Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OP([CH:9]([C:21]#[N:22])[CH:10]([CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[CH2:11][CH2:12][CH:13]=[CH2:14])(=O)OCC)C.[N+:23]([C:26]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:30][C:27]=1[CH:28]=O)([O-])=O.[Cl-].[NH4+]>C1COCC1>[O:34]([C:31]1[CH:30]=[C:27]2[C:26](=[CH:33][CH:32]=1)[N:23]=[C:21]([NH2:22])[C:9]([CH:10]([CH:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1)[CH2:11][CH2:12][CH:13]=[CH2:14])=[CH:28]2)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Reactant: C=CCCC(C1CCOCC1)C(C#N)P(=O)(OCC)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCCC(c1cc2cc(Oc3ccccc3)ccc2nc1N)C1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the oil isolated in Step B (23.28 g, 70.7 mmol) in THF (100 mL) at −78° C., LHDMS (1.0 M, 84.8 mL, 84.8 mmol) was added slowly. The reaction mixture was then stirred at room temperature for 1 hour. A solution of 2-nitro-5-phenoxybenzaldehyde (20.63 g, 75.5 mmol) in THF (100 mL) was added. The reaction mixture was stirred at room temperature overnight. Saturated aqueous ammonium chloride (200 mL) was added. The reaction mixture was extracted with ethyl acetate three times. The combined organic extracts were washed with brine and dried over magnesium sulfate. The reaction mixture was filtered and concentrated to yield a colorless oil which was a mixture of cis-[2-(2-nitro-5-phenoxy-benzylidene)-3-(tetrahydro-pyran-4-yl)-hept-6-enenitrile] and trans-[2-(2-nitro-5-phenoxy-benzylidene)-3-(tetrahydro-pyran-4-yl)-hept-6-enenitrile].
Reaction SMILES: Br[CH2:2][CH:3]([OH:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].O1C=CCCC1>C(Cl)Cl.CCOCC.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1>[O:10]1[CH2:2][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9]
Reactant: OCCCCCC(O)CBr
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: OCCCCCC1CO1
Temperature: 25 °C
Reaction time: 20 h
Yield: 225.1 %

Procedure:
A solution of 4 (123 mg, 0.58 mmol) and dihydropyran (0.22 mL, 2.33 mmol) in methylene chloride (2 mL) containing pyridinium tosylate (25 mg, 0.1 mmol) was stirred at room temperature for 20 hours. It was diluted with ether and washed with saturated aqueous sodium chloride. The separated aqueous layer was extracted once with ether and the combined ether layer was dried over magnesium sulfate. The crude product was purified on a silica gel column to give 170 mg of 7-bromo-1,6-bistetrahydropyranyl heptanyl ether (6). PMR (CDCl3): δ4.86-4.48 (m, 2H), 4.00-3.41 (m, 9H), 1.93-1.18 (m, 20H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]#[C:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:12]=1)[CH3:2].[C:18]([O:22][C:23]([N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH2:35][CH2:36][O:37][C:38]3[CH:39]=[C:40]4[C:44](=[CH:45][CH:46]=3)[NH:43][CH:42]=[CH:41]4)[N:33]=2)[CH2:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH2:35][CH2:36][O:37][C:38]3[CH:39]=[C:40]4[C:44](=[CH:45][CH:46]=3)[N:43]([C:6]([C:7]3[CH:8]=[N:9][CH:10]=[C:11]([S:13]([CH3:16])(=[O:14])=[O:15])[CH:12]=3)=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[O:17])[CH:42]=[CH:41]4)[N:33]=2)[CH2:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Reactant: CCOC(=O)C#Cc1cncc(S(C)(=O)=O)c1
Product: CCOC(=O)C=C(c1cncc(S(C)(=O)=O)c1)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Yield: 80 %

Procedure:
The title compound was synthesized from (5-methanesulfonyl-pyridin-3-yl)-propynoic acid ethyl ester and 7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure described in Example 16, step (d1), in 80% yield. Mass Spectrum (LCMS, ESI) calculated for C29H31N4O5S: 547.2 (M-Boc+H); found 547.3 (−Boc).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[CH2:25]([NH:33][C:34]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH2:25]([NH:33][C:34](=[O:35])[C:36]1[CH:41]=[CH:40][C:39]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[N:8][C:9]=3[NH2:11])[N:4]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=2)=[CH:38][CH:37]=1)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(NCCc1ccccc1)c1ccc(B(O)O)cc1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(C(=O)NCCc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Yield: 23 %

