Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:19])[N:4]([CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:5]=[CH:6][C:7]=1Cl.[CH3:20][NH2:21].O>CS(C)=O>[Cl:1][C:2]1[C:3](=[O:19])[N:4]([CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:5]=[CH:6][C:7]=1[NH:21][CH3:20]
Reactant: CC1(C)CC(n2ncc(Cl)c(Cl)c2=O)CC(C)(C)C1
Reactant: CN
Solvent: O
Solvent: CS(C)=O
Product: CNc1cnn(C2CC(C)(C)CC(C)(C)C2)c(=O)c1Cl
Temperature: 100 °C
Yield: 34.1 %

Procedure:
4,5-Dichloro-2-(3,3,5,5-tetramethylcyclohexyl)pyridazin-3-one (0.3 g, 1.475 mmoles) was dissolved in DMSO (20 mL) and a 40% aqueous solution of methylamine (0.6 mL, 1.7 mmoles) was added with stirring. Heated at 100° C. overnight. Allowed to cool and then poured into water. A solid precipitated out and was filtered off. Purified using a silica cartridge eluted with ethyl acetate:isohexane (3:7) to give the product as a cream solid (150 mg). 1H NMR (300 MHz CDCl3) 7.65 (s, 1H), 5.35 (m, 1H), 4.7 (brs, 1H), 3.05 (d, 3H, J=5 Hz), 1.55 (m, 4H), 1.3 (m, 1H), 1.15 (m, 1H), 1.15 (s, 6H), 0.95 (s, 6H).
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][O:3]1.[CH:17]1([C:20]2[CH:21]=[C:22]([CH3:32])[C:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[N:24][CH:25]=2)[CH2:19][CH2:18]1>>[CH:17]1([C:20]2[CH:21]=[C:22]([CH3:32])[C:23]([N:26]3[CH2:27][CH2:28][N:29]([C:12]([C:11]4[CH:10]=[CH:9][C:8]([N:7]5[CH2:6][CH2:5][CH2:4][O:3][C:2]5=[O:1])=[CH:16][CH:15]=4)=[O:14])[CH2:30][CH2:31]3)=[N:24][CH:25]=2)[CH2:19][CH2:18]1
Reactant: O=C(O)c1ccc(N2CCCOC2=O)cc1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCOC3=O)cc2)CC1
Yield: 74.4 %

Procedure:
Using 4-(2-oxo[1,3]oxazinan-3-yl)benzoic acid (111 mg) and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (109 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 87, the title compound (157 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13]>[Pd]>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([CH:13]=[CH:12][C:11]([O:15][CH2:16][CH3:17])=[O:14])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C=CC(=O)OCC
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: [Pd]
Product: CCOC(=O)C=Cc1ccc([N+](=O)[O-])cc1
Yield: 88 %

