Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[O:11][C:10](=[O:15])[CH2:9]2)[CH:7]=1.[NH3:19]>O1CCCC1.CO>[NH2:19][C:10](=[O:15])[CH2:9][CH:8]([C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N+:16]([O-:18])=[O:17])[CH2:13][C:12]([OH:11])=[O:14]
Reactant: O=C1CC(c2cc(Cl)ccc2[N+](=O)[O-])CC(=O)O1
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)CC(CC(=O)O)c1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
Adapting literature known protocols (Ji, et al., Tetrahedron Lett., 2009, 50(45), 6166-6168; and Hoekstra, et al., Org. Proc. Dev. Dev., 1997, 1(1), 26-38), 5-amino-3-(5-chloro-2-nitro-phenyl)-5-oxo-pentanoic acid (18d) is prepared from 4-(5-chloro-2-nitro-phenyl)tetrahydropyran-2,6-dione (18a) (2.70 g, 10.0 mmol) in tetrahydrofuran (THF) (20 mL) with a concentrated solution of ammonia (NH3) in methanol (MeOH) (˜7.0 M; about 100 mL) at room temperature for about 14 hours. The reaction course is followed by TLC and/or LC/MS till completion. The reaction mixture is concentrated to dryness under reduced pressure using a rotary evaporator. The residue is triturated with ethyl acetate (EtOAc) (2×). The solids remaining after titruation are acidified at a temperature of about 0° C. (ice bath) with 1.0 M hydrochloric acid. Aqueous work-up yields the title compound (18d). The crude material may either be used directly in the next step or may be further purified by silica gel column chromatography using methanol (MeOH), dichloromethane (DCM), and hexane mixtures or by re-crystallization.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].[N+:15]([CH:18]=[C:19]1[NH:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:20]1)([O-:17])=[O:16]>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:19]([NH:23][CH2:22][CH:21]([OH:20])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:18][N+:15]([O-:17])=[O:16])[N:9]=1)[CH3:1]
Reactant: O=[N+]([O-])C=C1NCC(c2ccccc2)O1
Reactant: CN(C)Cc1nc(CSCCN)cs1
Solvent: CCO
Product: CN(C)Cc1nc(CSCCNC(=C[N+](=O)[O-])NCC(O)c2ccccc2)cs1
Yield: 68.7 %

Procedure:
With 2 ml of ethanol was mixed 1 g of 2-{[2-(dimethylamino)methyl-4-thiazolyl]methylthio}ethylamine and 1.1 g of 2-nitromethylene-5-phenyl-oxazolidine, and the resulting mixture was subjected to reaction under reflux for 1 hour. After completion of the reaction, the reaction mixture was filtered with cooling, and the solvent was removed by distillation under reduced pressure, after which the resulting residue was purified by a column chromatography (Wako Silica Gel C-200, eluent; chloroform:ethanol=20:1 by volume) to obtain 1.3 g (yield 68%) of N-{2-[[2-(dimethylamino)methyl-4-thiazolyl]methylthio]ethyl}-N'-(β-hydroxyphenethyl)-2-nitro-1,1-ethenediamine having a melting point of 100°-101° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([N+:23]([O-:25])=[O:24])=[C:17]([S:19](Cl)(=[O:21])=[O:20])[CH:18]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([N+:23]([O-:25])=[O:24])=[C:17]([S:19]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)(=[O:20])=[O:21])[CH:18]=1
Reactant: Cc1ccc([N+](=O)[O-])c(S(=O)(=O)Cl)c1
Reactant: Nc1cccc2cccnc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc([N+](=O)[O-])c(S(=O)(=O)Nc2cccc3cccnc23)c1
Yield: 12.1 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoquinoline (0.350 g, 2.4 mmol), 5-methyl-2-nitro-benzenesulfonyl chloride (Intermediate 449) (0.86 g, 3.6 mmol), pyridine (1 ml) DMAP (cat) and DCM (5 ml) gave the title compound (100 mg, 12%) after purification by column chromatography with n-hexane/EtOAc (10:90) as the eluent. The structure was confirmed by 1H NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[Cl:20][C:21]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[C:23](Cl)[N:22]=1.C(N(CC)CC)C>CN1CCCC1=O>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:8]([C:23]2[CH:24]=[CH:25][C:26]([C:27]([F:29])([F:30])[F:28])=[C:21]([Cl:20])[N:22]=2)[CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][CH:18]=2)=[CH:11][CH:12]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1Cl
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ccc(C(F)(F)F)c(Cl)n2)cc1
Temperature: 120 °C