Procedure:
cis-3-Iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.226 mmol), 4-[(phenethylamino)carbonyl]phenylboronic acid (60 mg, 0.249 mmol), palladium tetrakistriphenyphosphine (16 mg, 0.014 mmol) and sodium carbonate (58 mg, 0.544 mmol) were mixed with ethylene glycol dimethyl ether (3 mL) and water (1.5 mL). The reaction mixture was heated at reflux overnight. Organic solvent was removed under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by preparative thin layer column chromatography using dichloromethane/methanol (80:20) as mobile phase to give cis-N1-phenethyl-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}benzamide (28 mg, 23%). 1H NMR (DMSO-d6) δ 1.62 (m, 4H), 2.24 (m, 16H), 2.88 (m, 2H), 3.54 (m, 2H), 4.82 (m, 1H), 7.29 (m, 7H), 8.73 (d, J=8.10 Hz, 2H), 7.99 (d, 8.17 Hz, 1H), 8.67 (m, 1H). LC/MS (Micromass-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 3.5 mL/min.): MH+ =539.3, Rt=2.50 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[CH:14]=[C:13]3[O:18][CH2:19][O:20][C:12]3=[CH:11][C:10]=2[NH:9][CH:8]=1)=[O:6].[H-].[Na+].Br.Br[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[CH:14]=[C:13]3[O:18][CH2:19][O:20][C:12]3=[CH:11][C:10]=2[N:9]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH:8]=1)=[O:6]
Reactant: BrCc1ccccn1
Reactant: Cc1ccc(C(=O)c2c[nH]c3cc4c(cc3c2=O)OCO4)cc1C
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3ccccn3)c3cc4c(cc3c2=O)OCO4)cc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 71 mg (0.22 mmol) of 7-(3,4-dimethyl-benzoyl)-5H-[1,3]dioxolo[4,5-g]quinolin-8-one, 23 mg of 60% sodium hydride, 72 mg of 2-bromomethylpyridine hydrobromide and 1.3 mL of N,N-dimethylformamide. Yield: 75 mg of a white solid: LC-MSD, m/z for C25H20N2O4 [M+H]+=413.5; HPLC retention time: 2.1 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=2[N+:17]([O-])=O)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.BrC1C=C(C=CC=1)N>>[C:21]1([NH:20][C:14]([C:12]2[S:13][C:9]([S:8][C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)=[C:10]([NH2:17])[CH:11]=2)=[O:16])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2ccc(O)cc2)s1
Solvent: Nc1cccc(Br)c1
Product: Nc1cc(C(=O)Nc2ccccc2)sc1Sc1ccc(O)cc1

Procedure:
The product from Example 351C was reacted with aniline according to the procedure of Example 351D substituting aniline for 3-bromoaniline followed by reduction of the nitro group according to the procedure from Example 351E to provide the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30]C)[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16].[CH:32]1(C2N=C(N[C@@H]3C4C(=CC=CC=4)C[C@@H]3O)C(C)=NC=2C2C=CC(Cl)=CC=2Cl)CC1>>[CH:15]1([C:14]2[N:13]=[C:12]([NH:17][C@@H:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][C@@H:19]3[O:27][CH2:28][CH3:29])[C:11]([CH3:30])=[N:10][C:9]=2[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH2:32][CH2:16]1
Reactant: Cc1nc(-c2ccc(Cl)cc2Cl)c(C2CC2)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1C

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-{[6-cyclopropyl-5-(2,4-dichlorophenyl)-3-methylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.75–1.13, 1.53–1.59, 2.31, 2.98–3.09, 3.35–3.40, 3.57–3.65, 4.23–4.25, 5.37, 5.62, 7.12–7.42; MS (ESI+) for C25H25Cl2N3O m/z 454 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.C(N(CC)CC)C.Cl[CH2:18][N:19]([CH:26]=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH:26]([N:19]([CH2:18][N:5]1[CH:4]=[C:3]([Cl:2])[CH:8]=[N:7][C:6]1=[O:9])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:27]
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: O=CN(CCl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=CN(Cn1cc(Cl)cnc1=O)c1ccccc1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
5-Chloropyrimidin-2-one hydrochloride (3.0 mmol) and triethylamine (6 mmol) were stirred together in CH2Cl2 (50 ml) for 15 minutes before a solution of N-chloromethylformanilide (see Prepartion 12) (3 mmol) in CH2Cl2 was added. The mixture was stirred at 40° C. for 18 hours before the solvent was distilled off. The residue was washed with water and ether. Yield: 0.79 g (50%), m. p. 200° C. (EtOH). 1H NMR (DMSO-d6, δ): 5.68 (s, CH2), 7.32 (Ph), 8.05-8.65 (CHO, H-4 and H-6). IR (KBr, cm-1): 1660 (CO), 1680 (CO). MS (70 eV, m/e (% rel. int.)): 263 (M+, 1), 143 (7), 134 (41), 116 (6), 107 (6), 106 (100), 105 (57), 104 (10), 79 (10), 78 (7), 77 (41), 52 (11), 51 (20).
Reaction SMILES: [CH2:1]([C:3]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH3:10])[C:4]1=O)[CH3:2].[H-].[Li+].[Al+3].[H-].[H-].[H-].O>O1CCCC1>[CH2:1]([C:3]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH3:10])[CH2:4]1)[CH3:2]
Reactant: CCC1(c2cccc(O)c2)CCCCN(C)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCC1(c2cccc(O)c2)CCCCN(C)C1
Yield: 64.3 %