Procedure:
The procedure described in Example 26 is repeated, but using 5.05 g (25 mmols) of 4-bromonitrobenzene and 2.99 ml (27.5 mmols) of ethyl acrylate. After a reaction time of 3 hours at 130° C., 4.86 g (22.0 mmols) of ethyl 4-nitrocinnamate are obtained, corresponding to a yield of 88% of theory (conversion figure 8800; Pd content 0.01 mol %).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH3:9].[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCC[CH2:17]1>>[CH2:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:3]1[CH2:2][NH:1][CH3:17])[CH3:9]
Reactant: CCN1CCC[C@H]1CN
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCN1CCC[C@H]1CNC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of the compound obtained in (1) mentioned above in tetrahydrofuran (10 ml) was added dropwise to a suspension of lithium aluminum hydride (590.5 mg) in tetrahydrofuran (20 ml), and the resulting mixture was stirred at room temperature for 0.5 hour, and under reflux by heating for 6 hours. The reaction mixture was cooled to room temperature, then distilled water, 25% aqueous sodium hydroxide and distilled water were added to the reaction mixture in this order under ice cooling, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered thorough Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (510 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]([CH3:13])[CH3:12])[C:3]=1[C:4]#[N:5].O=[C:15]([CH3:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[CH2:20]([O:19][C:17]([C:16]1[C:15]([CH3:22])=[N:1][C:2]2[C:3]([C:4]=1[NH2:5])=[C:6]([O:10][CH:11]([CH3:13])[CH3:12])[CH:7]=[CH:8][CH:9]=2)=[O:18])[CH3:21]
Reactant: CC(C)Oc1cccc(N)c1C#N
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OC(C)C)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-isopropoxybenzonitrile (Tachdjian, C. et al. PCT Int. Appl. 2008, WO 2008154221) and ethyl 3-oxobutanoate as an off-white solid (32%). 1H NMR (400 MHz, DMSO-d6) δ 1.32 (t, J=7.6 Hz, 3H), 1.38 (d, J=6.0 Hz, 6H), 2.54 (s, 3H), 4.3 (q, J=7.2 Hz, 2H), 4.83-4.89 (m, 1H), 6.93 (d, J=8.0 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.50 (t, J=8.4 Hz, 1H), 8.14 (s, 2H). MS 289 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15]/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)/C=C/Cc1ccccc1OCc1ccccc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)CCCc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
To a mixture of methyl 4-(2-benzyloxyphenyl)crotonate (14.4 g) and nickel chloride hexahydrate (1.19 g) in methanol (200 ml) was added portionwise sodium borohydride (3.78 g). During addition, the reaction temperature was kept at 20° C. by ice cooling. After the addition was completed, the mixture was stirred at ambient temperature for 1 hour and filtered. The filtrate was concentrated under reduced pressure. To the residue, water (100 ml) was added and the solution was extracted with diethyl ether. The organic layer was washed with brine, dried and evaporated in vacuo and the residue was purified by column chromatography on silica gel [eluting with ethyl acetate - n-hexane (1:1)] to give methyl 4-(2-benzyloxyphenyl)butyrate (11.5 g).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:19]([NH:21][NH2:22])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]1(=O)[O:33][C:31](=[O:32])[CH2:30][CH2:29][CH2:28]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:19]([NH:21][N:22]1[C:31](=[O:32])[CH2:30][CH2:29][CH2:28][C:27]1=[O:33])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@@H](C(=O)NN)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Reactant: O=C1CCCC(=O)O1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](C(=O)NN1C(=O)CCCC1=O)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 49.2 %

Procedure:
A solution of 1.0 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvalerohydrazide, 0.35 g of glutaric anhydride and 0.85 ml of triethylamine in 30 ml of dry toluene was heated at reflux under a nitrogen atmosphere for 7 hours. The mixture was cooled to room temperature and washed with 2M aqueous hydrochloric acid, 5% aqueous sodium hydrogen carbonate and brine. The organic phase was dried over anhydrous magnesium sulphate and the solvent was then evaporated. The residue was triturated with diethyl ether to give 0.623 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methyl-N-(2,6-dioxopiperidino)valeramide in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][C:8](=[O:11])[NH:7][C:6]=2[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[C:4]([F:25])[CH:3]=1.[C:26](OC)(=O)[C:27](C)=O.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:10]2[O:9][C:8](=[O:11])[C:26]([CH3:27])=[N:7][C:6]=2[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[N:14]([CH3:23])[C:13]2=[O:24])=[C:4]([F:25])[CH:3]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3oc(=O)[nH]c23)c1=O
Reactant: COC(=O)C(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c2oc1=O
Yield: 43 %

Procedure:
3-[7-Chloro-5-fluoro-2(3H)benzoxazolinon-4-yl]-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (0.50 g) was dissolved in anhydrous toluene (15 ml) and methyl pyruvate (0.15 g) was added. The solution was refluxed with azeotropic removal of water for 2 hours and the solvent was then removed under reduced pressure. The residue was chromatographed on silica gel using hexane-ethyl acetate (3:1) as the eluent to afford the title compound (0.23 g).
Reaction SMILES: Br[C:2]1[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[C:10]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[C:13]([O:12][C:10]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=2)[CH2:19][CH2:18]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Brc1cnc(Br)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cc2Br)CC1
Yield: 97.5 %

