Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]2[N:10]([C:14]3[CH:19]=[C:18]([O:20][CH2:21][C:22]4[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[C:24]([F:30])[C:23]=4[F:31])[C:17]([O:32][CH2:33][CH2:34][OH:35])=[CH:16][C:15]=3[Cl:36])[C:11](=[O:13])[NH:12][C:7]2=[CH:6][CH:5]=1)(O)=[O:2].B.O1CCCC1.O.[Cl-].[NH4+]>O1CCCC1>[Cl:36][C:15]1[CH:16]=[C:17]([O:32][CH2:33][CH2:34][OH:35])[C:18]([O:20][CH2:21][C:22]2[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[C:24]([F:30])[C:23]=2[F:31])=[CH:19][C:14]=1[N:10]1[C:8]2=[N:9][C:4]([CH2:1][OH:2])=[CH:5][CH:6]=[C:7]2[NH:12][C:11]1=[O:13]
Reactant: COc1ccc(F)c(F)c1COc1cc(-n2c(=O)[nH]c3ccc(C(=O)O)nc32)c(Cl)cc1OCCO
Agent: B
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(F)c(F)c1COc1cc(-n2c(=O)[nH]c3ccc(CO)nc32)c(Cl)cc1OCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
To a solution of 5-carboxy-3-[2-chloro-5-(2,3-difluoro-6-methoxybenzyl-oxy)-4-(2-hydroxyethoxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (28 mg) in tetrahydrofuran (3 mL) was added borane-tetrahydrofuran complex (1.2 mol/L tetrahydrofuran solution, 0.21 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture were added water and a saturated aqueous ammonium chloride solution, and the resulting mixture was stirred at room temperature for 5 minutes. The mixture was extracted with ethyl acetate twice, and the extracts were dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−ethyl acetate−ethyl acetate/methanol=10/1) to give the title compound (6 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:16]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCOCCCCCCCl
Reactant: O=C1CCNCC1
Product: CCCCOCCCCCCN1CCC(=O)CC1

Procedure:
1-(6-Butoxyhexyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-6-butoxyhexane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[S:3]([C:6]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:7]=1[CH2:8][NH:9][C:10]([C:12]1[C:21]([OH:22])=[C:20]2[C:15]([CH:16]=[CH:17][CH:18]=[N:19]2)=[C:14]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][S:24]2(=[O:30])=[O:29])[N:13]=1)=[O:11])(=[O:5])=[O:4].[OH-].[Na+:38]>C(#N)C>[CH3:1][N:2]([CH3:36])[S:3]([C:6]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:7]=1[CH2:8][NH:9][C:10]([C:12]1[C:21]([O-:22])=[C:20]2[C:15]([CH:16]=[CH:17][CH:18]=[N:19]2)=[C:14]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][S:24]2(=[O:30])=[O:29])[N:13]=1)=[O:11])(=[O:5])=[O:4].[Na+:38]
Reactant: CN(C)S(=O)(=O)c1cc(F)ccc1CNC(=O)c1nc(N2CCCCS2(=O)=O)c2cccnc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CN(C)S(=O)(=O)c1cc(F)ccc1CNC(=O)c1nc(N2CCCCS2(=O)=O)c2cccnc2c1[O-]

