Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li]CCCC.[Br:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][O:20][CH3:21])[CH:15]=[C:14](Br)[CH:13]=1.[Br-].[Li+]>O1CCCC1>[Br:11][C:12]1[CH:13]=[C:14]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:15]=[C:16]([O:18][CH2:19][O:20][CH3:21])[CH:17]=1
Reactant: COCOc1cc(Br)cc(Br)c1
Reactant: C1CCNC1
Agent: [Br-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1cc(Br)cc(N2CCCC2)c1
Temperature: 78 °C
Yield: 16.8 %

Procedure:
A solution of pyrrolidine (1.66 g, 23.27 mmol), in dry tetrahydrofuran (20 ml) was cooled to −78° C. under argon atmosphere. A solution of n-BuLi (15.5 ml, 1.5 M in hexanes) was added via slow drop-wise addition over 5 minutes. After complete addition the cooling bath was removed and the mixture allowed to warm to ice bath temperature over 30 minutes. A second oven dried flask was charged with 1,3-dibromo-5-methoxymethoxy-benzene (5.74 g, 19.4 mmol) and lithium bromide (1.68 g, 19.4 mmol) and taken up in dry tetrahydrofuran (10 ml). This flask was then cooled to 78° C. under argon. The contents of the first flask (slurry containing the lithio salt of pyrrolidine) was taken up in a syringe with wide bore needle and added via drop-wise addition to the second flask (over 10 minutes). The mixture was allowed to slowly warm to ambient temperature over night. The mixture was quenched via the addition of 1 N HCl (23 ml), saturated aqueous NH4Cl (34 ml) and water (40 ml). Ethyl acetate (80 ml) was added and the material shaken in a separtatory funnel. The ethyl acetate phase was collected and washed with an equal volume of 50% diluted brine solution. The aqueous phases were back extracted with ethyl acetate (2×50 ml), the organics combined, dried (MgSO4), filtered and stripped to provide a yellow remainder. The oil was purified by silica gel chromatography using 4%-8% EtOAc in hexanes as eluant to provide 930 mg of 1-(3-Bromo-5-methoxymethoxy-phenyl)-pyrrolidine as a light yellow mobile oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([S:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[C:8]([CH2:12][C:13]([CH3:19])([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[NH:9]2)=[CH:5][CH:4]=1.[CH3:25][Si]([N-][Si](C)(C)C)(C)C.[K+].IC>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C.C1(C)C=CC=CC=1>[CH3:25][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=2)[C:7]([S:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[C:8]1[CH2:12][C:13]([CH3:19])([CH3:18])[C:14]([O:16][CH3:17])=[O:15]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)C(C)(C)Cc1[nH]c2cc(OC)ccc2c1SC(C)(C)C
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2ccc(OC)cc2n1C
Reaction time: 0.25 h

