Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[OH:12])[CH3:3].N1C[CH2:17][S:16][CH2:15]C1>C1(C)C=CC=CC=1>[N:2]1([CH:4]=[N:5][C:6]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[OH:12])[CH2:1][CH2:17][S:16][CH2:15][CH2:3]1
Reactant: C1CSCCN1
Reactant: CN(C)C=Nc1ccncc1O
Solvent: Cc1ccccc1
Product: Oc1cnccc1N=CN1CCSCC1

Procedure:
A mixture prepared from 4-[[(dimethylamino)methylene]amino]-3-pyridinol (5.14 g), thiomorpholine (10.5 ml, distilled from CaH2) and dry toluene (120 ml) was refluxed overnight. The reaction mixture was concentrated, triturated with diethyl ether, adhered to silica (methanol), flash chromatographed (10% methanol/ethyl acetate), and triturated with diethyl ether to yield 6.06 g of product. A 3.5 g sample was recrystallized from methanol, and dried under high vacuum and refluxing isopropanol to yield 2.13 g of crystals, m.p. 197°-198.5° C.
Reaction SMILES: C1(C2CC(O)C3C(=CC=C(O)C=3)O2)C=CC=CC=1.[CH2:19]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]2[CH2:36][C:35](=[O:37])[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([OH:38])[CH:33]=3)[O:28]2)=[CH:23][CH:22]=1)[CH3:20]>>[CH2:19]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]2[CH2:36][CH:35]([OH:37])[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([OH:38])[CH:33]=3)[O:28]2)=[CH:23][CH:22]=1)[CH3:20]
Reactant: CCc1ccc(C2CC(=O)c3cc(O)ccc3O2)cc1
Agent: Oc1ccc2c(c1)C(O)CC(c1ccccc1)O2
Product: CCc1ccc(C2CC(O)c3cc(O)ccc3O2)cc1

Procedure:
2-(4Ethylphenyl)chroman-4,6-diol was prepared as described for 2-phenylchroman-4,6-diol in Example 8(a) starting from 474 mg of 2-(4-ethylphenyl)-6-hydroxychroman-4one. 1H NMR (400 MHz, d6-DMSO) δ: 8.81 (s, 1H), 7.34 (d, 2H, J 8.0 Hz), 7.22 (d, 2H, J 8.0 Hz), 6.88 (d, 1H, J 2.8 Hz), 6.57 (d, 1H, J 8.6 Hz), 6.53 (dd, 1H, J 8.6, 2.8 Hz), 5.39 (d, 1H, J 7.1 Hz), 5.06 (d, 1H, J 10.7 Hz), 4.86 (m, 1H), 2.61 (q, 2H, J 7.6 Hz), 2.29 (m, 1H), 1.84 (m, 1H), 1.19 (t, 3H, J 7.6 Hz).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>CN(C)C=O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:4]([NH:5][C:1](=[O:11])[C:2]=12)=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrCCCCCCCCBr
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2c(CCCCCCCCBr)cccc21

Procedure:
Potassium phthalimide (5.4 mmoles) was added to a solution of 1,8-dibromooctane (4.41 g; 16.2 mmoles) in dimethylformamide (8 ml) and heated to 80° C. approx. under stirring. Reaction times and process as per Example 4.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][CH:3]=1.CC(O)(C#C)C.[S:31]1[CH:35]=[CH:34][N:33]=[C:32]1[C:36]([OH:40])([C:38]#[CH:39])[CH3:37]>>[NH2:17][C:13]1[N:12]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:39]#[C:38][C:36]([C:32]4[S:31][CH:35]=[CH:34][N:33]=4)([OH:40])[CH3:37])[CH:10]=3)[C:6]([CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:7]2)[CH:16]=[CH:15][N:14]=1
Reactant: Nc1nccc(-n2nc(CN3CCOCC3)c3ccc(Br)cc32)n1
Reactant: C#CC(C)(O)c1nccs1
Agent: C#CC(C)(C)O
Product: CC(O)(C#Cc1ccc2c(CN3CCOCC3)nn(-c3ccnc(N)n3)c2c1)c1nccs1
Reaction time: 1.5 h

