Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=O)=[CH:4][C:3]=1[CH3:11].[NH3:12].[BH4-].[Na+]>CCCO.CCCO.CCCO.CCCO.[Ti].C(OCC)(=O)C.CO>[CH3:11][C:3]1[CH:4]=[C:5]([CH:8]([NH2:12])[CH3:10])[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: CC(=O)c1ccc(C)c(C)c1
Reactant: N
Agent: [Ti]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCCO
Product: Cc1ccc(C(C)N)cc1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 18 %

Procedure:
16.4 ml (150.0 mmol) of tetrapropyl orthotitanate were added to a solution of 4.46 g (30.0 mmol) of 3,4-dimethylacetophenone in a 2 M ethanolic ammonia solution (75 ml), and the mixture was stirred for 6 hours at RT. 1.7 g (45.0 mmol) of sodium borohydride were then added, and stirring was continued for a further 16 hours at RT. Thereafter, the reaction solution was poured into a saturated aqueous ammonia solution (75 ml). The precipitate that formed was filtered off with suction, and then washing with ethyl acetate was carried out. The aqueous filtrate was concentrated in vacuo, followed by extraction twice with ethyl acetate. The combined ethyl acetate phases were extracted three times with 2 M hydrochloric acid. The combined aqueous phases were adjusted to pH 11 with a 2 M aq. NaOH solution and then extracted three times with ethyl acetate. The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. CC (ethyl acetate/MeOH 9:1) yielded 799 mg (5.4 mmol, 18%) of 1-(3,4-dimethylphenyl)ethylamine.
Reaction SMILES: [CH3:1][C@@H:2]1[C@:19]([OH:21])([CH3:20])[C@:18]([OH:23])([CH3:22])[C:16](=[O:17])[O:15][CH2:14][C:11]2=[CH:12][CH2:13][N:9]3[C@H:10]2[C@@H:6]([CH2:7][CH2:8]3)[O:5][C:3]1=[O:4].C1(Cl)C(Cl)=C(Cl)C(=O)C(=O)C=1Cl>C(Cl)(Cl)Cl>[CH3:1][C@@H:2]1[C@:19]([OH:21])([CH3:20])[C@:18]([OH:23])([CH3:22])[C:16](=[O:17])[O:15][CH2:14][C:11]2[CH:12]=[CH:13][N:9]3[C:10]=2[C@@H:6]([CH2:7][CH2:8]3)[O:5][C:3]1=[O:4]
Reactant: C[C@H]1C(=O)O[C@@H]2CCN3CC=C(COC(=O)[C@](C)(O)[C@]1(C)O)[C@H]23
Agent: O=C1C(=O)C(Cl)=C(Cl)C(Cl)=C1Cl
Solvent: ClC(Cl)Cl
Product: C[C@H]1C(=O)O[C@@H]2CCn3ccc(c32)COC(=O)[C@](C)(O)[C@]1(C)O
Temperature: 2.5 °C
Reaction time: 0.08 h

Procedure:
To monocrotaline (20 mg) dissolved in chloroform (5 mL) was added a solution of o-chloranil (25 mg) in chloroform (5 mL). After 5 min, TLC (Thin layer Chromatography) showed that most of starting material was consumed and the mixture was shaken vigorously with a cooled (0-5° C.) solution, which contained 700 mg KOH and 20 mg NaBH4 in 1 mL water for 10-15 sec. The organic phase was separated, immediately dried with anhydrous Na2SO4 and concentrated under reduced pressure to give dehydromonocrotaline (DHM). The chemical reaction was depicted in FIG. 21.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][CH2:16][CH:17]([OH:27])[CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CS(C)=O>[CH2:8]([O:15][CH2:16][C:17](=[O:27])[CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: OC(COCc1ccccc1)COCc1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(COCc1ccccc1)COCc1ccccc1
Yield: 75.6 %