Procedure:
A solution of 1.75 g of the indole from Step A in 30 mL of THF and 3 mL HMPA was cooled to -78° C. and to this solution was slowly added a solution of 0.54M KHMDS in toluene (10.2 mL). The mixture was stirred at this temperature for 15 min. and treated with 0.34 mL of iodomethane. The mixture was stirred at -78° C. for 5 h, quenched with 1N HCl (100 mL), extracted with ethyl acetate, and the organic layer washed with H2O, dried over Na2SO4 and evaporated to dryness. The residue was chromatographed on flash silica gel using ethyl acetate:hexane (20:80) as eluant to afford the title compound as a solid; m.p. 97°-98° C.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]([F:43])([F:42])[O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]Br>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:37][C:36]3[CH:39]=[CH:40][CH:41]=[C:34]([O:33][C:32]([F:43])([F:42])[F:31])[CH:35]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Product: Cc1nc2c(ccn2Cc2cccc(OC(F)(F)F)c2)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 3-(trifluoromethoxy)benzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.52-7.42 (m, 1 H), 7.35 (t, J=8.2 Hz, 1 H), 7.26-7.12 (m, 4 H), 7.06 (t, J=3.2 Hz, 1 H), 6.97-6.91 (m, 1 H), 6.30 (dd, J=3.5, 11.3 Hz, 1 H), 5.63-5.46 (m, 3 H), 4.33-4.25 (m, 2 H), 2.97-2.79 (m, 2 H), 2.78-2.70 (m, 3 H), 2.15-2.03 (m, 2 H), 1.03-0.88 (s, 9 H); LC/MS (m/z) ES+=569.35 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:19](=[CH:20][CH:21]=1)[C:9]1[O:10][C:11]3([CH2:17][S:18][C:8]=1[C:7](=[O:22])[C:6]2=[O:23])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3.[CH2:24]([C@@H:31]1[CH2:33][O:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[OH:32][C@H:31]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:33][N:14]1[CH2:15][CH2:16][C:11]2([O:10][C:9]3[C:19]4[C:5]([C:6](=[O:23])[C:7](=[O:22])[C:8]=3[S:18][CH2:17]2)=[CH:4][C:3]([O:2][CH3:1])=[CH:21][CH:20]=4)[CH2:12][CH2:13]1
Reactant: COc1ccc2c(c1)C(=O)C(=O)C1=C2OC2(CCNCC2)CS1
Reactant: c1ccc(C[C@@H]2CO2)cc1
Product: COc1ccc2c(c1)C(=O)C(=O)C1=C2OC2(CCN(C[C@H](O)Cc3ccccc3)CC2)CS1

Procedure:
Compound 204 was synthesized using 8-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2R)-2-benzyloxirane and conditions outlined in procedure Y. M.p.=145-147° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.73 (d, J=8.6 Hz, 1H), 7.38 (d, J=7.6 Hz, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.31 (d, J=3.0 Hz, 1H), 7.28-7.12 (m, 4H), 4.43 (d, J=4.7 Hz, 1H), 3.84 (s, 3H), 3.03 (s, 2H), 2.80-2.68 (m, 2H), 2.58 (dd, J=7.4, 14.0 Hz, 1H), 2.47-2.26 (m, 3H), 1.99-1.90 (m, 2H), 1.87-1.72 (m, 2H). LCMS: 466 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](OCC)=[O:12])=[CH:5]2.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][OH:12])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc2cc(Cl)ccc2[nH]1
Temperature: 0 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
Ethyl 5-chloro-2-indole-carboxylate (1 eq) was dissolved in THF (0.45M) under N2. This solution was cooled to 0° C. for fifteen minutes and then 1.1 eq LiAlH4 (1M in THF) was added. The resulting dark brown solution was allowed to return to rt with stirring and kept overnight. Then water (1/25 of the volume of the LiAlH4 solution) was added slowly, followed by 15% NaOH(aq) (1/25 of the volume of the LiAlH4 solution) solution. Finally, water (1/25 of the volume of the LiAlH4 solution) was added along with a large amount of MgSO4. Solution was filtered and the solid was washed with EtOAc and the filtrate was collected. Solvent was stripped off to give (5-chloro-1H-indol-2-yl)methanol (yellow solid) in 85% yield.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[Br:17]Br>ClCCl>[Br:17][C:7]1[CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[C:4]([N:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[N:5][CH:6]=1
Reactant: BrBr
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Solvent: ClCCl
Product: FC(F)(F)c1cc(Br)cnc1N1CCNCC1
Temperature: 25 °C

Procedure:
To a solution of 1-(3-trifluoromethyl-pyridin-2-yl)-piperazine (8 g, 34.6 mmol, Oakwood) in dichloromethane (230 mL) was added dropwise bromine (3.92 mL, 76.12 mmol, Aldrich) with stirring at room temperature. The resulting mixture was stirred at room temperature for 16 h and the precipitate was filtered, washed with EtOAc (2×100 mL) and dried in vacuo to give the title compound as a yellow solid, which was used in the next step without additional purification. MS (ESI, positive ion) m/z: 310 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].Br[CH2:22][CH:23]1[CH2:25][CH2:24]1>>[CH:23]1([CH2:22][N:7]2[C:8]([C:9](=[O:18])[C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]2=[O:19])[CH2:25][CH2:24]1
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: BrCC1CC1
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(CC2CC2)c(=O)[nH]c1=O
Yield: 50.6 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and bromomethyl cyclopropane were reacted by the same way with the example 1 to obtain the titled compound (165 mg, yield: 50.6%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.C(O)C.[N:30]1(C(OC(C)(C)C)=O)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.N>C(Cl)Cl.C(Cl)(Cl)Cl.O>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: N
Solvent: O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)c(CNC(=O)c2cc(N3CCNCC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 120 °C
Yield: 55 %