Procedure:
The title compound was prepared by the procedure described in Example 6-c by substituting 4-{6-bromo-3-[(dimethylamino)methyl]-1H-indazol-1-yl}pyrimidin-2-amine with 4-[6-bromo-3-(morpholin-4-ylmethyl)-1H-indazol-1-yl]pyrimidin-2-amine and 2-methyl-but-3-yn-2-ol with 2-(1,3-thiazol-2-yl)but-3-yn-2-ol. The reaction was carried out at 60° C. for 1.5 hr. Title compound was obtained: 1H NMR (500 MHz, DMSO) δ 1.93 (3H, s), 2.45 (4H, br. s.), 3.55-3.57 (4H, m), 3.88 (2H, s), 6.98 (2H, br. s.), 7.05 (1H, d, J=5.52 Hz), 7.12 (1H, s), 7.35 (1H, dd, J=8.35, 1.26 Hz), 7.68 (1H, d, J=3.31 Hz), 7.78 (1H, d, J=3.31 Hz), 8.01 (1H, d, J=8.35 Hz), 8.27 (1H, d, J=5.52 Hz), 8.87 (1H, s); LC-MS: m/z=+462.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH2:3][CH:4]([C:17]([OH:19])=[O:18])[CH2:5][C:6](=[O:16])[C:7]=1[N:8]=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CO.[CH:22]1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:22][O:18][C:17]([CH:4]1[CH2:3][C:2](=[O:1])[C:7]([N:8]=[N:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([OH:16])[CH2:5]1)=[O:19]
Reactant: c1ccccc1
Reactant: O=C1CC(C(=O)O)CC(O)=C1N=Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)C1CC(=O)C(N=Nc2ccccc2)=C(O)C1

Procedure:
60 G. of 3-hydroxy-5-keto-4-phenylazo-3-cyclohexene-carboxylic acid, 200 ml. of methanol, 1200 ml. of benzene and 5 g. of p-toluenesulfonic acid were boiled together under reflux on a water separator for 18 hours. After cooling, the solution was washed with 500 ml. of a 5% sodium bicarbonate solution, then washed with water, dried and evaporated. The residue was dissolved in ethyl acetate and purified on an aluminum oxide column (500 g.; activity stage I). After evaporation of the ethylacetate, there was obtained 3-hydroxy-5-keto-4-phenylazo-3-cyclohexene-carboxylic acid methyl ester as a solid having a melting point of 144° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9](I)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.C1COCC1.C(N(CC)CC)C.[CH3:25][Si:26]([C:29]#[CH:30])([CH3:28])[CH3:27]>C(OCC)(=O)C.[Cu]I.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>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:30]#[C:29][Si:26]([CH3:28])([CH3:27])[CH3:25])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: C#C[Si](C)(C)C
Reactant: Ic1ccc(OCC2CC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(OCC2CC2)cc1
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
To a solution of 1-(cyclopropylmethoxy)-4-iodobenzene (2.49 g, 9.09 mmol) and copper(I) iodide (86.6 mg, 0.455 mmol) in a mixed solvent of THF-triethylamine (8 mL-2 mL) was added bis(triphenylphosphine)palladium(II) chloride (319 mg, 0.455 mmol), and the mixture was deaerated. Trimethylsilylacetylene (1.54 mL, 10.9 mmol) was added dropwise thereto, and the mixture was stirred under a nitrogen atmosphere for 30 min. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solution was purified by basic silica gel column chromatography (ethyl acetate), and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane to hexane:ethyl acetate=9:1) to give the title compound (1.52 g, yield 69%) as an oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([S:9](Cl)(=[O:11])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.Cl.[CH3:23][CH:24]1[CH:29]=[C:28]([CH3:30])[CH:27]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH3:39])=[CH:33][CH:32]=2)[O:26][NH:25]1>ClCCl>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([S:9]([N:25]2[CH:24]([CH3:23])[CH:29]=[C:28]([CH3:30])[CH:27]([C:31]3[CH:32]=[CH:33][C:34]([O:37][CH2:38][CH3:39])=[CH:35][CH:36]=3)[O:26]2)(=[O:11])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCOc1ccc(C2ONC(C)C=C2C)cc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccc(C2ON(S(=O)(=O)c3ccc(NC(C)=O)cc3)C(C)C=C2C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 4-N-acetylsulphanilyl chloride (1.14 g, 4.9 mmol) and triethylamine (0.82 g, 8.15 mmol) in dichloromethane (15 ml) was added a solution of 3,6-dihydro-3,5-dimethyl-6-(4-ethoxyphenyl)-2H-1,2-oxazine hydrochloride (0.88 g, 3.26 mmol) in dichloromethane (15 ml). The resulting solution was stirred at room temperature for 8 h then washed with water three times, aqueous sodium hydroxide (2M), water and brine. The organic phase was dried over magnesium sulphate, filtered and evaporated to a foam. The crude product was purified on flash silica eluting with ethylacetate-hexane (3:2) to give 2-(4-acetamidobenzenesulphonyl)-3,6-dihydro-3,5-dimethyl-6-(4-ethoxyphenyl)-2H-1,2-oxazine as a white foam. 1H NMR (CDCl3) δ 1.41(9H, m), 2.14(3H, s), 4.01(2H, q), 4.43(1H, m), 5.17(1H, s), 5.66(1H, d), 6.79(2H, d), 7.11(2H, d), 7.60(2H, d), 7.79(2H, d), 7.89(1H, bs).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[C:13]1[O:14]CC(C)(C)N=1.Cl.[OH2:21]>>[Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:10])([F:11])[F:12])[CH:5]=[CH:4][C:3]=1[C:13]([OH:14])=[O:21]
Reactant: O
Reactant: CC1(C)COC(c2ccc(OC(F)(F)F)cc2Br)=N1
Agent: Cl
Product: O=C(O)c1ccc(OC(F)(F)F)cc1Br
Temperature: 90 °C

