Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([O:13]C)=[CH:4][N:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([OH:13])=[CH:4][N:3]=1
Reactant: COc1cnc(Cl)c2cc(F)ccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cnc(Cl)c2cc(F)ccc12
Yield: 92.9 %

Procedure:
A solution of 1-chloro-7-fluoro-4-methoxyisoquinoline (0.75 g, 3.54 mmol) in DCM (10 ml) was added BBr3 (6.22 g, 24.81 mmol) at 0° C. drop wise. The reaction mass was refluxed for 5 h. The residue was cooled and quenched with methanol. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The precipitated solid was filtered, washed with water to get crude compound (0.65 g, 93%) as a pale yellow solid. 1H NMR (400 MHz, CD3OD): δ ppm 8.36-8.33 (m, 1H), 7.89-7.86 (d, J=12 Hz, 1H), 7.76 (s, 1H), 7.64 (t, J=10 Hz, 1H); MS: MS m/z 198.0 (M++1).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:25]([CH3:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])=[CH:5][C:4]=1[C:27]([F:30])([F:29])[F:28].C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[CH3:26][CH:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]1[S:9]([C:6]1[CH:7]=[CH:8][C:3]([OH:2])=[C:4]([C:27]([F:29])([F:28])[F:30])[CH:5]=1)(=[O:10])=[O:11]
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccccc3C2C)cc1C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)c(C(F)(F)F)c1
Yield: 9 %

Procedure:
The title compound was prepared from 5-{[4-methoxy-3-(trifluoromethyl)phenyl]sulfonyl}-6-methyl-5,6-dihydrophenanthridine (0.5 g, 1.15 mmol), cyclohexene (0.29 mL, 2.88 mmol), and 1.0 M boron tribromide in dichloromethane (6.92 mL, 6.92 mmol) according to the procedure and in the same manner as described in Example 1, step b. The crude product was purified by flash column chromatography on silica gel, eluting with dichloromethane to yield 4-[(6-methylphenanthridin-5(6H)-yl)sulfonyl]-2-(trifluoromethyl)phenol (0.044 g, 0.104 mmol, 9%) as an off-white solid, m.p. 213-215° C.;
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:34]=[C:14]3[N:15]=[CH:16][CH:17]=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[C:21]([O:29][CH2:30][CH:31]5[CH2:33][CH2:32]5)[CH:20]=4)[N:13]3[N:12]=2)=[CH:7][N:6]=1)=[O:4].[Li+].[OH-].Cl>CO>[CH:31]1([CH2:30][O:29][C:21]2[CH:20]=[C:19]([C:18]3[N:13]4[N:12]=[C:11]([C:8]5[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=5)[N:34]=[C:14]4[N:15]=[CH:16][CH:17]=3)[CH:24]=[CH:23][C:22]=2[O:25][CH:26]([F:27])[F:28])[CH2:33][CH2:32]1
Reactant: COC(=O)c1ccc(-c2nc3nccc(-c4ccc(OC(F)F)c(OCC5CC5)c4)n3n2)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(-c2nc3nccc(-c4ccc(OC(F)F)c(OCC5CC5)c4)n3n2)cn1
Yield: 34.1 %

Procedure:
In aqueous MeOH, dissolved was 5-[7-{3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl}-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]pyridine-2-carboxylic acid methyl ester (Compound 138) (0.05 g, 0.11 mmol), and LiOH (0.013 g, 0.32 mmol) was slowly added thereto. By using dilute HCl, pH of the reaction mixture was adjusted to 4˜5. The mixture was extracted three times with EA, and the extract was washed twice with brine, dried over MgSO4, filtered, and evaporated under reduced pressure to remove solvent. The mixture was purified via silica gel column chromatography (MeOH) to obtain desired compound, 5-[7-{3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl}-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]pyridine-2-carboxylic acid (Compound 137) (0.017 g, 35%).
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([C:24](=[O:34])[N:25]([CH2:31][CH2:32][CH3:33])[CH:26]2[CH2:30][CH2:29][CH2:28]C2)[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:23][C:21]1[CH:20]=[C:19]([CH:18]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:22]=1)[C:24]([N:25]([CH:26]1[CH2:38][CH2:37][CH2:28][CH2:29][CH2:30]1)[CH2:31][CH2:32][CH3:33])=[O:34]
Reactant: CCCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C1CCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)C1CCCCC1
Reaction time: 1 h

