br)c1
Temperature: 23 °C
Yield: 54.2 %

Procedure:
A mixture of 2,6-dibromo-4-fluoro-phenyl-cyanamide (0.167 g, 0.570 mmol), ethyl pyrazole-4-carboxylate (80.0 mg, 0.570 mmol), 4M HCl in dioxane (0.156 mL, 0.630 mmol), and 1,4 dioxane (2 mL) was heated to reflux for 2 h, during which time a precipitate formed. The mixture was allowed to cool to 23° C. Et2O (10 mL) was added to the mixture. The resulting precipitate was collected by filtration, washed with Et2O, and dried to yield the titled compound (0.134 g, 50%) as the HCl salt. MS (ESI/CI): mass calcd. for C13H11Br2FN4O2, 431.9; m/z found, 432.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 8.20 (s, 1H), 7.43 (s, 1H), 6.82 (d, J=7.9 Hz, 2H), 3.56 (q, J=7.1 Hz, 2H), 2.85 (s, 3H), 0.57 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6](=[O:25])[CH:7]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:15](I)=[CH:14][C:13]=2[F:24])[CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:2]1.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.[F-].[Cs+].O.CCOC(C)=O>COCCOC.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>[CH:1]1([CH2:4][O:5][C:6](=[O:25])[CH:7]([C:12]2[C:13]([F:24])=[CH:14][C:15]([C:31]3[CH:32]=[CH:33][C:28]([C:27]([F:38])([F:37])[F:26])=[CH:29][CH:30]=3)=[C:16]([O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)[CH:17]=2)[CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:2]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)CC(C(=O)OCC1CC1)c1cc(OCC2CC2)c(I)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)CC(C(=O)OCC1CC1)c1cc(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)cc1F

Procedure:
To a solution of 2-(5-cyclopropylmethoxy-2-fluoro-4-iodo-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.2 g, 0.43 mmol) in anhydrous DME (10 mL) under argon was added 4-trifluoromethylphenylboronic acid (0.1 g, 0.53 mmol), CsF (0.16 g, 1.05 mmol), and Pd(PPh3)4 (0.015 g, 0.013 mmol). The reaction mixture was refluxed for 18 h, a water/EtOAc 15/15 mL mixture was added and the organic phase was separated and dried over MgSO4. The solvent was then evaporated to give a yellow oil which was purified by column chromatography over silica gel (Heptane-EtOAc gradient) to give 0.18 of 2-(2-cyclopropylmethoxy-5-fluoro-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoic acid cyclopropylmethyl ester as a light yellow oil. 1H NMR (300 MHz, CDCl3/TMS): δ 7.70-7.64 (m, 4H), 7.05 (d, J=10.4 Hz, 1H), 7.01 (d, J=6.1 Hz, 1H), 4.09 (t, J=7.7 Hz, 1H), 4.02-3.87 (m, 2H), 3.78 (d, J=6.6 Hz, 2H), 2.04-1.90 (m, 1H), 1.74-1.65 (m, 1H), 1.60-1.45 (m, 1H), 1.25-1.05 (m, 2H), 0.95 (d, J=6.3 Hz, 6H), 0.60-0.40 (m, 4H), 0.30-0.10 (m, 4H). 13C NMR (75 MHz, CDCl3/TMS): δ 173.5, 154.3 (d, 1JCF=239.7 Hz), 151.9, 140.7, 132.0, 129.5, 126.6 (d, 2JCF=16.9 Hz), 124.8 (q, 3JCF=3.7 Hz), 124.0 (q, 1JCF=271.6 Hz), 117.0 (d, 2JCF=24.6 Hz), 113.6, 74.1, 69.6, 41.1, 41.5, 26.1, 22.7, 22.2, 10.2, 9.8, 3.2.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([SH:18])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:20]([S:18][C:9]1[NH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Yield: 52.6 %

Procedure:
A mixture of 4,5-diphenyl-2-imidazolethiol (2.5 g), 8-bromooctane (3.8 g), anhydrous potassium carbonate (13.7 g) and dry butanone (60 ml) was stirred at reflux for 2 h. The cooled reaction mixture was filtered to remove solid and the flitrate was evaporated to dryness. The residue was mixed with hexane and the resulting precipitate was collected by filtration. Recrystallisation from ethanol and water gave 2-octylthio-4,5-diphenylimidazole (1.9 g, 53%) as a white solid, m.p. 133°-4°.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[C:10]=[S:11])[CH3:2].[CH2:12]([NH:14][CH2:15][C:16](O)=[O:17])[CH3:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:12]([N:14]1[CH2:15][C:16](=[O:17])[N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:1][CH3:2])[C:10]1=[S:11])[CH3:13]
Reactant: CCc1ccccc1N=C=S
Reactant: CCNCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCc1ccccc1N1C(=O)CN(CC)C1=S
Yield: 36.8 %