Procedure:
To a mixture of 2,3,5-tribromopyridine (10 g), 1-Boc-piperazine (6 g) and potassium carbonate (20 g) was added 2-butanone (80 mL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated to give 4-(3,5-dibromopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (13 g). To a mixture of 4-(3,5-dibromopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (13 g), bis(tricyclohexylphosphine)palladium (II) dichloride (1.3 g), tripotassium phosphate (38 g) and cyclopropylboronic acid (8.4 g) were added toluene (100 mL) and water (5 mL), and the mixture was refluxed for 8 hr. After cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3,5-dicyclopropylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (7 g). 4-(3,5-Dicyclopropylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (7 g) was dissolved in chloroform (25 mL), 4N hydrogen chloride/ethyl acetate (25 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1N aqueous sodium hydroxide solution (100 mL), and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was dissolved in ethyl acetate (50 mL), 4N hydrogen chloride/ethyl acetate (8 mL) was added, and the mixture was filtered to give the title compound (3.2 g).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[NH2:12][C@H:13]1[CH:18]2[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]2)[CH2:14]1.[I:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.[OH-].[Na+]>CN(C=O)C>[I:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:12][C@H:13]2[CH:18]3[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]3)[CH2:14]2)=[O:27])=[CH:24][CH:23]=1
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CN2CCC1CC2)c1ccc(I)cc1
Reaction time: 3 h
Yield: 64.2 %

Procedure:
N,N′-Diisopropylethylamine (1.05 ml, 6.03 mmol) was added to a flask charged with DMF solution mixture of (S)-(−)-3-Aminoquinuclidine dihydrochloride (400 mg, 2.01 mmol) and 4-Iodobenzoyl chloride (616 mg, 2.31 mmol). The clear yellow solution was stirred for 3 hours. The reaction mixture was worked up by addition of 1N sodium hydroxide aqueous solution and extracted twice with ethyl acetate, combined organic layer was washed with saturated brine solution, dried over sodium sulfate, filtered, and concentrated to crude clear oil. The crude oil was purified via preparative HPLC to obtain pure product of (S)-4-iodo-N-(quinuclidin-3-yl)benzamide, (460 mg, 64% yield). 1H NMR (400 MHz, Methanol-D4) δ (ppm): 7.85 (d, J=8 Hz, 2H), 7.60 (d, J=8 Hz, 2H), 4.12 (m, 1H), 3.31 (m, 1H), 2.99 (m, 1H), 2.84 (m, 4H), 2.02 (m, 1H), 1.90 (m, 1H), 1.78 (m, 2H), 1.54 (m, 1H). C14H17IN2O=356.04 LCMS (M+H): m/z 357
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12]([C:16]1[CH:17]=[C:18]([CH2:27][CH2:28][C:29]([NH:31][NH2:32])=[O:30])[CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])([CH3:15])([CH3:14])[CH3:13]>O>[C:1]([NH:32][NH:31][C:29](=[O:30])[CH2:28][CH2:27][C:18]1[CH:19]=[C:20]([C:23]([CH3:24])([CH3:26])[CH3:25])[C:21]([OH:22])=[C:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:17]=1)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: CC(C)(C)c1cc(CCC(=O)NN)cc(C(C)(C)C)c1O
Solvent: O
Product: CC(C)(C)c1cc(CCC(=O)NNC(=O)C=Cc2ccccc2)cc(C(C)(C)C)c1O
Reaction time: 3 h
Yield: 70.3 %

Procedure:
To 50 ml of N-dimethylacetamide were added 2.30 g of cinnamoyl chloride and 4.04 g of β-(3,5-di-tert-butyl-4-hydroxyphenyl)propionylhydrazine, and the resulting mixture was stirred at 30° - 35° C for 3 hours. The reaction mixture was then poured into 2 liters of water, and the produced precipitate was collected by filtration and washed with water. The so obtained precipitate was then recrystallized twice from a mixture of ethanol (first grade) and water (1 : 1, volume ratio) and dried under reduced pressure to yield 4.1 g of N-cinnamoyl-N'-{β-(3,5-di-tert-butyl-4-hydroxyphenyl)propionyl}-hydrazine as white crystals, m.p. 224.5° - 225.0° C. Analysis for C26H34N2O8 : C, 73.90%, H, 8.11%; N, 6.63%, Found: C, 73.91%; H, 7.90%; N, 6.51%.
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5]([CH3:24])=[C:6]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[CH:32]=[CH2:33]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[N:4]([CH2:33][CH:32]=[CH2:31])[CH:5]([CH3:24])[C:6]([C:18]([O:20][CH:21]([CH3:22])[CH3:23])=[O:19])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:8]=1
Reactant: COC1=NC(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)C)=C(C)N1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCN1C(OC)=NC(c2cccc([N+](=O)[O-])c2)=C(C(=O)OC(C)C)C1C
Temperature: 25 °C
Reaction time: 10 h
Yield: 58.9 %

