Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:14](=[O:16])[CH3:15])[N:4]2[C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[S:6][C:5]=12.[F:17][C:18]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O>>[F:17][C:18]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=[CH:15][C:14]([C:3]1[N:4]2[C:5]([S:6][C:7]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]=32)=[N:1][CH:2]=1)=[O:16]
Reactant: CC(=O)c1cnc2sc3c(n12)CCCCC3
Reactant: O=Cc1cccc(F)c1F
Product: O=C(C=Cc1cccc(F)c1F)c1cnc2sc3c(n12)CCCCC3

Procedure:
1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)ethanone (Formula N-4), 1.87 g and 2,3-difluorobenzaldehyde (1.39 g) were condensed by non-critical variations in PREPARATION 15 to provide 3-(2,3-Difluorophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one (Formula N-5, X=2,3-difluoro), 1.35 g, m.p. 193-195°.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([N:14]=[C:15]=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:17][C:18]1[NH:22][N:21]=[C:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[CH:19]=1.Cl>C(OCC)(=O)C>[C:8]1([NH:14][C:15]([N:22]2[C:18]([CH3:17])=[CH:19][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:31])([F:32])[F:33])=[N:21]2)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1cc(Oc2ccccc2C(F)(F)F)n[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2ccccc2C(F)(F)F)nn1C(=O)Nc1ccccc1
Reaction time: 6 h
Yield: 89.9 %

Procedure:
Triethylamine (0.19 g, 1.4 mmol) and phenyl isocyanate (0.17 g, 1.4 mmol) were added to a solution of 5-methyl-3-(2-trifluoromethylphenyloxy)pyrazole (0.30 g, 1.2 mmol) in ethyl acetate (5 ml) at 0° C., and the mixture was allowed to have room temperature gradually and stirred for 6 hours. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (10 ml) and extracted with ethyl acetate (10 ml×2). An organic layer was washed with water (10 ml×2), dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/15), to give an orange solid of N-phenyl-5-methyl-3-(2-trifluoromethylphenyloxy)pyrazole-1-carboxamide (0.39 g, yield: 87.5%). mp: 87-89° C., 1H-NMR (CDCl3, TMS, ppm): δ 2.65 (d, J=0.7 Hz, 3H), 5.78 (d, J=0.7 Hz, 1H), 7.14 (ddd, J=1.2, 2.3 and 7.3 Hz, 1H), 7.28-7.38 (m, 4H), 7.51-7.60 (m, 3H), 7.69-7.73 (m, 1H), 8.90 (br s, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[C:7]2[C:16](=O)[C:15]3[N:14]=[C:13]([CH3:18])[CH:12]=[CH:11][C:10]=3[CH2:9][CH2:8]2)[N:3]=[CH:2]1.[H][H].Cl(O)(=O)(=O)=O.[OH-].[Na+]>FC(F)(F)C(O)=O.C(Cl)(Cl)Cl.C(O)(C)C.[Pt]=O>[NH:1]1[CH:5]=[C:4]([CH2:6][CH:7]2[CH2:16][C:15]3[N:14]=[C:13]([CH3:18])[CH:12]=[CH:11][C:10]=3[CH2:9][CH2:8]2)[N:3]=[CH:2]1
Reactant: Cc1ccc2c(n1)C(=O)C(=Cc1c[nH]cn1)CC2
Reactant: [H][H]
Agent: O=[Pt]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(n1)CC(Cc1c[nH]cn1)CC2