Procedure:
Add bis(4-methoxybenzyl)amine (35.7 g, 138.9 mmol) in 20 mL of N-methylpyrrolidone to a solution of 2,6-dichloro-3-trifluoromethylpyridine (20 g, 92.6 mmol) and triethylamine (19.4 mL, 138.9 mmol) in 100 mL of N-methylpyrrolidone. Raise the temperature to 120° C., and stir the reaction for 14 hours. Quench the reaction mixture by the addition of water (80 mL), followed by extraction with EtOAc (3×70 mL). Wash the combined organic extracts with water (2×70 mL) and brine (70 mL), and dry over anhydrous Na2SO4. Filter the dried extract and concentrate under vacuum to afford the crude product, which is purified by column chromatography to give a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.58 (d, 1H, J=8.4 Hz), 7.15 (m, 4H), 6.85 (m, 4H), 6.31 (d, 1H, J=8.8 Hz), 4.70 (s, 4H), 3.80 (s, 6H). Mass spec. (436.99, M+H).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]([C:20](N)=[O:21])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:23].[K+].Cl.O>C(O)CO>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]([C:20]([OH:21])=[O:23])[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [OH-]
Reactant: NC(=O)C1CN(c2ccccc2)CCN1Cc1ccccc1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: OCCO
Product: O=C(O)C1CN(c2ccccc2)CCN1Cc1ccccc1
Temperature: 150 °C

Procedure:
Suspend 4-phenyl-1-(phenylmethyl)-2-piperazinecarboxamide (14.5 g, 49 mmol) in ethylene glycol (400 mL) and add potassium hydroxide (27.5 g, 490 mmol). Heat this mixture to 150° C. for 18 h. After this time, remove the solvent in vacuo. Add 6M hydrochloric acid (81.5 mL, 0.49 mol) and water (300 mL) and filter the resultant solid to obtain the title compound.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.OS(O)(=O)=O.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([CH3:42])([CH3:41])[C:28]([CH:30]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:31]([O:33]CC)=O)=[O:29]>>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:22]=1[C:27]([CH3:42])([CH3:41])[C:28](=[O:29])[C:30]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:31]2[OH:33]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1ccccc1Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1=C(O)c2cccc(Cl)c2C(C)(C)C1=O
Reaction time: 0.5 h
Yield: 28.3 %

Procedure:
P2O5 (19.0 g, 134 mmol) was treated with concentrated H2SO4 (17.1 mL, 308 mmol) at 0° C., and the resulting mixture was stirred for 30 minutes. Diethyl 2-(2-(2-chlorophenyl)-2-methylpropanoyl)malonate (1.500 g, 3.83 mmol) was added, and the mixture was stirred at 25° C. for 1 hour. The solution was quenched with ice, and, on melting, was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4, and concentrated and dried in vacuo to give ethyl 8-chloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (0.320 g). MS m/e 295 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].[CH:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C.[C].[Pd]>[CH2:6]([NH:1][CH:2]([CH3:5])[CH2:3][OH:4])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C[C@H](N)CO
Reactant: O=Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(CO)NCc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of (S)-(+)-2-aminopropan-1-ol (50.0 g) and benzaldehyde (74 ml) in ethanol (500 ml) was added 5% palladium carbon (5.0 g), and the mixture was hydrogenated at room temperature under ordinary pressure for 8 hours. The reaction mixture was filtered through Celite, and concentrated under reduced pressure to give the titled compound (111.2 g).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[NH:15][S:16]([CH3:19])(=[O:18])=[O:17].[F:20][C:21]([F:32])([F:31])[CH2:22][S:23][CH2:24][C:25]([OH:30])([CH2:28][CH3:29])[C:26]#[CH:27]>>[CH3:19][S:16]([N:15]1[C:3]2[C:2](=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:4]=2)[CH:27]=[C:26]1[C:25]([OH:30])([CH2:28][CH3:29])[CH2:24][S:23][CH2:22][C:21]([F:20])([F:32])[F:31])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Nc1cc(C(F)(F)F)c([N+](=O)[O-])cc1I
Reactant: C#CC(O)(CC)CSCC(F)(F)F
Product: CCC(O)(CSCC(F)(F)F)c1cc2cc([N+](=O)[O-])c(C(F)(F)F)cc2n1S(C)(=O)=O