Procedure:
To a suspension of N-{2-[(dimethylamino)sulfonyl]-4-fluorobenzyl}-5-(1,1-dioxido-1,2-thiazinan-2-yl)-8-hydroxy-1,6-naphthyridine-7-carboxamide (147 mg, 0.27 mmol) in acetonitrile (1 mL) was added 1N sodium hydroxide (287 μL, 0.29 mmol). After the solution became homogeneous, the sample was concentrated in vacuo to afford the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:12]([I:13])=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[O:14][CH3:15])[CH:2]=[CH2:3].[CH:16]([C:18]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=1)=[O:19])=[CH2:17].C(O)C>S1C=CN=C1.C(N(CC)CC)C>[CH2:1]([O:4][C:5]1[C:12]([I:13])=[CH:11][C:8]([C:9](=[O:10])[CH2:17][CH2:16][C:18]([C:20]2[CH:21]=[C:22]([O:30][CH3:31])[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=2)=[O:19])=[CH:7][C:6]=1[O:14][CH3:15])[CH:2]=[CH2:3]
Reactant: C=CC(=O)c1cc(OC)c(OC)c(OC)c1
Reactant: C=CCOc1c(I)cc(C=O)cc1OC
Agent: c1cscn1
Solvent: CCO
Solvent: CCN(CC)CC
Product: C=CCOc1c(I)cc(C(=O)CCC(=O)c2cc(OC)c(OC)c(OC)c2)cc1OC
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 4-allyloxy-5-iodo-3-methoxybenzaldehyde (46 g, 0.15 mol), 3,4,5-trimethoxyphenyl vinyl ketone (38 g, 0.16 mol) and thiazole catalyst (6 g, 0.07 mol) in triethylamine (200 ml) was heated, with stirring, at 70° C. for 2 hours, and kept at room temperature overnight. Ethanol was added to the solid mass, filtered, and the filtrate was evaporated to a residue, which was purified by HPLC (hexane-ethyl acetate; 2:1, v/v) to afford 1-(4-allyloxy-5-iodo-3-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,4-butanedione, m.p. 113°-114° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[C:27]1[NH:31][C:30](=[O:32])[O:29][N:28]=1)[O:5][CH2:6][C:7]1[S:11][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:9][C:8]=1[CH:22]=O.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.C([BH3-])#N.[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([O:5][CH2:6][C:7]2[S:11][C:10]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:16][CH:17]=3)=[N:9][C:8]=2[CH2:22][N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[CH:24]=[CH:25][C:26]=1[C:27]1[NH:31][C:30](=[O:32])[O:29][N:28]=1
Reactant: C1CCNC1
Reactant: O=Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(-c2noc(=O)[nH]2)c(F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]c(-c2ccc(OCc3sc(-c4ccc(C(F)(F)F)cc4)nc3CN3CCCC3)cc2F)no1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 50 mg of 5-[3-fluoro-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxymethyl]-2-(4-trifluoromethyl-phenyl)-thiazole-4-carbaldehyde in 2 mL of methanol was added 0.03 mL of pyrrolidine. The resulting solution was stirred at room temperature for 1.5 h then 13.5 mg of sodium cyanoborohydride was added. After stirring at room temperature for 4 h, the reaction mixture was concentrated under reduced pressure. Ethyl acetate/water was added to the residue. The organic layer was separated and the aqueous layer extracted three times with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (dichloromethane 80/methanol 20) to give 9 mg of 3-{2-fluoro-4-[4-pyrrolidin-1-ylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-4H-[1,2,4]oxadiazol-5-one as a beige solid.
Reaction SMILES: C(O[CH2:4][N:5]1[C:9]2=[N:10][C:11]3[N:12]([CH3:26])[C:13](=[O:25])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([OH:24])[CH3:23])[C:15](=[O:17])[C:16]=3[N:8]2[CH2:7][CH2:6]1)C.[H][H]>[Pd].C(O)(=O)C>[CH3:26][N:12]1[C:11]2[N:10]=[C:9]3[N:5]([CH3:4])[CH2:6][CH2:7][N:8]3[C:16]=2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([OH:24])[CH3:23])[C:13]1=[O:25]
Reactant: [H][H]
Reactant: CCOCN1CCn2c1nc1c2c(=O)n(CCCC[C@@H](C)O)c(=O)n1C
Agent: [Pd]
Solvent: CC(=O)O
Product: C[C@@H](O)CCCCn1c(=O)c2c(nc3n2CCN3C)n(C)c1=O

Procedure:
A mixture of (R)-7,8-dihydro-8-ethoxymethyl-3-(5-hydroxyhexyl)-1-methyl-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione (60 mg, 0.164 mmol) and 10% palladium on carbon (50% water, 100 mg) in acetic acid (25 ml) was treated with hydrogen gas (50 psi) on a Parr sharker at room temperature for 18 hours. After filtration through a pad of celite, concentration of the filtrate under reduced pressure provided (R)-7,8-dihydro-1,8-dimethyl-3-(5-hydroxyhexyl)-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione (CT-31878) as a white powder.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([Br:26])[C:22]([N+:23]([O-])=O)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1[CH2:32][CH2:31][C@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:29]1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([Br:26])[C:22]([N:23]3[CH2:32][CH2:31][C@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:39])[CH3:38])[CH2:29]3)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: O=C1c2cccc3c([N+](=O)[O-])c(Br)cc(c23)C(=O)N1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2c(Br)cc3c4c(cccc24)C(=O)N(OCc2ccccc2)C3=O)C1
Yield: 80.8 %

