Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:12].Cl[CH2:14][CH:15]1[O:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:14][CH:15]1[O:17][CH2:16]1
Reactant: ClCC1CO1
Reactant: Oc1ccc2ccccc2c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Brc1c(OCC2CO2)ccc2ccccc12

Procedure:
A suspension containing 22.3 g of 1-bromonaphth-2-ol, 27.75 g of 1-chloro-2,3-epoxypropane and 27.6 g of potassium carbonate in 200 ml of butanone is refluxed overnight. The inorganic salts are filtered off and drained and the filtrate is then evaporated under vacuum. The oil obtained is distilled under 0.01 mm of mercury.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C1([Mg]Cl)C=CC=CC=1.[CH3:21][C:22]([CH3:26])([CH3:25])[CH:23]=[O:24]>C1COCC1>[CH3:12][O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH:23]([OH:24])[C:22]([CH3:26])([CH3:25])[CH3:21])[CH:3]=1
Reactant: COc1ccc([N+](=O)[O-])c(I)c1
Reactant: CC(C)(C)C=O
Agent: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])c(C(O)C(C)(C)C)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
To a solution of 3-iodo-4-nitroanisole (2.79 g, 10.0 mmol) in anhydrous THF (10 mL) at minus 40° C. under a nitrogen atmosphere, phenylmagnesium chloride (2 M in THF, 4.2 mL, 8.3 mmol) was added dropwise at a rate such that the temperature would not exceed minus 35° C. Upon completion of the addition, the mixture was stirred at minus 40° C. for two hours, followed by addition of trimethylacetaldehyde (1.1 mL, 10 mmol). The mixture was stirred at minus 40° C. for two hours and then at room temperature for another one hour. The reaction was then quenched with brine (100 mL), and the mixture was extracted with CH2Cl2 (40 mL) three times. The combined organic phase was dried over Na2SO4, concentrated in vacuo, and the residue was purified by silica gel column chromatography to yield racemic (R/S)-1-(5-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propanol (1.76 g, 88%). 1H NMR (400 MHz, CDCl3): δ 7.89 (d, 1H, J=9.2 Hz, Ph-H), 7.27 (d, 1H, J=2.8 Hz, Ph-H), 6.84 (dd, 1H, J=8.8 and 2.8 Hz, Ph-H), 5.62 (d, 1H, J=4.0 Hz, PhCH), 3.89 (s, 3H, OCH3), 2.08 (d, 1H, J=4.0 Hz, OH), 0.89 (s, 9H, C(CH3)3).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:16][CH2:17][C:18]([O:20]C)=[O:19])[CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCc1cccc(CNC(=O)OC(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1cccc(CCC(=O)O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 102.1 %

Procedure:
To 3.6 g of methyl 3-(3-tert-butyloxycarbonylaminomethylphenyl)propionate (C3) in 36 ml of tetrahydrofurane 14.8 ml of 1N aqueous sodium hydroxide solution are added and the mixture is stirred at RT for 2 days. After neutralization with 14.8 ml 1N hydrochloric acid solution and dilution with water the mixture is extracted three times with ethyl acetate. The combined extracts are dried over magnesium sulfate, filtered and the solvent removed in vacuo to give 3.5 g of the title compound as a brownish oil which solidifies on standing in a refrigerator. The mass spectrum shows the molecular peak MNH4+ at 297 Da.
Reaction SMILES: C1COCC1.[C:6]12([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:29])[C:24]([O:26]CC)=[O:25])=[CH:18][CH:17]=3)[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2.[OH-].[Na+].Cl>C(O)C>[C:6]12([C:16]3[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:29])[C:24]([OH:26])=[O:25])=[CH:20][CH:21]=3)[CH2:7][CH:8]3[CH2:9][CH:10]([CH2:11][CH:12]([CH2:14]3)[CH2:13]1)[CH2:15]2
Reactant: CCOC(=O)C(=O)Nc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C(=O)Nc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Temperature: 70 °C
Yield: 89.8 %

