Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3([CH3:29])[C:18]4[CH:19]=[C:20]([CH:23]=[CH:24][C:25]([O:27]C)=[O:26])[CH:21]=[CH:22][C:17]=4[O:16][CH2:15]3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>C1COCC1>[CH3:1][C:2]1([CH3:30])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3([CH3:29])[C:18]4[CH:19]=[C:20]([CH:23]=[CH:24][C:25]([OH:27])=[O:26])[CH:21]=[CH:22][C:17]=4[O:16][CH2:15]3)[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)C=Cc1ccc2c(c1)C(C)(c1ccc3c(c1)C(C)(C)CCC3(C)C)CO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(C3(C)COc4ccc(C=CC(=O)O)cc43)ccc21

Procedure:
A mixture of methyl 3-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-3-methyl-2,3-dihydrobenzofuran-5-yl]acrylate (330 mg, 0.79 mmol), a 2N methanolic sodium hydroxide solution (4 ml, 7.9 mmol) in THF (3 ml) is heated for 5 hours at 60° C. The mixture is acidified to pH 1 with a concentrated hydrochloric acid solution, extracted with ethyl acetate and washed with water. After drying the organic phase is concentrated in vacuo at 40° C. in a rotary evaporator, the product is purified by flash chromatography on a silica column.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].C(N(CC)CC)C>C1COCC1>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:10]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[O:11])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: COc1ccc(N=C=O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.3 %

Procedure:
4-Methoxyphenyl isocyanate (0.4 g, 2.6 mmol) was added to a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.0 mmol) and triethylamine (0.3 g, 2.8 mmol) in THF (30 mL) at 5-10° C. After 10 minutes, the mixture was stirred at room temperature overnight. The reaction was quenched with methanol (1 mL), and the mixture was concentrated. The residue was stirred with 1N HCl (30 mL) for one hour and then filtered. The solid was slurried with hot ethanol (20 mL) to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-(4-methoxy-phenyl)-urea (0.5 g, 59%) as a white solid: mp 205-207° C.; 1H NMR (DMSO-d6) δ 2.05-2.09 (m, 1H), 2.49-2.65 (m, 2H), 2.84-2.97 (m, 1H), 3.68 (s, 3H, OCH3), 4.70 (d, J=5.7 Hz, 2H, CH2), 5.13-5.20 (dd, J=5.2 and 12.4 Hz, 1H, CH), 6.66 (t, J=5.7 Hz, 1H, NH), 6.79 (d, J=9.0 Hz, 2H, Ar), 7.27 (d, J=9.0 Hz, 2H, Ar), 7.75-7.88 (m, 3H, Ar), 8.59 (a, 1H, NH), 11.65 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.94, 48.86, 55.10, 113.86, 119.50, 121.82, 127.15, 131.59, 133.38, 133.62, 134.70, 140.46, 154.03, 155.45, 167.02, 167.60, 169.84, 172.22; Anal. calcd. for C22H20N4O6: C, 60.55; H, 4.62; N, 12.84. Found: C, 60.43; H, 4.42; N, 12.58.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)=O.[CH3:14][C:15]1[NH:16][CH:17]=[CH:18][N:19]=1>>[CH3:14][C:15]1[N:19]2[CH2:2][CH2:3][CH:4]=[C:5]([C:7]3[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=3)[C:18]2=[CH:17][N:16]=1
Reactant: Cc1ncc[nH]1
Reactant: Cc1ccc(C(=O)CCCCl)cc1
Product: Cc1ccc(C2=CCCn3c2cnc3C)cc1