Procedure:
A mixture of 7-(1H-imidazol-4-yl-methylene)-2-methyl-6,7-dihydro-5H-quinolin-8-one (Intermediate 200A4) (23.8 g, 99 mmol) in trifluoroacetic acid (120 mL) was hydrogenated under 50 psi of hydrogen in the presence of 70% perchloric acid (8 mL) and platinum oxide (12 g) for 16 h at rt. The mixture was filtered through a bed of celite, washed with ethyl acetate and evaporated to leave a residue. The residue was diluted with chloroform:isopropanol (3:1), basified with 2 M NaOH and the aqueous layer was extracted with chloroform:isopropanol (3:1). The organic layers were pooled and evaporated to give the crude product. This material was purified by chromatography on SiO2 with 3 to 4% NH3-MeOH: CH2Cl2 to give 7-(1H-imidazol-4-ylmethyl)-2-methyl-5,6,7,8-tetrahydro-quinoline (Intermediate 200A5) as a slightly yellow solid, 5.16 g (23%).
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:7][NH:6][C@@H:5]([CH2:8][C:9]([OH:11])=[O:10])[CH2:4]1.C(N(CC)CC)C.[C:19]1([C:25]2[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O.O1CCCC1>[C:25]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:26]=[CH:27][C:28]([C:29]([N:6]2[CH2:7][C@H:3]([OH:2])[CH2:4][C@H:5]2[CH2:8][C:9]([OH:11])=[O:10])=[O:30])=[CH:32][CH:33]=1
Reactant: O=C(O)C[C@H]1C[C@@H](O)CN1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(O)C[C@@H]1C[C@@H](O)CN1C(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of commercial [(2R,4R)-4-hydroxypyrrolidin-2-yl]acetic acid hydrochloride (5.03 g, 27.69 mmol), triethylamine (11.32 g, 110.77 mmol) in water (16.5 ml) and tetrahydrofuran (25 ml) at 0° C. under argon was added drop wise a solution of the 4-phenyl-benzoyl chloride in dry tetrahydrofuran (25 ml). The reaction was allowed to warm to RT and stirred overnight The reaction mixture was concentrated and the crude product was acidified under stirring at 5° C. adding 100 ml of HCl 1N. The white suspension was stirred at 5° C. for 10 minutes, filtered off under vacuum, rinsed with HCl 1N and water. After drying under vacuum the still wet white solid was taken up in 14 ml of tetrahydrofuran and brought to reflux until dissolution, and hexane was added to precipitate the solid. The whole was allowed to cool down to RT under stirring for 5 minutes and was filtered off and rinsed with hexane to give [(2S,4R)-1-(biphenyl-4-ylcarbonyl)-4-hydroxypyrrolidin-2-yl] acetic acid as a white powder (4.344 g). Yield: 72%. HPLC purity: 84%
Reaction SMILES: Br[C:2]1[C:3]([CH3:14])=[C:4]([CH3:13])[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]=2[C:11]=1[CH3:12].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:2]3[C:3]([CH3:14])=[C:4]([CH3:13])[C:5]4[O:9][CH:8]([CH3:10])[CH2:7][C:6]=4[C:11]=3[CH3:12])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: Cc1c(C)c2c(c(C)c1Br)CC(C)O2
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)O4)CC2)cc1
Yield: 38.9 %

Procedure:
By using 5-bromo-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran (4.02 g, 15.8 mmol) synthesized in Reference example 53 and 1-(4-methoxyphenyl)piperazine (6.08 g, 31.6 mmol), the reaction was carried out in the same manner as Example 1 to obtain the title compound 2.25 g (yield 39%).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:12][N:11]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@H:22]([CH2:24][OH:25])[O:21][C:20]3=[O:26])=[CH:15][C:14]=2[F:27])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O[C:29]1[CH:33]=[CH:32][O:31][N:30]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[Si:1]([O:8][CH:9]1[CH2:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@H:22]([CH2:24][O:25][C:29]4[CH:33]=[CH:32][O:31][N:30]=4)[O:21][C:20]3=[O:26])=[CH:15][C:14]=2[F:27])[CH2:12]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: Oc1ccon1
Reactant: CC(C)(C)[Si](C)(C)OC1CN(c2ccc(N3C[C@H](CO)OC3=O)cc2F)C1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1CN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)C1
Reaction time: 18 h