Procedure:
A solution of {2-[3-(propyl-cyclopentyl-carbamoyl)-5-chloro-phenoxy]-ethyl}-pyridin-4-yl-carbamic acid tert-butyl ester (0.07 g) in a mixture of dichloromethane (2 ml) and trifluoroacetic acid (2 ml) was stored at room temperature for 1 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.036 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[C:14]1([CH2:20][CH2:21][CH2:22]Br)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O>[C:14]1([CH2:20][CH2:21][CH2:22][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCCc1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
An ice-cold solution of diethyl malonate (5.81 ml, 40 mmol) in dimethylformamide (60 ml) was treated portionwise with sodium hydride (1.6 g, 40 mmol 60% dispersion in oil). After 0.25 h 3-phenylpropylbromide (6.71 ml, 44 mmol) was added and the reaction stirred overnight at room temperature. Work-up and chromatography as described in Example 37a) gave the title compound as a colourless oil (10.8 g, 97%);
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=O)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([NH2:23])[C:19]([CH3:22])([CH3:21])[CH3:20].P(Cl)(Cl)(Cl)=O.C([O-])(O)=O.[Na+]>CC1C=CC(C)=CC=1>[CH2:18]([NH:23][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:8][N:9]=1)[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: O=c1[nH]nc(-c2ccccc2)c2ccccc12
Reactant: CC(C)(C)CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccc(C)cc1
Product: CC(C)(C)CNc1nnc(-c2ccccc2)c2ccccc12

Procedure:
To a suspension of 100 g of 4-phenyl-1(2H)-phthalazinone and 96.2 g of neopentylamine in 300 ml of p-xylene were added dropwise 83.7 g of phosphorus oxychloride with stirring and the resulting mixture was stirred under reflux for 4 hours. After allowing to be cooled, a saturated aqueous solution of NaHCO3 was added to the reaction mixture. Then, the mixture was extracted with chloroform and the organic layer was separated, dried and then concentrated. The residue was recrystallized from ethanol to afford the title compound as a pale yellow crystal. 100.8 g (Yield, 77%) Melting point: 215.5°-216.5° C.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[OH-].[Li+]>CN(C=O)C.O.C1COCC1>[N+:13]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:6]([OH:8])=[O:7])([O-:15])=[O:14]
Reactant: C1CCNCC1
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(N2CCCCC2)c([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
A mixture of ethyl 4-fluoro-3-nitrobenzoate (Chontech 01072; 500 mg; 2.35 mmol; 1 eq.) and piperidine (Fluka 80640; 599.18 mg; 7.04 mmol; 3 eq.) in DMF (2 mL) was stirred at 50° C. for 3 hours. The reaction was then allowed to cool to room temperature and diluted with water. Extraction with ethyl acetate, drying over sodium sulfate and concentration in vacuo gave a yellow oil. The oil was taken up in THF (15 mL) and lithium hydroxide (280.86 mg; 11.73 mmol; 5 eq.) was added, followed by water (15 mL). The reaction mixture was then stirred at room temperature for 5 hours. THF was evaporated and the residue diluted with water. The aqueous phase was washed with Et2O and acidified to pH 5 with acetic acid. Extraction with Et2O followed by drying over magnesium sulfate and concentration in vacuo afforded the title compound (562 mg, 96%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][O:14][CH3:15])=[C:6](I)[CH:5]=1.[CH3:18][Zn]C.C1COCC1>C1COCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:5]=[C:6]([CH3:18])[C:7]([O:12][CH2:13][O:14][CH3:15])=[C:8]([O:10][CH3:11])[CH:9]=1
Reactant: C[Zn]C
Reactant: COCOc1c(I)cc(C(=O)OC)cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCOc1c(C)cc(C(=O)OC)cc1OC
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-iodo-5-methoxy-4-methoxymethoxybenzoic acid methyl ester (700 mg) in THF (7 mL) were added tetrakis(triphenylphosphine)palladium(0) (115 mg) and 2M dimethylzinc/THF solution (1.20 mL), and the mixture was stirred at 80° C. for 30 minutes. The reaction solution was diluted with ethyl acetate, washed with 1N hydrochloric acid, water, and saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title compound (767 mg) as a crude purified product of pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:22])=[CH:4][C:5]([F:21])=[C:6]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])[CH:7]=1.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1>[Cl:22][C:3]1[C:2]([NH:1][S:28]([C:24]2[S:23][CH:27]=[CH:26][CH:25]=2)(=[O:30])=[O:29])=[CH:7][C:6]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])=[C:5]([F:21])[CH:4]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N)c(Cl)cc2F)c1=O
Solvent: c1ccncc1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(NS(=O)(=O)c3cccs3)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
In 5 ml of pyridine was dissolved 0.32 g of 3-(5-amino-4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, and then 0.19 g of 2-thiophensulfonyl chloride was added to the solution at 5 ° C. or lower. Thereafter, the temperature was increased to room temperature and the reaction was continued overnight. Then, pyridine was removed by distillation and the residue was dissolved in ethyl acetate. The solution was washed successively with water, diluted hydrochloric acid and a saturated saline solution, and dried over anhydrous sodium sulfate followed by removing ethyl acetate by distillation to obtain a crude product. This was washed with diisopropyl ether to obtain 0.3 g of the desired compound as white crystal.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[N:5]1([CH2:11][CH2:12][C:13]([NH:15][NH2:16])=O)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1>CCO>[CH3:1][N:2]1[C:13]([CH2:12][CH2:11][N:5]2[CH2:6][CH2:7][O:8][CH2:9][CH2:10]2)=[N:15][N:16]=[C:3]1[SH:4]
Reactant: CN=C=S
Reactant: NNC(=O)CCN1CCOCC1
Solvent: CCO
Product: Cn1c(S)nnc1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Prepared according to a procedure reported for related compounds: Henichart, J. P. et al. J. Het Chem. 1977, 14, 615. Methyl isothiocyanate (9.08 g, 0.124 mol) in EtOH (50 mL) was added at room temperature to a stirred solution of 3-morpholin-4-ylpropanohydrazide (21.5 g, 0.124 mol) in EtOH (200 mL). The mixture was refluxed for 8 h, then removed from heat and stirred at room temperature for 16 h. The EtOh was removed under reduced pressure to give the crude material as a yellow oil. The oil was purified by column chromatography through silica gel, eluting with CH2Cl2/MeOH to afford the title compound. (6 g, 21.2%) 1H NMR (DMSO-d6) d 2.42 (m, 4H) 2.64 (m, 2H) 2.85 (m, 2H, 3.43 (s, 3H) 3.55 (m, 4H) 13.47 (s, 1H). MS (APCI) calcd for C9H16N4OS: 228.32; found (M−H+) 227.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[C:6]([CH2:14]O)=[C:5]2[O:16][CH3:17].S(Cl)([Cl:20])=O.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[C:6]([CH2:14][Cl:20])=[C:5]2[O:16][CH3:17]
Reactant: COc1c(CO)n(C)c(=O)c2ccc(Cl)cc12
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1c(CCl)n(C)c(=O)c2ccc(Cl)cc12
Yield: 89.4 %

