Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Ba+2].[OH-].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:9]1([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1ccc(Br)nc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(-c2ccccc2)nc1

Procedure:
A mixture of 2-bromo-5-methylpyridine (2.00 g, 11.63 mmol), phenylboronic acid (1.56 g, 12.79 mmol), barium hydroxide (5.50 g, 17.4 mmol), DME (80 mL) and water (15 mL) was purged with dry argon. Tetrakis(triphenylphosphine)palladium(0) (672 mg, 0.58 mmol) was added, and the resultant solution was stirred at 80° C. for 4 hours. The solvents were evaporated in vacuo, and the residue partitioned between EtOAc and water and acidified with 1M aq. HCl. The aqueous extract was separated, and extracted with EtOAc. The organic extracts were combined, washed with NaHCO3 and 5% aq. Na2S2O3, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The residue was purified by chromatography (Silica gel, CH2Cl2) to afford the title compound.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([C:29]([OH:31])=[O:30])[CH2:20][O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(O[C:36]([CH3:39])([CH3:38])[CH3:37])(=O)C.S(=O)(=O)(O)O>ClCCl>[C:36]([O:30][C:29](=[O:31])[C@@H:19]([CH2:20][O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[NH:18][C:16]([O:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:17])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(=O)OC(C)(C)C
Reactant: O=C(N[C@H](COCc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H](COCc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 77 %

Procedure:
N-[(9H-Fluoren-9-yl)methoxycarbonyl]-O-(benzyl)-D-serine (0.710 g, 1.70 mmole) in dichloromethane (8 mL) was treated with t-butyl acetate (3 mL) and concentrated sulfuric acid (40 μL) in a sealed flask at 0° C. Upon completion (TLC), the reaction was quenched with of dichloromethane (10 mL) and saturated aqueous potassium bicarbonate (15 mL). The organic layer was washed with distilled water, and evaporated. The resulting residue was purified by flash column chromatography (98:2 dichloromethane/methanol) to yield the title compound as a colorless oil (0.292 g, 77%); 1H NMR (CDCl3) δ 1.44 (s, 9H); 3.68 (dd, J=2.9 Hz, J=9.3 Hz, 1H); 3.87 (dd, J=2.9 Hz, J=9.3 Hz, 1H); 4.22 (t, J=7.1 Hz, 1H); 4.30–4.60 (m, 5H); 5.64–5.67 (m, 1H); 7.25–7.39 (m, 9H); 7.58–7.61 (m, 2H); 7.73–7.76 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@@H:13]2[NH:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@:15]3([C:30]4[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[C@H:14]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Br:39])[C:34]=2[F:40])=[O:12])=[C:6]([O:41][CH3:42])[CH:5]=1.[OH-].[Na+].Cl>CO.C1COCC1.O>[Br:39][C:35]1[C:34]([F:40])=[C:33]([C@H:14]2[C@H:13]([C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:43])=[O:2])=[CH:5][C:6]=3[O:41][CH3:42])=[O:12])[NH:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@@:15]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Br)c2F)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Br)c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of rac-4-{[(2′S,3′R,4′S,5′R)-4′-(3-bromo-2-fluoro-phenyl)-6-chloro-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-3-methoxy-benzoic acid methyl ester (0.2 g, 0.3 mmol) in MeOH (3 mL) and THF (9 mL) was added an aqueous solution (1N) of NaOH (6 mL, 6 mmol). The reaction mixture was stirred at room temperature for 18 h. The crude mixture was diluted with water (5 mL), and acidified to “pH” 5-6 by dilute aqueous HCl solution. The mixture was then extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated. The residue was triturated with dichlormethane and hexanes to give rac-4-{[(2′S,3′R,4′S,5′R)-4′-(3-bromo-2-fluoro-phenyl)-6-chloro-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-3-methoxy-benzoic acid as a white powder (Yield, 0.16 g, 82%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:10][C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[OH:29].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[O:29][C:2]1[C:3]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:10][C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1
Reactant: CSc1nc(Cl)c2c(n1)CCN(C(=O)OC(C)(C)C)C2
Reactant: Oc1ccc(Cl)cc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nc2c(c(Oc3ccc(Cl)cc3Cl)n1)CN(C(=O)OC(C)(C)C)CC2
Yield: 37.1 %