Procedure:
A mixture of sulfur trioxide/pyridine complex (2.33 g, 4 equivalents) in DMSO (3 ml) and triethylamine (2.05 ml, 4 equivalents) was stirred to give a pale yellow solution. To this was added a solution of 1,3-dibenzyloxy-2-propanol (1 g) in DMSO (1 ml) over 2 minutes. (The reaction mixture was kept in a water bath). The temperature of the reaction mixture reached 30° C. After 10 minutes the water bath was removed and the reaction mixture was stirred at room temperature (ca 20-25° C.) for 3 hours. The reaction mixture was diluted with ethyl acetate (15 ml) and water (15 ml), stirred and the organic extract was separated. The organic extract was washed with 5% w/v sodium chloride (2×10 ml) and water (10 ml). The separated organic extract was concentrated in vacuo to give an oil which solidified to provide 0.75 g of 1,3-dibenzyloxy-2-propanone in 75.8% yield. An NMR spectrum of product was concordant with a reference sample.
Reaction SMILES: [O:1]=[C:2]([CH3:13])[CH2:3][CH2:4][CH2:5][C:6]#[C:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]>C1(C)C=CC=CC=1.[Pd]>[O:1]=[C:2]([CH3:13])[CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CC(=O)CCCC#CCCC(=O)O
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CC(=O)CCC/C=C\CCC(=O)O

Procedure:
10 Grams of the 9-oxodec-4-ynoic acid of Example 18 is hydrogenated at room temperature in toluene containing about 0.5% quinoline with 5% palladium on barium sulfate as catalyst. The toluene solution is washed with 1 N hydrochloric acid, then water. The solution is dried over sodium sulfate and stripped of solvent to give, as a yellow oil, the title product.
Reaction SMILES: O[CH:2]([C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)[CH3:3].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>N1C=CC=CC=1>[CH:2]([C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)=[CH2:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C(C)O)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: C=Cc1ccc(OC(C)(C)C(=O)OCC)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A mixture of 116 g. of ethyl 2-[4-(1-hydroxyethyl)phenoxy]-2-methylpropionate and 92 g. of p-toluenesulfonyl chloride in 500 ml. of pyridine was heated at reflux for three hours, kept at room temperature for about 16 hours and then heated at reflux again for six hours. The reaction mixture was poured into ice water and extracted with hexane. The hexane solution was washed successively with dilute sulfuric acid, 10% potassium bicarbonate, water and saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was distilled at 104°-111°C. (0.03-0.08 mm.) to give60 g. of ethyl 2-(p-vinylphenoxy)-2-methylpropionate.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[N:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[CH:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([NH:27][C:28](=[O:30])[CH3:29])([CH3:26])[CH3:25])=[CH:20][CH:19]=1)[CH3:17]>>[N:3]1[CH:8]=[CH:7][CH:6]=[N:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([NH:27][C:28](=[O:30])[CH3:29])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[CH3:17])[CH2:11][CH2:10]1
Reactant: CC(=O)NC(C)(C)c1ccc(C(C)Cl)cc1
Reactant: c1cnc(N2CCNCC2)nc1
Agent: Cl
Product: CC(=O)NC(C)(C)c1ccc(C(C)N2CCN(c3ncccn3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using 1-(2-pyrimidyl) piperazine dihydrochloride instead of phenylpiperazine and N-(1-(4-(1-chloroethyl)phenyl)-1-methylethyl)acetamide instead of N-(4-chloromethylphenylmethyl)acetamide, the title compound was obtained as a white amorphous solid.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][NH:10][C:11](=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(Cl)Cl>[CH3:8][O:9][N:10]([C:11](=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:21](=[O:23])[CH3:22]
Reactant: CCCCCCCCC(=O)NOC
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCC(=O)N(OC)C(C)=O
Reaction time: 8 h

