Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH:12]1[CH2:14][CH2:13]1.[CH:15]([B-](F)(F)F)=[CH2:16].[K+]>CCO.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]>[CH:12]1([C:3]2[C:4]3[CH2:8][O:7][C:6](=[O:9])[C:5]=3[CH:10]=[CH:11][C:2]=2[CH:15]=[CH2:16])[CH2:14][CH2:13]1
Reactant: O=C1OCc2c1ccc(Br)c2C1CC1
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCO
Product: C=Cc1ccc2c(c1C1CC1)COC2=O

Procedure:
A mixture of 5-bromo-4-cyclopropyl-2-benzofuran-1(3H)-one (760 mg, 3.004 mmol), potassium vinyltrifluoroborate (805 mg, 6.01 mmol) and Pd(dppf)Cl2 (100 mg) in 20 mL of TEA and 20 mL of EtOH was heated to reflux under N2 for 8 hours. After TLC showed complete reaction, then most of the solvent was removed and the residue was dissolved in EtOAc (100 mL). The solution was washed with 0.1 N HCl, sodium bicarbonate, and brine, dried over sodium sulfate, filtered and concentrated. The resulting oil was purified by column chromatography to give the title compound.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]#[C:10][CH2:11][OH:12])[CH2:5][CH2:4]1.[Cl:13][C:14]1[N:15]=[N:16][C:17](Cl)=[CH:18][CH:19]=1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[Cl:13][C:14]1[N:15]=[N:16][C:17]([N:2]([CH3:1])[C@H:3]2[CH2:4][CH2:5][C@H:6]([C:9]#[C:10][CH2:11][OH:12])[CH2:7][CH2:8]2)=[CH:18][CH:19]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CN[C@H]1CC[C@H](C#CCO)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ccc(Cl)nn1)[C@H]1CC[C@H](C#CCO)CC1
Temperature: 80 °C

Procedure:
A mixture of 0.67 g (4 mmol) trans-3-(4-Methylamino-cyclohexyl)-prop-2-yn-1-ol, 2.76 g (18 mmol) of 3,6-dichloropyridazine and 1.76 ml (13.6 mmol) N-ethyldiisopropylamine was heated for 3.5 h at 80° C., diluted with 1 ml DMF and heated for 4 days at 80° C. and one day at 120° C. The reaction was cooled, evaporated and partitioned between aqueous saturated NaHCO3/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried (NaSO4) and evaporated. Flash chromatography on silica gel (MeCl2/Et2O 95:5 to 9:1) gave 0.61 g (54%) of trans-3-{4-[(6-Chloro-pyridazin-3-yl)-methyl-amino]-cyclohexyl}-prop-2-yn-1-ol, MS: 280 (MH+, 1Cl).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16](F)[N:15]=1)[CH3:7])([CH3:4])([CH3:3])[CH3:2].[C:21]1([C@@H:27]([NH2:29])[CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.O>CS(C)=O.CCCCCCC.C(OCC)(=O)C>[C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:29][C@H:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:28])[N:15]=1)[CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1c1ccnc(F)n1
Reactant: C[C@H](N)c1ccccc1
Solvent: CCCCCCC
Solvent: CS(C)=O
Solvent: O
Product: C[C@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)n1)c1ccccc1
Yield: 93 %

Procedure:
A solution of (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (112 mg, 0.40 mmol), (S)-1-phenylethanamine (58 mg, 0.48 mmol, 1.2 equiv), and DIPEA (153 mg, 1.2 mmol, 3.0 equiv) in DMSO (4.0 mL) was heated at 100° C. for 90 min. The reaction mixture was poured into 5 ml of water, extracted with EA (2×10 ml), the solvent was removed to yield the crude product. Silica gel column chromatography (ethyl acetate in heptane 10 to 50%) provided the pure product (142 mg, white solid) in a 93% yield. HRMS m/z 385.2231 (M+H)+, RT=3.35 min.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3](=[O:12])[CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[Br:15]Br>Br>[Br:15][CH:4]([C:3](=[O:12])[C:2]([CH3:14])([CH3:13])[CH3:1])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: BrBr
Reactant: CC(C)(C)C(=O)CCc1cccnc1
Agent: Br
Product: CC(C)(C)C(=O)C(Br)Cc1cccnc1
Yield: 100.9 %