Procedure:
This compound was prepared using the general Sonagashira procedure as described in General Procedures Example C, reacting N-(2-iodo-4-nitro-5- trifluoromethyl-phenyl) -methanesulfonamide (0.62 g, 1.5 mmol) and 3-(2,2,2-Trifluoro-ethylsulfanylmethyl) -pent-1yn-3-ol (0.32 g, 1.5 mmol) to yield the title compound as a yellow sticky oil.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[C:4](=[O:23])[C:3]=1[C:24](=O)[CH2:25][C:26]1[S:27][CH:28]=[CH:29][CH:30]=1.O.[NH2:33][NH2:34].C(=O)([O-])O.[Na+]>CN(C=O)C>[S:27]1[CH:28]=[CH:29][CH:30]=[C:26]1[CH2:25][C:24]1[C:3]2[C:4](=[O:23])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:20])([F:21])[F:22])[CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:34][N:33]=1
Reactant: O=C(Cc1cccs1)c1c(O)c2cccnc2n(-c2cccc(OC(F)(F)F)c2)c1=O
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3cccs3)n[nH]c2c2cccnc2n1-c1cccc(OC(F)(F)F)c1
Temperature: 115 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-hydroxy-3-(2-thienylacetyl)-1-(3-trifluoromethoxyphenyl)-1,8-naphthyridin-2(1H)-one (180 mg, 0.40 mmol) produced in Synthesis Example 41 in DMF (3 mL) was added hydrazine monohydrate (purity of 80%, 97 μL), and the mixture was stirred at 110 to 120° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, washed with water, recrystallized from methanol, and dried to give 3-(2-thienylmethyl)-5-(3-trifluoromethoxyphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (109 mg, yield 61%).
Reaction SMILES: C(#N)C.[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=O)[CH2:18][C:19](=O)[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].[CH2:29]([NH:31][NH2:32])[CH3:30]>O>[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[N:31]([CH2:29][CH3:30])[N:32]=[C:19]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=2)[CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CC(=O)Cc2ccccc2)CC1
Reactant: CCNN
Solvent: O
Solvent: CC#N
Product: CCn1nc(Cc2ccccc2)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 19 °C
Reaction time: 1 h

Procedure:
A 100 L cylindrical flask with a bottom valve was equipped with a mechanical stirrer, internal heating coil, 5 L dropping funnel, and thermocouple was charged with the acetonitrile (39 L) and 1-(1-(t-butoxycarbonyl)piperidin-4-yl)-4-phenylbutane-1,3-dione 4 (3.00 Kg, 8.68 mol). To the resulting clear light yellow solution was added water (18.6 l). The mixture was warmed to 19° C. and the mixture became clear. An ethyl hydrazine solution (35% in water, 1.66 Kg, 1.71 L, 9.55 mol) was added via a dropping funnel over 100 min. The batch temperature after the addition was 20° C. The reaction solution was aged for 1 h at 20 □ C then checked for completion by HPLC. If any 4 remained, additional ethyl hydrazine was added to complete the reaction. At the end of reaction the ratio of products 5:6:7 is 83.6:14.3:2.1 with complete consumption of 4.
Reaction SMILES: N1C=CC=CC=1.[C:7](Cl)(=[O:10])[CH2:8][CH3:9].[NH2:12][C:13]1[N:17]([C:18]2[C:23]([Cl:24])=[CH:22][C:21]([Cl:25])=[CH:20][N:19]=2)[N:16]=[CH:15][CH:14]=1>C(Cl)Cl>[C:7]([NH:12][C:13]1[N:17]([C:18]2[C:23]([Cl:24])=[CH:22][C:21]([Cl:25])=[CH:20][N:19]=2)[N:16]=[CH:15][CH:14]=1)(=[O:10])[CH2:8][CH3:9]
Reactant: CCC(=O)Cl
Reactant: Nc1ccnn1-c1ncc(Cl)cc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)Nc1ccnn1-c1ncc(Cl)cc1Cl
Reaction time: 5 h
Yield: 91.3 %

