Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[Na+].I.[CH2:4]([N:11]1[CH2:20][CH2:19][C:18]2[C:17](Cl)=[N:16][C:15]([CH2:22][O:23][CH3:24])=[N:14][C:13]=2[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1>O1CCOCC1>[CH2:4]([N:11]1[CH2:20][CH2:19][C:18]2[C:17]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:28][CH:27]=3)=[N:16][C:15]([CH2:22][O:23][CH3:24])=[N:14][C:13]=2[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: COCc1nc(Cl)c2c(n1)CN(Cc1ccccc1)CC2
Agent: I
Agent: [I-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COCc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(Cc1ccccc1)C2

Procedure:
Sodium iodide (720 mg, 4.8 mmol) and hydriodic acid (2.0 mL, 47% aqueous solution) were added to a mixture of 7-benzyl-4-chloro-5,6,7,8-tetrahydro-2-(methoxymethyl)pyrido[3,4-d]pyrimidine as prepared for Example 5.B. (1.2 g, 4.0 mmol) and 4-aminobenzotrifluoride (1.3 g, 8 mmol) in dioxane (20 mL) and the reaction solution was stirred at 100° C. overnight. Solvent was removed in vacuo and the residue was dissolved in water. Solid sodium carbonate was added to the solution to a pH>7 and the mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with brine, and dried over sodium sulfate. Solvent was removed and the residue was purified by column chromatography to yield the product as a beige solid (910 mg).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:15][C:16]([OH:18])=[O:17]>CN(C)C=O>[CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:15][C:16]([OH:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCl
Reactant: OCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)COCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
2-(Benzyloxy)ethanol (0.75 ml) is dissolved in N,N-dimethylformamide (3 ml), and added dropwise to a solution of sodium hydride (400 mg) in N,N-dimethylformamide under ice-cooling. The mixture is stirred for 40 minutes. To the reaction solution is added chloroacetic acid (500 mg) under ice-cooling, and the mixture is stirred at room temperature for 1 day. To the reaction solution is added ice-water, and the mixture is extracted with ethyl acetate. To the aqueous layer is added 6N HCl, and the solution is adjusted to pH 2 and extracted with ethyl acetate. The organic layer is washed with saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure to give 2-(benzyloxy)ethoxy acetic acid (895 mg). MS (m/z): 211 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH3:28])[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C@@H:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([CH3:27])[CH:21]=3)[CH2:18][CH3:19])[CH:11]=2)[CH2:6]1)=[O:4].[Li+].[OH-].Cl>C1COCC1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C@H:17]([NH:16][C:12]2[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=2)[CH2:9][N:7]2[CH2:6][C:5]([CH3:28])([C:3]([OH:4])=[O:2])[CH2:8]2)[CH2:18][CH3:19])=[CH:21][C:22]=1[CH3:27]
Reactant: CC[C@@H](Nc1cccc(CN2CC(C)(C(=O)OC)C2)c1)c1ccc(Cl)c(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC[C@@H](Nc1cccc(CN2CC(C)(C(=O)O)C2)c1)c1ccc(Cl)c(C)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of INT 15 (158 mg, 0.39 mmol) in THF (3.9 mL) at 0° C. was added LiOH (1.0 M in H2O, 1.97 mL, 1.97 mmol). The reaction mixture was stirred at room temperature for 5 hours. The mixture was acidified with 1 M HCl and concentrated. The residue was taken up in CH2Cl2/EtOAc and washed with brine. The aqueous layer was extracted with CH2Cl2/EtOAc (3×). The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by preparative HPLC (H2O/CH3CN) to afford the title compound Example 8.
