Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([OH:19])=[C:8]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]=2[O:4][C:3]=1C(O)=O.N1C2C(=CC=CC=2)C=CC=1.Cl>C(OCC)(=O)C.[Cu]>[CH3:1][C:2]1[C:6]2[C:7]([OH:19])=[C:8]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[C:10]([C:11]([CH3:12])([CH3:14])[CH3:13])[C:5]=2[O:4][CH:3]=1
Reactant: Cc1c(C(=O)O)oc2c(C(C)(C)C)cc(C(C)(C)C)c(O)c12
Agent: [Cu]
Agent: Cl
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: Cc1coc2c(C(C)(C)C)cc(C(C)(C)C)c(O)c12
Temperature: 210 °C

Procedure:
A mixture of 3-methyl-4-hydroxy-5,7-di-tert-butylbenzofuran-2-carboxylic acid (0.350 g, 1.14 mmol), quinoline (1.0 mL), and copper powder (0.072 g 1.14 mmol) was heated to 210° C. until gas evolution had ceased. The mixture was cooled, diluted with ethyl acetate (30 mL) and poured into 2N HCl. The biphasic mixture was filtered through a celite pad and the layers separated. The aqueous layer was extracted with ethyl acetate (50 mL) and the combined organic layers dried (Na2SO4) and concentrated. Flash chromatography afforded 3-methyl-4-hydroxy-5,7-di-tert-butylbenzofuran, compound 10b. 1H NMR d 1.46 (9H, s), 1.49 (9H, s), 2.46 (3H, s), 5.12 (1H, s), 7.11 (1H, s), 7.29 (1H, s).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].N12CCCN=C1CCCCC2.Br[CH:22]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C1(C)C=CC=CC=1.[Cu](Br)Br>[CH2:26]([O:25][C:23]([C:22]1([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:1][C:2]1([CH3:3])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:24])[CH3:27]
Reactant: C=C(C)c1ccccc1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: Br[Cu]Br
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C1(C(=O)OCC)CC1(C)c1ccccc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 45.2 %

Procedure:
To a solution of α-methylstyrene (570 mL, 4.4 mol), 1,8-diazabicyclo[5.4.0]undec-7-ene (240 mL, 1.6 mol) and copper (II) bromide (9.8 g, 44 mmol) in toluene (700 mL) was added diethyl bromomalonate (210 g, 0.88 mol) at 0° C., and the mixture was stirred for 22 hours at room temperature. The obtained solution was washed with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, and dried over sodium sulfate. Then, the solution was filtrated and the solvent was evaporated. The obtained residue was separated and purified by silica gel chromatography (hexane:ethyl acetate=20:1) to give the title compound (110 g, yield 45%) as a colorless oil.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC1C=CC=CC=1)=O)=NC(OCC1C=CC=CC=1)=O.[NH:49]1[C:57]2[C:52](=[CH:53][C:54](O)=[CH:55][CH:56]=2)[CH:51]=[N:50]1>O1CCCC1>[CH:1]1([O:7][C:54]2[CH:53]=[C:52]3[C:57](=[CH:56][CH:55]=2)[NH:49][N:50]=[CH:51]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccc2[nH]ncc2c1
Reactant: OC1CCCCC1
Agent: O=C(N=NC(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc2[nH]ncc2cc1OC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
Cyclohexanol (0.315 ml, 2.98 mmol), triphenylphosphine (442 mg, 1.64 mmol) and dibenzyl azodicarboxylate (534 mg, 1.17 mmol) were added at 0° C. to a solution of the 1H-indazol-5-ol (200 mg, 1.49 mmol) obtained in Reference Example 4 in tetrahydrofuran (16 ml). After 30 minutes, the mixture thus obtained was warmed up to room temperature. After stirring overnight, the reaction solution was concentrated under reduced pressure and a-1M aqueous sodium hydroxide solution (20 ml) was added to the resulting residue, followed by extraction with ethyl acetate (20 ml×2). The organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol, hexane/ethyl acetate) to obtain 5-(cyclohexyloxy)-1H-indazole (140 mg, 43%).