Procedure:
To a 10 mL microwave vial equipped with stir bar were added 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.060 g, 0.160 mmol), ethanol (1.5 mL), and 1,1-dimethylethyl 1-piperazinecarboxylate (0.299 g, 1.605 mmol). The stirring suspension was placed onto heat block and heated at 120° C. for 18 h, and then irradiated (microwave) at 160° C. for 2 hr. The contents were cooled to room temperature, diluted into water (40 mL), and then adjusted to pH 6-7 and stirred for 15 min. The contents were filtered, washed with water, and then dried in hi-vac oven at 50° C. for 5 hr. The collected solid (52 mg) was dissolved in CH2Cl2/TFA (3 mL, 2:1) and stirred at room temperature for 2 hr. The volatiles were removed in vacuo to afford a residue which was then dissolved in CH2Cl2 and 10% 2M Ammonia (in methanol) in Chloroform. The crude product was purified by silica gel chromatography (eluent: gradient of 10% 2M Ammonia (in Methanol/Chloroform) and Dichloromethane). The isolated solid was dried in vacuum oven at 45° C. for 18 hr. to afford the final product as 38 mg (55% yield). LCMS E-S (M+H)=423.9. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (d, J=6.82 Hz, 6H), 2.08-2.24 (m, 6H), 2.75-2.89 (m, 4H), 3.53-3.64 (m, 4H), 4.34 (d, J=4.80 Hz, 2H), 4.98 (quin, J=6.69 Hz, 1H), 5.89 (s, 1H), 7.10 (s, 1H), 8.00 (s, 1H), 8.65 (t, J=4.93 Hz, 1H), 11.55 (br. s., 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:7]([C:8]2[CH:13]=[C:12]([S:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([CH3:20])=[CH:10][C:9]=2[F:21])[N:6]=[C:5]([O:22][C:23]([F:31])([F:30])[CH:24]([F:29])[C:25]([F:28])([F:27])[F:26])[CH:4]=1.ClC1C=CC=C(C(OO)=[O:40])C=1>C(Cl)(Cl)Cl>[F:21][C:9]1[CH:10]=[C:11]([CH3:20])[C:12]([S:14]([CH2:15][C:16]([F:19])([F:18])[F:17])=[O:40])=[CH:13][C:8]=1[N:7]1[C:3]([NH:2][CH3:1])=[CH:4][C:5]([O:22][C:23]([F:30])([F:31])[CH:24]([F:29])[C:25]([F:26])([F:27])[F:28])=[N:6]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CNc1cc(OC(F)(F)C(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Solvent: ClC(Cl)Cl
Product: CNc1cc(OC(F)(F)C(F)C(F)(F)F)nn1-c1cc(S(=O)CC(F)(F)F)c(C)cc1F
Reaction time: 1 h
Yield: 96.8 %

Procedure:
0.4 g of 5-methylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(1,1,2,3,3,3-hexafluoropropoxy)pyrazole was dissolved in 10 mL of chloroform, and 190 mg of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for 1 hour under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogen carbonate solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 0.4 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-3-(1,1,2,3,3,3-hexafluoropropoxy)-5-methylaminopyrazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.[C:11]([NH:15][OH:16])([CH3:14])([CH3:13])[CH3:12]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:7]=[N+:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[O-:16])[CH:9]=1
Reactant: CC(C)(C)NO
Reactant: O=Cc1cc(Br)ccc1O
Product: CC(C)(C)[N+]([O-])=Cc1cc(Br)ccc1O