Procedure:
Following the procedure of Example W1, 2-benzyloxy-5-bromo-6-nitro-benzo[de]isoquinoline-1,3-dione (0.40 g, 0.94 mmol, from Example S1-A), (S)-pyrrolidin-3-yl-carbamic acid, tert-butyl ester (0.38 g, 2.1 mmol) and triethyl amine (0.18 g, 1.9 mmol) in DMF (5 mL) were reacted at 80° C. for 48 hours to give 0.43 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[Na+].[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29]Cl>CO>[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:10]2[CH:9]=[C:8]([C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=3)[O:12][N:11]=2)=[CH:15][CH:16]=1
Reactant: ClCc1ccccn1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3ccccn3)cc2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
To a mixture of 4-(5-(2-amino-pyridin-3-yl)isoxazol-3-ylmethyl)-phenol (4.2 mg, 0.016 mmol) described in Manufacturing Example 5-1-1 and methanol (0.4 mL) was added 1 N aqueous sodium hydroxide solution (16 μL, 0.016 mmol), which was then concentrated under a reduced pressure. To a mixture of the residue and N,N-dimethylformamide (0.5 mL) was added 2-picolyl chloride (3.1 mg, 0.019 mmol), which was stirred for 2 hours at room temperature. The reaction mixture was purified as is by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (3.6 mg, 39%) as a ditrifuoracetic acid salt.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2Cl)(=[O:3])[CH3:2].Cl[C:17]1[CH:18]=[C:19]([C@H:24]([NH2:26])[CH3:25])[CH:20]=[CH:21][C:22]=1F>C(O)(C)C>[C:19]1([C@H:24]([NH:26][C:8]2[C:7]3[C:12](=[CH:13][CH:14]=[C:5]([OH:4])[CH:6]=3)[N:11]=[CH:10][N:9]=2)[CH3:25])[CH:20]=[CH:21][CH:22]=[CH:17][CH:18]=1.[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2[NH:26][C@@H:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:17][CH:18]=1)[CH3:25])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2ncnc(Cl)c2c1
Reactant: C[C@@H](N)c1ccc(F)c(Cl)c1
Solvent: CC(C)O
Product: CC(=O)Oc1ccc2ncnc(N[C@H](C)c3ccccc3)c2c1
Product: C[C@@H](Nc1ncnc2ccc(O)cc12)c1ccccc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
A mixture of compound 0204 (1.0 g, 4.5 mmol) and (R)-1-(3-chloro-4-fluoro-phenyl)ethanamine (0.87 g, 5.0 mmol) in isopropanol (45 mL) was stirred at 90° C. for 1 hour. The mixture was cooled to room temperature and the resulting precipitate was isolated. The solid was washed in turn with isopropanol and methanol, dried to provide the title compound (R)-4-(1-phenylethylamino)quinazolin-6-yl acetate as a yellow solid (0.62 g, 61%): LCMS 308 [M+1]+.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14](O)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[N:24]1[C:32]2[C:27](=[N:28][CH:29]=[CH:30][CH:31]=2)[S:26][C:25]=1[NH2:33].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:14]([NH:33][C:25]3[S:26][C:27]4[C:32]([N:24]=3)=[CH:31][CH:30]=[CH:29][N:28]=4)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: Nc1nc2cccnc2s1
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(Nc1nc2cccnc2s1)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Yield: 63.7 %

Procedure:
The compound of example A79 was obtained by similar method described in example A75 using (4-cyclopropanesulfonyl-phenyl)-[(tetrahydro-pyran-4-yloxy)]-acetic acid (Preparation 14) (0.2 g, 0.58 mmol), thiazolo[5,4-b]pyridin-2-ylamine (0.133 g, 0.88 mmol), HOBt (0.119 g, 0.88 mmol), and EDCI (0.168 g, 0.88 mmol), N-methyl morpholine (0.178 g, 0.88 mmol) in DMF (10 mL) to provide the title compound (0.175 g).
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH2:24])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[OH-].[Na+].Cl>C1COCC1.CO>[NH2:24][CH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:13]=1[C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:25])=[O:2])[CH:6]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1CN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2′-Aminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.058 g, 0.17 mmol) in THF (0.59 mL) and MeOH (0.47 mL) was treated with 1N aqueous NaOH (0.17 mL, 0.17 mmol) and stirred overnight at room temperature. Analytical LCMS indicated that starting material was still present, so the reaction was stirred at 50° C. for 4.5 hours. Analytical LCMS showed that no change had occurred, so additional 1N aqueous NaOH (0.20 mL, 0.20 mmol) was added, and the reaction was stirred at 50° C. overnight. The mixture was cooled to room temperature and acidified with 1N aqueous HCl. The aqueous layer was extracted with CH2Cl2, and then diluted with brine and extracted twice with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: CC(C)([O-])C.[K+].COP([CH2:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=O)OC.[C:21]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][C:22]1=[O:29]>C(O)(C)(C)C>[CH3:19][C:16]([CH3:17])([CH3:18])[CH2:15][C:14](=[O:20])[CH2:13][C:21]1[C:22](=[O:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=1
Reactant: O=C1CCCCCCC1=O
Reactant: COP(=O)(CC(=O)CC(C)(C)C)OC
Agent: CC(C)(C)CC(=O)C/C1=C/CCCCCC1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)(C)CC(=O)CC1=CCCCCCC1=O