Procedure:
Combine 50 g (0.25 mol) of 4-chloro-4'-methylbutyrophenone with 124 g (1.5 mol) of 2-methylimidazole and heat to 175° C. for 70 hr. Crystallize from ether to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:23]2[C:22]([CH3:25])([CH3:24])[N:10]3[CH2:11][CH2:12][C:13]4[C:18]([C:9]3=[C:8]([CH3:26])[C:7]=2[CH:6]=[CH:5][C:4]=1[O:27][CH3:28])=[CH:17][C:16]1[O:19][CH2:20][O:21][C:15]=1[CH:14]=4.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:23]2[C:22]([CH3:25])([CH3:24])[N:10]3[CH2:11][CH2:12][C:13]4[C:18]([CH:9]3[CH:8]([CH3:26])[C:7]=2[CH:6]=[CH:5][C:4]=1[O:27][CH3:28])=[CH:17][C:16]1[O:19][CH2:20][O:21][C:15]=1[CH:14]=4
Reactant: COc1ccc2c(c1OC)C(C)(C)N1CCc3cc4c(cc3C1=C2C)OCO4
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1OC)C(C)(C)N1CCc3cc4c(cc3C1C2C)OCO4
Temperature: 0 °C
Reaction time: 1 h
Yield: 49.2 %

Procedure:
To a solution of 9,10-dimethoxy-8,8,13-trimethyl-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (60 mg, 0.16 mmol) in methanol (10 mL) was added sodium borohydride (15 mg, 0.39 mmol) in small portions at 0° C. After stirring at 0° C. for 1 h, the reaction solvent was concentracted (? concentrated?) in vacuo. The resulting residue was extracted with diethyl ether (2×50 mL), washed with water (2×25 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was re-crystallized from methanol to afford 9,10-dimethoxy-8,8,13-trimethyl-5,8,13,13a-tetrahydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (30 mg, 49%). LC/MS m/e calcd for C23H27NO4 (M+H)+: 382.48, observed: 382.2; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.78 (d, J=6.82 Hz, 3 H) 1.41 (s, 3 H) 1.57 (s, 3 H) 2.31-2.40 (m, 1 H) 2.55-2.62 (m, 1 H) 2.66-2.75 (m, 1 H) 2.94-3.02 (m, 1 H) 3.23-3.30 (m, 1 H) 3.79 (d, J=6.06 Hz, 6 H) 4.03 (s, 1 H) 5.95 (d, J=3.28 Hz, 2 H) 6.66 (s, 1 H) 6.81 (m, 2 H) 6.93 (d, J=8.59 Hz, 1 H).
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][NH:9][C:10]([C:11]3[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=3)=[C:6]2[C:5](=[O:17])[N:4]([CH3:18])[C:3]1=[O:19].Br[CH2:21][CH2:22][CH2:23][C:24]([N:26]([O:28][CH3:29])[CH3:27])=[O:25].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:21][CH2:22][CH2:23][C:24]([N:26]([O:28][CH3:29])[CH3:27])=[O:25])[C:10]([C:11]3[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=3)=[C:6]2[C:5](=[O:17])[N:4]([CH3:18])[C:3]1=[O:19]
Reactant: CON(C)C(=O)CCCBr
Reactant: Cn1ccc(-c2[nH]cc3c2c(=O)n(C)c(=O)n3C)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)CCCn1cc2c(c1-c1ccn(C)n1)c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 22 h