Procedure:
320.5 g (1.676 mol) of 4,4-dimethyl-1-pyridin-3-yl-pentan-3-one were dissolved in 320 ml of aqueous 48% strength hydrobromic acid, and 267.8 g (85.3 ml; 1.65 mol) of bromine were added dropwise at 80° to 95° C. in the course of 2 hours. When the addition had ended, the solution was cooled and concentrated. The solid which remained was comminuted well, stirred with about 1.5 liters of ethanol, filtered off, washed with ethanol and dried. 450 g (78% of theory) of 2-bromo-4,4-dimethyl-1-pyridin-3-yl-pentan-3-one of melting point 163°-64° C. were obtained. ##STR119##
Reaction SMILES: ClCCl.B(Br)(Br)Br.[OH:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[C:20]([C:26]4[CH:31]=[CH:30][C:29]([O:32]C)=[CH:28][C:27]=4[CH3:34])[NH:21][C:22]3=[O:25])=[CH:17][CH:16]=2)[CH2:10]1.C(=O)(O)[O-].[Na+]>ClCCl>[OH:32][C:29]1[CH:30]=[CH:31][C:26]([C:20]2[NH:21][C:22](=[O:25])[C:23]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[C:15]([N:11]2[CH2:12][CH2:13][CH2:14][CH:9]([OH:8])[CH2:10]2)[CH:24]=3)=[C:27]([CH3:34])[CH:28]=1
Reactant: COc1ccc(-c2cc3ccc(N4CCCC(O)C4)cc3c(=O)[nH]2)c(C)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(O)ccc1-c1cc2ccc(N3CCCC(O)C3)cc2c(=O)[nH]1
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
0.070 ml (0.070 mmol) of a 1 M boron tribromide dichloromethane solution was added at 0° C. to a dichloromethane solution (0.5 ml) containing 17 mg (0.0466 mmol) of the 7-(3-hydroxypiperidin-1-yl)-3-(4-methoxy-2-methylphenyl)-2H-isoquinolin-1-one obtained in Example 90. The obtained mixture was stirred at the same above temperature for 30 minutes. Thereafter, a saturated sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was then extracted with dichloromethane/methanol (5:1). The extract was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1 to 10:1), so as to obtain 10 mg (61%) of 3-(4-hydroxy-2-methylphenyl)-7-(3-hydroxypiperidin-1-yl)-2H-isoquinolin-1-one in the form of a light brown solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH:21]1[CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1>>[C:8]1([C:5]2[N:6]=[CH:7][C:2]([N:20]3[CH2:24][CH2:23][CH2:22][CH:21]3[CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][O:31]3)=[N:3][C:4]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: C(CCC1CCCN1)COC1CCCCO1
Product: c1ccc(-c2ncc(N3CCCC3CCCCOC3CCCCO3)nc2-c2ccccc2)cc1