Procedure:
The title compound was prepared by the procedure described in Example 16 using 16.3 g of 2-ethylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 200 mL of chloroform. Purification was achieved by flash chromatography on silica gel (5-10 % ethyl acetate in hexane) Crystallization from diethyl ether afforded the title compound (9.12 g) as a white solid, m.p. 71°-73° C. Anal. Calcd. for. C13H16N2O S: C,62.87; H, 6.49; N, 11.28. Found: C, 62.81; H, 6.43; N, 11.17. Mass spectrum (EI, M.+) m/z 248.
Reaction SMILES: [CH2:1]([O:15][CH2:16][CH:17]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:18][O:19]CC=C)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].FC(F)(F)C(O)=O>C(O)C.[Sn].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>[CH2:1]([O:15][CH2:16][CH:17]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:18][OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: C=CCOCC(COCCCCCCCCCCCCCC)OCCCCCCCCCCCCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Sn]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CCCCCCCCCCCCCCOCC(CO)OCCCCCCCCCCCCCC
Temperature: 80 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
1,2-Dimyristyloxy-3-allyloxypropane 1 (15.0 g, 28.6 mmol) was dissolved in ethanol (250 ml). Trifluoroacetic acid (20 ml) was added, followed by tetrakis(triphenylphosphine)palladium(0) (4.5 g, 3.9 mmol). The flask was wrapped in tin foil and flushed with nitrogen to reduce exposure to light and air, then left to stir at 80° C. overnight. The ethanol was removed on the rotary evaporator. TLC (100% CHCl3, developed in Molybdate) indicated that most of the starting material had reacted to form product. This resulting product was further purified by flash column chromatography (100% DCM) to yield 11.5 g (83.1%) 1,2-dimyristyloxypropan-3-ol 2.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:16]([O:19][C@H:20]1[CH2:25][CH2:24][C@H:23]2[C@H:26]3[C@H:35]([CH2:36][CH2:37][C@:21]12[CH3:22])[C@@H:34]1[C:29]([CH2:30][C@@H:31]([OH:38])[CH2:32][CH2:33]1)=[CH:28][CH2:27]3)(=[O:18])[CH3:17].O>CN(C)C1C=CN=CC=1.CN(C=O)C>[C:16]([O:19][C@H:20]1[CH2:25][CH2:24][C@H:23]2[C@H:26]3[C@H:35]([CH2:36][CH2:37][C@:21]12[CH3:22])[C@@H:34]1[C:29]([CH2:30][C@@H:31]([O:38][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:32][CH2:33]1)=[CH:28][CH2:27]3)(=[O:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@@H]4[C@H]3CC[C@]12C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]4[C@H]3CC[C@]12C

Procedure:
Prepare O93 from O92 by treating with acetic anhydride as described for the synthesis of J62 in example 10a, and then treat O93 with sodium borohydride to provide O94 as described for the preparation of J63 in example 10b. Add t-butyldimethylsilyl chloride (16.44 g, 109.1 mmol), 4-dimethylaminopyridine (0.62 g, 5.20 mmol) and triethylamine (15.9 mL, 114.3 mmol) to a stirred solution of estr-5-ene-3β,17β-diol 17-acetate (O94, 33.1 g, 103.9 mmol, Campbell, J. A. and Babcock, J. C., 1971, U.S. Pat. No. 3,597,418) in anhydrous DMF (350 mL) under nitrogen. Stir the resultant suspension at room temperature for 3 days and then pour into vigorously stirred water (2.5 L). Filter the resultant suspension to give 3β-[[(1,1-dimethylethyl)dimethylsilyl]oxy]estr-5-en-17β-ol 17 acetate (O95) as an off-white solid.
Reaction SMILES: C(OC1C([Cl:15])=NC=CC=1)C1C=CC=CC=1.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][NH:27][C:26](=O)[CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.P(Cl)(Cl)(Cl)=O>>[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([Cl:15])[CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Clc1ncccc1OCc1ccccc1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1cc(OCc2ccccc2)ccn1
Temperature: 90 °C
Yield: 47.1 %