Procedure:
A solution of 3-ethylhexahydro-3-(3-hydroxyphenyl)-1-methyl-2H-azepin-2-one (1.5 g) in dry tetrahydrofuran was added to a stirred suspension of aluminium lithium hydride (0.48 g) and heated under reflux for 5 hours. The reaction mixture was cooled and decomposed by the addition of water and the precipitate filtered. The precipitate was washed with tetrahydrofuran and the combined filtrate and washings evaporated to a solid. The solid was dissolved in water and ammonium chloride added. The precipitated oil was extracted with dichloromethane, dried over anhydrous magnesium sulphate and evaporated to leave a solid which was recrystallised from acetonitrile to give 0.91 g of the title compound, m.p. 127.5°-133° C., identical with material prepared by an alternative route described in U.K. Pat. No. 1,285,025.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[NH:18]1[C:22]2[CH:23]=[CH:24][C:25]([C:27](O)=[O:28])=[CH:26][C:21]=2[N:20]=[CH:19]1.N(CCCC)(CCCC)CCCC.[I-].ClC1C=CC=C[N+]=1C>CN(C)C=O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:27]([C:25]3[CH:24]=[CH:23][C:22]4[NH:18][CH:19]=[N:20][C:21]=4[CH:26]=3)=[O:28])=[CH:8][CH:9]=2)[N:4]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: Cc1nn(-c2ccccc2)c2cc(N)ccc12
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Product: Cc1nn(-c2ccccc2)c2cc(NC(=O)c3ccc4[nH]cnc4c3)ccc12
Temperature: 100 °C
Reaction time: 48 h

Procedure:
Into a 100-mL 3-necked round-bottom flask, was placed a solution of 3-methyl-1-phenyl-1H-indazol-6-amine (520 mg, 2.33 mmol, 1.00 equiv) in N,N-dimethylformamide (50 mL), 1H-benzo[d]imidazole-5-carboxylic acid (324 mg, 2.00 mmol, 0.86 equiv), NBu3 (925 mg, 5.00 mmol, 2.14 equiv). To the resulting mixture was then added 2-chloro-1-methylpyridiniumiodide (612 mg, 2.40 mmol, 1.03 equiv) at 50° C. The resulting solution was stirred for 2 days at 100° C. in an oil bath, then concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (50:1). The resulting mixture was washed with methanol (1×10 mL) and diethyl ether (1×10 mL) to yield N-(3-methyl-1-phenyl-1H-indazol-6-yl)-1H-benzo[d]imidazole-5-carboxamide as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.[C:14]([NH:21][CH2:22][CH2:23][CH2:24]Br)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:17]([O:16][C:14](=[O:15])[NH:21][CH2:22][CH2:23][CH2:24][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: O=Cc1ccc(O)c2ccccc12
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCOc1ccc(C=O)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a solution of 4-hydroxy-naphthalene-1-carbaldehyde (15.2 g, 58.1 mmol) in DMF (50 mL) at r.t. was added N-Boc 3-bromo-propylamine (15.2 g, 63.9 mmol), followed by potassium carbonate (12 g, 87.2 mmol). The reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture and extracted by CH2Cl2. The combined organic layers were washed with water, brine, dried over MgSO4, filtered, and concentrated. The residue was recrystallized from EtOAc/hexane to afford [3-(4-formyl-naphthalen-1-yloxy)-propyl]carbamic acid tert-butyl ester (13.8 g, 72%) as a light yellow solid.
Reaction SMILES: [C:1]1([N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]2[CH:11]=[C:12]3[N:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=4)[N:16]([CH3:29])[C:13]3=[N:14][CH:15]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:36].C(=O)([O-])[O-].[NH4+:41].[NH4+].C(OCC)(=O)C.C(O)C.N>C(O)C>[ClH:36].[C:1]1([N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]2[CH:11]=[C:12]3[N:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:22]=[CH:23][C:24]([C:27](=[NH:41])[NH2:28])=[CH:25][CH:26]=4)[N:16]([CH3:29])[C:13]3=[N:14][CH:15]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CN(C(=O)c1cnc2c(c1)nc(CCc1ccc(C#N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: N
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CN(C(=O)c1cnc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Yield: 84 %