Procedure:
In the same manner as in the step 1 of Example 9, except that 2-chloro-5,6-diphenylpyrazine was used in place of 2-chloro-5,6-di-p-tolylpyrazine and (±)-1-(2-pyrrolidinyl)-4-(2-tetrahydropyranyloxy)butane was used in place of 4-(methylamino)-1-butanol, the desired compound was prepared as a yellowish crystal having a melting point of 94 to 96° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]([OH:8])[CH2:6][N:5]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([F:21])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:22])[CH2:4]1.[Cl:23][C:24]1[C:33]([CH:34]=O)=[N:32][C:31]2[NH:30][C:29](=[O:36])[CH2:28][O:27][C:26]=2[CH:25]=1.C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[Cl:23][C:24]1[C:33]([CH2:34][NH:1][CH2:2][C@@H:3]2[C@H:7]([OH:8])[CH2:6][N:5]([CH2:9][CH2:10][N:11]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([F:21])[CH:19]=4)[CH:14]=[CH:13][C:12]3=[O:22])[CH2:4]2)=[N:32][C:31]2[NH:30][C:29](=[O:36])[CH2:28][O:27][C:26]=2[CH:25]=1
Reactant: O=Cc1nc2c(cc1Cl)OCC(=O)N2
Reactant: NC[C@H]1CN(CCn2c(=O)ccc3ccc(F)cc32)C[C@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C1COc2cc(Cl)c(CNC[C@H]3CN(CCn4c(=O)ccc5ccc(F)cc54)C[C@H]3O)nc2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-{2-[(3S,4S)-3-(aminomethyl)-4-hydroxy-1-pyrrolidinyl]ethyl}-7-fluoro-2(1H)-quinolinone (100 mg; 0.33 mmol) and 7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde (for a synthesis see WO2003064421, Example 15(c)) (70 mg, 0.33 mmol) in methanol (2 mL), methylene chloride (4 mL) was stirred at room temperature overnight. Sodium triacetoxyborohydride (130 mg; 0.6 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction was evaporated and chromatographed on silica gel, eluting with 0-10% methanol-DCM-1% NH4OH to give the title compound as a solid (80 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[O:5][N:4]=[C:3]1[O:8]CC1C=CC=CC=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]([CH:27]([CH3:29])[CH3:28])[C:24](Cl)=[O:25])=[CH:19][CH:18]=1>C(#N)C>[F:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]([CH:27]([CH3:29])[CH3:28])[C:24]([N:4]2[C:3](=[O:8])[N:2]([CH3:1])[C:6](=[O:7])[O:5]2)=[O:25])=[CH:21][CH:22]=1
Reactant: CC(C)N(C(=O)Cl)c1ccc(F)cc1
Reactant: Cn1c(OCc2ccccc2)noc1=O
Solvent: CC#N
Product: CC(C)N(C(=O)n1oc(=O)n(C)c1=O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 76.4 %

Procedure:
A 50 mL round bottom flask equipped with a thermometer, a stirrer and a nitrogen inlet was charged with 4-methyl-3-(phenylmethoxy)-1,2,4-oxadiazol-5(4H)-one (0.55 g, 2.66 mmol), (4-fluorophenyl)(1-methylethyl)carbamic chloride (0.581 g, 2.7 mmol), N,N′-dimethylaminopyridine (0.329 g, 2.7 mmol) and acetonitrile (10 mL). The reaction mixture was heated to reflux 2 h, and allowed to cool to room temperature. The entire mixture was flash chromatographed (silica gel, 9: 1, then 8:2 hexane-ethyl acetate) to provide 0.6 g (76%) of the title compound as a white solid melting at 135-136° C.
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[C:10]([F:16])[CH:9]=2)[S:4][C:3]=1[CH:17]1[O:21]CCO1.[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[O:29]C>>[Cl:22][C:23]1[CH:24]=[C:25]([C:2]2[C:6]([CH3:7])=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([F:16])[CH:9]=3)[S:4][C:3]=2[CH:17]=[O:21])[CH:26]=[CH:27][C:28]=1[OH:29]
Reactant: COc1ccc(B(O)O)cc1Cl
Reactant: COc1ccc(-c2sc(C3OCCO3)c(Br)c2C)cc1F
Product: Cc1c(-c2ccc(O)c(F)c2)sc(C=O)c1-c1ccc(O)c(Cl)c1
Yield: 19.5 %