Procedure:
1,3-Dimethyl-5-(1-methyl-1H-pyrazol-3-yl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (800 mg, 3.09 mmol), 4-bromo-N-methoxy-N-methylbutanamide (Intermediate P) (843 mg, 4.01 mmol) and cesium carbonate (2011 mg, 6.17 mmol) were suspended in DMF (11.100 ml) and the mixture was stirred at room temperature for 22 hours. The mixture was poured into water (50 ml) and extracted with DCM (3×100 ml). The combined organic extracts were washed with water (2×50 ml) and brine (50 ml), dried over sodium sulfate and evaporated under vacuum. Purification by mass-directed HPLC under the following conditions afforded the title compound.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([C:19]([F:22])([F:21])[F:20])[C:12]=2[CH3:23])[N:9]=[N:8][N:7]=1)(=O)C.O.[OH-].[Li+]>O.O1CCCC1>[OH:4][CH2:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([C:19]([F:22])([F:21])[F:20])[C:12]=2[CH3:23])[N:9]=[N:8][N:7]=1
Reactant: CC(=O)OCc1nnnn1-c1ccc(C#N)c(C(F)(F)F)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(-n2nnnc2CO)ccc(C#N)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of {1-[4-cyano-2-methyl-3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl acetate (Intermediate 47, 330 mg, 1.02 mmol) in water (2 mL) and tetrahydrofuran (4 mL), cooled in an ice bath, was added lithium hydroxide monohydrate (42.6 mg, 1.02 mmol). The reaction was stirred at room temperature for 1 hour and 30 min. The organic solvent was removed from the reaction under vacuum and the residual mixture diluted with water (30 mL) and extracted with DCM (2*50 ml). The organic extracts were combined, dried (hydrophobic frit) and the solvent removed to yield the titled compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH:9]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].CCCCCC>C(#N)C>[Cl:8][C:7]1[C:2]([N:15]2[CH2:16][CH2:17][N:12]([CH:9]([CH3:11])[CH3:10])[CH2:13][CH2:14]2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: CC(C)N1CCNCC1
Reactant: Clc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC#N
Product: CC(C)N1CCN(c2nccnc2Cl)CC1
Yield: 79.4 %

Procedure:
A mixture 2,3-dichloro-pyrazine (5.0 g, 34 mmol), 1-isopropylpiperazine (6.5 g, 51 mmol) and potassium carbonate (7.0 g, 51 mmol) in acetonitrile (100 mL) was stirred at ambient temperature for 2 h. Addition of hexane, followed by filtration and concentration of the filtrate gave 9.5 g of crude material as an orange liquid. Purification by filtration through silica using heptane/EtOAc (3:1), followed by EtOAc/acetone (1:1), provided 6.5 g (79%) of the title compound as a yellow oil which solidified upon cooling. HPLC purity: 98%. MS m/z 241 (M+H)+. HRMS m/z calcd for C11H17ClN4 (M)+ 240.1142, found 240.1138.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][N:17]=2)[C:13]#[N:14])[CH:6]=[CH:7][CH:8]=1.[OH:18][C:19]1[C:24]([CH2:25][CH2:26][CH3:27])=[C:23](O)[CH:22]=[CH:21][C:20]=1[C:29](=[O:31])[CH3:30]>>[C:29]([C:20]1[CH:21]=[CH:22][C:23]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([S:9][C:10]3[CH:11]=[C:12]([CH:15]=[CH:16][N:17]=3)[C:13]#[N:14])[CH:6]=[CH:7][CH:8]=2)=[C:24]([CH2:25][CH2:26][CH3:27])[C:19]=1[OH:18])(=[O:31])[CH3:30]
Reactant: N#Cc1ccnc(Sc2cccc(CO)c2)c1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Product: CCCc1c(OCc2cccc(Sc3cc(C#N)ccn3)c2)ccc(C(C)=O)c1O
Yield: 81.2 %

Procedure:
Using the method of Preparation 166 using 2-(3-(hydroxymethyl)phenylthio) isonicotinonitrile (1.25 g, 5.15 mmol) and 1-(2,4-dihydroxy-3-propylphenyl)ethanone (1.00 g, 5.15 mmol) affords the title compound (1.75 g, 81%). MS (APCI-neg) m/z (rel intensity): 417 (M−H, 100%).
Reaction SMILES: [CH2:1]([P:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])[O:4]CC)[CH3:2].Cl>C(O)C>[CH2:1]([P:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:4])[OH:7])[CH3:2]
Reactant: CCOP(=O)(CC)c1ccccc1
Agent: Cl
Solvent: CCO
Product: CCP(=O)(O)c1ccccc1
Reaction time: 6 h
Yield: 98 %

