Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][N:7]3[C:12](=O)[CH2:13][CH2:14][CH:6]3[C:5](=[O:16])[C:4]=2[CH:3]=1.[OH2:17].O.O.C([O-])(=O)C.[Na+].Cl.[NH2:26]O>C(O)C.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][N:7]3[CH2:12][CH2:13][C:14](=[N:26][OH:17])[CH:6]3[C:5](=[O:16])[C:4]=2[CH:3]=1
Reactant: O=C1c2cc(Cl)ccc2CN2C(=O)CCC12
Reactant: NO
Reactant: O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C1c2cc(Cl)ccc2CN2CCC(=NO)C12
Yield: 81.4 %

Procedure:
A stirred suspension of 12.65 g of 8-chloro-1,10a-dihydropyrrolo[1,2-b]isoquinoline-3,10[2H,5H]-dione (prepared in substantially the same manner as the 7-chloro compound in Example 12, m.p. 130°-136° C.) in 95% ethanol (85 ml) was treated with a premixed solution prepared from sodium acetate trihydrate (14.56 g) in water (48 ml) and hydroxylamine hydrochloride (7.44 g) in water (48 ml). The stirred suspension was heated to reflux, during which a solution formed followed by separation of a crystalline precipitate. After 2 hours of refluxing, the mixture was cooled and the precipitate was collected and washed twice with 50% aqueous ethanol. Drying at 40° C. overnight in vacuo gave 10.95 g of a solid, m.p. 227.5°-230.5° C. Recrystallization of the solid from n-propanol (300 ml) afforded 8.56 g of crystals, m.p. 229°-235° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[S:11]([O-:14])([O-])=[O:12].[Na+].[Na+].P(Cl)(Cl)(Cl)(Cl)[Cl:18]>>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH2:2][S:11]([Cl:18])(=[O:14])=[O:12])=[CH:4][CH:5]=1)#[N:8]
Reactant: O=S([O-])[O-]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Product: N#Cc1ccc(CS(=O)(=O)Cl)cc1

Procedure:
4-Bromomethylbenzonitrile was reacted with sodium sulphite followed by phosphorus pentachloride to give 4-cyanobenzylsulphonyl chloride which was reacted with pentylamine in a similar manner to N14 to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[C:4]([CH3:21])[CH:3]=1.[BH4-].[Na+].C1(N)CCCCC1>C(Cl)CCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH:14]([OH:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:13]=2)=[C:4]([CH3:21])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1-c1ccc(C(=O)CCC(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: NC1CCCCC1
Product: Cc1cc(Cl)ccc1-c1ccc(C(O)CCC(=O)O)cc1
Yield: 96 %

Procedure:
Prepared analogous to Example 25 by reduction of 4-(4'-chloro-2'-methyl-4-biphenylyl)-4-oxo-butyric acid (m.p. 153°-154° C.) with sodium borohydride. Yield: 96%. Melting point of the cyclohexylamine salt: 139°-140° C. (from ethylene chloride/ethyl acetate 5:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C@@H:14]([CH3:17])[CH2:15][OH:16])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:18]=O.[BH4-].[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH3:18])[C@@H:14]([CH3:17])[CH2:15][OH:16])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN[C@@H](C)CO)cc1OC
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(CCN(C)[C@@H](C)CO)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.1 %

Procedure:
To a solution of 6.25 g of (0.026 mole) (S)-2-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-1-propanol in 50 ml of MeOH under argon was added 3.9 ml (0.052 mole) of 37% aqueous formaldehyde and 4.7 g of sodiumborohydride pellets added one at a time. The solution was stirred at RT for 24 hr. an additional 1.0 ml of 37% aqueous formaldehyde and 1.0 g of sodium borohydride were added and the solution stirred for an additional 2.5 hr. Enough glacial acetic acid was added to react with the sodium borohydride. The reaction was made basic by addition of 3N sodium hydroxide. The methanol was evaporated in vacuo and the residue was extracted three times with ether. The organics were washed with brine an dried (K2CO3). Evaporation of the solvent in vacuo gave 5.74 g of (S)-2-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]-1-propanol as an oil (87% yield).
Reaction SMILES: [C:1]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#N)=[CH:12][CH:11]=2)=[C:6]([Cl:34])[C:5]=1[OH:35])(=[O:3])[CH3:2].[OH-:36].[K+].Cl.[OH2:39]>C(O)C>[C:1]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]([OH:39])=[O:36])=[CH:12][CH:11]=2)=[C:6]([Cl:34])[C:5]=1[OH:35])(=[O:3])[CH3:2]
Reactant: [OH-]
Reactant: CC(=O)c1ccc(OCc2ccc(C(OC3CCCCO3)c3cccc(C#N)c3)cc2)c(Cl)c1O
Reactant: O
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CC(=O)c1ccc(OCc2ccc(C(OC3CCCCO3)c3cccc(C(=O)O)c3)cc2)c(Cl)c1O
Yield: 96 %