Procedure:
The title compound was prepared according to the procedure described in Example 1 using 5-bromo-2-hydroxybenzaldehyde and N-tert-butylhydroxylamine. The title compound was isolated in 68.7% yield as a yellow crystalline solid, m.p. 118.7° C. (Rf=0.65 on a silica gel plate using 1:1 EtOAc/hexanes as an eluant).
Reaction SMILES: [CH:1]([O:3][N:4]=[C:5]([C:11]1([O:16][CH2:15][CH2:14][O:13]1)[CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH2:2].[OH-].[Na+].[CH:19]([Cl:22])(Cl)[Cl:20]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(O)C>[Cl:20][C:19]1([Cl:22])[CH2:2][CH:1]1[O:3][N:4]=[C:5]([C:11]1([O:13][CH2:14][CH2:15][O:16]1)[CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: C=CON=C(C(=O)OCC)C1(C)OCCO1
Reactant: ClC(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=NOC1CC1(Cl)Cl)C1(C)OCCO1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 2-vinyloxyimino-3,3-ethylenedioxybutyrate (syn isomer)(1.15 g) and benzyl-triethylammonium chloride (114 mg) in a mixture of chloroform (2.4 ml) and ethanol (0.05 ml) was added sodium hydroxide (2.4 ml) under ice-cooling. The mixture was stirred at the same temperature for 30 minutes, allowed to be stirred at ambient temperature for 3 hours and finally stirred at 50° C. for an hour. The mixture was poured into ice-water and extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo to give ethyl 2-(2,2-dichlorocyclopropyloxyimino)-3,3-ethylenedioxybutyrate (syn isomer)(1.41 g) as an oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([O:13]C)=O)[CH:8]=2)[NH:3]1.O.[NH2:16][NH2:17]>CCO>[O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([NH:16][NH2:17])=[O:13])[CH:8]=2)[NH:3]1
Reactant: COC(=O)c1ccc2c(c1)CC(=O)N2
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 80 °C
Reaction time: 6 h
Yield: 63 %

Procedure:
To a solution of methyl 2-oxoindoline-5-carboxylate (0.40 g, 4.8 mmol) in EtOH (8 ml) was added hydrazine monohydrate (2 ml), and the mixture was stirred for 6 h at 80° C. The mixture was cooled to room temperature, and the resulting precipitate was filtered and dried to afford 2-oxoindoline-5-carbohydrazide (0.25 g, 63%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][C:11]=3[CH3:24])=[CH:20][N:19]=2)=[O:23])[CH2:27][CH2:26]1
Reactant: Cc1onc(-c2ccc(F)cn2)c1COc1ccc(C(=O)O)nc1
Reactant: NC1CC1
Product: Cc1onc(-c2ccc(F)cn2)c1COc1ccc(C(=O)NC2CC2)nc1
Yield: 75 %

Procedure:
As described for example 23f, 5-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridine-2-carboxylic acid (75 mg, 0.23 mmol) was converted, using cyclopropylamine instead of isopropylamine, to the title compound (63 mg, 75%), which was obtained as a white solid. MS: m/e=369.2 [M+H]+.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][N:11]=1.[CH:18](OC)=[O:19].C([O-])(O)=O.[Na+]>C1COCC1>[Cl:9][C:10]1[C:15]([Cl:16])=[C:14]([CH:18]=[O:19])[C:13]([Cl:17])=[CH:12][N:11]=1
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: COC=O
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1c(Cl)cnc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
A solution of lithium diisopropylamide (7.3 mL, 1.5 M in cyclohexane, 11 mmol) in 10 mL of dry THF under nitrogen at −78° C. was treated with 2,3,5-trichloropyridine (2 g, 11 mmol) in 20 mL THF over a 30 minute period, stirred an additional 30 minutes, then methyl formate (1.4 mL, 1.3 g, 22 mmol) in 14 mL THF was added slowly to the brown solution over 15 minutes, allowed to slowly warm to room temperature and stirred overnight. The resultant dark brown solution was poured onto ice and saturated NaHCO3, extracted with ethyl acetate, washed with brine, dried (Na2SO4) and concentrated. The brown oil was flash chromatographed on silica gel with 20-33% ethyl acetate/hexane to provide the title compound (1.7 g, 74%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.CO[CH:21]=[C:22]([C:27]([O:29][CH3:30])=[O:28])[C:23]([O:25][CH3:26])=[O:24].O>CN(C)C=O>[C:13]([NH:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:1][CH:21]=[C:22]([C:27]([O:29][CH3:30])=[O:28])[C:23]([O:25][CH3:26])=[O:24])=[N:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1)(=[O:18])[C:14]([CH3:15])([CH3:17])[CH3:16]
Reactant: COC=C(C(=O)OC)C(=O)OC
Reactant: CC(C)(C)C(=O)Nc1ccc2c(N)ncnc2c1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(=CNc1ncnc2cc(NC(=O)C(C)(C)C)ccc12)C(=O)OC
Temperature: 100 °C
Reaction time: 0.42 h
Yield: 82.5 %