Reaction SMILES: C([NH:5][S:6]([C:9]1[C:10]([CH:38]([F:40])[F:39])=[N:11][CH:12]=[C:13]([C:15]2[N:20]3[CH:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:19]3[C:18]([NH:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)=[N:17][N:16]=2)[CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[F:40][CH:38]([F:39])[C:10]1[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:14][C:13]([C:15]2[N:20]3[CH:21]=[CH:22][C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[C:19]3[C:18]([NH:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)=[N:17][N:16]=2)=[CH:12][N:11]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cc(-c2nnc(NCc3ccccn3)c3c(-c4ccccc4)ccn23)cnc1C(F)F
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cc(-c2nnc(NCc3ccccn3)c3c(-c4ccccc4)ccn23)cnc1C(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 12.7 %

Procedure:
N-(tert-Butyl)-2-(difluoromethyl)-5-(8-phenyl-1-((pyridin-2-ylmethyl)amino)pyrrolo[1,2-d][1,2,4]triazin-4-yl)pyridine-3-sulfonamide (0.035 g, 0.062 mmol) was dissolved in TFA (2.00 mL, 26.0 mmol) and stirred at room temperature for 4 h. TFA was removed under reduced pressure and reaction mixture was diluted with saturated NaHCO3 (10 mL). The reaction mixture was extracted with EtOAc (3×20 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Condition B-13 described in general methods) to afford 2-(difluoromethyl)-5-(8-phenyl-1-((pyridin-2-ylmethyl)amino)pyrrolo[1,2-d][1,2,4]triazin-4-yl)pyridine-3-sulfonamide (0.004 g, 10%) as a pale yellow solid. LCMS Method B-7: retention time 1.55 min, [M+1]=508.0, Purity 99.3%. LCMS Method B-8: retention time 1.14 min, [M+1]=508.0, Purity 99.3%. 1H NMR (400 MHz, CD3OD) δ ppm: 4.77 (s, 2H), 6.96 (d, J=2.8 Hz, 1H), 7.26-7.29 (m, 1H), 7.40 (d, J=7.6 Hz, 1H), 7.51-7.66 (m, 6H), 7.70 (d, J=2.8 Hz, 1H), 7.75-7.79 (m, 1H), 8.34 (br d, J=5.2 Hz, 1H), 8.89 (dd, J=0.8 Hz, 1.2 Hz, 1H), 9.35 (d, J=2.0 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)[CH3:2].[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:13])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:17](=[O:18])[C:16]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]3[C:14]2=[O:19])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Nc1ccc(N)cc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: CCOC(=O)Nc1ccc(N2C(=O)c3ccccc3C2=O)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
(4-Amino-phenyl)-carbamic acid ethyl ester (118 g, 0.65 mol) is dissolved in glacial acetic acid (2.0 L) under nitrogen and the mixture is heated to 90° C. Phthalic anhydride (102.0 g, 0.69 mol) is added portionwise over 30 minutes and the reaction is kept at 90° C. for 2 hours. The mixture is allowed to cool to ambient temperature and the precipitated solid is filtered off. The solid is washed on the filter with water (2 L) followed by diethylether (3 L) and then dried in vacuo. Yield 127 g (62%) title compound as white crystalline compound. LC/MS (m/z) 311.3 (MH+); tR=2.57 min. 1H NMR (DMSO-d6): 1.26 (t, 3H); 4.15 (q, 2H); 7.34 (dd, 2H); 7.58 (dd, 2H); 7.90 (ddd, 2H); 7.95 (ddd, 2H); 9.80 (s, 1H, NH).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][C:15](=[O:17])[N:14]([C:18]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[S:20][C:19]=3[C:29]([OH:31])=[O:30])[C@H:13]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1.CCN(CC)CC>CN(C=O)C>[CH:32]1([C@@H:13]2[CH2:12][N:11]([S:8]([C:5]3[CH:6]=[N:7][C:2]([N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH2:16][C:15](=[O:17])[N:14]2[C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[S:20][C:19]=2[C:29]([OH:31])=[O:30])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: C1CCNC1
Reactant: O=C(O)c1sc(-c2ccccc2)cc1N1C(=O)CN(S(=O)(=O)c2ccc(Cl)nc2)C[C@H]1C1CCCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)c1sc(-c2ccccc2)cc1N1C(=O)CN(S(=O)(=O)c2ccc(N3CCCC3)nc2)C[C@H]1C1CCCCC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 32.7 %

Procedure:
To a solution of 3-[(R)-4-(6-chloro-pyridine-3-sulfonyl)-2-cyclohexyl-6-oxo-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylic acid (100 mg, 0.18 mmol, 1.0 equiv) in DMF (0.8 mL) at room temperature was added pyrrolidine (127 mg, 1.79 mmol, 10.0 equiv) and Et3N (0.37 mL, 2.68 mmol, 15.0 equiv). The mixture was stirred at 70° C. for 2 hours. The mixture was then cooled to room temperature and filtered. The filtrate was concentrated and purified by HPLC (0.1% NH4OH) to give product (35 mg, 33%) as white solid. MS: 595 [M−H+]. 1H-NMR (400 MHZ, MeOD): δ 1.10-1.23 (m, 5H), 1.40-2.00 (m, 10H), 3.04-3.12 (m, 2H), 3.20 (t, 2H), 3.42 (d, 2H), 3.88 (d, 1H), 3.97 (br, 1H), 4.07 (d, 1H), 6.62 (s, 1H), 7.19 (s, 1H), 7.32 (t, 1H), 7.40 (t, 2H), 7.63 (d, 2H), 7.83 (m, 1H), 8.44 (d, 1H).
