Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH3:6])=[O:4].[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.COC1C=CC=CC=1OC>>[CH3:6][O:5][C:3]([CH2:2][O:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4]
Reactant: COC(=O)CCl
Reactant: Oc1ccccc1
Solvent: COc1ccccc1OC
Product: COC(=O)COc1ccccc1

Procedure:
Illustrative Embodiment 1 is repeated with a feed mixture of 94 g of methyl chloroacetate, 68 g of phenol and 5 g of dimethoxybenzene (as a gas chromatograph standard). A catalyst of 22 percent Y2O3 on α-Al2O3 produces methyl phenoxy acetate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[C:4]2[C:10]([N+:11]([O-])=O)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl[Sn]Cl.[OH-].[Na+].C(Cl)Cl>Cl>[Cl:1][C:2]1[C:3]([F:14])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1c[nH]c2ncc(Cl)c(F)c12
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: ClCCl
Product: Nc1c[nH]c2ncc(Cl)c(F)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
5-Chloro-4-fluoro-3-nitro-1H-pyrrolo[2,3-b]pyridine (1.20 g, 5.57 mmol) was placed in 6M HCl (30 mL). SnCl2 (5.28 g, 27.8 mmol) was then added, and the reaction was stirred for 30 minutes at room temperature. The reaction was then poured into a mixture of 1M NaOH and ice. The resulting suspension was then raised to a pH of 8 and then extracted with 3:1 DCM:i-PrOH. The combined organic fractions were dried, filtered, and concentrated to give the crude product, which was triturated with 10:1 hexanes:DCM to give the product 5-chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.8 g, 77% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][N+:10]([O-])=O)=[CH:4][C:3]=1[F:13].[BH4-].[Li+].C[Si](Cl)(C)C.CO>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][C:3]=1[F:13]
Reactant: O=[N+]([O-])C=Cc1ccc(Cl)c(F)c1
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: NCCc1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 78 h
Yield: 115.9 %

Procedure:
1-Chloro-2-fluoro-4-(2-nitro-vinyl)-benzene (I-33a: 1.1 g, 4.97 mmol) in dry THF (8 mL) was added to a stirred solution of lithium borohydride (433 mg, 19.90 mmol) and trimethylsilyl chloride (5 mL, 39.66 mmol) in dry THF (8 mL) at 0° C. The resulting mixture was stirred at room temperature for 78 hours. The reaction was monitored by TLC (10% methanol in DCM). The reaction mixture was cooled to 0° C., quenched with methanol and concentrated under reduced pressure to afford 1 g of the product (100% yield).
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[H-].[Na+].[C:15](#[N:17])[CH3:16]>C1(C)C=CC=CC=1>[CH3:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([CH2:16][C:15]#[N:17])=[O:12])=[CH:9][CH:8]=1
Reactant: CC#N
Reactant: COC(=O)c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)CC#N)cc1
Reaction time: 20 h

Procedure:
166.2 grams (1 mole) of 4-methoxybenzoic acid methyl ester and 60 grams (2 moles) of sodium hydride (80 weight % suspension in white oil) were heated to 65° C. in 750 ml of dry toluene. Within 2 hours there were dropped in 82.1 grams (2 moles) of acetonitrile at 85° C. and then stirring was continued for a further 20 hours at 90° C. The precipitate was filtered off with suction, 200 ml of glacial acetic acid slowly stirred in with cooling and subsequently the mixture was added to 1 liter of ice water. The precipitated crystal mass was filtered off with suction, post washed with water and recrystallized from acetone. There were thus obtained 149 grams (85% of theory) of 4-methoxybenzoylacetonitrile having a melting point of 127°-129° C.
Reaction SMILES: [BH4-].[Na+].C([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH3:16])[N:9]=1)=O)C.O>CCO>[CH2:15]([O:14][C:10]1[N:9]=[C:8]([CH2:6][OH:5])[CH:13]=[CH:12][CH:11]=1)[CH3:16]
Reactant: CCOC(=O)c1cccc(OCC)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1cccc(CO)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74 %

Procedure:
NaBH4 (5.7 g, 151 mmol) was added in portions during 35 minutes to 6-ethoxy-pyridine-2-carboxylic acid ethyl ester (1.5 g, 7.5 mmol) in EtOH (75 mL). The resulting mixture was stirred at ambient temperature for two days. Water was added and the mixture was extracted with CH2Cl2. The organic phase was dried (Na2SO4), filtered and then concentrated to give the title product (0.85 g) in 74% yield as an oil. This material was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12]([OH:14])=[O:13])[CH2:6][CH2:5]2.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[K+].Cl>O.[I-].[Na+].C(O)C>[CH2:15]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12]([OH:14])=[O:13])[CH2:6][CH2:5]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)C1CCc2cc(O)ccc2C1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(O)C1CCc2cc(OCc3ccccc3)ccc2C1
Temperature: 100 °C
Yield: 92.8 %