Procedure:
A solution of ethyl (ethyl)(phenyl)phosphinate (130 mg, 0.66 mmol) in ethanol (0.5 ml) was treated with 4N HCl (1 ml) and refluxed for 22 hours. Tlc analysis revealed some residual starting material. The ethanol was removed on the rotary evaporator, an additional aliquot of 4N HCl (1 ml) was added, and reflux was resumed for a further six hours whereupon tlc analysis revealed complete consumption of starting material. The mixture was lyophillized to afford 110 mg (99%) of the title compound as a white solid; MS: 171 m/z (M+H)+ ; analysis calculated for C8H11O2P: C, 56.47; H, 6.53; P, 18.20; Found: C, 56.23; H, 6.35; P, 18.52.
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[CH2:12][C:13]#[N:14].[N:15](OCCC(C)C)=[O:16]>CO>[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[C:12](=[N:15][OH:16])[C:13]#[N:14]
Reactant: N#CCc1ccc(Cl)cc1Cl
Reactant: CC(C)CCON=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#CC(=NO)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.1 %

Procedure:
Under an ice cooling, sodium methoxide (2.70 g) was dissolved in methanol (100 ml), and 2,4-dichlorophenylacetonitrile (9.30 g, 50 mmol) and isoamyl nitrite (5.85 g) were added thereto. The mixture was stirred for 18 hours at a room temperature. The solvent was distilled off, and the residue was crystallized by adding diethyl ether (100 ml) to the residue. The resulting crystal was separated by filtration and azeotropically dried with benzene to give the title compound (9.68 g, 90%).
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]1[CH2:17][CH2:16][N:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]1>CC(C)=O.C(=O)(O)[O-].[Na+].C(OCC)C>[CH3:1][S:2][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]1[CH2:17][CH2:16][N:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]1
Reactant: C[S-]
Reactant: CC(C)(C)OC(=O)NN1CCC(c2ccccc2CCl)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: CSCc1ccccc1C1CCN(NC(=O)OC(C)(C)C)CC1
Reaction time: 6 h
Yield: 52.4 %

Procedure:
Sodium thiomethoxide (0.220 g) tetra-n-butylammonium bromide (0.100 g) and tert-butyl 4-(2-chloromethylphenyl)piperidinecarbamate (0.867 g) were combined in acetone (20 mL) under nitrogen and stirred for 6 h, then heated under reflux for 90 min. The reaction was diluted with aqueous sodium bicarbonate and diethyl ether. The organic phase was dried and evaporated and the residue purified by chromatography (6:1 hexanes:ethyl acetate) to give tert-butyl 4-(2-methylthiomethylphenyl)piperidinecarbamate (0.471 g) as a yellow oil. MS: m/z222 (M-Boc). 1H NMR (CDCl3) δ 7.18 (m, 4H, Ar—H), 3.68 (s, 2H, Ar—CH2—S), 3.04 (m, 1H), 2.80 (m,3H), 2.04 (s, 3H, S—CH3), 1.70 (m, 5H), 1.49 (s, 9H). This material was N-deprotected with HCl according to the conditions described for Example 21d to afford 4-(2-methylthiomethylphenyl)piperidine. 1H NMR (CDC13) δ 7.30 (m, 4H, Ar—H), 3.77 (s, 2H), 3.63 (m, 2H), 3.10 (m, 3H), 2.25 (m, 2H), 2.04 (s, 3H, S—CH3), 1.95 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[N:6]([C@H:7]2[O:24][CH2:23][C@H:18]([O:19]C(=O)C)[C@H:13]([O:14]C(=O)C)[C@@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[C:26]([Cl:30])[C:27]([Cl:29])=[CH:28][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[Br:1][C:2]1[N:6]([C@H:7]2[O:24][CH2:23][C@H:18]([OH:19])[C@H:13]([OH:14])[C@@H:8]2[OH:9])[C:5]2[CH:25]=[C:26]([Cl:30])[C:27]([Cl:29])=[CH:28][C:4]=2[N:3]=1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)OC[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O[C@@H]1[C@H](O)[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)OC[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
An alcoholic solution of 2-bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl-beta-L-ribopyranosyl)-1H-benzimidazole (0.50 g, 0.95 mmol) was deprotected according to General Procedure VI with 0.61 g (5.8 mmol) of sodium carbonate in 5 ml of water. After stirring overnight at ambient temperature, the mixture was filtered and treated as described in General Procedure VI to give 2-bromo-5,6-dichloro-1-beta-L-ribopyranosyl-1H-benzimidazole (0.27 g, 0.68 mmol, 72% yield); MS (API+): m/z (rel. intensity) 398 (1.0, M+); 1H NMR (DMSO-d6) δ7.96 (s,1H), 7.07 (s, 1H), 5.64-5.62 (d, J=9.2 Hz), 5.19-5.17 (d, 1H, J=6.4 Hz), 5.13-5.12 (d, 1H, J=3.2 Hz), 4.86-4.84 (d, 1H, J=6.5 Hz), 4.12-4.06 (m, 1H), 3.98-3.92 (m, 2H), 3.68-3.63 (m, 2H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[S:14][C:13]([CH2:15][C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:21]=[N+:22]([O-:40])[CH:23]=[C:24]([Cl:39])[C:25]=1[CH2:26][C@@H:27]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=1)O.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[Cl:39][C:24]1[CH:23]=[N+:22]([O-:40])[CH:21]=[C:20]([Cl:19])[C:25]=1[CH2:26][C@H:27]([O:17][C:16](=[O:18])[CH2:15][C:13]1[S:14][C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:11][CH:12]=1)[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=1
Reactant: COc1ccc([C@@H](O)Cc2c(Cl)c[n+]([O-])cc2Cl)cc1OC
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(CC(=O)O)s1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)Cc2ccc(CO[Si](C)(C)C(C)(C)C)s2)cc1OC
Yield: 46 %