Reaction SMILES: N([O-])=O.[Na+].[Br:5][C:6]1[CH:7]=[CH:8][C:9]([F:13])=[C:10]([CH:12]=1)N.S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.BrC1C=CC(F)=C([N+]#N)C=1.BrC1C=CC(F)=C([N+]#N)C=1.[I-:44].[K+]>O>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([F:13])=[C:10]([I:44])[CH:12]=1
Reactant: Nc1cc(Br)ccc1F
Reactant: [I-]
Agent: N#[N+]c1cc(Br)ccc1F
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: Fc1ccc(Br)cc1I
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A solution of sodium nitrite (1.71 g) in water (4 cm3) was added dropwise to a stirred mixture of 5-bromo-2fluoroaniline (4.5 g), water (15 cm3), ice (15 g) and concentrated sulphuric acid (1.8 cm3) at a temperature maintained at 0°-5° C. The reaction mixture was stirred for 30 minutes, and further concentrated sulphuric acid (0.4 cm3) added. The resultant solution, containing 5-bromo-2-fluorobenzenediazonium sulphate, was then added dropwise to a solution of potassium iodide (4.23 g) in water (10 cm3) at a temperature of 5°-6° C.; vigorous effervescence was observed during the addition. When the addition was complete, the reaction mixture was allowed to warm to the ambient temperature (22° C.) and was then extracted twice with diethyl ether. The combined extracts were washed successively with brine and sodium thiosulphate solutions, dried over anhydrous magnesium sulphate, filtered and concentrated by evaporation of the solvent under reduced pressure. The residual oil was purified by flash column chromatography, using a silica gel support and eluting with petroleum ether (boiling range 40°-60° C.) containing 4% by volume diethyl ether, to give 4-bromo-1-fluoro-2-iodobenzene (4.63 g) as a colourless oil.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[CH2:19]([O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([C:36](O)=[O:37])=[CH:30]2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O.C(N(CC)CC)C>[CH2:19]([O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([C:36]([N:16]1[CH2:17][CH2:18][N:13]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[C:3]([CH3:6])([CH3:4])[CH3:5])[CH2:14][CH2:15]1)=[O:37])=[CH:30]2)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2cc3cc(OCc4ccccc4)ccc3[nH]2)CC1
Temperature: 25 °C
Yield: 81 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (2.0 g), 5-(benzyloxy)-1H-indole-2-carboxylic acid (2.03 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.92 g), 1-hydroxy-1H-benzotriazole monohydrate (1.53 g), triethylamine (2.79 mL), and N,N-dimethylformamide (30 mL) was stirred at room temperature for over-night. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to provide the title compound (2.6 g, 81%) as crystals.
