Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[CH:9]=[CH:8]1.[C:16](=O)(O)[O-:17].[Na+]>CN(C=O)C>[CH3:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]([CH:16]=[O:17])=[CH:8]1
Reactant: O=C([O-])O
Reactant: Cn1ccc2cccnc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1cc(C=O)c2cccnc21
Temperature: 0 °C
Yield: 83 %

Procedure:
Phosphoryl chloride (5.15 ml, 55.3 mmol) was added dropwise to DMF (70 ml) under stirring at 0° C. After the reaction mixture was stirred at 0° C. for 10 minutes, a solution of 1-methyl-1H-pyrrolo(2,3-b)pyridine (4.87 g, 36.8 mmol) in DMF (5 ml) was added dropwise at the same temperature. After completion of the dropwise addition, the reaction mixture was stirred at 0° C. for 4 hours and at 60° C. for 3.5 hours. The reaction mixture was poured in ice water—a saturated aqueous solution of sodium bicarbonate to neutralize the mixture therewith, followed by extraction with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from ethyl acetate eluate fractions, 1-methyl-1H-pyrrolo(2,3-b)pyridine-3-carbaldehyde (4.87 g, 83%) was obtained as a yellow solid.
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([C:7](=[O:17])[CH2:8][CH2:9][C:10]2[O:14][N:13]=[C:12]([CH2:15][Cl:16])[N:11]=2)=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)C>[C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:2]=[CH:3][C:4]([CH:7]([OH:17])[CH2:8][CH2:9][C:10]2[O:14][N:13]=[C:12]([CH2:15][Cl:16])[N:11]=2)=[CH:5][CH:6]=1
Reactant: O=C(CCc1nc(CCl)no1)c1ccc(-c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC(CCc1nc(CCl)no1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.5 %

Procedure:
To a solution of 1.03 g of 5-[3-(4-biphenylyl)-3-oxopropyl]-3-chloromethyl-1,2,4-oxadiazole obtained in Example 3 in 100 ml of ethanol was added 0.12 g of sodium borohydride. After stirring for 10 minutes at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was treated with ice-water and extracted with chloroform. The organic phase was washed with water, dried over sodium sulfate and evaporated to give 1.0 g of 5-[3-(4-biphenylyl)-3-hydroxypropyl]-3-chloromethyl-1,2,4-oxadiazole, m.p. 48°-49° C.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]=[C:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)C.[OH-].[Na+]>CCO>[CH:17]1[C:18]2[C:6](=[CH:5][C:4]([OH:19])=[O:3])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)C=C1c2ccccc2-c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C=C1c2ccccc2-c2ccccc21
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 99 %

Procedure:
1.85 g (7.39 mmol, 1 eq) of 4 are introduced into 40 mL of EtOH. 14.8 mL (14.78 mmol, 2 eq) of 1 N sodium hydroxide are added and the mixture is stirred for 45 min at 60° C. The reagent dissolves completely while hot. The ethanol is concentrated, the residue is taken up in the water and AcOEt is added. The aqueous phase is acidified to pH 3, then extracted with AcOEt. The organic phase is washed with brine, dried, filtered and concentrated (m=1.62 g, yield=99%).
Reaction SMILES: ClC(Cl)C(O)=[O:4].[CH3:7][C:8]1[C@@H:13]2[C:14]([CH3:16])([CH3:15])[C@@H:11]([CH2:12]2)[CH2:10][CH:9]=1>O>[CH3:7][C:8]1[CH2:13][CH2:12][C@@H:11]([C:14]([OH:4])([CH3:16])[CH3:15])[CH2:10][CH:9]=1
Reactant: CC1=CC[C@@H]2C[C@H]1C2(C)C
Reactant: O=C(O)C(Cl)Cl
Solvent: O
Product: CC1=CC[C@H](C(C)(C)O)CC1
Reaction time: 8 h
Yield: 61.7 %