Procedure:
To a solution of 2-[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-thienyl]acetic acid (995 mg, 3.48 mmol) in dichloromethane (40 mL) was added (S)-3,5-dichloro-4-(2-(3,4-dimethoxyphenyl)-2-hydroxyethyl)pyridine 1-oxide (1.43 g, 4.17 mmol), followed by 4-(dimethylamino)-pyridine (212 mg, 1.74 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.33 g, 6.96 mmol). The resultant solution was stirred at room temperature for 72 h. The reaction solution was washed with saturated aqueous sodium bicarbonate (2×30 mL), the organic phase passed through a hydrophobic frit and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with 0-100% ethyl acetate in iso-hexane to give the title compound as a pale yellow oil (980 mg, 46%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4][OH:5].C(N(CC)CC)C.[C:20](Cl)(=[O:22])[CH3:21]>ClCCl.C(OCC)(=O)C>[F:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4][O:5][C:20](=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(F)c(CO)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)OCc1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2-fluoro-5-nitrobenzyl alcohol (1 g, 5.84 mmol) in 5 mL dichloromethane and triethylamine (0.81 ml, 5.84 mmol), was added acetyl chloride (0.415 ml, 1 eq) dropwise. The solution was stirred at room temperature for 12 hours, diluted with ethyl acetate and extracted with brine. Combine organic layers was dried over sodium sulfate, concentrated in vacuo to give acetic acid 2-fluoro-5-nitro-benzyl ester.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[CH2:4][C:3]=1[C:12]([OH:14])=O.S(Cl)([Cl:17])=O>>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[CH2:4][C:3]=1[C:12]([Cl:17])=[O:14]
Reactant: O=S(Cl)Cl
Reactant: CC1=C(C(=O)O)Cc2ccc(C)cc21
Product: CC1=C(C(=O)Cl)Cc2ccc(C)cc21