Procedure:
THF (18 mL) and ethanol (6 mL) were added to 600 mg (1.83 mmol) of ethyl {[4-(adamantan-1-yl)phenyl]amino}(oxo)acetate. Thereafter, 2.7 mL of 1N aqueous sodium hydroxide solution was added, and the mixture was heated at 70° C. for 2 hours. Next, 1N hydrochloric acid was added to acidify the mixture, and the organic solvent was distilled off under reduced pressure. The resulting solids were filtered and washed with H2O and n-hexane, followed by drying, thereby giving 492 mg of {[4-(adamantan-1-yl)phenyl]amino}(oxo)acetic acid (yield: 90%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[S:4][C:3]=1[C:8]([O:10]C)=O.Cl[C:13]1[N:18]=[CH:17][C:16]([C:19]([NH2:21])=[O:20])=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[CH3:7][C:5]1[S:4][C:3]2[C:8](=[O:10])[N:18]3[CH:17]=[C:16]([C:19]([NH2:21])=[O:20])[CH:15]=[CH:14][C:13]3=[N:1][C:2]=2[CH:6]=1
Reactant: COC(=O)c1sc(C)cc1N
Reactant: NC(=O)c1ccc(Cl)nc1
Solvent: ClC(Cl)Cl
Product: Cc1cc2nc3ccc(C(N)=O)cn3c(=O)c2s1
Yield: 14.6 %

Procedure:
A mixture of 2.7 g (0.0158 mol) of 3-amino-5-methyl-2-thiophene-carboxylic acid, methyl ester (German Patent No. 1055007, Apr. 16, 1959) and 2.5 g (0.0158 mol) of 6-chloro-3-pyridinecarboxamide (Aldrich Chemical Company) is heated in an oil bath at 180°-190° C. for one hour. The mixture is cooled and then suspended in hot chloroform and filtered to give 0.6 g of 2-methyl-10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxamide; mp 375°-377° C. after recrystallization from pyridine.
Reaction SMILES: O=P(Cl)(Cl)Cl.O=[C:7]1[CH:13]([NH:14][CH:15]=[O:16])[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[S:10][C:9]2[CH:21]=[CH:22][CH:23]=[CH:24][C:8]1=2>C1(C)C=CC=CC=1>[O:16]1[C:7]2[C:8]3[CH:24]=[CH:23][CH:22]=[CH:21][C:9]=3[S:10][C:11]3[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=3[C:13]=2[N:14]=[CH:15]1
Reactant: O=CNC1C(=O)c2ccccc2Sc2ccccc21
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)Sc1ccccc1-c1ocnc1-2

Procedure:
To a solution of POCl3 (0.137 g, 0.892 mmole) in dry toluene (5 ml), N-(11-oxo-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-formamide (III; X=S, Y=Z=H. A=NH, R1=H) (0.06 g, 0.223 mmole) dissolved in toluene (10 ml) was added. The reaction mixture was heated under reflux for 2 hours. Then toluene was evaporated to dryness and water was added and it was extracted with ethyl acetate. The organic extract was washed with a saturated NaHCO3 solution and water and dried over anhydrous Na2SO4. The solvent was evaporated and, after purifying by chromatography on a column, an oily product was isolated.
Reaction SMILES: C[O:2][C:3](=[O:12])/[CH:4]=[CH:5]/[C:6]1[S:7][C:8]([Cl:11])=[CH:9][CH:10]=1.O.[OH-].[Li+]>C1COCC1.CO.O>[Cl:11][C:8]1[S:7][C:6](/[CH:5]=[CH:4]/[C:3]([OH:12])=[O:2])=[CH:10][CH:9]=1
Reactant: COC(=O)/C=C/c1ccc(Cl)s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)/C=C/c1ccc(Cl)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
To a mixture of 3-(5-chloro-thiophen-2-yl)-(E)-acrylic acid methyl ester (0.60 g, 2.96 mmol) in 15 mL of 1:1:1 THF/MeOH/H2O at 0° C. is added lithium hydroxide monohydrate (0.62 g, 14.7 mmol). The mixture is stirred at 0° C. for 1 h, then at room temperature for 1 h and concentrated in vacuo. The residue is diluted with EtOAc and washed with 1N HCl. The aqueous layer is extracted with EtOAc and the combined organics are washed with water (2×), dried, filtered and concentrated to provide the title compound (0.54 g, 2.86 mmol) as a white solid. The crude material can be used in the subsequent step without further purification. 1H NMR (CDCl3, 300 MHz) δ7.65 (d, 1H), 7.05 (d, 1H), 6.90 (d, 1H), 6.10 (d, 1H).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].C([N:8]([CH2:15][CH3:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C.N1C2C(=CC=CC=2)CC1=O.O>C1(C)C=CC=CC=1>[Cl:3][C:15]1[NH:8][C:9]2[C:10]([CH:16]=1)=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: CCN(CC)c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C1Cc2ccccc2N1
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1cc2ccccc2[nH]1
Yield: 92.7 %