Reaction SMILES: CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[Cl:20][C:21]1[CH:41]=[CH:40][C:24]([C:25]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:39])[CH2:35][C:36]([OH:38])=O)=[CH:29][CH:28]=2)=[O:26])=[CH:23][CH:22]=1>CC(C)=O>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([C:27]2[CH:28]=[C:29]3[C:30](=[CH:31][CH:32]=2)[NH:33][C:34](=[O:39])[CH:35]=[C:36]3[OH:38])=[O:26])=[CH:40][CH:41]=1
Reactant: O=C(O)CC(=O)Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CC(C)=O
Product: O=C(c1ccc(Cl)cc1)c1ccc2[nH]c(=O)cc(O)c2c1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
A 2-L 4-neck flask equipped with a thermocouple controller, a mechanical stirrer, and a nitrogen inlet/outlet adapter was charged with CH3SO2OH (236.0 mL, 3.60 mol), P2O5 (34.6 g, 241.1 mmol) was added and the mixture was vigorously stirred at 80° C. for 90 min. Solid 3-((4-(4-chlorobenzoyl)phenyl)amino)-3-oxopropanoic acid (111.0 g, 321.4 mmol) was added portionwise over 3 min at 80° C., and the resulting mixture was stirred at 80° C. for 2 h. The hot mixture was poured slowly into ice-water (5 L) and vigorously agitated for 1 h. The resulting solid was collected by filtration, washed with deionized water (2 L×2), and dried by air-suction for 20 h to yield a slightly yellowish solid. The solid was suspended in acetone (990 mL) at 53° C. and sonicated for 30 min. The resulting yellowish slurry was stirred at 20° C. for 10 min. The solid was collected by filtration, washed with acetone (50 mL), dried by air-suction for 1 h and then under high vacuum (22 mmHg) at 60° C. for 20 h to yield 6-(4-chlorobenzoyl)-4-hydroxyquinolin-2(1H)-one as a light beige-yellowish solid. Elemental analysis: Calculated for C16H10ClNO5+0.1H2O+0.21CH3COCH3; MW=313.72. Theoretical: C, 63.67; H, 3.68; Cl, 11.30; N, 4.46; % H2O, 0.60; Measured: C, 63.58; H, 3.23; Cl, 11.53; N, 4.64; % H2O, 0.53
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:31]=[CH:30][C:13]3[S:14][C:15]([CH2:17][CH:18]4[CH2:22][CH2:21][N:20]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:19]4=[O:29])=[CH:16][C:12]=3[CH:11]=2)=[CH:6][CH:5]=1.O[Li].O.O1CCOCC1.Cl>O>[CH:23]1([N:20]2[CH2:21][CH2:22][CH:18]([CH2:17][C:15]3[S:14][C:13]4[CH:30]=[CH:31][C:10]([C:7]5[CH:8]=[CH:9][C:4]([C:3]([OH:32])=[O:2])=[CH:5][CH:6]=5)=[CH:11][C:12]=4[CH:16]=3)[C:19]2=[O:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: COC(=O)c1ccc(-c2ccc3sc(CC4CCN(C5CCCCC5)C4=O)cc3c2)cc1
Agent: Cl
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(-c2ccc3sc(CC4CCN(C5CCCCC5)C4=O)cc3c2)cc1
Yield: 39.6 %

Procedure:
Heat a mixture of 4-[2-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-benzo[b]thiophen-5-yl]-benzoic acid methyl ester (250 mg, 0.64 mmol), LiOH.H2O (10 eq) into a dioxane (5 mL) and water (2 mL) at 80° C. for 1 hour. Add 2 M HCl (1 mL) and extract the mixture with ethyl acetate. Dry over sodium sulfate, filter, and concentrate. Purify by silica gel (20-50% ethyl acetate in hexanes) to give the title compound as a white powder (110 mg, 65%): MS (APCI-pos mode) m/z (rel intensity): 434.1 (M+H, 100%).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:6][C:7](=[O:9])[CH3:8])(=[O:5])[CH3:4].CCCCCC.C([Li])CCC.[CH:21]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1)=[CH2:22].Cl>CCCCCC.ClCCl.O.CN(C)P(=O)(N(C)C)N(C)C.O1CCCC1>[CH:21]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][CH2:8][C:7](=[O:9])[CH2:6][C:3](=[O:5])[CH3:4])=[CH:25][CH:24]=1)=[CH2:22]
Reactant: C=Cc1ccc(CCl)cc1
Reactant: CC(=O)CC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: ClCCl
Product: C=Cc1ccc(CCC(=O)CC(C)=O)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