Procedure:
3-(4-(3-t-Butyldimethylsilyloxy-1-azetidinyl)-3-fluorophenyl)-5(R)-hydroxymethyloxazolidin-2-one (WO 96/13502; 2.47 g, 6.25 mmol), 3-hydroxyisoxazole (580 mg, 6.86 mmol), and tributylphosphine (1.58 g, 7.8 mmol) were dissolved by stirring in dry tetrahydrofuran (100 ml) under nitrogen. The mixture was cooled in an ice-bath, and 1,1′-(azodicarbonyl)dipiperidine (1.96 g, 7.8 mmol) added dropwise over 10 minutes. The solution was stirred 18 hours, allowing the temperature to rise to ambient. Reduced azo compound was filtered off, and the solution evaporated to dryness and the residue triturated with ether. The residue was purified by chromatography on a silica flash column, eluting with a gradient from 50 to 75% EtOAc in isohexane. Relevant fractions were combined and evaporated to the product as an oil (1.31 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:28][C:29]2[CH:34]=[C:33]([CH3:35])[C:32](=[O:36])[N:31]([CH3:37])[CH:30]=2)[C:9]2[C:10]([CH3:27])=[N:11][N:12]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[C:13]=2[C:14](O)=[O:15])=[CH:4][CH:3]=1>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9]3[C:10]([CH3:27])=[N:11][N:12]([C:17]4[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=4)[C:13]=3[C:14](=[O:15])[N:28]2[C:29]2[CH:34]=[C:33]([CH3:35])[C:32](=[O:36])[N:31]([CH3:37])[CH:30]=2)=[CH:6][CH:7]=1
Reactant: COc1ncc(-n2nc(C)c(C(Nc3cc(C)c(=O)n(C)c3)c3ccc(Cl)cc3)c2C(=O)O)c(OC)n1
Solvent: CCOC(C)=O
Product: COc1ncc(-n2nc(C)c3c2C(=O)N(c2cc(C)c(=O)n(C)c2)C3c2ccc(Cl)cc2)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-((4-chlorophenyl)((1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)amino)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-3-methyl-1H-pyrazole-5-carboxylic acid (Step 52.4). tR: 4.25 min (HPLC 1); tR: 0.98 min (LC-MS 2); ESI-MS: 507 [M+H]+ (LC-MS 2); Rf=0.11 (EtOAc); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.89 (s, 3H) 1.99 (s, 3H) 3.33 (s, 3H) 3.93 (s, 3H) 3.96 (s, 3H) 6.17 (s, 1H) 7.27-7.32 (m, 2H) 7.34-7.41 (m, 3H) 7.69-7.71 (m, 1H) 8.56 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[N:7]([CH2:9][CH2:10][CH2:11][NH2:12])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:21]([O:23][CH2:24][CH:25]1[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22]>O.O1CCOCC1>[C:1]([O:5][C:6](=[O:13])[N:7]([CH2:9][CH2:10][CH2:11][NH:12][C:21]([O:23][CH2:24][CH:25]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=2[C:32]2[C:37]1=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:22])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CCCN)C(=O)OC(C)(C)C
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CN(CCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
To a stirred solution of N-(3-aminopropyl)-N-methylcarbamic acid tert-butyl ester (2.00 g, 10.6 mmol) and sodium carbonate (2.81 g, 26.6 mmol) in water (7 mL) at 0° C. was added a solution of 9-fluorenylmethyl chloroformate (2.75 g, 10.6 mmol) in 1,4-dioxane (5 mL). The resulting mixture was stirred at room temperature for 2 h and then poured into water (10 mL). This mixture was extracted with diethyl ether (2×50 mL) and the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a clear oil. The oil was purified by silica gel flash chromatography (0-70% EtOAc in hexanes) to give the title compound (4.24 g, 77% yield) as a clear oil (product contained a minor impurity, but was used without further purification).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].C(=O)([O-])[O-].[K+].[K+].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:22][CH2:23][NH:24][CH3:25])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>CN(C)C=O>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:22][CH2:23][N:24]([CH2:2][CH2:3][CH2:4][Cl:5])[CH3:25])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CCN(C)CCCCl)cc1OC
Reaction time: 2 h