Procedure:
Following a procedure described in Matsubara, et al., Chem. Abstr., 84:165069b (1976), 64.5 g of dichloroacetic acid was added dropwise over 20 minutes at 5°-6° C. to a magnetically stirred mixture of 68.0 g of (+)-alpha-pinene ([alpha]D +47.1°) and 9.0 g of water. After stirring overnight at 5°-30° C. (ice allowed to melt slowly), the mixture was extracted with 400 ml of methylene chloride. The extract was washed successively with water, aqueous potassium carbonate solution and water, dried and Claisen distilled at 4 mm to give 11.2 g of forecut, b.p. 40°-71° C. and 47.5 g of the desired (+)-alpha-terpineol, b.p. 71°-83° C. Redistillation through a micro Vigreaux column gave 40.5 g of (+)-alpha-terpineol with [alpha]D +79.3° (CHCl3), b.p. 58°-60° C. (1 mm).
Reaction SMILES: [N:1]1([C:7]2[O:8][C:9]3[CH:10]=[N:11][CH:12]=[CH:13][C:14]=3[N:15]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:16]([O:21][C@@H:22]([C:24]1[N:29]=[C:28](Cl)[CH:27]=[CH:26][N:25]=1)[CH3:23])(=[O:20])[CH2:17][CH2:18][CH3:19].C(N(CC)CC)C>C(O)(C)C>[C:16]([O:21][C@@H:22]([C:24]1[N:25]=[C:26]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[O:8][C:9]4[CH:10]=[N:11][CH:12]=[CH:13][C:14]=4[N:15]=3)[CH2:2][CH2:3]2)[CH:27]=[CH:28][N:29]=1)[CH3:23])(=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: c1cc2nc(N3CCNCC3)oc2cn1
Reactant: CCCC(=O)O[C@H](C)c1nccc(Cl)n1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCCC(=O)O[C@H](C)c1nccc(N2CCN(c3nc4ccncc4o3)CC2)n1
Temperature: 25 °C
Yield: 79 %

Procedure:
To a solution of 2-(1-piperazinyl)oxazolo[5,4-c]pyridine (775 mg, 3.8 mmol; J. Org. Chem. 1995, 60, 5721) in isopropanol (38 mL) was added (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of Preparation Seven, 868 mg, 3.8 mmol) followed by triethylamine (1.6 mL, 11.4 mmol). This mixture was stirred at reflux overnight, cooled to room temperature, and evaporated. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with chloroform (3×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (2×; 3% methanol/chloroform then 6→8% methanol/ethyl acetate, where used herein, the arrow symbol, →, indicates a gradient) to give 1.2 g (79%) of the title compound of Example 2, Step A as a pale yellow oil which solidified upon standing. 1H NMR (CDCl3, 250 MHz) δ8.57 (s, 1H), 8.39 (d, 1H), 8.28 (d, 1H), 7.30 (d, 1H), 6.44 (d, 1H), 5.70 (q, 1H), 3.85 (s, 8H), 2.42 (t, 2H), 1.78-1.61 (c, 2H), 1.60 (d, 3H), 0.98 (t, 3H); MS (APCI) 397 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)Br)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=1)[O:24][CH2:25][C:26]([NH2:28])=[S:27]>C(#N)C.C(O)C.CO>[Cl:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=1)[O:24][CH2:25][C:26]1[S:27][C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:28]=1
Reactant: NC(=S)COc1cccc(Cl)c1
Reactant: CSc1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Solvent: CO
Solvent: CCO
Solvent: CC#N
Product: CSc1ccc(-c2sc(COc3cccc(Cl)c3)nc2-c2ccc(F)cc2)cc1
Temperature: 0 °C