Procedure:
To a 50 ml round bottom flask fitted with a magnetic stirring bar and a reflux condensor was loaded 2-[2-bromo-4-(trifluoromethoxy)phenyl]-4,4-dimethyl-4,5-dihydro-1,3-oxazole (0.56 g, 1.66 mmol) and 10 ml 5N HCl. The reaction mixture was heated at 90° C. overnight. After cooling to room temperature, the reaction mixture was diluted with 20 ml water and extracted with 40 ml ethyl acetate. The extracts were dried over sodium sulfate, filtered and concentrated to give 0.42 g light brown solid.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].[NH:17]1[CH2:21][CH2:20][NH:19][C:18]1=[O:22].O>CS(C)=O>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:17]2[CH2:21][CH2:20][NH:19][C:18]2=[O:22])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C1NCCN1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(CN2CCNC2=O)cc1
Reaction time: 0.5 h
Yield: 20.2 %

Procedure:
A mixture of 20.95 g (0.107 mole) of 4-cyanobenzyl bromide, 14.7 g (0.107 mole) K2CO3, 5.0 g KI, and 10.32 g (0.12 mole) 2-imidazolidinone in 125 ml dimethylsulfoxide was stirred at 100°-110° for 30 minutes, cooled, and poured into 400 ml cold tap water. The mixture was stirred at room temperature for 30 minutes and extracted with 250 ml chloroform. The chloroform extract was washed with 3 × 250 ml H2O, dried (MgSO4), and concentrated to dryness in vacuo to give an oily residue. Crystallization from 60 ml toluene gave 5.50 g of the crude product. Further recrystallization from toluene gave 4.34 g (20%) of the nitrile, m.p. 127°-133°. The analytical sample, m.p. 134°-136°, was obtained by recrystallization from toluene.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[C:4]([Cl:10])[CH:3]=1.[H][H]>O1CCCC1.C([O-])(=O)C.[Fe+2].C([O-])(=O)C.[Rh]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]([Cl:10])[CH:3]=1
Reactant: [H][H]
Reactant: C=Cc1ccc(Br)cc1Cl
Agent: [Fe+2]
Agent: [Rh]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: CCc1ccc(Br)cc1Cl
Yield: 46.5 %

Procedure:
A solution of 4-bromo-2-chloro-1-ethenylbenzene (883 mg), iron(II) acetate (7 mg) and 5% rhodium-activated carbon (167 mg) in tetrahydrofuran (17 mL) was stirred at room temperature for three hours in a hydrogen atmosphere. The reaction solution was filtered through celite and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane only) to give the title compound as a colorless oil (414 mg, 46%).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[S:8][C:9]([C:45]#[C:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:10][C:11]=1[N:12]([C:36]([CH:38]1[CH2:43][CH2:42][CH:41]([CH3:44])[CH2:40][CH2:39]1)=[O:37])[CH:13]1[CH2:18][CH2:17][C:16]([O:26][C:27]([CH:29]2[CH2:34][CH2:33][CH:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])([CH2:19][O:20][CH:21]2[CH2:25][CH2:24][O:23][CH2:22]2)[CH2:15][CH2:14]1)=[O:6].C1COCC1.O>CO>[CH3:49][C:47]([CH3:48])([CH3:50])[C:46]#[C:45][C:9]1[S:8][C:7]([C:5]([OH:6])=[O:4])=[C:11]([N:12]([C:36]([CH:38]2[CH2:39][CH2:40][CH:41]([CH3:44])[CH2:42][CH2:43]2)=[O:37])[CH:13]2[CH2:14][CH2:15][C:16]([O:26][C:27]([CH:29]3[CH2:34][CH2:33][CH:32]([CH3:35])[CH2:31][CH2:30]3)=[O:28])([CH2:19][O:20][CH:21]3[CH2:25][CH2:24][O:23][CH2:22]3)[CH2:17][CH2:18]2)[CH:10]=1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CCC(C)CC1)C1CCC(COC2CCOC2)(OC(=O)C2CCC(C)CC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1CCC(C(=O)OC2(COC3CCOC3)CCC(N(C(=O)C3CCC(C)CC3)c3cc(C#CC(C)(C)C)sc3C(=O)O)CC2)CC1
Temperature: 70 °C
Yield: 29.7 %