Reaction SMILES: [F:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:3]=1[CH:4]=[C:5]1[C:10](=[O:11])[O:9][C:8]([CH3:13])([CH3:12])[O:7][C:6]1=[O:14].[CH2:21]([Mg]Br)[CH3:22]>C1COCC1>[F:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:3]=1[CH:4]([CH:5]1[C:6](=[O:14])[O:7][C:8]([CH3:12])([CH3:13])[O:9][C:10]1=[O:11])[CH2:21][CH3:22]
Reactant: COc1cccc(C=C2C(=O)OC(C)(C)OC2=O)c1F
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(c1cccc(OC)c1F)C1C(=O)OC(C)(C)OC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
A 500 mL round bottom flask was charged with 5-(2-fluoro-3-methoxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione 77.B (5.00 g, 17.8 mmol) and THF (100 mL). The resulting slurry was cooled to 0° C., and to it was added ethylmagnesium bromide (available from Aldrich) (3.0 M/ether) (11.9 mL, 35.7 mmol) dropwise over 15 minutes. The cooling bath was removed, and the mixture was stirred for 1 hour at ambient temperature. The reaction was quenched with 1 N HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), and concentrated to afford 5-(1-(2-fluoro-3-methoxyphenyl)propyl)-2,2-dimethyl-1,3-dioxane-4,6-dione 77.C (5.17 g, 93.4% yield) as a yellow oil (5.2 g, 93%). The product thus obtained was used without further purification.
Reaction SMILES: C[C@H](NC)[C@H](O)C1C=CC=CC=1.Cl.C[C@H](NC)[C@H](O)C1C=CC=CC=1.C[C@H](NC)[C@H](O)C1C=CC=CC=1.OS(O)(=O)=O.[CH3:43][CH2:44][CH:45]([C:47]1([CH2:56][CH3:57])[C:54](=[O:55])[NH:53][C:51](=[O:52])[NH:50][C:48]1=[O:49])C>>[CH2:45]([C:47]1([CH2:56][CH3:57])[C:48](=[O:49])[NH:50][C:51](=[O:52])[NH:53][C:54]1=[O:55])[CH:44]=[CH2:43]
Reactant: CCC(C)C1(CC)C(=O)NC(=O)NC1=O
Agent: CN[C@@H](C)[C@H](O)c1ccccc1
Agent: Cl
Agent: O=S(=O)(O)O
Product: C=CCC1(CC)C(=O)NC(=O)NC1=O

Procedure:
The composition of claim 1 containing 4 to 25 mg. of ephedrine hydrochloride or ephedrine sulfate and from 2 to 15 mg. of butabarbital per 5 milliliters of elixir.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:13][CH:14]1[CH2:19][NH:18][CH:17]([CH3:20])[CH2:16][NH:15]1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:15]2[CH2:16][CH:17]([CH3:20])[NH:18][CH2:19][CH:14]2[CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1CNC(C)CN1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1CN(S(=O)(=O)c2ccc(Cl)c(Cl)c2)C(C)CN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3,4-dichlorobenzene-1-sulfonyl chloride (840 mg, 3.42 mmol) and 2,5-dimethylpiperazine (1.171 g, 10.26 mmol) in anhydrous dichloromethane (5 mL) was added diisopropylethylamine (1.2 mL, 6.84 mmol). The mixture was stirred overnight at room temperature. Reaction was complete as determined by TLC. The reaction mixture was diluted with dichloromethane, washed with water and dried over MgSO4. After solvent evaporation crude product was treated with ethyl acetate/hexanes. Solid impurity was filtered of and the filtrate was concentrated to afford 1-(3,4-dichlorophenylsulfonyl)-2,5-dimethylpiperazine in quantitative yield. It was carried to the next step without further purification.