Procedure:
A mixture of 10.60 g (50 mmol) of 1,2,3,4-tetrahydro-6-hydroxynaphthalene-2-carboxylic acid, 12.85 g (75 mmol) of benzyl bromide, 6.6 g (100 mmol) of 85% potassium hydroxide, 0.525 g (3.5 mmol) of sodium iodide, 200 ml of ethanol and 25 ml of distilled water was heated under reflux at 100° C. for 12 hours. To this reaction mixture was added 50 ml of 10% potassium hydroxide, followed by heating under reflux at that temperature for 2 hours. After allowing the reaction system to cool up to room temperature, the reaction mixture in cold water was acidified with 36% hydrochloric acid. The resulting deposited product was filtered, and recrystallized from toluene to obtain 13.08 g (46.4 mmol) of 1,2,3,4-tetrahydro-6-benzyloxynaphthalene-2-carboxylic acid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH2:17][NH:16][CH2:15][CH2:14]2)=[O:10].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][C:28](O)=[O:29].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][C:28]([N:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:9]([NH:8][O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)=[O:10])[CH:12]=2)[CH2:17]1)=[O:29]
Reactant: O=C(O)Cc1ccccn1
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CCNC2
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NOC1CCCCO1)c1ccc2c(c1)CCN(C(=O)Cc1ccccn1)C2
Reaction time: 8 h
Yield: 40.2 %

Procedure:
200 mg of N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide, 69 mg of 2-pyridineacetic acid, 111 mg HOBT, 276 mg EDC and 0.6 ml triethylamine are dissolved in 7 ml DMF and stirred overnight. The mixture is evaporated and the residue is treated with 5 ml water and 10 ml of dichloromethane. After separation, the water phase is washed with dichloromethane and the combined organic phases are filtered, dried and evaporated. 80 mg of a colorless oil are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[C:17]=2[CH:18]=1
Reactant: O=C(O)c1ccccc1COc1ccc(Br)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C1c2ccccc2COc2ccc(Br)cc21

Procedure:
Reflux 120 gm. of o-(p-bromophenoxymethyl)benzoic acid in 500 cc. of trifluoroacetic anhydride containing 0.5 cc. of boron trifluoride-ether complex for 31/2 hours. Cool, separate the solids by filtration, and wash with ether in order to obtain the title product (m.p. 136°-139° C.).
Reaction SMILES: [C:1]1([C:7](=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=2)C(O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(O)=O.[Na+]>>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([CH:11]=[CH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:13][C:14]=1[O:19][CH3:20]
Reactant: COc1cc(C=C(C(=O)O)c2ccccc2)ccc1O
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc(C=Cc2ccccc2)ccc1O
Yield: 72 %

Procedure:
A mixture of α-phenyl-4-hydroxy-3-methoxy cinnamic acid (0.0083 mol), NaHCO3 (10%, 5 mL) and polyethylene glycol (5 mL) were taken in a 100 ml round bottom flask fitted with a condenser. The flask was shaken well and placed inside the microwave oven and irradiated (200 W, 180° C.) for 10 minutes in parts. After completion of reaction, the reaction mixture was worked (yield 72%) as in example I. Spectral data as given in example I.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][OH:10].C(N(C(C)C)CC)(C)C.CS(C)=O.N1C=CC=CC=1.S(=O)(=O)=O>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[O:10]
Reactant: OCc1ccc(Cl)cc1Br
Agent: O=S(=O)=O
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: O=Cc1ccc(Cl)cc1Br
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a 0° C. solution of (2-bromo-4-chloro-phenyl)-methanol (5.57 g, 0.025 mol), dichloromethane (250 mL), diisopropylethylamine (22 mL, 0.126 mol), and dimethyl sulfoxide (15 mL, 0.211 mol) was added sulfur trioxide-pyridine (12.0 g, 0.075 mol), in portions, over 15 minutes. The resulting solution was stirred at 0° C. for 45 minutes. The reaction mixture was diluted with 250 mL dichloromethane, then washed with saturated aqueous NaHCO3 (500 mL). The organic phase was washed with saturated aqueous sodium thiosulfate (500 mL) to reduce excess oxidant. The organic phase was dried over Na2SO4, filtered and concentrated to afford a yellow oily solid. A solution of this crude product and CH2Cl2 (200 mL) was evaporated onto silica gel, and the dry silica gel-supported product was loaded onto a 120 g silica gel column. Flash chromatography was carried out using an ISCO purification system (95:5 hexanes-ethyl acetate). 2-Bromo-4-chloro-benzaldehyde was isolated as 4.43 g (81% yield) of a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 10.31 (s, 1 H), 7.88 (d, J=8.2 Hz, 1 H), 7.69 (d, J=1.6 Hz, 1 H), 7.44 (dd, J=8.2, 1.6 Hz, 1 H).
Reaction SMILES: [CH3:1][Al](C)C.[F:5][C:6]1[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:7]=1[CH:8]1[O:10][CH2:9]1>CCCCCC>[F:5][C:6]1[C:7]([CH:8]([CH3:1])[CH2:9][OH:10])=[C:11]([F:18])[C:12]([F:17])=[C:13]([F:16])[C:14]=1[F:15]
Reactant: Fc1c(F)c(F)c(C2CO2)c(F)c1F
Reactant: C[Al](C)C
Solvent: CCCCCC
Product: CC(CO)c1c(F)c(F)c(F)c(F)c1F
Temperature: 0 °C