Procedure:
A solution of potassium tert-butoxide (0.192 g) in tert-butanol (10 mL) under an argon atmosphere was treated at 50° C. with (4,4-dimethyl-2-oxo-pentyl)-phosphonic acid dimethyl ester (0.38 g) and cyclooctane-1,2-dione (0,2 g), and the mixture was then heated at reflux for 12 h under an argon atmosphere. The reaction mixture was partitioned between water and AcOEt, the layers were separated, the aqueous layer extracted twice with AcOEt. The combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (heptane/AcOEt 100% to 95%) to give (Z)-2-(4,4-dimethyl-2-oxo-pentyl)-cyclooct-2-enone (0.076 g) as a light yellow oil. MS (ESI): 237.0 (MH+).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[N:29]1([CH2:36][CH2:37][O:38][C:39]2[CH:40]=[CH:41][C:42]([C:45]([O-])=O)=[N:43][CH:44]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.[Na+]>>[N:29]1([CH2:36][CH2:37][O:38][C:39]2[CH:40]=[CH:41][C:42]([CH2:45][N:3]([CH2:1][CH3:2])[C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=3[CH:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[N:43][CH:44]=2)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C([O-])c1ccc(OCCN2CCCCCC2)cn1
Agent: [Na+]
Product: CCN(Cc1ccc(OCCN2CCCCCC2)cn1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 50.4 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (40 mg) and sodium 5-(2-azepan-1-ylethoxy)pyridine-2-carboxylate (120 mg) according to an analogous synthetic method to Example 152, the title compound (28 mg) was obtained.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13]C1C=CC(N[C:19]2[C:28]3[C:23](=[CH:24][C:25](O)=[C:26](OC)[CH:27]=3)[N:22]=[CH:21][N:20]=2)=C(F)C=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C>C(Cl)Cl>[ClH:13].[N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[N:20][CH:21]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCO
Product: Cl
Product: c1ccc2ncncc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 150.1 %

Procedure:
Diethyl azodicarboxylate (209 mg, 1.2 mmol) was added dropwise to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (128 mg, 0.4 mmol), (prepared as described for the starting material in Example 2), triphenylphosphine (314 mg, 1.2 mmol) and 22-morpholinoethoxy)ethanol (97 mg, 0.56 mmol) in methylene chloride (4 ml) under nitrogen. The mixture was stirred for 1 hour at ambient temperature, triphenylphosphine (105 mg, 0.4 mmol), 22-morpholinoethoxy)ethanol (49 mg, 0.28 mmol) and diethyl azodicarboxylate (70 mg, 0.4 mmol) were added. The mixture was stirred for 1 hour at ambient temperature and was purified by pouring directly onto a silica column eluting with methylene chloride/acetonitrile/methanol (6/3/1). The purified product was triturated with ether, collected by filtration and dissolved in methylene chloride. 2M Ethereal hydrogen chloride (0.5 ml) was added and the resulting precipitate was collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(22-morpholinoethoxy)ethoxy)quinazoline hydrochloride (100 mg, 45%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[CH3:14][C:15]1[NH:16][C:17]2[C:22]([C:23]=1[CH3:24])=[CH:21][C:20]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:19][CH:18]=2>>[C:10]([C:9]([C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][N:16]1[C:17]2[C:22](=[CH:21][C:20]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:19][CH:18]=2)[C:23]([CH3:24])=[C:15]1[CH3:14])([CH3:13])[CH3:12])#[N:11]
Reactant: C=CCOC(=O)c1ccc2[nH]c(C)c(C)c2c1
Reactant: CC(C)(C#N)c1cccc(CBr)c1
Product: C=CCOC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1cccc(C(C)(C)C#N)c1