Procedure:
Starting from 2-[3-bromo-5-(3-fluoro-4-methoxyphenyl)-4-methylthien-2-yl]-1,3-dioxolane (0.89 g, 2.4 mmol, made in Example 8, Step 1) and substituting 3-chloro-4-methoxyphenylboronic acid (0.53 g, 2.8 mmol) in place of 3-methoxyphenylboronic acid (Step 2), the title compound (0.17 g, 33%, m.p. 252-54° C.) was synthesized in essentially the same manner as described in Example 1, Steps 2-4.
Reaction SMILES: [C:1]([C:3]1[NH:7][C:6]([CH2:8][CH2:9][CH3:10])=[N:5][C:4]=1[N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)#[N:2].CC(C)([O-])C.[K+].C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:29]2[C:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]3[CH:45]=[CH:44][C:43]([CH2:46]Br)=[CH:42][CH:41]=3)=[N:32][N:31]=[N:30]2)C=CC=CC=1>>[C:1]([C:3]1[N:7]([CH2:46][C:43]2[CH:44]=[CH:45][C:40]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[C:33]3[NH:29][N:30]=[N:31][N:32]=3)=[CH:41][CH:42]=2)[C:6]([CH2:8][CH2:9][CH3:10])=[N:5][C:4]=1[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15]1)#[N:2]
Reactant: CCCc1nc(-n2cccc2)c(C#N)[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCc1nc(-n2cccc2)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Using the method described in Example 15, 5-cyano 2 propyl-4-(1H-pyrrol-1-yl)imidazole (Example 19, 2.0 g), potassium tert butoxide (1.2 g) and N-triphenylmethyl-5-[4'-(bromomethyl)biphenyl-2yl]tetrazole (Example 12, 7.0 g) were reacted to give the title product in its triphenylmethyl protected form after purification by chromatography. This material was dissolved in methanol (200 mL), treated with aqueous 10% citric acid (10 mL) and heated at reflux for 2.5 hours. The resulting solution was diluted with water (40 mL) and washed twice with hexanes. The methanol-water layer was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate and evaporated to a gum. This gum was dissolved in tert-butyl methyl ether and evaporated to a gum which was allowed to stand until seed crystals formed. Trituration with tert-butyl methyl ether gives the title compound as a crystalline solid, mp 179°-181° C. MS (CI, CH4 +NH3) 435 (m+1).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].CS([C:12]1[N:13]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[CH:26][CH:25]=2)[C:14](=[O:23])[C:15]2[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:16]=2[N:17]=1)=O.O>O1CCCC1>[F:1][C:2]([F:6])([F:5])[CH2:3][O:4][C:12]1[N:13]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[CH:28][CH:29]=2)[C:14](=[O:23])[C:15]2[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:16]=2[N:17]=1
Reactant: OCC(F)(F)F
Reactant: CS(=O)c1nc2c(c(=O)n1-c1ccc(OCC(F)(F)F)cc1)CCC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCc2c(nc(OCC(F)(F)F)n(-c3ccc(OCC(F)(F)F)cc3)c2=O)N1
Reaction time: 0.08 h

Procedure:
To a solution of 2,2,2-trifluoroethanol (0.472 mL) in tetrahydrofuran (20 mL) was added sodium hydride (60% in oil, 0.184 g). The reaction mixture was stirred for 5 min, 2-(methylsulfinyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]-5,6-dihydropyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (0.88 g) was added thereto, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water, 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. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and recrystallized from ethyl acetate/hexane to give the title compound (0.80 g).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH2:20]([NH2:30])[C:21]1[CH:29]=[CH:28][C:27]2[O:26][CH2:25][O:24][C:23]=2[CH:22]=1>>[CH2:25]1[O:26][C:27]2[CH:28]=[CH:29][C:21]([CH2:20][NH:30][C:5]3[N:10]=[C:9]([N:11]4[C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=5[N:13]=[CH:12]4)[CH:8]=[CH:7][N:6]=3)=[CH:22][C:23]=2[O:24]1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: NCc1ccc2c(c1)OCO2
Product: c1ccc2c(c1)ncn2-c1ccnc(NCc2ccc3c(c2)OCO3)n1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with piperonylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 346.2 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.61 (s, 1H); 8.42 (br s, 1H); 8.11 (br s, 1H); 7.86 (m, 1H); 7.38 (m, 2H); 6.89 (m, 2H); 6.83 (m, 2H); 5.97 (s, 2H); 5.79 (br s, 1H); 4.65 (d, J=5.7 Hz, 2H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]=[C:11]=[S:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl.[CH3:14][NH:15][O:16][CH2:17][C:18]([OH:20])=[O:19].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]([N:15]([CH3:14])[O:16][CH2:17][C:18]([OH:20])=[O:19])=[S:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: S=C=Nc1ccc2c(c1)CCC2
Reactant: CNOCC(=O)O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(OCC(=O)O)C(=S)Nc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.8 %