Procedure:
A solution of 1,4-dihydro-2-methoxy-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, 1-methylethyl ester (4.0 g, 12.0 mmol; see Example 1A) in dry dimethylformamide (10 ml) was treated with finely ground potassium carbonate (6.6 g, 48.0 mmoles) and allyl bromide (1.7 ml, 20.0 mmole). The resulting suspension was allowed to stir under argon at room temperature for 10 hours. The reaction was diluted with ethyl acetate, filtered and the filtrate was washed with water and brine. It was dried over anhydrous magnesium sulfate and evaporated to provide a yellow oil. Purification by flash chromatography (20% ethyl acetate in hexanes) yielded the title compound (2.64 g) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:15])[CH:5]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:7]=1.[H-].[Na+].[Si:18](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C.C(OC)(C)(C)C>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[C:4]([O:15][Si:18]([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:3]=1
Reactant: Oc1cc(Br)cc(Nc2cccnc2)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CC(C)(C)[Si](Oc1cc(Br)cc(Nc2cccnc2)c1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.1 %

Procedure:
3-Bromo-5-(pyridin-3-ylamino)-phenol (11.62 g, 43.83 mmol) was dissolved in DMF (115 mL) under dry argon and cooled to 0° C. Then 60% NaH (1.93 g, 48.21 mmol) was added in small portions over a period of 45 min. Stirring was continued for 15 min, followed by drop wise addition of TBDPS-chloride (11.2 mL, 43.83 mmol). The mixture was warmed to room temperature and stirred for 20 h. The reaction mixture was diluted with tert-butylmethyl ether (200 mL) and washed with water and brine (2×50 mL each). The organic layer was dried (MgSO4) and concentrated to give the crude product which was purified by flash chromatography on silica gel (600 g, AcOEt/heptane 1:2→1:1). [3-Bromo-5-(tert-butyl-diphenyl-silanyloxy)-phenyl]-pyridin-3-yl-amine (21.2 g, 96%) was obtained as a yellow resin.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10](I)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:27]([O:31][CH3:32])(=[O:30])[CH:28]=[CH2:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([CH:29]=[CH:28][C:27]([O:31][CH3:32])=[O:30])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc2c(c1)c(I)nn2C(=O)OC(C)(C)C
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)C=Cc1nn(C(=O)OC(C)(C)C)c2ccc(OC)cc12
Temperature: 50 °C

Procedure:
A solution of 3-iodo-5-methoxy-indazole-1-carboxylic acid tert-butyl ester [0.500 g, Reference Example 22(a)] in dioxane (15 ml) and under an atmosphere of nitrogen was treated with triethylamine (1.86 ml) followed by methyl acrylate (1.20 ml), triphenylphosphine (0.105 g), and palladium (II) acetate (60 mg). The resulting mixture was heated at 50° C. for 16 hours, then cooled to ambient temperature and then evaporated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, then dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and 40/60 petrol (1:9, v/v) to yield 5-methoxy-3-(2-methoxycarbonyl-vinyl)-indazole-1-carboxylic acid tert-butyl ester (282 mg). LC-MS (METHOD B): RT=3.33 minutes; 333 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([OH:34])[CH:32]=2)[CH:27]=[CH:26][N:25]=1>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:34][C:31]2[CH:32]=[C:33]3[C:28]([CH:27]=[CH:26][N:25]=[CH:24]3)=[CH:29][CH:30]=2)=[N:3][CH:4]=1
Reactant: Oc1ccc2ccncc2c1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2ccc3ccncc3c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and isoquinolin-7-ol: 1H-NMR (CDCl3) δ 9.27 (1H, s), 8.59 (2H, m), 8.13–8.10 (2H, m), 8.00 (2H, d, J=8.4 Hz), 7.94 (1H, d, J=8.9 Hz), 7.74 (2H, m), 7.50 (1H, dd, J=8.9, 2.3 Hz), 7.45 (2H, d, J=8.4 Hz), 5.40 (1H, m), 3.89 (3H, s), 1.61 (3H, d, J=7.0 Hz).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:21]([O-:23])=[O:22])[CH:18]=3)[CH2:13]2)[C:11](=[O:24])[N:10](CC2C=CC(OC)=CC=2)[C:9]1=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>C(#N)C.O>[CH2:1]([N:8]1[C:12]2([CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:21]([O-:23])=[O:22])[CH:18]=3)[CH2:13]2)[C:11](=[O:24])[NH:10][C:9]1=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN2C(=O)N(Cc3ccccc3)C3(Cc4ccc([N+](=O)[O-])cc4C3)C2=O)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: O=C1NC(=O)C2(Cc3ccc([N+](=O)[O-])cc3C2)N1Cc1ccccc1
Reaction time: 3 h