That is, 1.23 g (60% in oil) (31 mmol) of sodium hydride was weighed in a nitrogen atmosphere and 60 ml of dry tetrahydrofuran (hereinafter abbreviated as THF) was added thereto and the mixture was cooled to 0° C. in an ice bath. To the suspension was dripped a mixed solution of 2.5 g 124 mmol) of acetylacetone and 1 ml of hexamethyl phosphoric triamide to produce colorless precipitate. After stirring the mixture at 0° C. for 10 minutes, 17.5 ml (28 mmol) of a hexane solution (1.6 M) of n-butyllithium was dripped therein to dissolve the precipitate and the mixture was further stirred at 0° C. for 20 minutes. To the obtained pale yellow solution was dripped 4.0 g (26 mmol) of 4-vinylbenzyl chloride and the reaction mixture was warmed back to room temperature and stirred for 20 minutes. Then, dilute hydrochloric acid was added thereto to render the water layer acidic. The organic layer was washed with saturated sodium chloride solution and dried over magnesium sulfate, and the solvent was distilled off by using a rotary evaporator. The obtained reaction mixture was charged in a silica gel column and developed with a mixed solvent of hexane/dichloromethane (1:1 (by volume)) to separate a main product. Distilling off the solvent from the obtained solution afforded 3.0 g (14 mmol) of the objective 6-(4-vinylphenyl)-2,4-hexanedione as a brown liquid. Yield was 56%. Identification was performed by elementary analysis of C and H, and 1H-NMR.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[C:13]([CH3:25])=[C:14]([CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])[CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][C:5]=1[C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[F:34].[OH-].[Na+].Cl>CO.C1COCC1.O>[CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[C:13]([CH3:25])=[C:14]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][C:5]=1[C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[F:34]
Reactant: CCOC(=O)CCc1cccc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(COc3cccc(CCC(=O)O)c3C)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.7 %

Procedure:
To a solution of ethyl 3-(3-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-2-methylphenyl)propanoate (400 mg) in methanol (5.0 mL) and THF (10 ml) was added a solution of sodium hydroxide (336 mg) in water (10 mL), and the mixture was stirred at room temperature for 15 hr. 1N Hydrochloric acid was added to the reaction mixture to adjust to pH<4, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (210 mg) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=2[N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.[CH3:20][CH:21]([CH3:37])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=1)=[O:23]>>[CH3:20][CH:21]([CH3:37])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]2[CH2:36][CH2:35][N:34]([CH2:13][C:12]3[CH:15]=[CH:16][C:9]([S:8][C:5]4[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=4)=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=3)[CH2:33][CH2:32]2)[CH:26]=1)=[O:23]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: Cc1ccc(Sc2ccc(C=O)cc2[N+](=O)[O-])cc1
Product: Cc1ccc(Sc2ccc(CN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)cc2[N+](=O)[O-])cc1

Procedure:
Prepared by Procedure F and Scheme R using 4-[(4-methylphenyl)sulfanyl]-3-nitrobenzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 504.2 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[CH2:8][C:9]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2>C(Cl)(Cl)Cl>[O:4]1[CH2:5][CH2:6][N:1]([CH2:8][C:9]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]3[C:10]=2[CH:11]=[CH:12][CH:13]=[N:14]3)[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: Oc1ccc(CCl)c2cccnc12
Solvent: ClC(Cl)Cl
Product: Oc1ccc(CN2CCOCC2)c2cccnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
Morpholine (1.9 ml; 21.8 mmol) was added to a solution of 5-chloromethyl-8-hydroxyquinoline (1.98 g; 8.34 mmol) in CHCl3 (50 ml) at 5° C. The reaction mixture was stirred overnight at room temperature. Then CHCl3 (100 ml) was added and the solution was washed with 5% NaHCO3 (2×50 ml), followed by brine (50 ml), and dried over Na2SO4. The solution was filtered and evaporated under vacuum to dryness. The residue was crystallized from hexane-CHCl3 and gave 1.2 g (59%) of the title product. M.p. 130° C. TLC (CHCl3; MeOH; NH3=8:2:0.5. Rf=0.69.