Procedure:
A mixture of 4-amino-7-pivalamidoquinazoline (10.5 g) and dimethyl methoxymethylenepropanedioate (10.9 g) in N,N-dimethylformamide (32 ml) was stirred at 100° C. for 1 hour and 25 minutes. After the reaction mixture was cooled to ambient temperature, water was added. The resulting solid was separated by filtration, washed with water and dried. The crystals were recrystallized from a mixture of ethyl acetate and ethanol to give crystalline dimethyl [[7-pivalamido-4-quinazolinylamino]methylene]propanedioate (13.7 g).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:19]([C:20](OCC)=[O:21])=[C:18]([CH:25]([CH3:27])[CH3:26])[CH:17]=[C:16]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:15]=2)=[CH:10][CH:9]=1>C1COCC1>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:19]([CH2:20][OH:21])=[C:18]([CH:25]([CH3:27])[CH3:26])[CH:17]=[C:16]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:15]=2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1c(C(C)C)cc(-c2ccccc2)nc1-c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1cc(-c2ccccc2)nc(-c2ccc(F)cc2)c1CO
Reaction time: 4.5 h

Procedure:
To a slurry of LiAlH4 (1.457 gm, 38.4 mmol) in dry THF at 0° C. was added a solution of 2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinecarboxylic acid, ethyl ester (3.37 gm, 9.27 mmol) in THF (7 ml). After 4.5 hours, the flask was charged with an additional 0.88 gm LiAlH4 and stirring was continued for 2 more hours. The mixture was quenched with H2O and diluted with H2O and EtOAc. The phases were shaken and separated, and the aqueous layer was extracted again with EtOAc and Et2O. The pooled organic layers were washed with H2O and brine, then dried (Na2SO4), filtered and stripped to give a white solid. The solid was recrystallized from hot EtOAc/hexane to afford 2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinemethanol as white crystals. The mother liquor was stripped and recrystallized again from hot EtOAc/hexane to give a total of 2.684 gm (90%) desired product.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][Si](C(C)(C)C)(C)C)=[CH:14][CH:15]=2)[O:10][C:9]([CH3:26])([CH3:25])[CH:8]=1)(=O)=O.[F:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[O:10][C:9]([CH3:25])([CH3:26])[CH:8]=2)=[CH:32][CH:31]=1
Reactant: CC1(C)C=C(OS(=O)(=O)C(F)(F)F)c2ccc(O[Si](C)(C)C(C)(C)C)cc2O1
Reactant: OB(O)c1ccc(F)cc1
Product: CC1(C)C=C(c2ccc(F)cc2)c2ccc(O)cc2O1

Procedure:
The compound obtained in (1) described above (8 g) and 4-fluorophenylboronic acid (3.07 g) were treated in the same manner as Reference Example 37(4) to give the titled compound (4.6 g) as a colorless powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([N:13]3[C:17]4[CH:18]=[CH:19][C:20]([CH2:22][OH:23])=[CH:21][C:16]=4[N:15]=[CH:14]3)[CH:10]=[CH:11][CH:12]=2)[CH:2]=1.C1([Se](O)=O)C=CC=CC=1>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([N:13]3[C:17]4[CH:18]=[CH:19][C:20]([CH:22]=[O:23])=[CH:21][C:16]=4[N:15]=[CH:14]3)[CH:10]=[CH:11][CH:12]=2)[CH:2]=1
Reactant: OCc1ccc2c(c1)ncn2-c1cccc(-c2cccnc2)c1
Agent: O=[Se](O)c1ccccc1
Solvent: Cc1ccccc1
Product: O=Cc1ccc2c(c1)ncn2-c1cccc(-c2cccnc2)c1
Temperature: 70 °C