Procedure:
Preparation of 4-(benzyloxy-2-chloropyridine: A 250 mL round-bottomed flask was charged with 4-(benzyloxy)pyridin-2(1H)-one (10.0 g, 49.7 mmol) and phosphorus oxychloride (55.6 mL, 596 mmol). The reaction mixture was heated at 90° C. overnight, then cooled and carefully quenched with sodium carbonate and sodium hydroxide to pH 7. The aqueous layer was extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography with dichloromethane as eluent to afford 4-(benzyloxy)-2-chloropyridine (5.14 g, 47.1% yield) as white solid. 1H NMR (CDCl3) δ 8.19 (d, 1H), 7.34-7.44 (m, 5H), 6.91 (d, 1H), 6.81 (dd, 1H), 5.10 (s, 2H). LC/MS: (5 to 95) Rt=2.64 min (ESI) m/z=220 (M+H) (40%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=2)[CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])=[N:5][N:4]=[N:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=2)[CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1-c1cccc(CCOCCC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nnnc1-c1cccc(CCOCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of tert-butyl 3-(3-(1-methyl-1H-tetrazol-5-yl)phenethoxy)propanoate [Example 7, Step iii)] (135 mg), DCM (4 mL) and TFA (4 mL) was stirred at 25° C. for 30 min and concentrated under vacuum to afford the subtitled compound as a gum. 1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.53-7.41 (m, 3H), 4.18 (s, 3H), 3.78-3.72 (m, 4H), 2.96 (t, J=5.9 Hz, 2H), 2.59 (t, J=5.9 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.C(OC([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][C:29]2[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=2)[CH2:24][CH2:23]1)=O)(C)(C)C.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:33](=[O:34])[C:32]2[CH:31]=[CH:30][C:29]([CH2:28][CH:25]3[CH2:24][CH2:23][NH:22][CH2:27][CH2:26]3)=[CH:37][CH:36]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(C(=O)O)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CC2CCNCC2)cc1

Procedure:
75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 125 mg of 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)benzoic acid via Procedure G. The crude product was treated with 4N HCl in Dioxane, evaporated and purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(piperidin-4-ylmethyl)benzamide. MS (Q1) 406.1 (M)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12]([CH:14]=O)[N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:25][CH2:26][CH2:27]P(OCC)(OCC)=O)(=[O:24])[CH3:23].CN(C)C=O.[H-].[Na+]>O>[CH2:1]([O:8][C:9]1[CH:13]=[C:12](/[CH:14]=[CH:23]/[C:22]([O:25][CH2:26][CH3:27])=[O:24])[N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc(OCc2ccccc2)nn1-c1ccccc1
Reactant: CCOP(=O)(CCOC(C)=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cc(OCc2ccccc2)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
To a mixture of 3-benzyloxy-1-phenyl-1H-pyrazole-5-carbaldehyde (6.24 g), diethylphosphonoethyl acetate (5.55 g) and N,N-dimethylformamide (50 ml) was added sodium hydride (60% in oil, 960 mg) at 0° C. and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl (E)-3-(3-benzyloxy-1-phenyl-1H-pyrazol-5-yl)propenoate (7.33 g, yield 94%) was obtained as a pale-yellow oil from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([OH:36])=O)=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[NH2:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=1>>[CH3:47][O:46][C:43]1[CH:42]=[CH:41][C:40]([CH2:39][N:8]([CH2:7][C:6]2[CH:48]=[CH:49][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:31]=[CH:32][C:33]([C:34]([NH:50][CH2:51][C:52]6[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=6)=[O:36])=[CH:37][CH:38]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:45][CH:44]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Reactant: NCc1ccccn1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)NCc4ccccn4)cc3)cn2)cc1
Yield: 174.6 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid (60.0 mg, 0.0909 mmol) obtained in Step A in Example 1-D-19 and 2-(aminomethyl)pyridine (18.4 μl, 0.182 mmol) instead of 3-(aminomethyl)pyridine, amidation was carried out in the same manner as Step B in Example 1-D-19, to obtain a crude product of 4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-N-pyridin-2-ylmethyl-benzamide as a brown solid (119 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-282) as a yellow powder (41.8 mg, 90%).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:3][CH2:2]1.Br[CH2:17][CH2:18][CH2:19][N:20]([CH3:40])[C:21]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:10]2[CH2:11][CH2:12][N:13]([CH2:17][CH2:18][CH2:19][N:20]([CH3:40])[C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:14][CH2:15]2)[CH2:3][CH2:2]1
Reactant: c1ccc(N2CCNCC2)c(C2CC2)c1
Reactant: CN(CCCBr)C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CCCN1CCN(c2ccccc2C2CC2)CC1)C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 96 °C
Yield: 18.2 %