Procedure:
A mixture of 5-indanyl-isothiocyanate (18.5 g), N-methyl aminooxy acetic acid hydrochloride (16.2 g), triethylamine (25 g) and chloroform (150 mL) was heated at reflux for one half hour, stirred at ambient temperature for one hour, then evaporated to dryness. The residue was dissolved in ethyl acetate (500 mL) and washed with 2N HCl (2×400 mL) then with water (400 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness affording (31.3 g) of [[[[(5-indanyl)amino]thioxomethyl]methylamino]oxy]acetic acid as an oil. 1H-NMR (DMSO-d6; 300 MHz) δ13.1 (br s, 1H), 10.5 (s, 1H), 7.38 (s, 1H), 7.18 (m, 2H), 4.62 (s, 2H), 3.50 (s, 3H), 2.82 (m, 4H), and 2.03 ppm (m, 2H). The acid (26.1 g) was dissolved in benzene (200 mL). Phosphorus pentachloride (25 g) was added in portions. The mixture was heated at reflux for one half hour then evaporated to dryness. The residue was dissolved in ethyl acetate (400 mL) and washed with sodium bicarbonate saturated solution (2×300 mL) then with water (300 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was chromatographed on silica gel (10% ethyl acetate in hexane). Crystallization from ether afforded the title compound (4.3 g) as a solid, m.p. 135-137° C. Mass spectrum (El, M.+) m/z 262. 1H-NMR (CDCl3; 400 MHz) δ7.31 (d, 1H), 7.04 (s, 1H), 6.96 (d, 1H), 4.84 (ABq, 2H), 3.75 (s, 3H), 2.96 (t, 4H), and 2.11 ppm (m, 2H).
Reaction SMILES: [O:1]=[C:2]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[C:3]([OH:5])=[O:4].S(Cl)(Cl)=O.[CH2:15]([N:17]([CH2:24][CH3:25])[CH2:18][C:19]#[C:20][CH:21](O)[CH3:22])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>ClCCl.O.N1C=CC=CC=1>[O:1]=[C:2]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[C:3]([O:5][CH:21]([CH3:22])[C:20]#[C:19][CH2:18][N:17]([CH2:24][CH3:25])[CH2:15][CH3:16])=[O:4]
Reactant: CCN(CC)CC#CC(C)O
Reactant: O=C(O)C(=O)c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCN(CC)CC#CC(C)OC(=O)C(=O)c1cccs1
Reaction time: 18 h
Yield: 30.7 %

Procedure:
To a solution of 4.3 g α-oxo-2-thiopheneacetic acid in dichloromethane was added 0.5 ml pyridine, and 6.75 g thionyl chloride was then added dropwise under ice cooling. The mixture was heated under reflux for seven hours and concentrated under reduced pressure, diethyl ether was added to the residue, the insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The oily substance thus obtained (4.1 g) was added dropwise to an etheral solution of 4.5 g 5-diethylamino-3-pentyn-2-ol under ice cooling, and the mixture was stirred for 18 hours under cooling with water and basified with an aqueous solution of potassium carbonate. The separated etheral layer was collected, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The oily residue was purified by silica gel column chromatography (Wako Gel C-200; ethyl acetate), giving 2.48 g of the objective compound as oil.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C([Li])(C)(C)C.C([Sn](Cl)(CCCC)CCCC)CCC.[NH2:26][C:27]1[N:32]=[C:31](Br)[C:30]([C:34]#[N:35])=[C:29]([S:36][CH3:37])[N:28]=1>C1COCC1.O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:26][C:27]1[N:32]=[C:31]([C:6]2[O:1][CH2:2][CH2:3][CH2:4][CH:5]=2)[C:30]([C:34]#[N:35])=[C:29]([S:36][CH3:37])[N:28]=1
Reactant: C1=COCCC1
Reactant: CSc1nc(N)nc(Br)c1C#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CSc1nc(N)nc(C2=CCCCO2)c1C#N