Procedure:
A mixture of tert-butyl 4-chloro-2-methylthio-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidine-6-carboxylate (100 mg, 0.317 mmol), 2,4-dichlorophenol (57 mg, 0.348 mmol) and sodium bis(trimethylsilyl)amide (1.0 M solution in THF, 412 μl, 0.412 mmol) in tetrahydrofuran (2 ml) was heated at reflux over night. The mixture was partitioned between ethyl acetate and water. Organic layer was separated and washed with brine, dried (MgSO4) and filtered. Concentration of filtrate afforded crude product (180 mg), which was purified by flash chromatography (0.5% methanol in dichloromethane as eluent) to give tert-butyl 4-(2,4-dichlorophenoxy)-2-methylthio-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidine-6-carboxylate as a white foam (52 mg, yield 37%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][NH:14][C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=1.[OH-].[K+].C(O)C.O.Cl>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][NH:14][C:15]1[CH:25]=[CH:24][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1ccc(NCCOc2ccc3ccccc3c2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(NCCOc2ccc3ccccc3c2)cc1

Procedure:
A mixture of 3.0 g. of ethyl p-{[2-(2-naphthyloxy)ethyl]amino}benzoate, and 3.0 g. of potassium hydroxide in 200 ml. of ethanol-water (95:5) is refluxed for 3 hours. The mixture is diluted with 100 ml. of water and brought to pH 6.0 with concentrated hydrochloric acid. The mixture is filtered and the solid washed with 50 ml. of water and 20 ml. of cold ethanol-water (4:1) to give the product, m.p. 208°-211° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([NH:10][CH2:11][CH2:12][N:13]([CH2:26][CH2:27][C:28]12[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2)[C:14]([NH:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=[O:15])(=O)C.C(OCC)(=O)C.[OH-].[Na+]>C(OCC)C.O1CCCC1>[C:28]12([CH2:27][CH2:26][N:13]([CH2:12][CH2:11][NH:10][CH3:7])[C:14]([NH:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[O:15])[CH2:35][CH:34]3[CH2:33][CH:32]([CH2:31][CH:30]([CH2:36]3)[CH2:29]1)[CH2:37]2
Reactant: CC(=O)NCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)NCCCc1ccncc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CNCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)NCCCc1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.8 %