Procedure:
At room temperature, POCl3 (1 ml, 10.82 mmol, 2 eq) is added to a well stirred suspension of N,N-diethylaniline (1 ml, 5.41 mmol, 1 eq) and 1,3-dihydro-2H-indol-2-one x159 (0.72 g, 5.41 mmol, 1 eq) in dry toluene (15 ml). The mixture is heated at reflux during 3 hours. After cooling, water (15 ml) is carefully added and the organic layer is washed with water (3×25 ml). The organic layer is dried on anhydrous MgSO4, filtered off and concentrated under reduced pressure to obtain 0.76 g of 2-chloro-1H-indole x160 as an orange solid (0.76 g, 93%).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[N:12]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:11]([CH2:27][CH3:28])[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([F:29])[CH:9]=3)[C:4]=2[CH:3]=1.[S:30]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31]1.ClCCl.[OH-].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:27]([CH:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:29])[CH:9]=2)[C:4]2[CH:3]=[C:2]([C:32]3[CH:33]=[CH:34][S:30][CH:31]=3)[CH:15]=[CH:14][C:13]=2[N:12]1[S:16]([C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)(=[O:17])=[O:18])[CH3:28]
Reactant: OB(O)c1ccsc1
Reactant: CCC1c2cc(F)ccc2-c2cc(Br)ccc2N1S(=O)(=O)c1ccc(OC)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Na+]
Solvent: ClCCl
Product: CCC1c2cc(F)ccc2-c2cc(-c3ccsc3)ccc2N1S(=O)(=O)c1ccc(OC)cc1
Yield: 51.4 %

Procedure:
The title compound was prepared from 2-bromo-6-ethyl-8-fluoro-5-[(4-methoxyphenyl)sulfonyl]-5,6-dihydrophenanthridine (Example 44, Step c, 0.35 g, 0.73 mmol), 3-thiopheneboronic acid (0.09 g, 0.73 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (0.02 g, 0.02 mmol), and a 5 N aqueous sodium hydroxide solution (0.3 mL, 1.5 mmol) according to the procedure and in the same manner as described in Example 47, Step a. The crude material was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:4) to yield 6-ethyl-8-fluoro-5-[(4-methoxyphenyl)sulfonyl]-2-thien-3-yl-5,6-dihydrophenanthridine as a solid (0.18 g, 51%);
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)=[N:9][NH:10][C:6]=2[CH:5]=[CH:4][NH:3]1.[H-].[Na+].CC1C=CC(S(O[CH2:34][CH:35]2[CH2:38][O:37][CH2:36]2)(=O)=O)=CC=1>CN(C=O)C>[O:37]1[CH2:38][CH:35]([CH2:34][N:10]2[C:6]3[CH:5]=[CH:4][NH:3][C:2](=[O:1])[C:7]=3[C:8]([C:11]3[CH:12]=[CH:13][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:15][CH:16]=3)=[N:9]2)[CH2:36]1
Reactant: Cc1ccc(S(=O)(=O)OCC2COC2)cc1
Reactant: NS(=O)(=O)c1ccc(-c2n[nH]c3cc[nH]c(=O)c23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(-c2nn(CC3COC3)c3cc[nH]c(=O)c23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.5 %