Procedure:
To a solution of 6-chloro-3-hydroxymethyl-4-methoxy-2-methyl-1(2H)-isoquinolinone (0.76 g, 3 mmol) in tetrahydrofuran (20 ml) was added thionyl chloride (0.26 ml, 3.6 mmol). The obtained mixture was refluxed under heating for 2 h. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 6-chloro-3-chloromethyl-4-methoxy-2-methyl-1(2H)-isoquinolinone (0.73 g, 90.1%) as crystals.
Reaction SMILES: [N:1]1([C:6]2([C:16]#N)[CH2:15][CH2:14][C:9]3([O:13][CH2:12][CH2:11][O:10]3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Mg]Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+]>C1COCC1>[CH2:16]([C:6]1([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N#CC1(N2CCCC2)CCC2(CC1)OCCO2
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: c1ccc(CC2(N3CCCC3)CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 40.0 g 8-pyrrolidin-1-yl-1,4-dioxaspiro[4.5]decane-8-carbonitrile in 150 ml analytical grade tetrahydrofuran was added dropwise to 127 ml 2.0 molar benzylmagnesium chloride solution in THF under a nitrogen atmosphere and the mixture was stirred overnight at room temperature. For working up, 50 ml saturated ammonium chloride solution were added, while cooling with ice, the phases were separated, the aqueous phase was extracted three times with 50 ml diethyl ether each time, the combined organic phases were dried over sodium sulfate, filtered and concentrated and the residue was largely freed from solvent residues in vacuo. The crude 1-(8-benzyl-1,4-dioxaspiro[4.5]dec-8-yl)pyrrolidine obtained (54.0 g of yellow solid) was stirred, without further purification, with a mixture of 128 ml conc. hydrochloric acid (32 per cent by weight) and 74 ml water for 24 hours at room temperature. The reaction mixture was then first washed twice with 50 ml diethyl ether each time and then rendered alkaline by addition of sodium hydroxide solution (32 per cent by weight), while cooling with ice, and extracted three times with 100 ml methylene chloride each time, the combined methylene chloride extracts were dried over sodium sulfate, filtered and concentrated and the residue was largely freed from solvent residues in vacuo. 40.3 g 4-benzyl-4-pyrrolidin-1-yl-cyclohexanone were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[CH2:12][CH:11]([C:13]([OH:15])=O)[C:8]2([CH2:10][CH2:9]2)[C:7]1=[O:16].[CH2:23]([C@@H:30]1[CH2:34][O:33][C:32](=[O:35])[NH:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN=C=NCCCN(C)C.Cl.O>C(Cl)(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:23]([C@@H:30]1[CH2:34][O:33][C:32](=[O:35])[N:31]1[C:13]([CH:11]1[C:8]2([CH2:9][CH2:10]2)[C:7](=[O:16])[N:6]([CH2:5][C:4]2[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:3]=2[O:2][CH3:1])[CH2:12]1)=[O:15])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(CN2CC(C(=O)O)C3(CC3)C2=O)c(OC)c1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc(CN2CC(C(=O)N3C(=O)OC[C@H]3Cc3ccccc3)C3(CC3)C2=O)c(OC)c1
Reaction time: 4 h