Procedure:
29 ml of 1-bromo-3-chloropropane were dissolved in 300 ml of dimethylformamide and 24 g of potassium carbonate were added to the solution. A solution of 18 g N-[2-(3,4-dimethoxyphenyl)-ethyl]-N-methylamine in 50 ml of dimethylformamide were added to the reaction mixture with stirring, dropwise within 2 hours. Then the reaction mixture was stirred for another hour. Then the salts formed were filtered off. The filtrate was concentrated at a maximum bath temperature of 50° C. The residue was dissolved in 200 ml of 0.5 m citric acid solution and the solution was extracted to remove unreacted bromochloropropane with methyl-tert-butyl ether. The aqueous phase was then made slightly alkaline by adding sodium hydrogen carbonate and extracted several times with ethyl acetate. Then the combined ethyl acetate extracts were dried with magnesium sulfate and concentrated. 21 g of 3-[N-(2-(3,4-dimethoxyphenyl)-ethyl)-N-methylamino]-propyl chloride were obtained as the residue.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[CH:12]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[CH2:19][CH2:18][CH2:17]2)=[O:13].[Cl-].[NH4+]>O1CCCC1>[OH:13][CH:12]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[CH2:19][CH2:18][CH2:17]2)[C:3]#[C:2][C:1]([O:5][CH3:6])=[O:4]
Reactant: C#CC(=O)OC
Reactant: O=Cc1ccc2c(c1)CCC2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C#CC(O)c1ccc2c(c1)CCC2
Reaction time: 0.17 h

Procedure:
A solution of 2.8 ml (32 mmol) of methyl propiolate in 60 ml of tetrahydrofuran was treated at -78° under argon with 20 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -78° for 10 minutes and then a solution of 4.7 g (32 mmol) of 5-formylindane in 80 ml of tetrahydrofuran was added within 15 minutes. The reaction mixture was stirred at -78° for a further 10 minutes, then brought to room temperature and treated with 60 ml of saturated ammonium chloride solution. The aqeuous phase was extracted twice with ether. The combined organic phases were washed in succession with saturated sodium chloride solution and with water, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography on 500 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1). There was obtained methyl 4-hydroxy-4-(5-indanyl)-2-butynoate as a yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]([CH2:13]O)[CH2:11][CH2:10][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:40]I>C(#N)C.CCOCC>[CH2:1]([N:8]1[C@H:12]([CH2:13][I:40])[CH2:11][CH2:10][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: II
Reactant: O=C1CC[C@@H](CO)N1Cc1ccccc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CC#N
Product: O=C1CC[C@@H](CI)N1Cc1ccccc1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
To a solution of 13-1 (18.5 g, 90.1 mmol), triphenylphosphine (40.1 g, 153 mmol), and imidazole (11.03 g, 162 mmol) in 225 mL of acetonitrile and 150 mL of ether at 0° C. was added iodine (34.3 g, 135 mmol) in 5 portions over 5 minutes. After 10 minutes, the reaction was heated to 50° C., and a stream of argon passed over the reaction to purge the evaporating ether. After an additional 30 minutes, the mixture was diluted with ether, the organic layer washed with NaHCO3 (sat.) and brine, dried over K2CO3, and the solvent evaporated. Flash chromatography of the residue (silica, 7-15% EtOAc/CHCl3) gave 13-2 as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:8](=O)[N:7]2[CH2:10][CH2:11][NH:12][CH2:13][CH:6]2[C:5](=O)[NH:4]1.B.C1COCC1.Cl>CO>[CH2:5]1[NH:4][C@@H:3]([CH2:2][OH:1])[CH2:8][N:7]2[CH2:10][CH2:11][NH:12][CH2:13][CH:6]12
Reactant: O=C1NC(CO)C(=O)N2CCNCC12
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: OC[C@H]1CN2CCNCC2CN1
Temperature: 80 °C