Procedure:
Lithium aluminum hydride (890 mg, 23.5 mmol) was suspended in anhydrous diethyl ether (10 ml) under a nitrogen atmosphere, and a solution of 1-[2-(acetylamino)ethyl]-1-[2-(1-adamantyl)ethyl]-3-[3-(4-pyridyl)propyl]urea (Compound No. 1-103) (4.86 g, 11.4 mmol) in anhydrous tetrahydrofuran (60 ml) was added dropwise to the suspension under ice-cooling with stirring over two hours. The temperature was raised to room temperature, and the mixture was stirred for 70 hours. Ethyl acetate (25 ml) was added to the reaction mixture under ice-cooling, then a 1 N aqueous sodium hydroxide solution (25 ml) was added thereto, and the whole was filtered with Celite to remove an insoluble matter. The filtrate was distributed with ethyl acetate (25 ml) and water (25 ml), and the organic layer was washed with a saturated aqueous sodium chloride solution (20 ml). The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the titled compound (2.33 g, colorless crystals, 49.8%).
Reaction SMILES: [Mg].Cl[CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.CN(C)[CH:11]=[CH:12][C:13](=[O:15])[CH3:14].Cl>O1CCCC1>[O:6]1[CH2:7][CH2:8][CH:3]([CH:11]=[CH:12][C:13](=[O:15])[CH3:14])[CH2:4][CH2:5]1
Reactant: CC(=O)C=CN(C)C
Reactant: ClC1CCOCC1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(=O)C=CC1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
5.0 g of magnesium were introduced into 100 ml of anhydrous tetrahydrofuran. 25 g of 4-chlorotetrahydropyran were added dropwise under reflux under a nitrogen atmosphere, and the mixture was refluxed for 2 hours. A solution of 23.5 g of 1-(dimethylamino)but-1-en-3-one in 20 ml of anhydrous tetrahydrofuran was subsequently added dropwise to the reaction mixture, cooled to from 0° to 5° C., at a rate such that the internal temperature did not exceed 50° C., and the mixture was stirred at room temperature for a further 2 hours. For work-up, the reaction mixture was poured into a mixture of ice and dilute HCl, and extracted 3 times with 200 ml of chloroform, and the extracts were washed with saturated sodium chloride solution and dried over MgSO4. Removal of the solvent gave 24.0 g (75%) of 1-(4-tetrahydropyranyl)but-1-en-3-one having a boiling point of 117° C./10 mmHg.
Reaction SMILES: [F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C@@H:15]3[S:21][CH3:22])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:24])[CH:4]=[CH:5][C:6](=[O:23])[CH:7]=1.ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C@@H:15]3[S:21]([CH3:22])=[O:33])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:24])[CH:4]=[CH:5][C:6](=[O:23])[CH:7]=1
Reactant: CS[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CS(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Yield: 95.5 %

Procedure:
To a solution of (11β,17β)-9-fluoro-11-hydroxy-17-(methylthio)androsta-1,4-dien-3-one (701 mg, 2.0 mmole; see example 5) in chloroform (30 ml) was added a solution of 85% m-chloroperbenzoic acid (398 mg, 2.0 mmole) in chloroform (10 ml). An instantaneous reaction was observed (tlc). The solution was then washed with a 10% potassium carbonate solution and water, dried (anhydrous magnesium sulfate) and evaporated to afford the title compound as a solid (700 mg). One crystallization of this from acetone-hexane followed by drying (100° C., 0.3 mm of Hg, 10 hours) gave the analytical specimen of the title compound (600 mg) melting point 270°-272° C. dec., as a mixture of sulfoxide stereoisomers, with consistent spectral data.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][C:6](=[O:8])[CH:5]=[C:4]([C:9]([OH:11])=[O:10])[O:3]1.[H][H]>O1CCCC1.[C].[Pd]>[CH3:1][C:2]1([CH3:12])[CH2:7][C:6](=[O:8])[CH2:5][CH:4]([C:9]([OH:11])=[O:10])[O:3]1
Reactant: CC1(C)CC(=O)C=C(C(=O)O)O1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC1(C)CC(=O)CC(C(=O)O)O1

Procedure:
In 8 ml of tetrahydrofuran was dissolved 0.5 g of 3,4-dihydro-2,2-dimethyl-4-oxo-2H-pyran-6-carboxylic acid, followed by adding thereto 50 mg of 10% palladium-carbon, and the reaction was carried out with stirring in a hydrogen stream at room temperature for 3 hours.
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:10].N([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=C=O>O1CCOCC1>[O:10]=[C:2]1[NH:3][C:4]2=[N:5][CH:6]=[CH:7][CH:8]=[C:9]2[O:1]1.[CH3:21][CH2:20][CH:19]([C:2]([NH2:3])=[O:1])[CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: CCCCCCCCN=C=O
Agent: O=c1[nH]c2ncccc2o1
Solvent: C1COCCO1
Product: CCCCCC(CC)C(N)=O