Procedure:
A solution of 1-(4-fluorophenyl)-2-(4-methylthiophenyl)-2-bromo-ethanone (1.98 g, 5.84 mmol) (Example 1, Step 3) and 3-chlorophenoxy thioacetamide (1.18 g, 5.85 mmol) in 15 mL of acetonitrile and 10 mL of ethanol was heated to reflux for 16 hours. The solution was diluted with methanol, cooled to 0° C. in an ice bath and a precipitate formed that was removed by filtration. The solid was air dried and then recrystallized from methanol to provide (1.67 g; 65%),of pure 2-((3-chlorophenoxy)methyl)-4-(4-fluorophenyl)-5-(4-methylthiophenyl)thiazole: mp 106°-110° C., 1NMR (CDCl3) 300 MHz 7.50 (m, 2H), 7.30-7.15 (m, 5H), 7.09-6.87 (m, 5H), 5.38 (s, 2H), 2.50 (s, 3H). 19F NMR (CDCl3) -113.58 (m). Mass spectrum M+ =441.
Reaction SMILES: [C:1]([C@@H:5]1[C@@H:16]2[C:17]3[C:8](=[CH:9][C:10]([O:24][CH3:25])=[CH:11][C:12]=3[CH2:13][C@@H:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15]2)[C:7](O)=[CH:6]1)([O:3][CH3:4])=[O:2].C(OCC)(=O)C.Cl.[H][H]>CO.[Pd]>[C:1]([C@H:5]1[C@@H:16]2[C:17]3[C:8](=[CH:9][C:10]([O:24][CH3:25])=[CH:11][C:12]=3[CH2:13][C@@H:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15]2)[CH2:7][CH2:6]1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)[C@H]1C=C(O)c2cc(OC)cc3c2[C@@H]1C[C@H](c1ccccc1)C3
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CCc2cc(OC)cc3c2[C@@H]1C[C@H](c1ccccc1)C3

Procedure:
To a solution of 0.46 g. (1.3 mmol) of [1R,8S,9aR] 1-carbomethoxy-5-methoxy-3-hydroxy-8-phenyl-7,8,9,9a-tetrahydrophenalene, from Step 3, in 50 mL of methanol, 50 mL of ethyl acetate, and 0.1 mL of concentrated hydrochloric acid is added 0.2 g of 5% palladium supported on carbon and the mixture is shaken under 4 atmospheres of hydrogen until the hydrogen uptake ceases. The catalyst is filtered through Celite filter aid and concentrated to give the title compound, which is carried on without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]([CH2:17][CH3:18])(O)[CH2:14][CH3:15])=[CH:10][C:9]=2[CH:19]=1)=[O:4].[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29])([CH3:22])[CH3:21].B(F)(F)F.CC[O:36][CH2:37][CH3:38]>>[CH3:3][C:5]([CH3:6])([CH3:19])[C:37](=[O:36])[CH2:38][O:29][C:24]1[CH:25]=[CH:26][C:27]([CH:14]([CH:13]([C:11]2[O:12][C:8]3[CH:7]=[CH:6][C:5]([C:3]([OH:2])=[O:4])=[CH:19][C:9]=3[CH:10]=2)[CH2:17][CH3:18])[CH3:15])=[CH:28][C:23]=1[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)c1ccccc1O
Reactant: CCOCC
Reactant: CCC(O)(CC)c1cc2cc(C(=O)OC)ccc2o1
Agent: FB(F)F
Product: CCC(c1cc2cc(C(=O)O)ccc2o1)C(C)c1ccc(OCC(=O)C(C)(C)C)c(C(C)C)c1
Yield: 153.5 %

Procedure:
2-(1-Ethyl-1-hydroxy-propyl)-benzofuran-5-carboxylic acid methyl ester (0.92 g, 3.507 mmol) and 2-isopropylphenol (0.716 g, 5.26 mmol) and BF3-Et2O (249 mg, 1.753 mmol) are reacted analogous to Example 1D to give the title compound (1.25 g, 94%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[CH:11][N:10]([C:13]3[S:14][C:15]([C:25]([NH2:27])=[O:26])=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=4)[N:17]=3)[C:9]=2[CH:28]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>[I-].[K+].CN(C)C=O>[Cl:24][C:20]1[CH:19]=[C:18]([C:16]2[N:17]=[C:13]([N:10]3[C:9]4[CH:28]=[C:5]([O:4][CH2:3][CH2:2][N:39]5[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]5)[CH:6]=[CH:7][C:8]=4[N:12]=[CH:11]3)[S:14][C:15]=2[C:25]([NH2:27])=[O:26])[CH:23]=[CH:22][CH:21]=1
Reactant: CN1CCNCC1
Reactant: NC(=O)c1sc(-n2cnc3ccc(OCCCl)cc32)nc1-c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCN(CCOc2ccc3ncn(-c4nc(-c5cccc(Cl)c5)c(C(N)=O)s4)c3c2)CC1
Reaction time: 6 h
Yield: 76.5 %