Procedure:
4.3 ml (0.053 mole) of pyridine and 3.6 ml (0.051 mole) of propionyl chloride are successively added dropwise to 11 g (0.048 mole) of 5-amino-1-(3,5-dichloropyrid-2-yl)-pyrazole in 80 ml of methylene chloride at room temperature, with stirring. When the addition has ended, stirring is continued for a further 5 hours, the mixture is diluted with 70 ml of methylene chloride, washed successively with dilute hydrochloric acid, saturated sodium bicarbonate solution and sodium chloride solution and dried over magnesium sulphate and the solvent is removed in vacuo. 12.5 g (91.4% of theory) of 5-propionamido-1-(3,5-dichloropyrid-2-yl)-pyrazole of melting point 116°-124° C. are obtained.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]1([C:12]2[CH:16]=[C:15]([C:17](=[O:21])[CH:18]=[CH:19][CH3:20])[O:14][N:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>C(OCC)(=O)C>[C:6]1([C:12]2[CH:16]=[C:15]([C:17](=[O:21])[CH2:18][CH:19]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH3:20])[O:14][N:13]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C1CCNC1
Reactant: CC=CC(=O)c1cc(-c2ccccc2)no1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(CC(=O)c1cc(-c2ccccc2)no1)N1CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Pyrrolidine (5 ml) was added to 1.1 g (5.2 mmol) of 3-phenyl-5-(2-butenoyl) isoxazole prepared above in the procedure (1). The resulting mixture was stirred at room temperature for 3 hours. Water and ethyl acetate were added to the reaction mixture, so that a product formed was extracted in an organic layer. The organic layer was collected, dried over anhydrous magnesium sulfate, and then concentrated, whereby 3-phenyl-5-{3-(1-pyrrolidinyl)butyryl}isoxazole was obtained as colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[CH:6][O:5][N:4]=1.Cl.[NH2:9][CH2:10][CH2:11][SH:12].[BrH:13]>>[BrH:13].[NH2:9][CH2:10][CH2:11][S:12][CH2:2][C:3]1[CH:7]=[CH:6][O:5][N:4]=1
Reactant: NCCS
Reactant: ClCc1ccon1
Agent: Br
Agent: Cl
Product: NCCSCc1ccon1

Procedure:
A solution of 3-chloromethylisoxazole (5.8 g) and cysteamine hydrochloride (6.25 g) in aqueous hydrobromic acid (48%, 100 ml) was heated under reflux for 6 hours. Concentration in the presence of water and subsequently n-propanol, followed by recrystallisation of the residue from isopropyl alcohol-ethanol afforded 3-[(2-aminoethyl)-thiomethyl]isoxazole hydrobromide, m.p. 131°-133°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11]>O1CCOCC1>[Br:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][C:10](=[O:11])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Br)ccc1O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: O=c1[nH]c2cc(Br)ccc2o1
Temperature: 120 °C
Yield: 91 %