Procedure:
200 mg (1.47 mmol) of 3H-oxazolo[4,5-b]pyridin-2-one were reacted in analogy to Example 1 with 273.7 mg (1.76 mmol) of 1-isocyanatooctane in dioxane at 80° C. Yield: 40 mg (9%), M+H+: 292.10.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:4][CH:3]1[C:5]([O:7][CH2:8][CH3:9])=[O:6]>C1C=CC=CC=1>[OH:4][CH:3]([C:2]([CH3:10])=[CH2:1])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C1OC1(C)C
Solvent: c1ccccc1
Product: C=C(C)C(O)C(=O)OCC
Temperature: 81 °C
Yield: 77.8 %

Procedure:
Tosic acid monohydrate (0.132 g, 0.694 mmol) was dehydrated by aezotropic destillation with benzene (3×10 ml) in a rotary evaporator flushed with nitrogen. Thereafter benzene (100 ml) and ethyl 3,3-dimethyloxirane-2-carboxylate (1 g, 6.94 mmol) were added and the resulting mixture was stirred at reflux (81° C.) overnight. The clear reaction mixture was then cooled to room temperature, cooled to 4° C. for a couple of hours, and then filtered over a glass filter to remove the crystallized tosic acid. The filtrate was concentrated in vacuo (40° C., 50 mbar) to yield 778 mg of crude product (containing 2.5 wt % benzene) which was used without further purification in the next step.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[N:29]2[C:24]([CH:25]=[N:26][C:27]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[CH:33][CH:32]=3)=[N:28]2)=[CH:23][CH:22]=1.[CH:43]([C:45]1[CH:46]=[C:47](B(O)O)[CH:48]=[CH:49][CH:50]=1)=[O:44].C(=O)([O-])[O-].[Na+].[Na+].O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[N:37]1([C:34]2[CH:33]=[CH:32][C:31]([NH:30][C:27]3[N:26]=[CH:25][C:24]4=[CH:23][CH:22]=[C:21]([C:49]5[CH:50]=[C:45]([CH:46]=[CH:47][CH:48]=5)[CH:43]=[O:44])[N:29]4[N:28]=3)=[CH:36][CH:35]=2)[CH2:38][CH2:39][O:40][CH2:41][CH2:42]1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: Brc1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cccc(-c2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Into a 8-dram vial, Palladium Acetate (0.021 g, 0.000094 mol) and Triphenylphosphine (0.069 g, 0.00026 mol) were added. The mixture was purged under an atmosphere of Nitrogen for 10 minutes. 1,4-Dioxane (7.10 mL) was added and stirred for 10 minutes at room temperature. (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-(4-morpholin-4-yl-phenyl)-amine (0.35 g, 0.00094 mol), 3-Formylphenyl boronic acid (0.280 g, 0.00187 mol), N,N-Dimethylformamide (14 mL), and 1.50 M of Sodium carbonate in Water (5.61 mL, 8.42 mmol) were added. The reaction was heated at 90° C. for 3 hours. The reaction was partitioned with water and EtOAc. The organic was separated, washed with Brine, and dried over magnesium sulfate. The solid was filtered and washed with EtOAc. The solvent was removed under vacuum. The product was isolated via column chromatography with DCM and Methanol as eluant (0 to 10% MeOH). The collected fractions afforded a solid. The solid was triturated with Et2O and filtered to give 3-[2-(4-Morpholin-4-yl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-benzaldehyde as a yellow (0.20 g, 50%).