Procedure:
To a flask containing (3S,9aS or 9aR)-3-(hydroxymethyl)tetrahydro-2H -pyrazino[1,2-a]pyrazine-1,4(3H,6H)-dione and (3S,9aR or 9aS)-3-(hydroxymethyl)tetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-dione (D83, Diastereoisomer 1 plus D84,Diastereoisomer 2, 976 mg, 4.9 mmol) was added 1M BH3-THF solution (49 mL) under nitrogen and the reaction was brought to reflux (80° C.) overnight. The reaction flask was cooled to 0° C. and treated with 25 mL of MeOH. Conc. HCl was added and the resulting solution was heated to 60° C. for 5 h. The reaction was checked by direct MS (m/z=184 (M+BH3) ). The reaction mixture was purified by SCX, obtaining 528 mg of product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:16]3[N:15]=2)[C:5]([OH:8])=[N:6][CH:7]=1.[H-].[Li+].Br[CH2:30][C@H:31]([CH3:44])[CH2:32][N:33]1[C:41](=[O:42])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]1=[O:43]>CN(C=O)C.CCOC(C)=O>[O:43]=[C:34]1[C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:41](=[O:42])[N:33]1[CH2:32][C@@H:31]([CH3:44])[CH2:30][N:6]1[CH:7]=[C:2]([F:1])[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:16]3[N:15]=2)[C:5]1=[O:8]
Reactant: C[C@@H](CBr)CN1C(=O)c2ccccc2C1=O
Reactant: COC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3O)nc12
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cn(C[C@H](C)CN4C(=O)c5ccccc5C4=O)c3=O)nc12
Temperature: 70 °C
Reaction time: 2 h
Yield: 34.8 %

Procedure:
To a solution of (R)-methyl 5-(2-(5-fluoro-2-hydroxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (202 mg, 0.565 mmol) in DMF (5 mL) was added lithium hydride (22.5 mg, 2.83 mmol) and (R)-2-(3-bromo-2-methylpropyl)isoindoline-1,3-dione (prepared according to the procedure described in Euro. J. Med. Chem. 2000, 147-156) (239 mg, 0.848 mmol). The reaction was stirred for 2 hours at 70° C., and then cooled to ambient temperature. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (2×10 mL). The organic layer was dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography, eluting with 66% EtOAc/Hexanes to afford the product (110 mg, 34.8% yield). MS (apci) m/z=559.0 (M+H).
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([NH2:30])[CH:24]=1.FC(F)(F)C(O)=O>O1CCCC1>[NH2:30][C:25]1[CH:24]=[C:23]([F:22])[CH:28]=[CH:27][C:26]=1[NH:29][C:17](=[O:19])[C:16]1[CH:15]=[CH:14][C:13]([CH2:12][NH:11][C:1](=[O:10])[CH:2]=[CH:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:21][CH:20]=1
Reactant: Nc1ccc(F)cc1N
Reactant: O=C(C=Cc1ccccc1)NCc1ccc(C(=O)O)cc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(F)ccc1NC(=O)c1ccc(CNC(=O)C=Cc2ccccc2)cc1
Temperature: 45 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
To a suspension of 0.29 g (1.78 mmol) of N,N′-carbonyldiimidazole in tetrahydrofuran (15 ml) is added 0.50 g (1.78 mmol) of 4-[N-cinnamoylaminomethyl]benzoic acid, followed by stirring at 45° C. for 1 hour. After cooling, the reaction mixture is added to a separately prepared tetrahydrofuran (10 ml) solution including 0.28 g (2.22 mmol) of 4-fluoro-1,2-phenylenediamine and 0.20 g (1.78 mmol) of trifluoroacetic acid at room temperature. After reaction at room temperature for 16 hours, the deposited white solid is collected by filtration, washed with tetrahydrofuran, and then dried to give the title compound (0.45 g, 65%). 1H NMR (300 MHz, DMSO-d6): δppm: 4.42 (2H, d), 4.92 (2H, br.s), 6.62 (1H, t), 6.78 (2H, m), 7.01 (1H, t), 7.32 (5H, m), 7.54 (5H, m), 8.76 (1H, br.t), 9.58 (1H, br.s). IR (KBr) cm−1: 3306, 1618, 1517, 1308, 745. HRMS calcd for C23H20N3O2F: 389.4292. Found: 389.4294. MA calcd for C23H20N3O2F: C, 70.94%; H, 5.18%; N, 10.79%. Found: C, 70.72%; H, 5.18%; N, 10.88%.
Reaction SMILES: [CH:1]([NH:3][CH:4]([CH:11](O)[C:12](=[CH2:21])[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:2].S(Br)([Br:25])=O.O>ClCCl>[CH:1]([NH:3][CH:4]([CH:11]=[C:12]([CH2:21][Br:25])[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:2]
Reactant: C=C(CCCC(=O)OCC)C(O)C(CC(=O)OCC)NC=O
Reactant: O=S(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CCCC(=CC(CC(=O)OCC)NC=O)CBr
Reaction time: 1 h