Reaction SMILES: [NH:1]([C:3]1[CH2:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[N:4]=1)[NH2:2].[C:21]([O:26][CH3:27])(=[O:25])[C:22]([CH3:24])=O>>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:7]1[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[N:4]=[C:3]([NH:1][N:2]=[C:22]([C:21]([O:26][CH3:27])=[O:25])[CH3:24])[CH2:9][N:8]=1
Reactant: COC(=O)C(C)=O
Reactant: NNC1=Nc2ccccc2C(c2ccccc2Cl)=NC1
Product: COC(=O)C(C)=NNC1=Nc2ccccc2C(c2ccccc2Cl)=NC1

Procedure:
In the manner given in Example 1, 2-hydrazino-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can be stirred with methyl pyruvate at room temperature to give 5-(o-chlorophenyl)-2-[[1-(methoxycarbonyl)ethylidene]-hydrazino]-3H-1,4-benzodiazepine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:30][N:21]4[N:22]=[C:23]5[C:28]([CH:27]=[CH:26][C:25](Br)=[CH:24]5)=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:39]([O:43][C:44]([N:46]1[C:50](B(O)O)=[CH:49][CH:48]=[N:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[C:39]([O:43][C:44]([N:46]1[C:50]([C:25]2[CH:26]=[CH:27][C:28]3[C:23]([CH:24]=2)=[N:22][N:21]2[CH:30]=[C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:18]([C:15]4[CH:16]=[CH:17][C:12]([C:8]5([NH:7][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:38])[CH2:11][CH2:10][CH2:9]5)=[CH:13][CH:14]=4)=[N:19][C:20]=32)=[CH:49][CH:48]=[N:47]1)=[O:45])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c5ccc(Br)cc5nn4cc3-c3ccccc3)cc2)CCC1
Reactant: CC(C)(C)OC(=O)n1nccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c5ccc(-c6ccnn6C(=O)OC(C)(C)C)cc5nn4cc3-c3ccccc3)cc2)CCC1
Temperature: 105 °C

Procedure:
100 mg (0.18 mmol) {1-[4-(8-Bromo-3-phenylpyrimido[1,2-b]indazol-2-yl)phenyl]-cyclobutyl}carbamic acid tert-butyl ester, intermediate example Int-2-2, 74.5 mg (0.35 mmol) [1-(tert-butoxycarbonyl)-1H-pyrazol-5-yl]boronic acid, 14.3 mg (0.02 mmol) 1,1 bis(diphenylphosphino)ferrocenedichloro-palladium(II) and 55.8 mg (0.53 mmol) sodium carbonate in 1.8 mL dioxane and 0.3 mL water (both solvents had been degassed) were heated in the microwave for 30′ at 105° C. The reaction mixture was poured on water/dichloromethane/saturated ammonium chloride and vigorously stirred for 30′. The organic phase was separated, washed twice with brine, dried (sodium sulfate) and filtrated. The solvent was evaporated and the crude residue (181 mg>100%) was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26](OCC)=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:34][O:35][CH2:36][CH2:37][NH2:38]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26]([NH:38][CH2:37][CH2:36][O:35][CH3:34])=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O
Reactant: COCCN
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-(4-fluorobenzyl)-4-hydroxy-2-oxo-1-[2-(2-oxopyrrolidin-1-yl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-methoxyethylamine by methods similar to those described in Example 6. The product was obtained as a white solid: 1H NMR (CDCl3) δ 10.27 (1H, br m), 8.55 (1H, s), 8.06 (1H, s), 7.24 (2H, m), 6.99 (2H, t, J=8.6 Hz), 4.35 (2H, t, J=7 Hz), 4.14 (2H, s), 3.65 (2H, m), 3.59 (2H, m), 3.50 (2H, t, J=7 Hz), 3.44 (2H, m), 3.42 (3H, s), 2.31 (2H, t, J=8 Hz), 1.97 (2H, m); ES+ MS: 483 (M+H+, 100).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11]2[N:14]=[C:15]([SH:17])[NH:16][C:10]=2[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](=O)([O-])[O-].[K+].[K+].IC>ClCCl.CO>[CH2:1]([N:8]1[CH:13]=[CH:12][C:11]2[N:14]=[C:15]([S:17][CH3:19])[NH:16][C:10]=2[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1c2[nH]c(S)nc2ccn1Cc1ccccc1
Agent: [K+]
Solvent: CO
Solvent: CI
Solvent: ClCCl
Product: CSc1nc2ccn(Cc3ccccc3)c(=O)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.0 g (15.55 mmol) of 5-benzyl-2-mercapto-3,5-dihydro-imidazo[4,5-c]pyridin-4-one were suspended in a mixture of 100 ml of dichloromethane and 50 ml of methanol, then 2.15 g (15.55 mmol) of potassium carbonate and 0.97 ml (15.55 mmol) of iodomethane were added and the mixture was stirred for 1 hour at ambient temperature. Then it was filtered, the filtrate was evaporated down and the residue was further reacted in its crude form.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[N:20][CH:21]=2)[CH:13]=[CH:12][N:11]=1.Cl.[F:23][CH:24]([F:42])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[CH2:34][N:35]1[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]1)[C:28](Cl)=[O:29].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[F:42][CH:24]([F:23])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[CH2:34][N:35]1[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]1)[C:28]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[CH:17]=[N:18][CH:19]=[N:20][CH:21]=3)[CH:13]=[CH:12][N:11]=2)[CH:4]=1)=[O:29]