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:22]3[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=3)=[N:9][C:10]3[C:15]([CH:16]=2)=[C:14]([C:17]2[CH:18]=[N:19][NH:20][CH:21]=2)[N:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:30][CH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CN1C(=O)CCC1>[CH3:35][C:32]([CH3:36])([CH2:31][NH:30][CH2:26][C:25]1[CH:24]=[CH:23][C:22]([C:8]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[N:13][C:14]=3[C:17]3[CH:21]=[N:20][NH:19][CH:18]=3)[N:9]=2)=[CH:29][CH:28]=1)[CH2:33][OH:34]
Reactant: CC(C)(CN)CO
Reactant: O=Cc1ccc(-c2nc3ccnc(-c4cn[nH]c4)c3cc2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: CC(C)(CO)CNCc1ccc(-c2nc3ccnc(-c4cn[nH]c4)c3cc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[3-phenyl-5-(1H-pyrazol-4-yl)-1,6-naphthyridin-2-yl]benzaldehyde (1-3) (0.11 g, 0.29 mmol) in NMP (10 mL) was added 3-amino-2,2-dimethylpropan-1-ol (0.030 g, 0.29 mmol) and acetic acid (0.026 g, 0.43 mmol). After stirring at room temperature for 2 hours, sodium triacetoxyborohydride (0.092 g, 0.43 mmol) was added and the reaction was stirred at room temperature for 15 hours. The reaction was poured into saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. Purification by reverse phase chromatography (5-95% acetonitrile/water/0.1% TFA; Water Sunfire C18) gave 2,2-dimethyl-3-({4-[3-phenyl-5-(1H-pyrazol-4-yl)-1,6-naphthyridin-2-yl]benzyl}amino)propan-1-ol (1-4) as a off white solid. HRMS (M+H)+: calculated 464.2207; found 464.2194
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:26][C:25](=O)[CH:24]([F:28])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[Cl:29][C:30]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:31]=1[CH2:32][NH2:33].[OH-].[Na+]>ClCCCl.C(O)(=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:23][CH:24]([F:28])[CH:25]([NH:33][CH2:32][C:31]2[CH:34]=[CH:35][C:36]([Cl:38])=[CH:37][C:30]=2[Cl:29])[CH2:26]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CC(=O)C(F)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC(F)C(NCc2ccc(Cl)cc2Cl)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
Add sodium triacetoxyborohydride (156 mg, 0.73 mmol) to a mixture of 3-fluoro-4-oxopyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 0.5 mmol) and 2,4-dichlorobenzylamine (65 μL, 0.5 mmol) in 1,2-dichloroethane (1.5 mL), followed by 2 drops of glacial acetic acid and stir overnight at room temperature. Pour the crude mixture into 2 N sodium hydroxide and extract with ethyl acetate, wash with water, dry (magnesium sulfate), concentrate and chromatograph on silica gel to give 3-(2,4-dichlorobenzylamino)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (40 mg, 20%). 1H NMR (300 MHz, CDCl3) δ 7.36-7.44 (2H, m), 7.20-7.28 (1H, m), 5.03 (1H, d, J=54.07 Hz), 3.21-3.95 (6H, m), 2.99-3.15 (1H, m), 1.45 (9H, s), MS (ES): m/z=363 [M+].
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13].C(Cl)C>>[C:1]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOP(OCC)OCC
Agent: CCCl
Product: CCOP(=O)(OCC)C(=O)c1ccccc1
Yield: 97.4 %