Procedure:
A mixture of 0.043 g (0.1 mmole) of 2-[6-(2-chloro-ethoxy)-benzoimidazol-1-yl]-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (I.28a), 1 mL of dimethylformamide, 0.069 g (0.5 mmole) of potassium carbonate, 0.001 g of potassium iodide and 0.033 mL (0.3 mmole) of 1-methyl-piperazine was stirred at 100 degrees for 6 hours. The mixture was cooled, the solid was removed by filtration and the filtrate purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient 30:70-100:0) to give 0.038 g of 4-(3-chloro-phenyl)-2-{6-[2-(4-methyl-piperazin-1-yl)-ethoxy]-benzoimidazol-1-yl}-thiazole-5-carboxylic acid amide (I.28) as a white solid. MH+/Z=497
Reaction SMILES: [CH3:1][CH:2]([NH2:11])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:12]([C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[O:16][CH2:17][CH:18]1[O:20][CH2:19]1)#[N:13]>C(O)C>[C:12]([C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[O:16][CH2:17][CH:18]([OH:20])[CH2:19][NH:11][CH:2]([CH3:1])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)#[N:13]
Reactant: CC(N)CCc1ccccc1
Reactant: N#Cc1ccccc1OCC1CO1
Solvent: CCO
Product: CC(CCc1ccccc1)NCC(O)COc1ccccc1C#N
Yield: 613.3 %

Procedure:
In this example, 1.5 g of 1-methyl-3-phenylpropylamine and 1.8 g of 1-(2-cyanophenoxy)-2,3-epoxypropane are refluxed for 1.5 hours in 50 ml of99.5% ethanol. After completion of the reaction, the reaction solution is concentrated under reduced pressure. The residue is then charged on a column packed with silica gel and the elution is carried out with methanol. The main fraction of the eluate is concentrated under reduced pressure. Then, the residue is recrystallized from 200 ml of n-hexane to obtain 20 g of 1-(2-cyanophenoxy)-3-(1-methyl-3-phenylpropylamino)-2-propanol as crystals. (Yield: 62%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:9])=[CH:4][CH:3]=1.C1([Li])C=CC=CC=1.[CH2:24]=[O:25].O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:9])=[C:6]([CH:7]=1)[CH2:24][OH:25]
Reactant: C[C@@H](NC(=O)C(C)(C)C)c1ccc(Br)cc1
Reactant: C=O
Agent: [Li]c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)C(C)(C)C)c1ccc(Br)cc1CO
Reaction time: 4 h
Yield: 66.9 %

Procedure:
In 10 ml of tetrahydrofuran is dissolved 2 g of N-[(1R)-1-(4-bromophenyl)ethyl]-2,2-dimethylpropanamide, and to this solution is dropwise added 14.3 ml of phenyllithium (1.48 M cyclohexane-diethyl ether solution), after which the temperature of the resulting mixture is elevated to −5° C. and the mixture is stirred at the same temperature for 4 hours. Subsequently, 1.06 g of paraformaldehyde is added thereto and the mixture is stirred at 5° C. for 1 hour, after which 6 ml of water is added to the reaction mixture and the organic layer is separated. The organic layer obtained is dried over anhydrous magnesium sulfate and the solvent is removed by distillation under reduced pressure. The residue obtained is purified by silica gel chromatography (eluant; n-hexane:ethyl acetate=2:1) to obtain 1.48 g (yield: 66.9%) of 5-bromo-2-{(1R)-1-[(2,2-dimethylpropanoyl)amino]-ethyl}benzyl alcohol.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH3:7][CH:8]1[CH2:12][CH2:11]C(C)O1.[OH-].[Na+]>C(O)(=O)C>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[N:1]1[CH:11]=[CH:12][CH:8]=[CH:7]1
Reactant: Nc1nccs1
Reactant: CC1CCC(C)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: c1ccn(-c2nccs2)c1