Procedure:
10.3 g (35.9 mmol) of diethyl 2-formylamino-3-hydroxy-4-methylene-heptane-1,7-dicarboxylate are dissolved in 100 ml of dichloromethane and 3.34 ml (43.1 mmol) of thionyl bromide are added dropwise to the solution at room temperature. After 1 hour, 10 ml of water are added and the batch is thoroughly stirred. The organic phase is separated, washed in succession with water, saturated potassium hydrogencarbonate solution and again with water, dried over magnesium sulfate and concentrated by evaporation, giving diethyl 2-formylamino-4-bromomethyl-hept-3-ene-1,7-dicarboxylate as a brownish oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[N:9]=[CH:8][N:7]=[C:6]2[O:21]C1C=CC=CC=1.N>Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=1)[N:9]=[CH:8][NH:7][C:6]2=[O:21]
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1OCc1ccncc1
Agent: Cl
Agent: N
Product: COc1cc2c(=O)[nH]cnc2cc1OCc1ccncc1
Yield: 56.7 %

Procedure:
A solution of 6-methoxy-4-phenoxy-7-(4-pyridylmethoxy)quinazoline (200 mg, 0.56 mmol) in 2M hydrochloric acid (15 ml) was heated at reflux for 90 minutes. The reaction mixture was allowed to cool and neutralised to pH6-7 with aqueous ammonia. The precipitated product was extracted with methanol/methylene chloride (1:9) and the extract solution dried (MgSO4). Removal of the solvent by evaporation gave 6-methoxy-7-(4-pyridylmethoxy)-3,4-dihydroquinazolin-4-one (90 mg, 57%) as a grey solid. 1H NMR Spectrum: (DMSOd6) 3.93(s, 3H); 5.35(s, 2H); 7.18(s, 1H); 7.48(s, 1H); 7.50(m, 2H); 8.04(s, 1H); 8.62(m, 2H) MS-ESI: 284 [MH]+
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Br:10])[CH:9]=1)(=[O:3])[CH3:2].[F:11][C:12]([Si](C)(C)C)([F:14])[F:13].O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[Br:10][C:8]1[CH:9]=[C:4]([C:1]([OH:3])([CH3:2])[C:12]([F:14])([F:13])[F:11])[CH:5]=[N:6][CH:7]=1
Reactant: CC(=O)c1cncc(Br)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(O)(c1cncc(Br)c1)C(F)(F)F
Temperature: 25 °C

Procedure:
To a flask containing 3-acetyl-5-bromopyridine (2.27 g, 11.4 mmol) was added a solution of (trifluoromethyl)trimethylsilane in tetrahydrofuran (0.5 M, 40 mL, 20 mmol) at 0° C. A solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 11.4 mL, 11.4 mmol) was then added, and the reaction stirred at room temperature until the reaction was complete. The reaction was then concentrated under reduced pressure, diluted with ethyl acetate, and washed with water and saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, filtered and concentrated to give a residue that was purified by flash chromatography on silica gel (10-50% ethyl acetate in hexanes) to provide the racemic title compound: LCMS m/z 269.85 [M+2+H]+; 1H NMR (500 MHz, CD3OD) δ 8.70 (s, 1H), 8.65 (1H), 8.13 (s, 1H), 1.81 (s, 3H). The racemic title compound was resolved by supercritical fluid chromatography on a chiral AD column, eluting with 10% ethanol:CO2. Data for enantiomer A: LCMS m/z 271.85 [M+H]+; 1H NMR (500 MHz, CDCl3) 8.71 (s, 1H), 8.68 (d, J=2.0 Hz, 1H), 8.10 (s, 1H), 1.82 (s, 3H). Data for enantiomer B: LCMS m/z 271.83 [M+H]+; 1H NMR (500 MHz, CDCl3) 8.71 (s, 1H), 8.68 (s, 1H), 8.10 (s, 1H), 1.81 (s, 3H).