Procedure:
To 140.57 grams (1.0 mole) of benzoyl chloride at 90° C. there were added 166.2 grams (1.0 mole) of triethyl phosphite over a period of 1 hour. Ethyl chloride evolution ceased at the end of this period. The unreacted benzoyl chloride and triethyl phosphite were removed by distillation at reduced pressure, terminal conditions being 100° C. and 8 mm. leaving a residue of 236 grams (90% yield) of diethyl benzoylphosphonate which was reacted with diethyl sodium phosphite as in Example 1 to produce tetraethyl phenyl hydroxymethane diphosphonate. This was hydrolyzed and the hydrolysis product purified in the same manner as in Example 1 to produce phenyl hydroxymethane diphosphonic acid as a viscous syrup having an acid number of 822 mg. KOH/mg (Theory is 836 mg. KOH/gm); % P 22.8 (Theory 22.9%).
Reaction SMILES: C([Li])CCC.[C:6]([C:10]1[CH:15]=[C:14](I)[C:13]([O:17][CH3:18])=[CH:12][C:11]=1[F:19])([CH3:9])([CH3:8])[CH3:7].[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C.Cl>C1COCC1>[C:6]([C:10]1[C:11]([F:19])=[CH:12][C:13]([O:17][CH3:18])=[C:14]([B:20]([OH:25])[OH:21])[CH:15]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: COc1cc(F)c(C(C)(C)C)cc1I
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(F)c(C(C)(C)C)cc1B(O)O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyl lithium (1.6 M in hexanes, 406 μL, 0.649 mmol) was added to a stirred solution of 1-tert-butyl-2-fluoro-5-iodo-4-methoxybenzene (200 mg, 0.649 mmol) in dry THF (2 mL) at −78° C. under N2. The reaction was stirred at −78° C. for 1 h then triisopropyl borate (214 mg, 262 μL, 1.14 mmol) was added dropwise. The reaction was stirred at −78° C. for 1 h and 0° C. for 1 h. 1N HCl was added and the reaction was extracted with EtOAc (3×). The combined extracts were dried (Na2SO4) and concentrated in vacuo to afford (5-tert-butyl-4-fluoro-2-methoxyphenyl)boronic acid. 1H NMR (600 MHz, CDCl3): δ 6.86 (d, J=8.0 Hz, 1H); 6.57 (d, J=13.0 Hz, 1H); 3-85 (s, 3H); 1.33 (s, 9H).
Reaction SMILES: [C:1]12([CH2:11][N:12]3[CH:16]=[C:15]([Cl:17])[CH:14]=[N:13]3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[O:2]1)[CH2:8]2.[CH2:18]([Li])CCC.IC>O1CCCC1.CCOCC>[C:1]12([CH2:11][N:12]3[C:16]([CH3:18])=[C:15]([Cl:17])[CH:14]=[N:13]3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[O:2]1)[CH2:8]2
Reactant: Clc1cnn(CC23CC4CC(CC(C4)O2)C3)c1
Reactant: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(Cl)cnn1CC12CC3CC(CC(C3)O1)C2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of EXAMPLE 59A (0.25 g) in tetrahydrofuran (3 mL) was cooled to −78° C. butyllithium was (0.48 mL) added dropwise. Additional tetrahydrofuran (2 mL) was added and the reaction mixture was stirred for 1 hour at −78° C. To the reaction mixture was added iodomethane (0.08 mL) in one portion and the reaction was allowed to warm to 0° C. After 30 minutes, the reaction was diluted with ether (50 mL), washed with water (30 mL) and brine (30 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with a gradient of 3% to 20% ethyl acetate/hexanes provided the title compound.
Reaction SMILES: CC(C(C)C=C)C=O.[CH3:9][C:10]([CH:15]([CH2:17][CH3:18])[CH3:16])([CH2:13][OH:14])[CH2:11][OH:12].C=O>>[CH3:9][C:10]([CH2:13][OH:14])([CH:15]([CH3:16])[CH:17]=[CH2:18])[CH2:11][OH:12]
Reactant: CCC(C)C(C)(CO)CO
Agent: C=CC(C)C(C)C=O
Agent: C=O
Product: C=CC(C)C(C)(CO)CO

Procedure:
I have now found a novel method for producing mebutamate diol which includes the process steps of reacting crotyl alcohol and allyl chloride to produce a mixture of isomers of allyl crotyl ether, heating said crotyl ether to produce 2,3-dimethyl-pent-4en-aldehye. The aldehyde is then converted to 2-methyl-2-(sec butyl)-1, 3-propanediol by reacting 2,3-dimethyl-pent-4en-aldehyde and formaldehyde to produce 2,3-dimethyl-2-hydroxymethyl-pent-4en-ol and subsequently hydrogenating the said alcohol in the presence of a catalyst to produce 2-methyl-2-(sec butyl)-1,3-propanediol.