Procedure:
49a (0.68 g, 2.26 mmol) in toluene (5 ml) was added benzeneseleninic acid (0.64 g, 3.39 mmol). The mixture was heated to 70° C. for 5 hours. After cooling the product was filtered off and washed with warm toluene and CH2Cl2 successively. Yield 0.58 g (86%). Mp 200°-202° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:7]=1[CH3:8].Br[CH2:16][CH:17]=O>>[CH3:8][C:7]1[C:2]2[N:3]([CH:16]=[CH:17][N:1]=2)[N:4]=[C:5]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=1
Reactant: Cc1cc(-c2ccccc2)nnc1N
Reactant: O=CCBr
Product: Cc1cc(-c2ccccc2)nn2ccnc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.2 g of 3-amino-4-methyl-6-phenylpyridazine are added to the filtrate (bromoacetaldehyde solution) and the mixture is stirred for 24 hours at room temperature.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].O>CN1CCCC1=O>[CH2:17]([O:16][C:14]([N:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)[CH2:9][C:10]([OH:12])=[O:11])=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)CNc1ccc(O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(O)CN(C(=O)OCc1ccccc1)c1ccc(O)cc1
Reaction time: 0.67 h
Yield: 75 %

Procedure:
N-(4-hydroxyphenyl)glycine (55.0 g, 0.330 mol) was dissolved in 275 mL of N-methylpyrrolidone in a 1 L round-bottomed flask. Benzyl chloroformate (50.1 mL, 0.352 mol) was added with stirring over a 40 min period and then stirred at ambient conditions for 18 h. Deionized water was added until slightly turbid and then stored at 4° C. for 24 h. The product was isolated and recrystallized in warm ethanol, dried in vacuum oven at 40° C. overnight (yield 75%, mp=196-198° C.). 1H-NMR (500 MHz, DMSO-d6) δ 12.80 (s, 1H, COOH), 9.50 (s, 1H, phenol), 7.58-6.95 (m, 7H, aryl), 6.74 (s, 2H, aryl), 5.10 (d, J=21.9, 2H, —CH2-benzyl), 4.22 (d, J=21.7, 2H, N—CH2-).
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[O:8][CH2:9][CH2:10][CH2:11][NH2:12])[C:2]([NH2:4])=[NH:3].[NH2:16][C:17]1[C:21](OC)=[N:20][S:19](=[O:24])[N:18]=1>CO>[NH2:16][C:17]1[C:21]([NH:12][CH2:11][CH2:10][CH2:9][O:8][C:7]2[CH:13]=[CH:14][CH:15]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[CH:6]=2)=[N:20][S:19](=[O:24])[N:18]=1
Reactant: COC1=NS(=O)N=C1N
Reactant: N=C(N)Nc1cccc(OCCCN)c1
Solvent: CO
Product: N=C(N)Nc1cccc(OCCCNC2=NS(=O)N=C2N)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of crude 3-(3-guanidinophenoxy)propylamine [prepared in Step D] in 10 ml of methanol was added 3-amino-4-methoxy-1,2,5-thiadiazole 1-oxide (0.59 g; 4.0 mmoles) and the mixture was stirred at ambient temperature for 17 hours and then heated at 50° for 2.5 hours. The reaction mixture was filtered, evaporated under reduced pressure and the residue was chromatographed by flash chromatography on 75 g of silica gel (230-400 mesh) using methanol-methylene chloride. The appropriate fractions were combined and evaporated under reduced pressure to yield 0.25 g of the title compound as an oil; TLC [silica gel/CH2Cl2 :CH3OH (4:1)] gave Rf=0.21.