Procedure:
3,5-Dimethyl-indene-2-carboxylic acid (37.3 g) is converted to its acid chloride by treatment with thionyl chloride (580 ml). Excess thionyl chloride is distilled off. Yield 40.5 g, 99%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:17][C:18](=[O:24])[C:19]([O:21]CC)=[O:20])[CH:6]=[C:7]([NH:9][C:10](=[O:16])[C:11]([O:13]CC)=[O:12])[CH:8]=1)#[N:2].[OH-].[Na+]>>[C:1]([C:3]1[CH:8]=[C:7]([NH:9][C:10](=[O:16])[C:11]([OH:13])=[O:12])[CH:6]=[C:5]([NH:17][C:18](=[O:24])[C:19]([OH:21])=[O:20])[CH:4]=1)#[N:2]
Reactant: CCOC(=O)C(=O)Nc1cc(C#N)cc(NC(=O)C(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1cc(NC(=O)C(=O)O)cc(NC(=O)C(=O)O)c1

Procedure:
A solution of 1.51 gram (0.0045 mole) of diethyl N,N'-(5-cyano-m-phenylene)dioxamate in 10 ml. of 5% sodium hydroxide solution is stirred for 25 minutes and filtered. To the filtrate is added dilute hydrochloric acid. The resulting precipitate is removed by filtration; weight 0.86 grams, M. P. 230°C.
Reaction SMILES: [BH4-].[Li+].C[O:4][C:5]([C@@H:7]1[CH2:11][C@H:10]([N:12]=[N+:13]=[N-:14])[CH2:9][N:8]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=O>C(OCC)C>[C:18]([O:17][C:15]([N:8]1[CH2:9][C@@H:10]([N:12]=[N+:13]=[N-:14])[CH2:11][C@H:7]1[CH2:5][OH:4])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1C[C@@H](N=[N+]=[N-])C[C@H]1CO
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
Add lithium borohydride (0.16 mol, 3.6 g) to a solution of (2S,4S)-4-azido-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.16 mol, 40 g) in anhydrous diethyl ether (400 mL) at −10 to −20° C. under a nitrogen atmosphere. Upon complete addition, stir the reaction mixture for 30 min at the same temperature. Quench the reaction mixture with saturated sodium bicarbonate solution at −70° C. and allow it to come to room temperature slowly. Separate the organic layer and extract the aqueous layer with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under vacuum to obtain the title compound (32 g, crude) as a thick, yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.46 (s, 9H), 2.32-2.35 (m, 1H), 3.30 (dd, 1H), 3.65-3.79 (m, 4H), 4.07-4.29 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][C:13]2[C:21]3[C:16](=[N:17][CH:18]=[N:19][C:20]=3[NH2:22])[N:15]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[N:14]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.NC1N=CN=C2N([CH:51]3[CH2:56][CH2:55][N:54]([C:57](=O)C=C)[CH2:53][CH2:52]3)N=C(C#CC3C=C(OC)C=C(OC)C=3)C=12.C[O:62]C1C=C(C#CC2C3C(=NC=NC=3N)N([C@H]3CCNC3)N=2)C=C(OC)C=1>>[NH2:22][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[N:15]([CH:23]3[CH2:24][CH2:25][N:26]([C:52](=[O:62])[CH:51]=[CH:56][CH2:55][N:54]([CH3:57])[CH3:53])[CH2:27][CH2:28]3)[N:14]=[C:13]([C:12]#[C:11][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=3)[C:21]=12
Reactant: COc1cc(C#Cc2nn([C@H]3CCNC3)c3ncnc(N)c23)cc(OC)c1
Reactant: COc1cc(C#Cc2nn(C3CCNCC3)c3ncnc(N)c23)cc(OC)c1
Reactant: C=CC(=O)N1CCC(n2nc(C#Cc3cc(OC)cc(OC)c3)c3c(N)ncnc32)CC1
Product: COc1cc(C#Cc2nn(C3CCN(C(=O)C=CCN(C)C)CC3)c3ncnc(N)c23)cc(OC)c1