Procedure:
Prepared analogously to Example 1 from 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-ethoxycarbonylmethyl-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 84% of theory, C27H28N6O3 (484.56) Rf value: 0.44 (silica gel; ethyl acetate/ethanol/ammonia=50:45:5) EKA mass spectrum: (M+H)+ =485
Reaction SMILES: [Na].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16].[CH2:17]([O:19][C:20](=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24]Br)[CH3:18]>CC(O)C>[CH2:17]([O:19][C:20](=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH:9]=[CH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1)[CH3:18]
Reactant: CCOC(=O)CCCCBr
Reactant: Oc1ccccc1C=Cc1ccccn1
Agent: [Na]
Solvent: CC(C)O
Product: CCOC(=O)CCCCOc1ccccc1C=Cc1ccccn1

Procedure:
To the solution of 2.3 g (0.1 mol) sodium in 250 ml ethanol one adds 19.7 g 2-[2-(2-pyridinyl)-ethenyl]-phenol, stirs for 10 min at room temp., adds thereto 17.4 ml (0.11 mol) 5-bromovaleric acid ethyl ester and heats to reflux for 16 h. One evaporates, mixes with water, extracts with dichloromethane, dries the extract and evaporates. There remain 32.4 g of title compound (100% of theory) as oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]#[C:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[S:17][C:10]=12.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42](O)=[O:43])[C:37]2=[O:45])=[CH:32][CH:31]=1.O=C1C(C(OC)=O)=CC=CO1.FC1C=CC(N)=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([NH:28][C:42]([C:38]2[C:37](=[O:45])[N:36]([C:33]3[CH:32]=[CH:31][C:30]([F:29])=[CH:35][CH:34]=3)[CH:41]=[CH:40][CH:39]=2)=[O:43])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]#[C:19][CH2:20][N:21]3[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]3)[S:17][C:10]=12
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Reactant: CN1CCN(CC#Cc2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Agent: COC(=O)c1cccoc1=O
Agent: Nc1ccc(F)cc1
Product: CN1CCN(CC#Cc2cc3nccc(Oc4ccc(NC(=O)c5cccn(-c6ccc(F)cc6)c5=O)cc4F)c3s2)CC1
Yield: 19 %