Procedure:
A 100 mL round-bottom flask equipped with a magnetic stir bar, argon inlet and pressure equalizing addition funnel is charged with methylene chloride (22.5 mL), triethylamine (3.80 g, 2 eq) and N-methoxynonanamide (3.5 g, 1 eq). The reaction mixture is stirred and cooled in an ice bath. Acetic anhydride (2.88 g, 1.5 eq) is then added dropwise. The reaction slowly warms to room temperature overnight. The reaction mixture is diluted with methylene chloride (50 mL) and washed with 0.05 M hydrochloric acid solution 1×50 ml), saturated aqueous sodium bicarbonate solution (3×50 mL) and brine 1×50 miL). The organic layer is dried over sodium sulfate, filtered and concentrated under vacuum.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]2[CH2:7][CH:6]([CH2:11][N:12]3[C:17]4=[N:18][C:19]([C:23]5[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=5)=[CH:20][C:21](=[O:22])[N:16]4[CH2:15][C:14]([CH3:30])([CH3:29])[CH2:13]3)[CH2:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.[NH:84]1[CH2:88][CH2:87][CH2:86][CH2:85]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:29][C:14]1([CH3:30])[CH2:15][N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[N:18]=[C:17]2[N:12]([CH2:11][CH:6]2[CH2:5][C:4]3[N:3]=[C:2]([N:84]4[CH2:88][CH2:87][CH2:86][CH2:85]4)[CH:10]=[CH:9][C:8]=3[CH2:7]2)[CH2:13]1
Reactant: CC1(C)CN(CC2Cc3ccc(Cl)nc3C2)c2nc(-c3ccncc3)cc(=O)n2C1
Reactant: C1CCNC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Product: CC1(C)CN(CC2Cc3ccc(N4CCCC4)nc3C2)c2nc(-c3ccncc3)cc(=O)n2C1

Procedure:
To a solution of 0.2 g (0.474 mmol) of (+/−)9-(2-chloro-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one in 20 ml of anhydrous pyrrolidine was treated with 0.216 g (0.664 mmol) of cesium carbonate, 8.85 mg (0.142 mmol) of (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and 6.5 mg (0.07 mmol) of tris(dibenzylideneacetone)dipalladium(0). After being stirred under reflux for 24 h, water was added, the mixture was extracted with dichloromethane. The organic phase was dried and evaporated to give crude product, which was purified by silica gel chromatography, eluting with dichloromethane/methanol/ammonia in the proportions 99/1/0.1 to give 0.184 g of pure product obtained in the form of free base. Mp: 170-171° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][CH:41]([C:44]([NH2:46])=[O:45])[CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:38]3[CH2:43][CH2:42][CH:41]([C:44]([NH2:46])=[O:45])[CH2:40][CH2:39]3)=[O:36])[C:16]([C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)([CH3:27])[C:17]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: NC(=O)C1CCNCC1
Product: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(C(N)=O)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with piperidine-4-carboxylic acid amide (isonipecotamide, Aldrich) to give the title compound as a racemic mixture. HR-MS (ES, m/z) calculated for C34H41N6O3Cl2 [(M+H)+] 651.2612, observed 651.2613.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:5]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)=[N:6][C:7]([CH3:11])=[N:8][C:9]=1[CH3:10])=[O:3].[C:21]([N:25]1[C:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2B(O)O)=[N:28][N:27]=[N:26]1)([CH3:24])([CH3:23])[CH3:22].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.CCO.CCOC(C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]([C:4]1[C:5]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[C:29]3[N:25]([C:21]([CH3:24])([CH3:23])[CH3:22])[N:26]=[N:27][N:28]=3)=[CH:16][CH:15]=2)=[N:6][C:7]([CH3:11])=[N:8][C:9]=1[CH3:10])=[O:3]
Reactant: CC(C)(C)n1nnnc1-c1ccccc1B(O)O
Reactant: CC(=O)c1c(C)nc(C)nc1NCc1ccc(Br)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)c1c(C)nc(C)nc1NCc1ccc(-c2ccccc2-c2nnnn2C(C)(C)C)cc1
Reaction time: 2.5 h
Yield: 75.1 %