Procedure:
To a 10 ml of ice-cooled 1M solution of trimethylaluminum in hexane, was added dropwise a solution of 1.05 g of (+)-2,3,4,5,6-pentafluorostyrene oxide (over 95%ee) in 5 ml of hexane, to react for five hours at 0° C and for another one hour at room temperature. The similar work-up to Example 1 gave 1.10 g of (+)-2-(pentafluorophenyl)-1-propanol. The specific rotation was compared with that of Example 1, and the optical purity was determined to be 15%ee.
Reaction SMILES: [OH-].[Mg+2:2].[OH-].[C:4]([CH2:7][C:8](=[O:10])[CH3:9])(=[O:6])[CH3:5]>>[CH3:9][C:8]([O-:10])=[CH:7][C:4]([CH3:5])=[O:6].[CH3:9][C:8]([O-:10])=[CH:7][C:4]([CH3:5])=[O:6].[Mg+2:2]
Reactant: CC(=O)CC(C)=O
Agent: [Mg+2]
Agent: [OH-]
Product: CC(=O)C=C(C)[O-]
Reaction time: 4 h
Yield: 100.5 %

Procedure:
350 g (6 mol) of magnesium hydroxide was supplied to the kneader used in Comparative Example 1, and stirred. Thereafter, 1,443 g [14.4 mol, magnesium hydroxide/acetylacetone=1/2.4 (molar ratio)] of acetylacetone was added dropwise into the kneader over 3 hours. The reaction temperature was between 35 and 64° C. After completion of the dropping, at a temperature of 64 to 65° C., the reaction mixture was stirred and mixed for aging for 4 hours until the reaction was complete. The resulting product was warmed under a flow of nitrogen gas. When the temperature was elevated up to 65° C., the product was subjected to the drying step, and dried at 104 to 125° C. for 12 hours until the product attained a moisture content of 0.17% by weight. The dried product was cooled to give 1,342 g of white magnesium acetylacetonate [yield 99.3 mol % (magnesium hydroxide basis), purity 98.9% by weight].
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:14])=[C:6]([O:12][CH3:13])[CH:7]=[C:8]([CH:11]=1)[CH:9]=[O:10])([O-:3])=[O:2].[CH2:15](I)[CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:15]([O:14][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[O:12][CH3:13])[CH2:16][CH3:17]
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1c(OC)cc(C=O)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 24 h
Yield: 49.4 %

Procedure:
A mixture of 5-nitrovanillin (10 g), propyl iodide (25 g), potassium carbonate (10 g) and N,N-dimethylformamide (200 ml) is stirred at 100° C. for 24 hours. After cooling, water (500 ml) is added to the reaction mixture, followed by extraction with ethyl acetate (200 ml). The extract solution is washed with water, dried and, then, distilled off under reduced pressure. The residue is purified by means of a silica gel column chromatography (hexane: ethyl acetate=2:1-1:1) to afford 4-propoxy-3-methoxy-5-nitrobenzaldehye (6 g) as a pale yellow oily product. This product is dissolved in acetone (200 ml), and potassium permanganate (18 g) is added to the solution. The mixture is stirred at room temperature overnight. To the reaction mixture are added ethanol (50 ml), water (50 ml) and acetone (200 ml). The whole mixture is stirred for two hours, and filtered off. The filtrate is concentrated under reduced pressure. Precipitating crystals are collected by filtration to give 3-methoxy- 5-nitro-4-propoxy benzoic acid (2.2 g) as colorless crystals. This product is recrystallized from a mixture of ethanol and water to give colorless needles, m.p. 121°-123° C.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[O:11])[CH:5]=1.O.[OH-].[Li+].Cl>C1COCC1>[CH3:16][S:13]([NH:12][C:10]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:17])=[O:2])=[O:11])(=[O:15])=[O:14]
Reactant: COC(=O)c1cccc(C(=O)NS(C)(=O)=O)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)NC(=O)c1cccc(C(=O)O)c1