Procedure:
NaOH (1.17 mL of a 1.0N aqueous solution) was added dropwise to a solution of 5-(3,3-dimethyl-but-1-ynyl)-3-{(4-methyl-cyclohexanecarbonyl)-[4-(4-methyl-cyclohexanecarbonyloxy)-4-(tetrahydro-furan-3-yloxymethy)-cyclohexyl]-amino}-thiophene-2-carboxylic acid methyl ester (80 mg, 0.117 mmol) in methanol (2 mL)/THF (2 mL)/H2O (2 mL) at room temperature. The solution was heated at 70° C. overnight and then cooled to room temperature. Volatiles were removed under vacuum and the resulting residue purified by HPLC with CH3CN (0.1% TFA)/H2O (0.1% TFA) to provide the Compound 4 (23.3 mg, 36%) as colorless solid. MS (m/z): 546.0[M+H]+; HPLC retention time 4.169 min (2-98% acetonitrile: water with 0.05% trifluoroacetic acid).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4]1[CH:5]=[C:6]([Cl:11])[C:7](I)=[N:8][CH:9]=1.C([Mg]Cl)(C)C.[CH:19](=[O:21])[CH3:20]>C1COCC1>[CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4]1[CH:5]=[C:6]([Cl:11])[C:7]([CH:19]([OH:21])[CH3:20])=[N:8][CH:9]=1
Reactant: CC=O
Reactant: COC(OC)c1cnc(I)c(Cl)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COC(OC)c1cnc(C(C)O)c(Cl)c1
Reaction time: 0.5 h
Yield: 38 %

Procedure:
A solution of 5-[bis(methyloxy)methyl]-3-chloro-2-iodopyridine (239 mg, 0.762 mmol) in THF (1.5 ml) was slowly added to a solution of i-PrMgCl (400 μl, 0.800 mmol) in THF (1.5 ml) at −20° C. under N2 and the mixture was stirred at that temperature. After 30 min a small amount of starting material was still observed by LCMS. After 2 h, LCMS still showed some starting material. More i-PrMgCl (60 μl) was added and after 40 min disappearance of the starting material was observed by LCMS. Acetaldehyde (47 μl, 0.841 mmol) was added and the mixture stirred at −20° C. for 10 min. Partial conversion was observed by LCMS and no evolution was observed after 1 h. Excess acetaldehyde was added but no changes were observed after 30 min by LCMS. Then, it was quenched with saturated NH4Cl, extracted with EtOAc, dried (MgSO4), filtered, and concentrated to afford 177.4 mg of crude material as a brown oil. The mixture was purified by flash chromatography using Flashmaster II, a 10 g Merck silica gel cartridge, and mixtures of hexane and EtOAc as eluent. 1-{5-[bis(methyloxy)methyl]-3-chloro-2-pyridinyl}ethanol (67 mg, 38%) was isolated as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH3:18])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[C:19]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([SH:29])=[CH:25][CH:24]=1)(=[O:21])[CH3:20]>>[CH3:18][C:13]1=[N:14][NH:15][C:16](=[O:17])/[C:12]/1=[C:4]1\[NH:5][C:6]2[C:11]([C:2]([S:29][C:26]3[CH:25]=[CH:24][C:23]([NH:22][C:19](=[O:21])[CH3:20])=[CH:28][CH:27]=3)=[CH:3]\1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: CC1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Product: CC(=O)Nc1ccc(SC2=C/C(=C3/C(=O)NN=C3C)Nc3ccccc32)cc1