Procedure:
To a stirred solution of (±)-3-benzyl-1-(4-methoxybenzyl)-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione from Step B (110 mg, 0.24 mmol) in acetonitrile (1.5 mL) was added dropwise a solution of ammonium cerium (IV) nitrate (395 mg, 0.72 mmol) in H2O (1 mL). After 3 h at ambient temperature, the precipitate was isolated by filtration and dried in vacuo to afford the title compound. MS: m/Z=338 (M+1).
Reaction SMILES: [C:1]1([NH2:12])[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:13]([N:20]=[C:21]=[S:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)(=O)C>[CH2:13]([NH:20][C:21]([NH:12][C:1]1[C:10]2[C:5](=[C:6]([NH:11][C:21](=[S:22])[NH:20][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[S:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cccc2c(N)cccc12
Reactant: S=C=NCc1ccccc1
Solvent: CCOC(C)=O
Product: S=C(NCc1ccccc1)Nc1cccc2c(NC(=S)NCc3ccccc3)cccc12
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 30.7 %

Procedure:
1,5-Naphthalenediamine (0.791 g, 5 mM) was dissolved in 20 ml of ethyl acetate, and 2 equivalents of benzylisothiocyanate (1.492 g, 10 mM) were added. The mixture was stirred at 80° C. for 30 minutes. After cooling, the reaction mixture was filtered, and washed with ethylacetate/n-hexane to obtain 0.70 g (30.7% yield) of a colorless crystal of compound A-29.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:16])=O>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([Cl:16])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Product: O=C(Cl)Cc1ccc([N+](=O)[O-])cc1
Yield: 100 %

Procedure:
A stirred mixture of 4-nitrophenylacetic acid (25 g, 0.138 mol) in thionyl chloride (50 ml, 0.685 mol) was heated at reflux for 2 hours then concentrated to yield 4-nitrophenylacetyl chloride (27.55 g) as a tan solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].I[CH:20]([CH3:22])[CH3:21].C(OCC)(=O)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:20]([CH3:22])[CH3:21])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(O)c(Br)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC(C)C)c(Br)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 101.7 %

Procedure:
Methyl 3-bromo-4-hydroxybenzoate (2.5 g, 10.8 mmol) in DMF (35 ml) was treated with potassium carbonate (3.0 g, 21.6 mmol), 2-iodopropane (2.76, 21.6 mmol) and then stirred at 25° C. for 48 h. Work-up with ethyl acetate gave the title compound (3.0 g).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH3:12])[C:4]=1[CH3:13])=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:22])C=1>C(Cl)Cl>[CH3:13][C:4]1[C:5]([O:11][CH3:12])=[C:6]([CH:9]=[CH:10][C:3]=1[CH:1]1[CH2:2][O:22]1)[C:7]#[N:8]
Reactant: C=Cc1ccc(C#N)c(OC)c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1c(C#N)ccc(C2CO2)c1C
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 4-ethenyl-3-methyl-2-(methyloxy)benzonitrile (3.90 g, 22.5 mmol) and m-CPBA (85%, 11.7 g, 67.6 mmol) in 300 mL of DCM was stirred at room temperature for 120 hours. The reaction mixture was cooled to 0° C. and was washed subsequently with saturated NaHCO3 (50 mL), saturated Na2SO3 (50 mL), 5% NaOH (50 mL×2) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography (PE:EtOAc=20:1) to afford 3-methyl-2-(methyloxy)-4-oxiran-2-ylbenzonitrile.