Procedure:
A mixture of 2-amino-4-bromophenol (6.0 g, 31.9 mmol) and 1,1′-carbonyldiimidazole (6.2 g, 38.3 mmol) in p-dioxane (30 mL) was heated at 120° C. for 3 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with 1N hydrochloric acid (3 20 mL), water (20 mL) and brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated in hexanes/diethyl ether (1:1 v/v, 50 mL) and washed with hexanes (20 mL) to afford 5-bromobenzo[d]oxazol-2(3H)-one in 91% yield (6.2 g) as a beige solid: 1H NMR (300 MHz, DMSO-d6) δ11.85 (br s, 1H), 7.28-7.25 (m, 3H); MS (ES+) m/z 212.0 (M+1), 214.0 (M+1).
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([N:6]1[CH2:10][CH2:9][N:8]=[C:7]1SC)=[O:5].[CH3:17][N:18]([CH3:20])[NH2:19]>COCCOCCOC.O>[CH3:17][N:18]([CH3:20])[N:19]1[C:2]2[C:3](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:4](=[O:5])[N:6]2[CH2:10][CH2:9][N:8]=[C:7]12
Reactant: CN(C)N
Reactant: CSC1=NCCN1C(=O)c1ccccc1F
Solvent: COCCOCCOC
Solvent: O
Product: CN(C)N1C2=NCCN2C(=O)c2ccccc21
Yield: 77 %

Procedure:
A solution of 2.40 g (10.1 mmoles) of the product of Example 1 and 3 ml of 1,1-dimethylhydrazine in 6 ml of diglyme was heated at 165° C. for 3 hours in a sealed glass tube. Upon cooling, the solution was diluted with water and the resulting solid was collected and air-dried to give 1.80 g of 2,10-dihydro-10-(dimethylamino)imidazo[2,1-b]quinazolin-5(3H)-one. Melting point 197°-198° C. Total yield 77%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21]O)=[C:17]([O:23][CH3:24])[CH:16]=2)=[CH:9][C:8]=1[F:25])[CH3:2].P(Br)(Br)[Br:28]>ClCCl.O>[Br:28][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:26])=[C:8]([F:25])[CH:9]=2)=[CH:16][C:17]=1[O:23][CH3:24]
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(CO)c(OC)c2)cc1F
Reactant: BrP(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CCc1ccc(OCc2ccc(CBr)c(OC)c2)cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93.7 %

Procedure:
To a solution of 3-[2-fluoro-4-(4-hydroxymethyl-3-methoxy-benzyloxy)-phenyl]-propionic acid ethyl ester (1.0 g, 2.76 mmol) in dichloromethane (25 mL) is added phosphorus tribromide (0.4 mL, 4.41 mmol) at 0° C. and the reaction mixture is stirred for 15 min at 0° C. The mixture is cooled to 0° C., diluted with water, and extracted with dichloromethane (2×100 mL). The combined extracts are washed with saturated brine, dried over Na2SO4, filtered, and concentrated to give the title compound (1.1 g, crude). 1H NMR (DMSO, 400 MHz) δ 7.34-7.32 (d, J=8 Hz, 1H), 7.12-7.08 (t, J=8 Hz, 1H), 6.96-6.94 (d, J=8 Hz, 2H), 6.67-6.64 (d, J=12 Hz, 2H), 4.98 (s, 2H), 4.55 (s, 2H), 4.12-4.09 (q, 2H), 2.90-2.88 (t, 2H), 2.60-2.56 (t, J=8 Hz, 2H), 1.25-1.22 (t, J=8 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4][CH:3]1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[CH3:21]C1C(=O)CCN(C(OC(C)(C)C)=O)C1>>[CH3:21][CH:8]1[CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4][CH:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:2]1=[O:1]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O
Product: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC(C)C1=O
Yield: 100 %