Procedure:
The title compound was prepared from (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one and 4-actamidothiophenol using the procedure described in Example 6. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.94 (s, 3H) 2.11 (s, 3H) 6.77 (s, 1H) 7.65-7.69 (m, 3H) 7.83-7.93 (m, 3H) 7.99 (d, J=8.08 Hz, 1H) 8.16 (d, J=8.34 Hz, 1H) 10.35 (s, 1H); ESI-MS: m/z calc'd for C21H18N4O2S 390.12. found 391.2 (M+H)+.
Reaction SMILES: C[O-].[Na+].C([N:7]1[CH2:15][C@@H:14]2[C@@H:10]([CH2:11][CH2:12][CH2:13]2)[O:9][C:8]1=[O:16])(=O)C>CO>[C@@H:10]12[CH2:11][CH2:12][CH2:13][C@@H:14]1[CH2:15][NH:7][C:8](=[O:16])[O:9]2
Reactant: CC(=O)N1C[C@H]2CCC[C@H]2OC1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1NC[C@H]2CCC[C@H]2O1
Yield: 82.2 %

Procedure:
After adding 5 g of sodium methylate, a solution of 183 g (1 mol) of cis-4-acetyl-2-oxa-4-aza-bicyclo[4.3.0]nonan-3-one in anhydrous methanol is heated to the reflux temperature for 5 hours. After the solvent has been distilled off, the residue is recrystallised from diethyl ether. 116 g (82% of theory) of cis-2-oxa-4-aza-bicyclo[4.3.0]nonan-3-one (melting point: 56°-58° C.) are obtained. (See J. Org. Chem. 32, 540 (1967); melting point: 55°-56° C.).
Reaction SMILES: NC(N)=O.[NH2:5][C:6]([NH:8][N:9]([CH2:17][C:18]([O:20]C)=O)[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)=[O:7].C[O-].[Na+].Cl>CO>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([N:9]2[CH2:17][C:18](=[O:20])[NH:5][C:6](=[O:7])[NH:8]2)=[CH:11][CH:12]=1
Reactant: COC(=O)CN(NC(N)=O)c1ccc(Br)cc1
Agent: C[O-]
Agent: Cl
Agent: NC(N)=O
Solvent: CO
Product: O=C1CN(c2ccc(Br)cc2)NC(=O)N1
Reaction time: 8 h
Yield: 18 %