Procedure:
To a heated solution of methyl(4-(4-bromobenzylamino)-2,6-dimethylpyrimidin-5-yl)ketone (1.67 g, 5.00 mmol) and tetrakis(triphenylphosphine) palladium(0) (0.29 g, 0.25 mmol) in toluene (20 mL) was added a partial solution of 2-[(1-tert-butyl)-1H-tetrazol-5-yl]phenylboronic acid (1.50 g, 6.10 mmol) (prepared according to J. W. Ellingboe, et al. U.S. Pat. No. 5,149,699) and Na2CO3 (1.06 g, 10.00 mmol) in water (10 mL) and EtOH (5 mL) in several portions over 1 h. Heating was continued for 2.5 h. The mixture was diluted with EtOAc and the layers were separated. The organic phase was washed with 0.1N NaOH, brine, dried MgSO4) and concentrated. Purification by flash chromatography (40-50% EtOAc/hexane) and trituration with hexane gave 1.71 g (75% ) of product as a white solid. An analytical sample was recrystallized from ether, mp 131°-132° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:9]=[C:10]([C:15]3[C:16](=[O:21])[NH:17][N:18]=[CH:19][CH:20]=3)[CH:11]=[CH:12][C:13]=2[CH3:14])[C:4]([CH3:7])=[CH:5][CH:6]=1.[CH3:22][Si](C)(C)N[Si](C)(C)C.[K].CI.O>CN(C=O)C>[CH3:7][C:4]1[N:3]([C:8]2[CH:9]=[C:10]([C:15]3[C:16](=[O:21])[N:17]([CH3:22])[N:18]=[CH:19][CH:20]=3)[CH:11]=[CH:12][C:13]=2[CH3:14])[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: Cc1ccc(-c2ccn[nH]c2=O)cc1-n1c(C)ccc1C
Agent: [K]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccnn(C)c2=O)cc1-n1c(C)ccc1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a solution of 4-[3-(2,5-dimethyl-pyrrol-1-yl)-4-methyl-phenyl]-2H-pyridazin-3-one (1.0 g, 3.58 mmol) in DMF (10 ml) was added potassium hexamethyldisilazane (7.88 ml of 0.5M toluene solution, 3.94 mmol) at 0° C. The mixture was stirred at 0° C. for 10 minutes, and methyl iodide (0.267 ml, 4.30 mmol) was added. The mixture was aloud to reach room temperature and was stirred for 24 hours. Water was added and the product was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hex:EtOAc/6:4) gave 1.05 g (100%) of 4-[3-(2,5-dimethyl-pyrrol-1-yl)-4-methyl-phenyl]-2-methyl-2H-pyridazin-3-one as a yellow solid.
Reaction SMILES: Cl.C([Si]([O:9][CH:10]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH2:42][CH3:43])([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[O:33][C:34]([CH:37]=[CH:38][O:39]C)=[CH:35][CH:36]=3)=[C:28]([CH3:41])[CH:27]=2)[CH2:24][CH3:25])=[CH:19][C:18]=1[CH3:44])[C:11]([CH3:14])([CH3:13])[CH3:12])(C)C)(C)(C)C.C(=O)(O)[O-:46].[Na+].P([O-])(O)(O)=O.[Na+].Cl[O-].[Na+].CC(=CC)C.S(=O)(=O)(O)[O-].[K+]>O1CCCC1.C(OCC)(=O)C>[CH2:42]([C:23]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:33][C:34]([CH2:37][C:38]([OH:46])=[O:39])=[CH:35][CH:36]=2)=[C:28]([CH3:41])[CH:27]=1)([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH2:15][CH:10]([OH:9])[C:11]([CH3:13])([CH3:12])[CH3:14])=[C:18]([CH3:44])[CH:19]=1)[CH2:24][CH3:25])[CH3:43]
Reactant: O=C([O-])O
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(C=COC)o2)c(C)c1
Agent: CC=C(C)C
Agent: Cl
Agent: O=P([O-])(O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)O)o2)c(C)c1
Temperature: 65 °C
Reaction time: 2 h
Yield: 7 %