Reactant: CN1CCN(Cc2ccc(C(=O)Cl)cc2C(F)F)CC1
Reactant: Cc1ccc(N)cc1Nc1nccc(-c2cncnc2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)F)c2)cc1Nc1nccc(-c2cncnc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.7 %

Procedure:
1.98 g of 4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]aniline (Reference Example 18) was dissolved in 35 ml of anhydrous pyridine and 2.90 g of 3-difluoromethyl-4-(4-methylpiperazin-1-ylmethyl)benzoyl chloride hydrochloride (Reference Example 9) was added, followed by stirring at room temperature for 2 hours. To the reaction solution, ice water and an aqueous saturated sodium hydrogen carbonate solution were added and then the mixture was subjected to extraction with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The crude crystals were washed with chloroform-diethyl ether (1:1) to obtain 2.66 g of the objective compound as pale brown crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][CH:15]=[N:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([I:24])C(=O)C1>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][C:15]([I:24])=[N:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]cnc2C1
Reactant: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2[nH]c(I)nc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
To a solution of 1,4,6,7-tetrahydro-imidazo[4,5-c]pyridine-5-carboxylic acid tert-butyl ester (Preparation 20, 18.g, 80.62 mmol) in THF (300 mL) was added NIS (27.2 g, 121 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc (800 mL), washed with sodium thiosulfate aqueous solution (3×700 mL) and brine (500 mL), dried over MgSO4 and concentrated in vacuo to give the title compound as a yellow solid (18.25 g) in a 64.8% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][C:16]=1[Cl:17])[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7](=[O:18])[C:6]([C:19]([NH:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[O:20])=[C:5]2[OH:30]>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][C:16]=1[Cl:17])[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7](=[O:18])[C:6]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])=[C:5]2[OH:30]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Cl)c(Cl)cc2C2(CCOCC2)C1=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC(=O)C1=C(O)c2cc(Cl)c(Cl)cc2C2(CCOCC2)C1=O
Reaction time: 1 h
Yield: 87.3 %

Procedure:
1,1-Dimethylethyl N-((6,7-dichloro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-yl)carbonyl)glycinate (350 mg, 767 μmol) was dissolved in TFA (3 mL). The resulting mixture was stirred for 1 hour and then concentrated, precipitated with hexanes, sonicated, filtered, washed with hexanes, and dried in a vacuum oven to give the title compound (268 mg, 87.3% yield) as a white solid. MS (m/z)=400 (M+H)+. Calculated for C17H15Cl2NO6 399.03.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:17]C)=[C:11]([C:14]([OH:16])=[O:15])[CH:12]=2)[C:7]([CH3:19])=[N:6]1.[Br-].[Br-].[Br-].B>C(Cl)Cl>[Cl:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:2]([Cl:1])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:17])=[C:11]([C:14]([OH:16])=[O:15])[CH:12]=2)[C:7]([CH3:19])=[N:6]1
Reactant: COc1cc2c(C)nn(Cc3c(Cl)cccc3Cl)c2cc1C(=O)O
Agent: B
Agent: [Br-]
Solvent: ClCCl
Product: Cc1nn(Cc2c(Cl)cccc2Cl)c2cc(C(=O)O)c(O)cc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
To a suspension of the compound [179] (7.4 mg) in methylenechloride (0.2 mL) was added 1M methylenechloride solution of borane tribromide (0.2 mL) under ice-cooling, and then the reaction mixture was stirred at 0° C. for 3 hours. The reaction mixture was quenched with water, and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by reverse phase preparative liquid chromatography to give the titled compound (3.7 mg) as a pale brown solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[S:8][CH:9]([CH3:11])[CH2:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>ClCCCC>[C:12]([NH:1][C:2]1[C:7]2[S:8][CH:9]([CH3:11])[CH2:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:14])[CH3:13]
Reactant: CC1Cc2cccc(N)c2S1
Reactant: CC(=O)OC(C)=O
Solvent: CCCCCl
Product: CC(=O)Nc1cccc2c1SC(C)C2

Procedure:
To a solution of 18.0 g of 7-amino-2,3-dihydro-2-methylbenzo[b]thiophene (Example 7) in 100 ml of 1-chlorobutane was added a solution of 13.0 ml of acetic anhydride in 20 ml of 1-chlorobutane. After the exothermic reaction subsided, the mixture was refluxed for 0.3 hour, cooled in an ice-bath and filtered. The isolated solid was washed with 1-chlorobutane to yield 15.2 g of the title compound; m.p. 125°-127° C.