Procedure:
To a solution of 4-(4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide (52.0 mg) obtained in Step B of Example 100 in DMF (3 mL) was added sodium hydride (60% dispersion in mineral oil, 8.60 mg), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added oxetan-3-ylmethyl 4-methylbenzenesulfonate (52.1 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/methanol) to give the title compound (10.0 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][NH:12][C:13]([C:15]2[C:31]([OH:32])=[C:18]3[C:19](=[O:30])[N:20]([CH3:29])[CH2:21][C@H:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:17]3[N:16]=2)=[O:14])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C1C=[N:37][C:36]2N(O)N=NC=2C=1.C(Cl)CCl.CN.C1COCC1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][NH:12][C:13]([C:15]2[C:31]([OH:32])=[C:18]3[C:19](=[O:30])[N:20]([CH3:29])[CH2:21][C@H:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:17]3[N:16]=2)=[O:14])=[C:6]([C:7]([NH:37][CH3:36])=[O:8])[CH:10]=1
Reactant: CN1C[C@H](c2ccccc2)n2nc(C(=O)NCc3ccc(F)cc3C(=O)O)c(O)c2C1=O
Reactant: On1nnc2cccnc21
Agent: CN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CNC(=O)c1cc(F)ccc1CNC(=O)c1nn2c(c1O)C(=O)N(C)C[C@@H]2c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-fluoro-2-[({[(7S)-3-hydroxy-5-methyl-4-oxo-7-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]carbonyl}amino)methyl]benzoic acid (47 mg, 0.106 mmol) in DMF (1 mL) were added HOAT (44 mg, 0.322 mmol), and EDC (62 mg, 0.322 mmol). The reaction mixture was stirred at ambient temperature 15 minutes then 2M methylamine in THF (214 μL, 0.429 mmol) and triethylamine (45 μL, 0.322 mmol) were added. The reaction was stirred at ambient temperature for 5 hours. The crude reaction was purified by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA). Collection and concentration of the appropriate fractions afforded the product as a light pink solid. 1H NMR (400 MHz, d6-DMSO) δ 8.55 (t, J=6.2 Hz, 1H), 8.48 (m, 1H), 7.3-7.4 (m, 4H), 7.25 (m, 2H), 7.03 (m, 2H), 5.75 (t, J=4.0 Hz, 1H), 4.68 (ABX, J=15.2, 6.4 Hz, 2H), 4.18 (dd, J=13.4, 4.6 Hz, 1H), 3.79 (dd, J=13.4, 3.8 Hz, 1H), 2.87 (s, 3H), 2.75 (d, J=4.6 Hz, 3H); HRMS (FT-ICR) C23H22FN5O4+H=452.1735; calculated 452.1729.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]([CH3:18])[C:16](=[O:19])[C:15]3[C:10](=[C:11]([C:20]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[O:21])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[B-](F)(F)(F)[CH2:70][N:71]1[CH2:75][CH2:74][CH2:73][CH2:72]1.[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].O>[CH3:18][N:17]1[C:16](=[O:19])[C:15]2[C:10](=[C:11]([C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[O:21])[CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([CH2:70][N:71]2[CH2:75][CH2:74][CH2:73][CH2:72]2)=[CH:3][CH:4]=1
Reactant: F[B-](F)(F)CN1CCCC1
Reactant: Cn1c(-c2ccc(Br)cc2)nc2c(C(=O)Nc3ccccn3)cccc2c1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Product: Cn1c(-c2ccc(CN3CCCC3)cc2)nc2c(C(=O)Nc3ccccn3)cccc2c1=O
Temperature: 150 °C
Yield: 62.3 %

Procedure:
Degassed THF/H2O (4 mL, 10:1) was added to a microwave vial containing 2-(4-bromophenyl)-3-methyl-4-oxo-N-(pyridin-2-yl)-3,4-dihydroquinazoline-8-carboxamide 28 (100 mg, 0.23 mmol), Cs2CO3 (224 mg, 0.69 mmol), Pd(OAc)2 (1.5 mg, 0.007 mmol), XPHOS (65 mg, 0.014 mmol), and potassium 1-trifluoroboratomethylpyrrolidine (48 mg, 0.25 mmol). The reaction mixture was heated at 150° C. in a microwave reactor for 30 min., poured into H2O and extracted with EtOAc. The combined organics were washed with brine, dried, concentrated and the crude residue purified by MPLC eluting with CH2Cl2/MeOH (0-10%) to give Compound 275 (63 mg, 63% yield). MS (ESI) calc. for C26H25N5O2: 439.20. found: 440 [M+H].
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]#[C:9][Si](C)(C)C)=[C:6]([NH2:14])[N:5]2[N:15]=[CH:16][N:17]=[C:4]2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CO.O1CCCC1.O>[C:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]2[N:5]([N:15]=[CH:16][N:17]=2)[C:6]=1[NH2:14])#[CH:9]
Reactant: Cc1nc2ncnn2c(N)c1C#C[Si](C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C#Cc1c(C)nc2ncnn2c1N
Yield: 40.4 %