Procedure:
2 N Hydrochloric acid aqueous solution (0.2 mL) was added to a solution of t-butyl-(1-{2-[4-(1-ethyl-1-{4-[5-(2-methoxy-vinyl)-furan-2-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)-dimethyl-silane (Example 4-(1); 20 mg, 0.033 mmol) in tetrahydrofuran (0.5 mL) at room temperature, and the mixture was stirred at 65° C. for two hours. Tetrahydrofuran (0.3 mL) and 4 N hydrochloric acid aqueous solution (0.2 mL) were further added to the mixture at room temperature, and the mixture was stirred at 65° C. for two hours. A saturated aqueous sodium bicarbonate solution and ethyl acetate were added to the reaction mixture. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (hexane/ethyl acetate=3/1). The resulting product (6 mg) was dissolved in water (0.1 mL) and t-butanol (0.4 mL). Sodium dihydrogenphosphate (2.9 mg, 0.019 mmol), sodium hypochlorite (3.4 mg, 0.038 mmol) and 2-methyl-2-butene (0.013 mL, 0.126 mmol) were added at room temperature, and the mixture was stirred at the same temperature for one hour. A saturated aqueous potassium bisulfate aqueous solution and ethyl acetate were added to the reaction mixture. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (hexane/ethyl acetate=2/1) to give the title compound (1.2 mg, 7%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9](C=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH:13]S(O)(=O)=O.OO>CO>[OH:13][C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1
Reactant: O=S(=O)(O)O
Reactant: O=Cc1ccc2c(c1)OCCO2
Agent: OO
Solvent: CO
Product: Oc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1,4-Benzodioxan-6-carboxaldehyde (5.20 g) was dissolved in MeOH (60 mL) containing conc. H2SO4 (0.6 mL). At 0° C. an aqueous solution of 30% H2O2 (4.7 mL) was added to the mixture over 5 minutes. The mixture was warmed to room temperature, stirred an additional 18 h and evaporated. The residue was taken up with H2O and extracted with CH2Cl2. The extract was dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography (silica gel; eluent: hexane to hexane/EtOAc 3:1) to give 6-hydroxy-1,4-benzodioxan (3.85 g). ESMS: m/z 153 MH+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10](I)=[C:9]([O:14][CH3:15])[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])=[C:9]([O:14][CH3:15])[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1c(I)c(=O)c2ccc(Cl)cc2[nH]c1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1c(C#C[Si](C)(C)C)c(=O)c2ccc(Cl)cc2[nH]c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.9 %