Reaction SMILES: C(=[NH:14])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].Br[C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH2:33][CH2:32][CH:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH2:30][CH:29]=2)=[N:26][CH:27]=1.Cl>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[N:34]1([CH:31]2[CH2:32][CH2:33][C:28]([C:25]3[N:26]=[CH:27][C:22]([NH2:14])=[CH:23][CH:24]=3)=[CH:29][CH2:30]2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1
Reactant: Brc1ccc(C2=CCC(N3CCOCC3)CC2)nc1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Nc1ccc(C2=CCC(N3CCOCC3)CC2)nc1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
Palladium (II) acetate (65 mg), benzophenonimine (4.1 ml), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (180 mg) and sodium tert-butoxide (3.33 g) were added to a toluene solution (51 ml) of 4-[4-(5-bromopyridin-2-yl)cyclohex-3-en-1-yl]morpholine (7.46 g) described in Reference Example 77, and stirred at 120° C. for two hours. After completion of the reaction, the reaction vessel was taken out from an oil bath, 3N hydrochloric acid aqueous solution (50 ml) was added and the mixture was stirred at room temperature for two hours. Next, the reaction solution was filtered through Celite, the aqueous layer of the filtrate was separated from the organic layer with a separating funnel. The resulting aqueous layer was cooled to 0° C., 1N aqueous solution of sodium hydroxide was added and the precipitated solid was filtered. The resulting residue was purified with NH silica gel column chromatography (n-hexane/ethyl acetate) to give the titled compound (5.73 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]1([C:14](=[O:15])[NH:13][C:12](=[O:16])[N:11]1[CH3:17])[CH2:5]2.[Cl:18]N1C(=O)CCC1=O>CC(O)=O>[NH2:1][C:2]1[C:3]([Cl:18])=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]1([C:14](=[O:15])[NH:13][C:12](=[O:16])[N:11]1[CH3:17])[CH2:5]2
Reactant: CN1C(=O)NC(=O)C12Cc1ccc(N)cc1C2
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: CN1C(=O)NC(=O)C12Cc1ccc(N)c(Cl)c1C2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(−)-5′-Amino-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione (265 mg, 1.15 mmol, described in Intermediate 8) was dissolved in AcOH (7 mL) and N-chlorosuccinimide (145 mg, 1.09 mmol) was added in one portion. The mixture was stirred at ambient temperature for 5 h, then the solvent was removed in vacuo. The residue was partitioned between saturated aqueous NaHCO3 (20 mL) and CH2Cl2 (76 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc—100:0 to 0:100, to give 5′-amino-4′-chloro-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione, which eluted first, and the title compound, which eluted second. MS: m/z 266 (M+1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[CH2:22][O:23][C:24]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][N+:33]([O-:35])=[O:34])=[O:25])=[C:12](\[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)/[C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Br-].Br[CH2:38][CH2:39][NH+:40]([CH2:43][CH3:44])[CH2:41][CH3:42].C([O-])([O-])=O.[K+].[K+].[NH4+].[Cl-:52]>CN(C=O)C>[Cl-:52].[CH2:39]([NH+:40]([CH2:43][CH3:44])[CH2:41][CH2:42][O:14][C:13](=[O:15])/[C:12](/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:11](/[C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=1)\[CH2:22][O:23][C:24]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][N+:33]([O-:35])=[O:34])=[O:25])[CH3:38]
Reactant: CC[NH+](CC)CCBr
Reactant: CS(=O)(=O)c1ccc(/C(COC(=O)OCCCCCO[N+](=O)[O-])=C(/C(=O)O)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC[NH+](CC)CCOC(=O)/C(=C(\COC(=O)OCCCCCO[N+](=O)[O-])c1ccc(S(C)(=O)=O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (2Z)-3-[4-(methylsulfonyl)phenyl]-4-[({[5-(nitrooxy)pentyl]oxy}carbonyl)oxy]-2-phenylbut-2-enoic acid (1 eq, 0.2M) in DMF was added 2-bromo-N,N-diethylethanaminium bromide (1 eq) and K2CO3 (2 eq). The reaction was stirred at rt for 12 h and saturated aqueous NH4Cl was added. The mixture was extracted with EtOAc and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluted with 100% EtOAc and concentrated. The neutral amine was dissolved in Et2O and an excess of 2M HCl in Et2O was added. The mixture was stirred for 2 h and concentrated. The residue was dissolved in water and freeze dried to give the titled compound. 1H NMR (acetone-d6, 500 M Hz): δ 7.76 (d, 2H), 7.44 (d, 2H), 7.21–7.13 (m, 5H), 5.41 (s, 2H), 4.78–4.74 (m, 2H), 4.53 (t, 2H), 4.08 (t, 2H), 3.44–3.40 (m, 2H), 3.04 (s, 3H), 3.04–3.0 (m, 4H), 1.76–1.71 (m, 2H), 1.65–1.60 (m, 2H), 1.45–1.40 (m, 2H), 1.22 (t, 6H).