Procedure:
To a solution of 5-(2,4-dimethoxybenzyl)-4-oxo-5-azaspiro[2.4]heptane-7-carboxylic acid (1.59 g) in chloroform (16 ml) were sequentially added (R)-4-benzyl-2-oxazolidinone (1.11 g), WSC.HCl (1.20 g) and N,N-dimethyl-4-aminopyridine (318 mg) at room temperature, and the mixture was stirred for 4 hours. To this reaction mixture was added water, and the organic layer was separated from the solution, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1) to separate a low-polarity component as the titled compound (1.39 g).
Reaction SMILES: [OH:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[S:14].[Na].[C:16](Cl)(=[O:18])[CH3:17]>C(Cl)Cl>[C:16]([O:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[S:14])(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: Cn1c(=O)c2ccccc2n(O)c1=S
Agent: [Na]
Solvent: ClCCl
Product: CC(=O)On1c(=S)n(C)c(=O)c2ccccc21
Reaction time: 0.08 h
Yield: 71 %

Procedure:
A slurry of 6.00 g (0.0260 mole) of 1-hydroxy-3-methyl-2- thioxo-1,2-dihydroquinazoline 4(3H)-one, sodium salt (IIa-Na) in 48 ml of methylene chloride was added to 2.1 g (0.0265 mole) of acetyl chloride at reflux. After 5 minutes, the colorless solution developed a white precipitate. After 1 hour at reflux, the reaction was cooled, filtered and the solvent was removed in vacuo to give 6.50 g of the crude product. The product was then recrystallized from 55 ml of methylene chloride and 150 ml of petroleum ether to give 4.62 g of compound IIi. The yield was 94.6%. Compound IIj-IIl were made in a similiar manner to compound IIi by using the appropriate acid chlorides and compound IIa-Na.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=2)[N:3]=1.Br[C:24]1C2C(=CC=CC=2[N+]([O-])=O)N(CC2C=CC=C(C(C)C)N=2)N=1>>[CH3:24][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=2)[N:3]=1
Reactant: Cc1cccc(CCn2nc(Br)c3c([N+](=O)[O-])cccc32)n1
Reactant: CC(C)c1cccc(Cn2nc(Br)c3c([N+](=O)[O-])cccc32)n1
Product: Cc1cccc(CCn2nc(C)c3c([N+](=O)[O-])cccc32)n1
Yield: 83 %

Procedure:
Prepared according to Preparation D, Step E, substituting 3-bromo-1-(2-(6-methylpyridin-2-yl)ethyl)-4-nitro-1H-indazole for), 3-bromo-1-((6-isopropylpyridin-2-yl)methyl)-4-nitro-1H-indazole, to give the title compound (83%).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH:11]2[CH2:13][CH2:12]2)[CH:3]=1.[Li+].[Cl-].[CH2:16]([Sn](CCCC)(CCCC)CCCC)[CH:17]=[CH2:18]>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:18]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH:11]2[CH2:13][CH2:12]2)[CH:3]=1)[CH:17]=[CH2:16]
Reactant: N#Cc1ccc(Br)cc1OC1CC1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCc1ccc(C#N)c(OC2CC2)c1