Procedure:
A mixture of 55.5 g (0.5 mole) 2-aminothiazole (90% pure) and 66 g (0.5 mole) 2,5-dimethyltetrahydrofuran is placed in a 1-liter 3-neck flask equipped with a stirrer, addition funnel, thermometer, and condenser, and 200 ml glacial acetic acid is added dropwise with stirring while maintaining the temperature below 20°C. After stirring for an additional 15 minutes, the reaction mixture is refluxed for 30 minutes and then cooled, made basic (pH 9-10) with 375 ml 30% sodium hydroxide, and steam-distilled to yield 1500 ml distillate.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C:9]=12)=[O:4].[OH-].[Na+].Cl>CO>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][N:8]2[C:7]([C:21]([F:22])([F:23])[F:24])=[N:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]2[CH2:10]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1
Yield: 108.5 %

Procedure:
3-Trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-1,7-dicarboxylic acid 7-tert-butyl ester 1-methyl ester 27c (1.92 g, 5.5 mmol) was dissolved in 50 mL of methanol under stirring, and 30 mL of 4 N sodium hydroxide was then added to the solution. The reaction mixture was reacted for 30 minutes at room temperature and monitored by thin layer chromatography until the disappearance of the starting materials. The mixture was adjusted to pH 4-5 with 2 N hydrochloric acid, and then extracted with ethyl acetate (100 mL×3). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound 3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-1,7-dicarboxylic acid 7-tert-butyl ester 27d (2 g) as a white solid, which was directly used in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]([CH2:27][C:28]([O:30]CC)=[O:29])[CH2:22][CH2:21][CH2:20]3)[CH:10]=1.C(O)C.[OH-].[Na+].Cl>O.O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]([CH2:27][C:28]([OH:30])=[O:29])[CH2:22][CH2:21][CH2:20]3)[CH:10]=1
Reactant: CCOC(=O)CC1CCCc2cc(OCc3cccc(-c4c(C)cccc4C)c3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Cc1cccc(C)c1-c1cccc(COc2ccc3c(c2)CCCC3CC(=O)O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.1 %

Procedure:
To a solution of ethyl (6-[(2′,6′-dimethylbiphenyl-3-yl)methoxy]-1,2,3,4-tetrahydronaphthalen-1-yl)acetate (0.15 g, 0.35 mmol) in a mixed solvent of ethanol (1 mL) and tetrahydrofuran (1 mL) was added 2 M aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was acidified with 1 M hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (0.08 g, yield 57%) as colorless prism crystals.
Reaction SMILES: [NH2:1][C:2]1C=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[Cl:21]N1C(=O)CCC1=O.[CH2:29]([Cl:31])Cl>>[NH2:1][C:2]1[C:29]([Cl:31])=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[C:20]=1[Cl:21]
Reactant: ClCCl
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN1C(=O)CN=C(c2ccccc2)c2cc(N)ccc21
Product: CN1C(=O)CN=C(c2ccccc2)c2c1cc(Cl)c(N)c2Cl
Temperature: 25 °C
Reaction time: 27 h

Procedure:
A stirred suspension of 5 g (0.019 mol) of 7-amino-5-phenyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one in 70 ml of methylene chloride is treated at 0° C. with 5.83 g (0.044 mol) of N-chlorosuccinimide. Subsequently, the mixture is stirred at room temperature for 27 hours and diluted with methylene chloride. The organic phase is washed with 2 N sodium carbonate solution, dried and evaporated. The residue is chromatographed on 20 g of silica gel with methylene chloride/ethyl acetate (4:1), there being obtained 7-amino-6,8-dichloro-5-phenyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one. After recrystallisation from methylene chloride/ethyl acetate, the product has a melting point of 228° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[C@@H:9]3[CH2:22][C@@H:10]3[C:11]2=[O:21])[CH2:3]1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[C:23]([O:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[C@@H:9]3[CH2:22][C@@H:10]3[C:11]2=[O:21])[CH2:3]1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@H]1[C@@H]3[C@@H]4C[C@@H]4C(=O)[C@@]3(C)CC[C@@H]12
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4[C@@H]5C[C@@H]5C(=O)[C@@]4(C)CC[C@@H]32)C1
Temperature: 95 °C
Reaction time: 1.5 h