Procedure:
The title compound was prepared from 3-fluoro-4-(2-(3-(4-methylpiperazin-1-yl)prop-1-ynyl)thieno[3,2-b]pyridin-7-yloxy)aniline (Example 17, Step B) and 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (prepared from methyl 2-oxo-2H-pyran-3-carboxylate with 4-fluoroaniline and followed by hydrolysis using the methods described in US 2005/0239820) according to the procedure for Example 89. The crude was purified by silica gel flash column chromatography (5% MeOH in CH2Cl2) to afford 3 mg (19%) of the desired product. 1H NMR (400 MHz, CD3OD/CDCl3) δ 8.73 (dd, 1H), 8.45 (d, 1H), 7.98 (dd, 1H), 7.84 (dd, 1H), 7.58 (s, 1H), 7.48 (m, 2H), 7.40 (d, 1H), 7.31 (t, 2H), 6.74 (t, 1H), 6.63 (d, 1H), 3.64 (s, 2H), 2.60-2.76 (m, 8H), 2.33 (s, 3H); 19F NMR (376 MHz, CD3OD/CDCl3) δ −112.1, −127.6. LRMS (ESI pos) m/e 612.1 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:24]=[C:23]([CH2:25][CH3:26])[C:22]([C:27]2[NH:31][C:30]([CH2:32][CH2:33][O:34][CH3:35])=[N:29][N:28]=2)=[CH:21][C:4]=1[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:2].O1CCC(C(NN)=O)[CH2:37]1.COCCC(NN)=O>>[CH2:1]([C:3]1[CH:24]=[C:23]([CH2:25][CH3:26])[C:22]([C:27]2[NH:31][C:30]([CH:32]3[CH2:37][CH2:35][O:34][CH2:33]3)=[N:29][N:28]=2)=[CH:21][C:4]=1[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:14]=[CH:15][C:16]([C:17]#[N:18])=[CH:19][CH:20]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:2]
Reactant: CCc1cc(CC)c(-c2nnc(CCOC)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reactant: NNC(=O)C1CCOC1
Agent: COCCC(=O)NN
Product: CCc1cc(CC)c(-c2nnc(C3CCOC3)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of 4-(1-(2,4-diethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 209) but using tetrahydrofuran-3-carbohydrazide (compound 38.2) instead of 3-methoxypropanehydrazide (compound 143.1). m/z (ES+) 484.05 (M+H)+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[N:8][CH:9]=1.I[CH2:12][CH3:13]>C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7](=[O:10])[N:8]([CH2:12][CH3:13])[CH:9]=1
Reactant: Oc1ccc(Br)cn1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1cc(Br)ccc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of NaH (60% dispersion in mineral oil, 1.34 g, 0.056 mol) in THF (10 mL), a solution of 5-bromopyridin-2-ol (2.5 g, 0.014 mol) in THF (50 mL) was added and the resulting mixture was stirred at RT for 1 h. To this mixture, iodoethane (10.9 g, 0.07 mol) was added and the mixture was stirred at RT overnight. The mixture was quenched with water and washed with NH4Cl solution. The organic phase was separated, then concentrated in vacuo and the residue was purified by flash chromatography on silica gel (50-100% PE-AE) to afford 5-bromo-1-ethylpyridin-2(1H)-one.
Reaction SMILES: [CH2:1]([O:8][P:9](=[O:19])([OH:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O.C(#N)C>[O:10]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[P:9]([O:18][P:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:18])(=[O:19])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(O)(OCc1ccccc1)OCc1ccccc1
Solvent: CC#N
Solvent: O
Product: O=P(OCc1ccccc1)(OCc1ccccc1)OP(=O)(OCc1ccccc1)OCc1ccccc1
Reaction time: 2 h

Procedure:
A flask fitted with a nitrogen inlet, overhead stirrer, teflon-coated thermocouple probe, and pressure-equalizing addition funnel was charged with 350 milliliters of dry (water content ≤50 μg/mL), peroxide-free tetrahydrofuran, followed by 50.0 grams (174 millimoles) of dibenzylphosphoric acid (DBP), and the resulting mixture was stirred until the solid dissolved (about 10-15 minutes). A solution of 18.9 grams (91.6 millimoles) of dicyclohexylcarbodiimide (DCC) in 215 milliliters of THF was added from the addition funnel to a stirred, cooled (water-bath) solution of DBP at a rate to maintain the temperature at about 20°-25° C. The reaction is slightly exothermic and the addition took about 30 minutes. Within minutes, a precipitate of dicyclohexylurea formed in the mixture. Stirring was continued for about 2 hours at 20°-25° C. The reaction was monitored by HPLC assay using VYDAC C-18 (300A, 4.6×250 mm) column with water (0.02M KH2PO4) acetonitrile as eluent. The reaction was complete in about 1 hour (assay showing <2 percent unreacted DBP). The mixture was then filtered while excluding moisture to remove dicyclohexylurea. The filter cake was washed with two 25 milliliter portions of THF. The solution when assayed by HPLC showed 45.9 grams (98 percent) yield of tetrabenzyl pyrophosphate (TBPP) in 620 milliliters of THF (0.137M). The filtrate was then stored at 0° C. with exclusion of moisture until the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.[H][H].C(O)C>C1(C)C=CC=CC=1.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCCCCO
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Nc1cnc2ccccc2c1NCCCCO
Reaction time: 1 h
Yield: 105.6 %

Procedure:
Catalyst (5% Pd/C) was added to a suspension of 4-[(3-nitroquinolin-4-yl)amino]butan-1-ol (18.2 g, 69.6 mmol) in toluene (450 mL) in a Parr vessel. The vessel was placed on a shaker and pressurized with hydrogen. The next day ethanol (60 mL) and additional catalyst were added and the vessel was again pressurized with hydrogen. After 1 hour analysis by TLC indicated that all of the starting material had been consumed. The reaction mixture was filtered through a layer of CELITE filter aid and then concentrated under reduced pressure to provide 17 g of 4-[(3-aminoquinolin-4-yl)amino]butan-1-ol.