Procedure:
The urea, (Intermediate 59, 2.26 g, 7.5 mmol) and sodium methoxide (525 mg; 9.7 mmol) were stirred under nitrogen in methanol (20 ml) for 2 h. A further amount of sodium methoxide (100 mg; 1.9 mmol) was added and the reaction left overnight. The reaction was neutralised with acid (2N HCl) and the precipitate was filtered. The precipitate was recrystallised several times from dioxan to give the title compound (357 mg; 18%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:20][CH2:21][O:22]C(=O)C)[CH:5]=[C:6]([Br:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH:16]([CH3:18])[CH3:17])[N:10]=1.[OH-].[K+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:20][CH2:21][OH:22])[CH:5]=[C:6]([Br:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH:16]([CH3:18])[CH3:17])[N:10]=1
Reactant: CC(=O)OCCc1cc(Br)c(Oc2ccc(=O)n(C(C)C)n2)c(Br)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)n1nc(Oc2c(Br)cc(CCO)cc2Br)ccc1=O
Temperature: 55 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A solution of 2-[3,5-dibromo-4-(1-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-ethyl ester (40) (85 mg, 0.18 mmol) in methanol (0.5 mL) was treated with a 2N aqueous potassium hydroxide solution (90 μL, 0.18 mmol) at room temperature. The reaction mixture was heated to 55° C., stirred for 1 h and then was concentrated under reduced pressure. The resulting residue was diluted with methylene chloride (5 mL) and was washed with water (2×3 mL). The aqueous layers were re-extracted with methylene chloride (5 mL). The organic layers were combined and dried with sodium sulfate, filtered, and concentrated. The resulting solid was dried under high vacuum to afford 6-[2,6-dibromo-4-(2-hydroxy-ethyl)-phenoxy]-2-isopropyl-pyridazin-3-one (41) (77 mg, 100%) as a white solid that was used without further purification; LRMS for C15H16Br2N2O3 (M+CH3CN+H) m/z=474. Molecular Weight=432.1144; Exact Mass=429.9528
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[N:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:12]N1C(C)(C)C(=O)N(Cl)C1=O>ClC(Cl)=C(Cl)Cl>[NH2:1][C:2]1[C:11]([Cl:12])=[N:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Reactant: COC(=O)c1ccncc1N
Solvent: ClC(Cl)=C(Cl)Cl
Product: COC(=O)c1ccnc(Cl)c1N
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 18 g (118 mmol) of methyl 3-aminoisonicotinate and 12 g (60 mmol) of 1,3-dichloro-5,5-dimethylhydantoin in 1500 mL of tetrachloroethylene was warmed slowly to 80° C. with stirring and held there for 3 hours. The solution was then cooled, filtered, washed with dilute aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain a dark oil. This oil was purified by careful column chromatography to obtain 6.7 g (30 percent of theory) of the title compound as a colorless solid melting at 91°-92° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][NH2:15]>C(O)(C)C.[Cl-].[Na+].O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][NH:15][CH3:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(OCCCl)cc1
Reactant: CN
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CNCCOc1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 4-nitro-(2-chloroethoxy)benzene (781 mg, 3.9 mmol) and aqueous methylamine (15 mL, 40 wt. %) in isopropyl alcohol (15 mL) is heated in a sealed tube at 100° for 4 hours. After cooling in an ice water bath, the mixtured is poured into brine and extracted 2× with dichloromethane, dried over sodium sulfate, filtered, and concentrated in vacuo to give 4-nitro-(2-methylaminoethoxy)benzene (697 mg).
Reaction SMILES: [Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH:22]1[C:30]2[C:25](=[C:26]([C:31]3[CH:32]=[N:33][CH:34]=[C:35]([CH:39]=3)[C:36]([OH:38])=[O:37])[CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23]1.[OH2:40]>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[O:40]=[C:23]1[CH2:24][C:25]2[C:30](=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[CH:32]=[N:33][CH:34]=[C:35]([CH:39]=2)[C:36]([OH:38])=[O:37])[NH:22]1
Reactant: O=C(O)c1cncc(-c2cccc3[nH]ccc23)c1
Reactant: O
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CCO
Solvent: CC(=O)O
Product: O=C1Cc2c(cccc2-c2cncc(C(=O)O)c2)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
Pyridinium tribromide (90% (Aldrich), 9.8 g, 27.6 mmol) was added portion-wise over 10 minutes to a suspension of 5-(1H-indol-4-yl)-nicotinic acid (2.2 g, 9.2 mmol) in 2-methyl-2-propanol (54 mL), ethanol (36 mL) and acetic acid (108 mL). The mixture was stirred at room temperature for 2 hours and then acetic acid (10 mL) was added. After stirring for an additional hour, water (0.5 mL) and zinc dust (6 g, 92 mmol) were added and stirring was continued for another hour. Residual zinc dust was filtered and washed with methanol. The filtrate was concentrated and the syrupy residue was stirred in water (300 mL) overnight. The solid which formed was filtered, washed with water to remove zinc and pyridine salts and dried under high vacuum to give 2.3 g (98%) of 5-(2-oxo-2,3-dihydro-1H-indol-4-yl)-nicotinic acid.
Reaction SMILES: O.NN.O=C1C2C(=CC=CC=2)C(=O)[N:6]1[CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:27][CH:26]=2)=[CH:21][C:20]=1[C:36]1[CH:45]=[CH:44][C:43]2[C:42]([CH3:47])([CH3:46])[CH2:41][CH2:40][C:39]([CH3:49])([CH3:48])[C:38]=2[CH:37]=1.O.Cl>C(O)C>[NH2:6][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][CH:30]=2)=[CH:21][C:20]=1[C:36]1[CH:45]=[CH:44][C:43]2[C:42]([CH3:47])([CH3:46])[CH2:41][CH2:40][C:39]([CH3:48])([CH3:49])[C:38]=2[CH:37]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCN3C(=O)c4ccccc4C3=O)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2ccc(OCCCN)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Reaction time: 8 h
Yield: 37.1 %

Procedure:
100 μl of hydrazine monohydrate (2.05 mmol) are added to a solution of 650 mg (1 mmol) of ethyl 4′-[3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)propoxy]-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate in 50 ml of ethanol. The reaction mixture is stirred overnight at reflux. The reaction is stopped by adding water and hydrochloric acid to pH 4, and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off. The residue is purified by chromatography on silica gel (eluent: 70/30 ethyl acetate/methanol). 180 mg of ethyl 4′-(3-aminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a whitish solid (m.p.=155° C., yield=35%).