Procedure:
To a solution of 4-bromo-2-(cyclopropyloxy)benzonitrile (108 mg, 0.45 mmol) in 20 ml of toluene was added LiCl (38 mg, 0.9 mmol), Pd(PPh3)4 (15 mg), allyl tributyltin (180 g, 0.55 mmol), then the mixture was heated to reflux overnight. After the reaction was completed, the reaction solution was diluted with EtOAc and filtered, the filtrate was concentrated and purified with silica gel column chromatograph to give crude 4-allyl-2-(cyclopropyloxy)benzonitrile.
Reaction SMILES: O.[NH2:2][C:3]1[NH:7][N:6]=[N:5][N:4]=1.[N+:8]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14])([O-:10])=[O:9]>O>[N+:8]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH:2][C:3]1[NH:7][N:6]=[N:5][N:4]=1)=[O:14])([O-:10])=[O:9]
Reactant: Nc1nnn[nH]1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Solvent: O
Product: O=C(Nc1nnn[nH]1)c1ccccc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a solution of 10.3 g of 5-aminotetrazole monohydrate in 300 ml of tetahydrofuran and 15 ml of water was added 9.3 g of 2-nitrobenzoyl chloride. The solution was allowed to stand for 30 minutes before it was diluted with 200 ml of water and stored in a refrigerator for 72 hours. The solid which formed was separated by filtration to give 2-nitro-N-(1H-tetrazol-5-yl)-benzamide melting at about 272°-273° C. with decomposition.
Reaction SMILES: [CH3:1][CH:2]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:3][CH:4]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[OH:22])[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:6]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CC(C)=O>[CH2:34]([O:22][C:15]1[C:16]([CH3:21])=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[C:4](=[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[CH:6]1[OH:13])[CH2:3][CH:2]([CH3:1])[CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1cc(C)c(O)c(C(CC(C)CC(C)(C)C)c2cc(C)cc(C)c2O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1=CC(=C(CC(C)CC(C)(C)C)c2cc(C)cc(C)c2OCc2ccccc2)C(O)C(C)=C1
Yield: 66 %

Procedure:
A solution of 2,2'-(3,5,5-trimethylhexylidene)-bis(4,6-dimethylphenol) (184.0 g, 0.5 mole) in acetone (21) was stirred with anhydrous potassium carbonate (170 g) and benzylbromide (85.5 g, 0.5 mole) at room temperature overnight. The solution was filtered, excess acetone removed under vacuum and the residue refrigerated. The crystalline solid was filtered off, washed with cold acetone and dried under vacuum at 40° C. Yield=66%. M.p.=125°-126° C.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([CH:14]2[C:22]3[C:17](=[C:18]([O:25][CH3:26])[C:19]([O:23][CH3:24])=[CH:20][CH:21]=3)[CH2:16][CH2:15]2)[C:4]=1/[CH:27]=[CH:28]/[C:29]([NH:31][CH:32]1[CH2:37][CH2:36]OC(C)(C)C1)=[O:30])#[N:2].C(C1C2C(=NC(C)=CC=2C)N(C2C[C:60]3C(=CC=[C:58](OC)[C:59]=3[O:62]C)C2)C=1/C=C/C(O)=O)#N.CC1OC(C)CNC1>>[CH3:26][O:25][C:18]1[C:19]([O:23][CH3:24])=[CH:20][CH:21]=[C:22]2[C:17]=1[CH2:16][CH2:15][CH:14]2[N:5]1[C:6]2=[N:7][C:8]([CH3:13])=[CH:9][C:10]([CH3:12])=[C:11]2[C:3]([C:1]#[N:2])=[C:4]1/[CH:27]=[CH:28]/[C:29]([N:31]1[CH2:32][CH:37]([CH3:36])[O:62][CH:59]([CH3:60])[CH2:58]1)=[O:30]
Reactant: COc1ccc2c(c1OC)CC(n1c(/C=C/C(=O)O)c(C#N)c3c(C)cc(C)nc31)C2
Reactant: COc1ccc2c(c1OC)CCC2n1c(/C=C/C(=O)NC2CCOC(C)(C)C2)c(C#N)c2c(C)cc(C)nc21
Agent: CC1CNCC(C)O1
Product: COc1ccc2c(c1OC)CCC2n1c(/C=C/C(=O)N2CC(C)OC(C)C2)c(C#N)c2c(C)cc(C)nc21

Procedure:
In the same manner described in (4) of Example 2, 1-(4,5-dimethoxy-2,3-dihydro-1H-inden-1-yl)-2-[(E)-3.-(2,6-dimethyl-4-morpholinyl)-3-oxo-1-propenyl]-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile was synthesized from (E)-3-[3-cyano-1-(4,5-dimethoxy-2,3-dihydro-1H-inden-2-yl)-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl]-2-propenoic acid and 2,6-dimethylmorpholine.