Reaction SMILES: [CH:1]([C:3]1[C:4](=[O:13])[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:2].[H-].[Na+].[CH3:16]I.O>O1CCCC1>[CH3:16][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[C:3]([CH:1]=[O:2])[C:4]1=[O:13]
Reactant: O=Cc1cc2ccccc2[nH]c1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)c(C=O)cc2ccccc21
Temperature: 25 °C

Procedure:
2.7 Grams of 3-formylcarbostyril was dissolved in 150 ml of tetrahydrofuran, then 0.8 g of oil 50%-sodium hydride was added thereto at a room temperature with stirring. Next, 4.5 g of methyl iodide was added dropwise at a room temperature for 3 hours. The reaction mixture was concentrated under a reduced pussure, the residue thus obtained was poured into water and the crystals precipitated were collected by filtration. Recrystallized from ethanol to obtain 1.7 g of 1-methyl-3-formylcarbostyril in the form of yellow-brownish needle-like crystals.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]([O:11][C:12]([N:14]1[CH2:20][CH2:19][C:18]2[C:21]([C:26]#[CH:27])=[C:22]([Cl:25])[CH:23]=[CH:24][C:17]=2[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>>[C:7]([O:11][C:12]([N:14]1[CH2:20][CH2:19][C:18]2[C:21]([C:26]#[C:27][C:2]3[S:3][CH:4]=[CH:5][N:6]=3)=[C:22]([Cl:25])[CH:23]=[CH:24][C:17]=2[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: Brc1nccs1
Reactant: C#Cc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(C#Cc3nccs3)c2CC1
Yield: 88.4 %

Procedure:
Use a method similar to the General Procedure 8 to couple 2-bromo-thiazole (0.09 mL, 0.96 mmol) with 3-tert-butoxycarbonyl-7-chloro-6-ethynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (148 mg, 0.48 mmol). Purify by chromatography on silica gel eluting with isohexane/EtOAc (1:0 to 4:1 gradient over 30 min) to give the desired intermediate (165 mg, 89%). MS (ES+) m/z: 389 (M+H)+.
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:33])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][CH:10]([CH2:17][O:18][C:19]1[CH:32]=[CH:31][C:22]([CH2:23][CH:24]3[S:28][C:27](=N)[NH:26][C:25]3=[O:30])=[CH:21][CH:20]=1)[CH2:9][CH2:8]2)(=O)C.Cl.[OH2:35]>COCCO>[OH:4][C:5]1[C:6]([CH3:33])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][CH:10]([CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][CH:24]3[S:28][C:27](=[O:35])[NH:26][C:25]3=[O:30])=[CH:31][CH:32]=1)[CH2:9][CH2:8]2
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(COc1ccc(CC3SC(=N)NC3=O)cc1)O2
Reactant: O
Agent: Cl
Solvent: COCCO
Product: Cc1c(C)c2c(c(C)c1O)CCC(COc1ccc(CC3SC(=O)NC3=O)cc1)O2

Procedure:
290 mg of 5-[4-(6-acetoxy-5,7,8-trimethylchroman-2-ylmethoxy)benzyl]-2-iminothiazolidin-4-one (prepared as described in Example 4) were added to a mixture of 3 ml of concentrated hydrochloric acid, 1.5 ml of water and 5 ml of ethylene glycol monomethyl ether, and the mixture was heated under reflux for 3.5 hours. The reaction mixture was then processed and purified as described in Example 1(a), and the crude product, in the form of an oil, was subjected to column chromatography through silica gel. The title compound, melting at 158°-159° C., was obtained from the fractions eluted with a 4:1 by volume mixture of benzene and ethyl acetate.