Procedure:
A mixture of Example 32A (627 mg, 2.43 mmol) and lithium hydroxide monohydrate (112 mg, 2.67 mmol) in THF (15 mL) was stirred for 12 hours at room temperature after which the pH was adjusted to 6 by addition of 1 M HCl solution (3 mL, 3 mmol). The mixture was concentrated under reduced pressure, and the residue was partitioned between dichloromethane (30 mL) and H2O (10 mL). The aqueous layer was extracted with ethyl acetate (2×20 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to provide a white powder as the titled compound. MS (EST) m/e 244 (M+H)+, 242 (M−H)−; 1H NMR (500 MHz, CD3OD) δ ppm 3.38 (s, 3 H) 7.64 (t, 1 H) 8.11 (m, 1 H) 8.27 (m, 1 H) 8.54 (m, 1 H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Mg+2].[Cl-].[CH2:10]([N:17]1[CH2:22][CH:21]=[C:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH:19]([CH2:30][OH:31])[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>C1COCC1.O>[CH2:10]([N:17]1[CH2:22][CH2:21][C@@H:20]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[C@H:19]([CH2:30][OH:31])[CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: OCC1CN(Cc2ccccc2)CC=C1c1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OC[C@@H]1CN(Cc2ccccc2)CC[C@H]1c1ccc(F)cc1
Temperature: 50 °C
Yield: 81.1 %

Procedure:
Lithium aluminium hydride in THF (2.0 ml of a 1M solution) was carefully added to substantially anhydrous magnesium chloride (0.19 g, 1.5% H2O) under nitrogen. The mixture was stirred and heated to 50° C. and then a solution of (+)-1-benzyl-3-hydroxymethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine (0.60 g, preparation given in WO96136636) in THF (1.7 ml) was added dropwise over approximately 2 minutes. The reaction mixture was stirred and boiled under reflux for 4.2 hours. The mixture was cooled to ambient temperature and then stirred in an ice/water bath whilst water (0.1 ml) then 5M sodium hydroxide solution (0.1 ml) and water (0.1 ml) were added. The suspension was diluted with THF (5 ml) and the mixture filtered. The residue was washed with THF (3×5 ml) and the combined filtrate and washings were evaporated under reduced pressure to give a yellow oil (0.49 g). This oil was analysed by GLC, Chiral HPLC and 1H nmr.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].O>ClCCl>[CH3:22][S:23]([O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:14])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCOCCO
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCOCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
tert-Butyl[2-(2-hydroxyethoxy)ethyl]carbamate (Step 1, 3.73 g, 18 mmol) was diluted in dichloromethane (75 mL) and cooled to 0° C. Triethylamine (3.0 mL, 22 mmol) was added, followed by methanesulfonyl chloride (1.7 mL, 22 mmol). After stirring at rt for 1 h, water was added. The aqueous layer was separated and extracted with dichloromethane. The combined organics were dried and concentrated in vacuo to afford the title compound as an oil. 1H NMR (CDCl3) δ: 1.44 (9H, s), 3.06 (3H, s), 3.32 (2H, m), 3.56 (2H, t), 3.72 (2H, m), 4.36 (2H, m).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:22][S:23]([O:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:14])(=[O:25])=[O:24]
Reactant: CC(C)(C)OC(=O)NCCOCCO
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCOCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
Under a nitrogen atmosphere, a solution of tert-butyl 2-(2-hydroxyethoxy)ethylcarbamate (89.0 g, 434 mmol) in dichloromethane (1.5 L) was cooled to 0° C.; triethylamine (90.7 mL, 650 mmol) was added dropwise. Methanesulfonyl chloride (36.9 mL, 477 mmol) was then added over a period of 45 minutes. A precipitate formed, and the reaction became yellow. The reaction was allowed to warm to room temperature and stirred overnight. Saturated aqueous sodium bicarbonate (750 mL) was added. The organic layer was then sequentially washed with water (3×500 mL) and brine (250 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 119.2 g of 2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethyl methanesulfonate as a light orange oil.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[N:3]=1.C=O.[C:20](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+].[OH-].[Na+]>ClC(Cl)C>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:17][CH2:16][N:15]([CH3:20])[CH2:14][CH2:13]2)[N:3]=1
Reactant: Nc1ncnc2c1c(I)nn2C1CCNCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CN1CCC(n2nc(I)c3c(N)ncnc32)CC1
Reaction time: 4 h
Yield: 52.9 %