Procedure:
9.0 g (0. 0444 mol) of 1-(2-cyclopropylphenyl)piperazine, 200 ml of dimethylformamide, 17.5 g (0.0444 mol) of 3-bromo-N-methyl-N-(triphenylmethyl)propanamine and 9 g of potassium carbonate are introduced into a 500 ml round-bottomed flask equipped with a reflux condenser and placed under nitrogen, and the mixture is heated three times for 6 h at 96° C. The solvent is evaporated under reduced pressure, the residue is taken up with water and dichloromethane, the organic phase is separated, washed with water, dried over sodium sulphate and the solvent is evaporated under reduced pressure. There are obtained 4.17 g of 3-[4-(2-cyclopropylphenyl)piperazin-1-yl]-N-methyl-N-(tri-phenylmethyl)propanamine in the form of an oil which is dissolved in 200 ml of methanol, a stream of gaseous hydrochloric acid is passed therein for 10 min, the mixture is concentrated, allowed to stand for 2 days and the precipitate is separated by filtration. 2.94 g of compound are obtained.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[OH:5][CH:6]([CH2:16][NH:17][CH:18]([CH3:20])[CH3:19])[CH2:7][O:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1>C1(C)C=CC=CC=1.O1CCOCC1>[CH:18]([N:17]1[CH2:16][CH:6]([CH2:7][O:8][C:9]2[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[O:5][C:1]1=[O:2])([CH3:20])[CH3:19]
Reactant: O=C(Cl)Cl
Reactant: Cc1ccc(OCC(O)CNC(C)C)cn1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1ccc(OCC2CN(C(C)C)C(=O)O2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 10 g of phosgene in 40 ml of toluene is added dropwise at 5°-10° C. to 15.6 g of 3-(2'-hydroxy-3'-isopropylamino-propoxy)-6-methyl-pyridine, dissolved in 75 ml of dioxane, in the presence of 8 ml of 2,6-lutidine,whilst stirring. The reaction mixture is stirred overnight at room temperature and is then evaporated in vacuo. The evaporation residue is rendered alkaline with a little concentrated sodium hydroxide solution and is extracted with 200 ml of ethyl acetate. The organic phase is evaporated, initially at approx. 20 mm Hg and then at 0.1 mm Hg/60° C. bath temperature. Approx. 50 ml of ether are added to the residue which remains, giving crystalline 3-isopropyl-5-[(6-methylpyridin-3-yloxy)methyl]-oxazolidin-2-one of melting point 86°-88° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[CH:6]=[CH:5]2.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccc2cc(I)ccc2[nH]1
Product: Clc1ccc2cc(I)ccc2n1
Yield: 87 %

Procedure:
A mixture of 6-iodo-1H-quinolin-2-one (6.23 g, 23 mmol) in phosphorus oxychloride (25 mL) was refluxed under N2 for 2 h. After cooling, the solvent was removed by rotary evaporator and then by the oil pump. Sat. sodium bicarbonate (100 mL) was slowly added. The solid was collected by filtration, washed with sat. sodium bicarbonate, water and dried to obtain 2-chloro-6-iodo-quinoline (5.78 g, 87%) as a black solid. LC-MS m/e 290 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:19])[C:8]([C:11]2[CH:12]=[N:13][C:14]([CH:17]=O)=[CH:15][CH:16]=2)=[N:9][CH:10]=1)=[O:4].[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:27]=[C:28]([NH2:33])[C:29]([NH2:32])=[CH:30][CH:31]=2)[CH2:22][CH2:21]1>[N+](C1C=CC=CC=1)([O-])=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:19])[C:8]([C:11]2[CH:12]=[N:13][C:14]([C:17]3[NH:33][C:28]4[CH:27]=[C:26]([N:23]5[CH2:24][CH2:25][O:20][CH2:21][CH2:22]5)[CH:31]=[CH:30][C:29]=4[N:32]=3)=[CH:15][CH:16]=2)=[N:9][CH:10]=1)=[O:4]
Reactant: Nc1ccc(N2CCOCC2)cc1N
Reactant: COC(=O)c1cnc(-c2ccc(C=O)nc2)c(Cl)c1
Solvent: O=[N+]([O-])c1ccccc1
Product: COC(=O)c1cnc(-c2ccc(-c3nc4ccc(N5CCOCC5)cc4[nH]3)nc2)c(Cl)c1
Temperature: 25 °C
Yield: 67.5 %

Procedure:
0.50 g of 3-chloro-6′-formyl-[2,3]bipyridyl-5-carboxylic acid methyl ester (13) (1.81 mmol) prepared in Example 9 and 0.35 g of 4-morpholinobenzene-1,2-diamine(18) (1.81 mmol) prepared in Example 12 were dissolved in nitrobenzene (5.0 mL), and refluxed under heating for 2 hours. The reactant was cooled to room temperature, and concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: ethyl acetate/hexane=1/1) to obtain 0.55 g of 3-chloro-6′-(6-morpholin-4-yl-1H-benzoimidazol-2-yl)-[2,3]bipyridinyl-5-carboxylic acid methyl ester (yield 68%).