Procedure:
From 3,4-dihydro-2H-pyran, tert-butyllithium and tributyltin chloride in THF. Then treatment with 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile and bis(triphenylphosphine)palladium(II) chloride in dioxane. ES-MS m/e (%): 271 (M+Na+, 39), 249 (M+H+, 100).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.Cl>CN(C=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:23]([OH:24])[C:22]2[CH:26]=[CH:27][C:19]([C:18]([F:17])([F:28])[F:29])=[CH:20][CH:21]=2)[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(=O)Cc2cc([N+](=O)[O-])ccc21
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC(=O)N1C(=O)C(=C(O)c2ccc(C(F)(F)F)cc2)c2cc([N+](=O)[O-])ccc21

Procedure:
Prepared by reacting 1-acetyl-5-nitro-2-indolinone with one equivalent of 4-trifluoromethyl-benzoic acid in dry DMF in the presence of 1 equivalent each of TBTU and HOBT and 5 equivalents of Huinig's base (20° C., 4 hours), stirring into dilute hydrochloric acid, filtering the precipitate, dissolving the precipitate in EtOac, drying the organic phase and evaporation in vacuo and purifying the evaporation residue by column chromatography on silica gel with CH2Cl2 /MeOH (10:1) as eluant.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])=[CH:5][CH:4]=1.[C:22]1(=[O:32])[NH:26][C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.[K]>CN(C)C=O>[C:22]1(=[O:32])[N:26]([CH2:2][C:3]2[CH:21]=[CH:20][C:6]([CH2:7][O:8][N:9]3[C:13](=[O:14])[C:12]4=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]4[C:10]3=[O:19])=[CH:5][CH:4]=2)[C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C1c2ccccc2C(=O)N1OCc1ccc(CCl)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(CON2C(=O)c3ccccc3C2=O)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 83.1 %

Procedure:
A mixture of N-(4-chloromethylbenzyloxy)phthalimide (18.5 g.) and potassium phthalimide (15.4 g.) in N,N-dimethylformamide (180 ml.) was stirred at 60° C. for 5 hours. The mixture was poured into ice-water and the precipitates were collected by filtration. The precipitates were washed with water and acetone in turn to give N-(4-phthalimidomethylbenzyloxy)phthalimide (21.0 g.).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5]([CH3:9])=[N:6][C:7]=1Cl.[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][SH:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CO>[Br:1][C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5]([CH3:9])=[N:6][C:7]=1[S:18][CH2:17][C:16]1[CH:19]=[CH:20][C:13]([CH3:12])=[CH:14][CH:15]=1
Reactant: Cc1nc(Cl)c(Br)c(=O)n1C
Reactant: Cc1ccc(CS)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccc(CSc2nc(C)n(C)c(=O)c2Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
In 10 ml of methanol were dissolved 0.59 g of 5-bromo-6-chloro-2,3-dimethyl-4(3H)-pyrimidinone and 0.35 g of 4-methylbenzyl mercaptan and then 0.25 g of sodium carbonate was added thereto. The resulting mixture was stirred for 3 hours at room temperature. The solution thus obtained was poured into water and extracted with benzene. The extract was washed with water and dried over anhydrous sodium sulfate. Solvent was distilled off therefrom under reduced pressure to give an oil. The oil thus obtained was purified by means of column chromatography (on silica gel, eluting with benzene) to give 0.72 g of the intended product.