Procedure:
The title compound was prepared following the same general protocol as described in Step 2, Example 1, using 2-(3-(bromomethyl)phenyl)-2-methylpropanenitrile and allyl 2,3-dimethyl-1H-indole-5-carboxylate. ESI-MS (m/z): 387 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:27]=[CH:26][C:25]([NH:28]C(OC(C)(C)C)=O)=[CH:24][C:12]=3[C:13](=[O:23])[C:14]=2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:5][CH:4]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][C:12]=3[C:13](=[O:23])[C:14]=2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2oc3ccc(NC(=O)OC(C)(C)C)cc3c(=O)c2OCc2ccccc2)cn1
Solvent: ClCCl
Product: COc1ccc(-c2oc3ccc(N)cc3c(=O)c2OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a suspension of 2-(6-methoxypyridin-3-yl)-3-benzyloxy-6-(N-tertbutoxycarbonylamino)-4H-1-benzopyran-4-one (0.067 mol) in DCM (90 ml) trifluoroacetic acid (30 ml) was added. The mixture was stirred for 1 hour at r.t. and concentrated. Aqueous NaHCO3 was added and the mixture was extracted with ethyl acetate, washed with water, dried, and concentrated. The solid was suspended in ethyl ether, filtered and dried. Yield: 78%; TLC (9/1 Chloroform/Methanol) Rf: 0.56.
Reaction SMILES: [N:1]1[O:2][CH:3]=[C:4]2[C:9]=1[CH2:8][CH2:7][NH:6][CH2:5]2.Cl[C:11]1[N:16]=[C:15]([Cl:17])[CH:14]=[CH:13][N:12]=1.CCN(C(C)C)C(C)C>CCO>[Cl:17][C:15]1[N:16]=[CH:11][N:12]=[C:13]([N:6]2[CH2:7][CH2:8][C:9]3=[N:1][O:2][CH:3]=[C:4]3[CH2:5]2)[CH:14]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: c1onc2c1CNCC2
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc(N2CCc3nocc3C2)ncn1
Temperature: 150 °C
Yield: 69.7 %

Procedure:
4,5,6,7-Tetrahydro-isoxazolo[4,3-c]pyridine (162.0 mg, 1.3 mmol), 2,4-dichloropyrimidine (213.9 mg, 1.4 mmol), and DIPEA (421.6 mg, 0.57 mL, 3.3 mmol) in 3 mL of EtOH were added to a 5 mL microwave vial and microwave heated for 5 minutes at 150° C. The solvent was evaporated and the residue purified by chromatography (Biotage 25 S eluting with 100 mL each of 0, 10, 20, 30, and 40% THF/petroleum ether) to afford 215.3 mg, (69.7% yield) of the product. MS 237.2 (AP+, 100).
Reaction SMILES: COC1OCC(COC2C=CN=C(C[S:18]([C:20]3[NH:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[N:21]=3)=[O:19])C=2C)CO1.[Na:30].COC1OCC(COC2C=CN=C(CS(C3NC4C=CC=CC=4N=3)=O)C=2C)CO1.[CH3:60][C:61]1([CH3:79])[O:66][CH2:65][CH:64]([CH2:67][O:68][C:69]2[CH:74]=[CH:73][N:72]=[C:71]([CH2:75]O)[C:70]=2[CH2:77][CH3:78])[CH2:63][O:62]1>>[Na:30].[CH3:60][C:61]1([CH3:79])[O:66][CH2:65][CH:64]([CH2:67][O:68][C:69]2[CH:74]=[CH:73][N:72]=[C:71]([CH2:75][S:18]([C:20]3[NH:21][C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=4[N:24]=3)=[O:19])[C:70]=2[CH2:77][CH3:78])[CH2:63][O:62]1
Reactant: COC1OCC(COc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)CO1
Reactant: CCc1c(OCC2COC(C)(C)OC2)ccnc1CO
Agent: [Na]
Product: CCc1c(OCC2COC(C)(C)OC2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 25 %

Procedure:
The same procedure as in the steps (6d), (6e), and (6f) of Example 6 was repeated using the (4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-3-ethylpyridin-2-yl)methanol obtained in the step (92d) above to obtain the title compound (159 mg, overall yield: 25%) as a light yellow solid.