Procedure:
A mixture of Example 72A (122 mg, 0.5 mmol), potassium carbonate (138 mg, 1.0 mmol) in a mixed solvent of methanol/tetrahydrofuran/H2O(3 mL/3 mL/0.5 mL) was stirred at room temperature for 1.5 h. The reaction mixture was acidified with 1N HCl. The solid was filtered, washed with water and ethyl acetate to provide the title compound as an off-white solid (35 mg, 40% yield).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[C:8]1[CH:16]=O>O1CCCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)C=O>[CH:16]([C:8]1[O:7][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=1)=[CH2:1]
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1cc2ccccc2o1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=Cc1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
92 ml of a 1N solution of potassium tert-butoxide in tetrahydrofuran are added dropwise to a vigorously stirred mixture at 0° C. of 68.4 mmol of benzofuran-2-carboxaldehyde and 92 mmol of methyltriphenylphosphonium bromide in 200 ml of tetrahydrofuran and 150 ml of dimethylformamide. The medium is stirred for 2 h at room temperature, poured into 2 liters of ice-water and extracted with ether. After concentration of the solvents, the residue is taken up in 1 liter of petroleum ether and the precipitate is filtered off and washed with petroleum ether. The expected product is obtained by evaporation of the filtrate.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][C:23](=[CH:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)[CH2:22][CH2:21]2)=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:10]=1)=O)C.[NH3:34]>C(O)C>[C:4]([C:6]1[S:7][C:8]([CH2:18][CH2:19][N:20]2[CH2:21][CH2:22][C:23](=[CH:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)[CH2:24][CH2:25]2)=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[N:10]=1)(=[O:3])[NH2:34]
Reactant: N
Reactant: CCOC(=O)c1nc(-c2ccc(F)cc2)c(CCN2CCC(=Cc3cccc(F)c3)CC2)s1
Solvent: CCO
Product: NC(=O)c1nc(-c2ccc(F)cc2)c(CCN2CCC(=Cc3cccc(F)c3)CC2)s1

Procedure:
315 mg of 2-ethoxycarbonyl-4-(4-fluorophenyl)-5-[2-[4-(3-fluorobenzylidene)piperidin-1-yl]ethyl]thiazole and 0.05 ml of 28% aqueous ammonia were stirred in 1.5 ml of ethanol for 3 days. To the mixture was added 0.50 ml of 28% aqueous ammonia to carry out additional 3 days of reaction. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by a flash column chromatography (Wako Gel C200 (manufactured by Wako Pure Chemical Industries), eluant: hexane-ethyl acetate=3:1-1:1) and recrystallized from ethanol to obtain 201 mg of 2-carbamoyl-4-(4-fluorophenyl)-5-[2-[4-(3-fluorobenzylidene)piperidin-1-yl]ethyl]thiazole.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][C:13]([OH:15])=O)=[O:5])[CH3:2].[CH2:16]([N:18]([CH2:22][CH3:23])[CH2:19][CH2:20][NH2:21])[CH3:17].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.ClCCl.O>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][C:13](=[O:15])[NH:21][CH2:20][CH2:19][N:18]([CH2:22][CH3:23])[CH2:16][CH3:17])=[O:5])[CH3:2]
Reactant: CCN(CC)CCN
Reactant: CCOC(=O)c1c(C)c[nH]c1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1c(C)c[nH]c1CC(=O)NCCN(CC)CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 908.2 %