Procedure:
3-iodo-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.5 g, 1.45 mmol), formaldehyde (30% in water, 0.16 mL, 1.60 mmol) and sodium triacetoxyborohydride (0.43 g, 2.03 mmol) was mixed in dichloroethane (5 mL). After 4 hours, saturated sodium bicarbonate was added followed by sodium hydroxide (1.0N) to bring the pH to 10. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated to give 3-iodo-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.275 g, 53%). 1H NMR (DMSO-d6) δ 1.85 (m, 2H), 2.09 (m, 4H), 2.22 (s, 3H), 2.88 (m, 2H), 4.75 (m, 1H), 8.19 (s, 1H), 8.32 (s, 1H).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[C:11]3[C:25]([O:27]CC)=[O:26])=[CH:4][C:3]=2[O:2]1>CCO.[Pd]>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:11]3[C:25]([OH:27])=[O:26])=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1c1ccc2c(c1)OCO2
Agent: [Pd]
Solvent: CCO
Product: O=C(O)C1C(c2ccccc2)c2ccccc2C1c1ccc2c(c1)OCO2
Reaction time: 8 h
Yield: 69.8 %

Procedure:
To a solution of ethyl (RS)-1-(3,4-methylenedioxyphenyl)-3-phenylindene-2-carboxylate (1.00 g, 2.60 mmol) in EtOH (25 ml) was added 10% palladium on activated carbon (30 mg). The resulting suspension was stirred under an atmosphere of H2 overnight. Thin layer chromatographic analysis indicated that the reaction was incomplete, so additional 10% palladium on activated carbon (30 mg) was added, and the mixture was shaken on a Parr hydrogenator at 30 psi H2 for 2 d. At this time, thin layer chromatographic analysis again indicated that the reaction was incomplete. The reaction mixture was filtered through a pad of Celite, and 10% palladium on activated carbon (250 mg) was added. The reaction mixture was shaken on a Parr hydrogenator at 60 psi H2 overnight. Filtration and repetition of the latter hydrogenation conditions led to complete consumption of starting material. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to afford the title compound (650 mg, 65%), which was used without further purification.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:60][N:61]([CH3:65])[CH2:62][CH2:63][NH2:64]>C(OCC)(=O)C.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].O1CCOCC1>[CH3:60][N:61]([CH3:65])[CH2:62][CH2:63][NH:64][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: CN(C)CCN
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(NCCN(C)C)cc1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Methyl 4-iodobenzoate (1 g, 3.82 mmol), XANTPHOS (0.033 g, 0.057 mmol), Pd2(dba)3 (0.035 g, 0.038 mmol), Cs2CO3 (1.741 g, 5.34 mmol) was added to a sealed tube with septa and purged with argon 3×. N,N-dimethyl-1,2-ethanediamine (0.404 g, 4.58 mmol) and 1,4-Dioxane (4 mL) was then added and was stirred at 110° C. for Overnight. The reaction mixture was cooled to room temp and diluted with ethyl acetate and filtered through celite. The organic solvent was concentrated. The product was used without further purification. MS: cal'd 223 (MH+), exp 223 (MH+).
Reaction SMILES: [CH3:1][CH2:2][C:3](=[O:9])[CH2:4][C:5](=[O:8])[CH2:6][CH3:7].[CH2:10]([O:12][C:13](=[O:16])[CH2:14]Br)[CH3:11]>>[CH2:10]([O:12][C:13](=[O:16])[CH2:14][CH:4]([C:3](=[O:9])[CH2:2][CH3:1])[C:5](=[O:8])[CH2:6][CH3:7])[CH3:11]
Reactant: CCC(=O)CC(=O)CC
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CC(C(=O)CC)C(=O)CC

Procedure:
By a method analogous to that described in Example 34, 3,5-heptane dione was reacted with bromoacetic acid-ethyl ester to form 3,3-dipropionyl-propionic acid-ethyl ester, which was further reacted with phenylhydrazine to produce 3,5-diethyl-1-phenyl-pyrazol-4-acetic acid-ethyl ester which was saponified to form the free acid. Obtained was 3,5-diethyl-1-phenyl-pyrazol-4-acetic acid having a melting point of 129°-130° C.