Procedure:
8-Chloro-4-iodo-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (6.62 g) was dissolved in 146 mL of DMF at room temperature under argon. The solution was treated with trimethylsilyl acetylene (8.94 g, 12.9 mL) followed by triethylamine (3.68 g, 5.07 mL). The mixture was then treated with bis-chloro-bis-(triphenyl-phosphine) palladium (II) (0.64 g) followed by cuprous iodide (0.51 g). The solution was stirred at room temperature for 3 hours. The mixture was concentrated to a solid. It was treated with cold water and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, filtered, and concentrated to a dark solid (5.73 g). It was dissolved in chloroform and ethyl acetate and chromatographed on silica gel with 17% ethyl acetate in hexane to give a yellow solid (2.61 g). A portion (0.24 g) of the solid was recrystallized from toluene (5 mL). The crystals were cooled in an ice bath and filtered off to give light-yellow crystals (0.162 g); mp 218.8°-219.4° C. (dec); MS: m/z=334 (M+1). Analysis for C16H16ClNO3Si: Calculated: C, 57.56; H, 4.83; N, 4.20; Found: C, 57.49; H, 5.01; N, 4.27.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].Cl.[CH3:12][NH:13][O:14][CH3:15]>O1CCCC1.C(=O)(O)[O-]>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:13]([O:14][CH3:15])[CH3:12])=[O:5]
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: CNOC
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CON(C)C(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
2-Chloronicotinoyl chloride (36 g, 0.20 mol) was dissolved in tetrahydrofuran (290 mL) and separately N,O-dimethylhydroxylamine hydrochloride (48 g, 0.49 mol) was stirred in 290 mL saturated bicarbonate solution until the degassing subsided. Then the bicarbonate solution was added to the acid chloride solution and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate (2×), dried over sodium sulfate, filtered and evaporated to give the desired product (34 g, 83%). LCMS for C8H10ClN2O2 (M+H)+: m/z=201.0. Found: 200.9.
Reaction SMILES: [CH3:1][CH:2]([CH:4]([OH:16])[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O)[CH3:6])[CH3:3]>CCO.[Pd]>[CH3:3][CH:2]([CH:4]([OH:16])[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13])[CH3:6])[CH3:1]
Reactant: CC(C)C(O)C(C)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CC(C)C(O)C(C)c1ccccc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 15 ml hydrogenation reactor was charged a solution of 2-methyl-4-(2-nitro-phenyl)-pentan-3-ol (370 mg, 1.7 mmol) in EtOH (12 ml). Pd/C5% was added. The reaction mixture was stirred under hydrogen (4 bars) at room temperature for 2 hours. Filtration through celite and evaporation of ethanol afforded 2-methyl-4-(2-amino-phenyl)-pentan-3-ol as a white solid (320 mg-quantitative yield).
Reaction SMILES: [CH2:1]([C:8]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:9]=1[NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16](OCC)=[O:17]>>[CH2:1]([C:8]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:9]=1[NH:10][CH:16]=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC=O
Reactant: Nc1ccc(Br)cc1Cc1ccccc1
Product: O=CNc1ccc(Br)cc1Cc1ccccc1

Procedure:
Using the general procedure of Coll. Czech. Chem. Commun. 1965, 30, 1163-1172, 2-benzyl-4-bromo-aniline, prepared as in Khim. Geterotsikl. Soedin. 1983, 3, 411-414, is heated with ethyl formate to afford the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2([C:22]([O:24]C)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([NH:15][C:16]2([C:22]([OH:24])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:13])=[O:14])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC2(C(=O)OC)CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCOc1ccc(S(=O)(=O)NC2(C(=O)O)CCCCC2)cc1
Reaction time: 16 h

Procedure:
To a stirred solution of methyl 1-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)cyclohexane carboxylate (4.3 g, 11.8 mmol) in methanol:THF (4:1, 100 ml) 10 N sodium hydroxide (15 ml) was added at room temperature. It was stirred for 16 hrs and evaporated to dryness in vacuo. The residue was dissolved in 100 mL water, pH adjusted to 7 with 5N hydrochloric acid solution. It was extracted with chloroform/methanol (3:1), washed with water, dried and concentrated to give 1-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)cyclohexane carboxylic acid. Yield 4.0 g (98%), White solid, mp. 112-4° C. Electrospray Mass Spec 349 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].N1C=CN=C1.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][O:12][Si:22]([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(CCO)cc1Br
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CCO[Si](C)(C)C(C)(C)C)cc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution 45.0 g of the compound obtained in Step 216-2 in DMF (50 ml) was added 29.0 g of imidazole and 32.0 g of TBSCl, and stirred at room temperature for 16 hours. Water was added to the solution, and the resulting mixture was extracted with Et2O. The extract was dried over Na2SO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: n-hexane/EtOAc=10/1; v/v) to obtain 62.0 g of the title compound (colorless oil).