Procedure:
A solution of 95 g of 3β-hydroxy-15β,16β-methylene-5-androsten-17-one in 190 ml of pyridine was combined with 95 ml of acetic anhydride and stirred for 1.5 hours at 95° C. The precipitate obtained after pouring the mixture into ice water was filtered off, washed thoroughly with water, and dried, thus obtaining 107 g of 3β-acetoxy-15β,16β-methylene-5-androsten-17-one as a crude product. A sample extracted by boiling with diisopropyl ether melted at 140.5°-141° C.
Reaction SMILES: CS([O:5][CH:6]([CH2:16][N:17]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)=[C:24]2[C:19]([N:20]([CH3:36])[C:21](=[O:35])[N:22]([CH3:34])[C:23]2=[O:33])=[CH:18]1)[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])(=O)=O.[C:37]([O-])(=[S:39])[CH3:38].[K+]>CN(C=O)C.O>[C:37](=[S:39])([O:5][CH:6]([CH2:16][N:17]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)=[C:24]2[C:19]([N:20]([CH3:36])[C:21](=[O:35])[N:22]([CH3:34])[C:23]2=[O:33])=[CH:18]1)[CH2:7][O:8][Si:9]([C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:10])[CH3:11])[CH3:38]
Reactant: CC([O-])=S
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)n(CC(CO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O)cc2n(C)c1=O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=S)OC(CO[Si](C)(C)C(C)(C)C)Cn1cc2c(c1-c1cccc(F)c1)c(=O)n(C)c(=O)n2C
Temperature: 25 °C

Procedure:
A solution of 1-((tert-butyldimethylsilyl)oxy)-3-(5-(3-fluorophenyl)-1,3-dimethyl-2,4-dioxo-3,4-dihydro-1H-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)propan-2-yl methanesulfonate (705 mg, 1.241 mmol) and potassium thioacetate (709 mg, 6.20 mmol) in DMF (4964 μL) was heated at 70° C. for 4 hours. Further portions of potassium thioacetate (709 mg, 6.20 mmol) were added as necessary to allow the reaction to run to completion. The reaction mixture was cooled to room temperature, diluted with water (15 mL) and extracted with DCM (3×20 mL). The combined organic extracts were dried over magnesium sulfate and evaporated under vacuum. Purification by chromatography on silica, eluting with 0-50% EtOAc/hexane, afforded the title compound.
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][NH:7][C:8](=[O:51])[CH2:9][CH2:10][NH:11][C:12](=[O:50])[C@H:13]([OH:49])[C:14]([CH3:48])([CH3:47])[CH2:15][O:16][P:17]([OH:46])(=[O:45])[O:18][P:19]([OH:44])(=[O:43])[O:20][CH2:21][C@H:22]1[O:26][C@@H:25]([N:27]2[C:36]3[N:35]=[CH:34][N:33]=[C:31]([NH2:32])[C:30]=3[N:29]=[CH:28]2)[C@H:24]([OH:37])[C@@H:23]1[O:38][P:39]([OH:42])([OH:41])=[O:40])(=[O:3])[CH3:2].[CH2:52](O)C.C(OCC)(=O)C=C>O>[C:1]([S:4][CH2:5][CH2:6][NH:7][C:8](=[O:51])[CH2:9][CH2:10][NH:11][C:12](=[O:50])[C@H:13]([OH:49])[C:14]([CH3:47])([CH3:48])[CH2:15][O:16][P:17]([OH:46])(=[O:45])[O:18][P:19]([OH:44])(=[O:43])[O:20][CH2:21][C@H:22]1[O:26][C@@H:25]([N:27]2[C:36]3[N:35]=[CH:34][N:33]=[C:31]([NH2:32])[C:30]=3[N:29]=[CH:28]2)[C@H:24]([OH:37])[C@@H:23]1[O:38][P:39]([OH:42])([OH:41])=[O:40])(=[O:3])[CH:2]=[CH2:52]
Reactant: CCO
Reactant: CC(=O)SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O
Agent: C=CC(=O)OCC
Solvent: O
Product: C=CC(=O)SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O

Procedure:
A solution of acrylyl coenzyme A is prepared at a concentration of 890 ppm following a similar method to that outlined in Example 1a but prepared in water and using one third the amount of S-acetyl coenzyme A synthetase. To this, 44 mg/mL of ethanol and 100 mg/mL of Novozym 435 are added following example 1b. After 2 hours at 37° C. the concentration of ethyl acrylate is found to be 16.4 ppm.