Procedure:
A stirred solution of 2-carboxymethyl-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (2.11 g, 10 mmol) in N,N-dimethylformamide (5 ml) and dichloromethane (50 ml) was added with N1,N1-diethylethane-1,2-diamine (1.23 g, 11 mmol), N-ethyl-N′-(dimethylaminopropyl)-carbodiimide hydrochloride (5 g, 26 mmol) and 1-hydroxybenzotriazol (1.5 g, 11 mmol) in an ice-water bath. Upon completion of the addition, the mixture was stirred at room temperature overnight, added with cold water (50 ml), extracted with dichloromethane (50 ml×3). The combined organic extracts were washed with saturated sodium bicarbonate (50 ml), water (50 ml), brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-[(2-diethylamino-ethylcarbamoyl)-methyl]-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (28.1 g, 90.9%) as a colorless oil.
Reaction SMILES: [CH3:1][Mg]I.[CH:4]([C:7]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])([CH3:6])[CH3:5].S(=O)(=O)(O)O>CCOCC>[C:13]([C:7]1([CH:4]([CH3:6])[CH3:5])[CH2:11][CH2:10][CH2:9][C:8]1([CH3:1])[OH:12])([O:15][CH2:16][CH3:17])=[O:14]
Reactant: C[Mg]I
Reactant: CCOC(=O)C1(C(C)C)CCCC1=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCOC(=O)C1(C(C)C)CCCC1(C)O

Procedure:
Methylmagnesium iodide (0.22 mole) in ether (200 ml.) was added dropwise to a solution of 2-isopropyl-2-carbethoxycyclopentanone (40 g, 0.2 mole) in ether (150 ml.), and the mixture was heated under reflux for 17 hours. Dilute sulphuric acid was then added and the ether layer was separated and dried (MgSO4). The ether was removed to leave 2-carbethoxy-1-methyl-2-isopropylcyclopentanol. This compound was dissolved in pyridine (200 ml.) and cooled to -10° C. Thionyl chloride (25 ml.) was then added keeping the temperature at -5° C. After 2 hours at -5° C., ether (500 ml) and an excess of 2N sulphuric acid were added and the organic layer was separated. The aqueous layer was extracted with ether and the combined extracts were dried (MgSO4). The solvent was removed and the residue was distilled to give 1-carbethoxy-1-isopropyl-2-methylcyclopent-2-ene, bp. 107°-110°/17 mm.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:16]=[CH:15][C:6]2[C:7](=[O:14])[O:8][C:9]([O:11][CH2:12][CH3:13])=[N:10][C:5]=2[CH:4]=1.[C:17](=O)([O-])[O-].[K+].[K+]>CCOCC>[NH2:2][C:3]1[CH:16]=[C:15]([CH3:17])[C:6]2[C:7](=[O:14])[O:8][C:9]([O:11][CH2:12][CH3:13])=[N:10][C:5]=2[CH:4]=1
Reactant: CCOc1nc2cc(N)ccc2c(=O)o1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOCC
Product: CCOc1nc2cc(N)cc(C)c2c(=O)o1

Procedure:
1.0 g of 7-amino-2-ethoxy-4H-3,1-benzoxazin-4-one HCl suspended in 50 ml of ether is stirred with a twofold stoichiometric excess of dilute aqueous potassium carbonate solution until the salt is completely dissolved. The organic layer is then separated, washed twice with water, dried over magnesium sulfate and evaporated to yield 7-amino-2-ethoxy-5-methyl-4H-3,1-benzoxazin-4-one as the free base.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].CC(O)C.[BH4-].[Na+]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:18]=1[CH2:19][OH:20])[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(Cl)c3C=O)ncc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(Cl)c3CO)ncc2c1
Temperature: 25 °C
Yield: 65.2 %

Procedure:
2-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-chloro-benzaldehyde (125 g, 0.35 mol) was dissolved in DCM (1 L) with stirring at room temperature, and then 0.5 L of IPA was added to the solution. The resulting solution was cooled down to 4° C., and NaBH4 (5.9 g, 0.16 mol) was added portion wise. After 30 min stirring, the reaction was quenched by adding H2O (200 mL). The organic layer was collected by phase separation, and DCM was distilled out from the solution with adding additional IPA (1.6 L) in the same time at about 80° C. The desired product started to crystallize out from IPA at around 30° C. with seeding, then water (750 mL) was added to the solution dropwise. The resulting solution was cooled down to 5° C. and filtered to collect the crystal material. The filter cake was washed with IPA/water (2/1, 450 mL, pre-cooled to 5° C.), and dried under vacuum oven at 65° C. overnight to afford 82.3 g of the title compound (65.5% isolated yield) as a white solid. MS (ESI) 360, 362 (M+H)+.