Procedure:
In accordance with Example 4, except that 3-((3,5-dimethoxyphenyl)ethynyl)-1-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (i.e., the intermediate obtained in Example 31) was used in place of (S)-3-((3,5-dimethoxyphenyl)ethynyl)-1-(pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, the title compound was obtained as a light-yellow, amorphous substance. Table 1 shows the physical properties thereof.
Reaction SMILES: P(=O)(O)(O)[OH:2].[OH:6][CH2:7][CH2:8][CH2:9][P:10]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:12][CH2:13][OH:14]>O>[OH:6][CH2:7][CH2:8][CH2:9][P:10](=[O:2])([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:12][CH2:13][OH:14]
Reactant: O=P(O)(O)O
Reactant: OCCCP(CCCO)CCCO
Solvent: O
Product: O=P(CCCO)(CCCO)CCCO

Procedure:
The effect of concentrated phosphoric acid in amounts of 1 to 2.5 weight percent was determined by reacting in an autoclave (10.4 g, 0.05 mole) of tris-(3-hydroxypropyl) phosphine, concentrated phosphoric acid (0.15, 0.14 and 0.06 ml of 86% aqueous solution) and 1 ml of water. The yields of tris(3-hydroxypropyl) phosphine oxide after 4.5 to 5 hours at temperatures between 150° C. and 180° C. is summarized in Table III.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][OH:11])[CH:5]=[CH:4][N:3]=1.[CH3:12][S:13](OCCC1C=CN=C(F)C=1)(=[O:15])=[O:14]>>[CH3:12][S:13]([O:11][CH2:10][CH2:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=1)(=[O:15])=[O:14]
Reactant: OCCCc1ccnc(F)c1
Reactant: CS(=O)(=O)OCCc1ccnc(F)c1
Product: CS(=O)(=O)OCCCc1ccnc(F)c1
Yield: 69 %

Procedure:
This compound was prepared, starting from compound 48 (5.00 g, 32.2 mmol), according to the procedure developed for compound 43. Reaction time at 0° C.: 30 min; the purification was performed using column chromatography (SiO2, AcOEt/pentane, 8/2, v/v) to give compound 49 (4.82 g, 20.7 mmol) as a yellow oil. Yield 69%; Rf (SiO2, AcOEt/pentane, 8/2, v/v) 0.58; IR (CCl4) ν 1179, 1351, 1371, 1413, 1613 cm−1; 1H NMR (200 MHz, CDCl3) δ 2.12 (m, 2H), 2.83 (t, 2H, J=7.3 Hz), 3.05 (s, 3H), 4.28 (t, 2H, J=6.1 Hz), 6.80 (s, 1H), 7.07 (m, 1H), 8.15 (d, 1H, J=5.1 Hz).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:19])=[CH:13][CH:12]=2)[CH:7]=1)=[O:5])C.[K+].[Br-]>>[CH:21]1([NH:20][C:18](=[O:19])[NH:17][C:14]2[CH:13]=[CH:12][C:11]([C:8]3[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[O:10][N:9]=3)=[CH:16][CH:15]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCOC(=O)c1cc(-c2ccc(NC(=O)NC3CCCCC3)cc2)no1
Agent: [Br-]
Agent: [K+]
Product: O=C(Nc1ccc(-c2cc(C(=O)O)on2)cc1)NC1CCCCC1
Yield: 92 %

Procedure:
The title compound was prepared from 3-[4-(3-cyclohexyl-ureido)-phenyl]-isoxazole-5-carboxylic acid ethyl ester as set forth in Example 8 and was obtained in 92% yield. Mass (ES+): 330 (M++1); IR (KBr): 3318, 2927, 2853, 1711, 1637, 1563; 1H NMR (DMSO-d6) δ: 1.05-1.80 (4×m, 10H), 3.45 (br, 1H), 6.17 (d, 1H), 7.49 (d, 2H), 7.66 (s, 1H), 7.79 (d, 2H), 8.58 (s, 1H), 14.5 (br, ˜0.5H).