Procedure:
The title compound was prepared by a similar method to that of 1-tert-butyl 4-ethyl 5-oxoazepane-1,4-dicarboxylate (see WO2006029154, example 1a, p 34) from Tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate, yielding 100% of title compound which was taken on for pyrimidone formation without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[C:12]([CH3:15])[NH:11][C:10]2=[O:16].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][CH2:32]I)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C.CCOC(C)=O>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][CH2:32][N:11]2[C:10](=[O:16])[C:9]3[C:14](=[C:5]([O:4][CH3:3])[CH:6]=[CH:7][CH:8]=3)[N:13]=[C:12]2[CH3:15])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: COc1cccc2c(=O)[nH]c(C)nc12
Reactant: CC(C)(C)OC(=O)N1CCC(CCCI)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc2c(=O)n(CCCC3CCN(C(=O)OC(C)(C)C)CC3)c(C)nc12
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
Sodium hydride (91 mg, 2.37 mmol) was added to a solution of 8-methoxy-2-methyl-3H-quinazolin-4-one (300 mg, 1.58 mmol) in DMF (30 mL). The reaction mixture was stirred at 80° C. for 0.75 h and cooled to room temperature, then a solution of 4-(3-iodo-propyl)-piperidine-1-carboxylic acid tert-butyl ester (837 mg, 2.37 mmol) in DMF (1 mL) was added. The reaction mixture was heated at 85° C. for 17 h and diluted with EtOAc. The organic solution was washed with water and sat'd aq NaCl, dried and concentrated. Purification on SiO2-gel chromatography (50% EtOAc/hexanes) provided the desired product as a yellow oil. API-MS: 416 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]4[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[C:17]([CH3:23])[N:16]=4)[N:14]=[C:7]3[C:6]=2[CH:24]=1.C([O-])(=O)C.[K+].[CH3:30][N:31]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[N:32]1>C(#N)C.CCOC(C)=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>[CH:20]([N:19]1[C:15]([C:13]2[N:14]=[C:7]3[C:6]4[CH:24]=[C:2]([C:34]5[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=5)[CH:3]=[CH:4][C:5]=4[O:11][CH2:10][CH2:9][N:8]3[CH:12]=2)=[N:16][C:17]([CH3:23])=[N:18]1)([CH3:22])[CH3:21]
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(Br)ccc2OCC3)n(C(C)C)n1
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cn3c(n2)-c2cc(-c4cnn(C)c4)ccc2OCC3)n(C(C)C)n1
Temperature: 150 °C
Yield: 82.3 %

Procedure:
A microwave vial was charged with a suspension of 10-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.160 mg, 0.412 mmol) in 0.861 ml ACN/0.400 mL water. To this suspension was added potassium acetate (182 mg, 0.00185 mol) and 1-methylpyrazole boronic acid pinacol ester (107 mg, 515 mmol). The reaction suspension was degassed by bubbling nitrogen through the stirred mixture via a syringe. After several minutes the syringe was removed and tetrakis(triphenylphosphine)palladium(0) (38 mg, 33 mmol) was added and the reaction vial was quickly sealed. The sealed vial was flash heated in a microwave at 150° C. for 30 minutes. The cooled reaction was diluted with EtOAc and the organic solution was washed with water ×1, saline ×1 and dried (Na2SO4) before concentration in vacuo. The crude residue was purified by preparative RP-HPLC to give 132 mg of 454 (55% theoretical yield). MS: (ESI+)=390.2
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[OH:20])[CH2:9]1)=O)(C)(C)C.Br[CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([F:31])[CH:28]=2)[C:23]1=O.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:19][C:17]1[CH:16]=[CH:15][C:14]([O:20][CH:22]2[CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([F:31])[CH:28]=3)[CH2:23]2)=[C:13]([CH:18]=1)[O:12][CH:10]1[CH2:9][NH:8][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2O)C1
Reactant: O=C1c2ccc(F)cc2CC1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc2c(c1)CC(Oc1ccc(Cl)cc1OC1CNC1)C2
Temperature: 25 °C
Yield: 89.9 %

Procedure:
The mixture of 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (0.5 mmol), the title compound of Step A (0.5 mmol), and K2CO3 (1 mmol) in acetonitrile (3 mL) was heated at 100° C. in a microwave reactor for 1 h. The mixture was cooled to rt and purified via PTLC providing the title compound (150 mg). To this product was added DCE (5 mL), Et3SiH (1 mL) and TFA (3 mL). The mixture was stirred at 80° C. for 16 h. After concentration, the title compound was obtained (91 mg). MS (ESI): mass calcd. for C18H17ClFNO2, 333.1; m/z found, 334.1 [M+H]+. 1H NMR (CDCl3): 7.20-7.13 (m, 1H), 6.96-6.60 (m, 5H), 5.18-5.08 (m, 1H), 4.93-4.83 (m, 1H), 3.98-3.70 (m, 4H), 3.38-3.05 (m, 4H).