Procedure:
Heat a solution of 3-[[4-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile (10.00 g, 20.33 mmol) and potassium hydroxide (22.81 g, 406.5 mmol) in ethanol (100 mL) and water (25 mL) at reflux for 3 days. Evaporate volatiles and acidify with 1N hydrochloric acid and extract with CH2Cl2 (3×). Combine organic layers, dry (sodium sulfatesodium sulfate) and evaporate to afford the title compound as a white solid (10.00 g, 19.57 mmol, 96%): MS (m/z): 510 (M−H).
Reaction SMILES: [F:1][C:2]1[C:7]([Li:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].Br[C:14]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:15]=1[F:24].C([Li:29])CCC.[S:30](=O)=[O:31]>C(OCC)C.CCCCCC>[F:1][C:2]1[C:7]([Li:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].[F:20][C:19]1[C:14]([S:30][O-:31])=[C:15]([F:24])[C:16]([F:23])=[C:17]([F:22])[C:18]=1[F:21].[Li+:29]
Reactant: O=S=O
Reactant: [Li]CCCC
Reactant: Fc1c(F)c(F)c(Br)c(F)c1F
Agent: [Li]c1c(F)c(F)c(F)c(F)c1F
Solvent: CCOCC
Solvent: CCCCCC
Product: [Li+]
Product: [O-]Sc1c(F)c(F)c(F)c(F)c1F

Procedure:
Up to now, several synthetic reactions for pentafluorophenyl alkali metal salt are known. For example, a method of producing pentafluorophenyllithium through bromine-metal exchange reaction using relatively expensive bromopentafluorobenzene as a starting raw material for a source of pentafluorophenyl group and butyllithium is already known. For example, in Synthesis of Fluoroorganic Compounds, p. 190, Springer-Verlag (1985), pentafluorophenyllithium is prepared in diethylether-hexane at -70° C. and is reacted with sulfur dioxide to give lithium pentafluorophenylsulfenate with 94% yield. Also, a method of producing pentafluorophenyllithium through hydrogen-metal exchange reaction using pentafluorobenzene as a starting raw material for a source of pentafluorophenyl group and butyllithium is already known. For example, in J. Org. Chem., 29, 2385 (1964), pentafluorophenyllithium prepared from pentafluorobenzene and butyllithium is reacted with carbon dioxide gas to give pentafluorobenzoic acid wherein the reaction yield is unknown, but the purification yield, depending on reaction solvent system, is 68% in diethylether-hexane system, 80.9% in diethylether type and 82% in diethylether-tetrahydrofuran system respectively.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=O)[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.CCN(C(C)C)C(C)C.[C:34]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])(=[O:37])[NH:35][NH2:36]>ClCCl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([NH:36][NH:35][C:34]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:13])[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc2cccnc12
Reactant: CC(C)(C)OC(=O)NN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NNC(=O)c1cccc2cccnc12
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a solution of 8-quinolinecarboxylic acid (750 mg, 4.33 mmol, commercially available from e.g. Sigma-Aldrich, Acros or Apollo) and oxalyl chloride (0.417 ml, 4.76 mmol) in dichloromethane (50 ml) stirred under argon at 0° C. was added neat DMF (34 μl, 0.439 mmol). The reaction mixture was stirred at 0° C. for 18 hr, then evaporated in vacuo and azeotroped with toluene (2×5 ml). The residue was dissolved in dichloromethane (50 ml), and to this were added DIPEA (0.908 ml, 5.20 mmol) and t-butyl carbazate (1259 mg, 9.53 mmol). The reaction mixture was stirred at room temp for 6 hr. The reaction mixture was partitioned between dichloromethane (˜50 ml) and saturated sodium bicarbonate solution (˜25 ml). The aqueous phase was extracted with dichloromethane (2×50 ml) and the combined organic extracts washed with saturated sodium bicarbonate solution (˜50 ml), dried over sodium sulphate and evaporated in vacuo to give the crude product as a burgundy gum. This was purified via Biotage (5:1 DCM/MeOH; 40+M Biotage column; flow rate 20 ml/min) to afford impure product as a burgundy foam. This was further purified via Biotage (1:1 Hex/EtOAc; 40+M Biotage column) and dried overnight in a vacuum oven at 40° C. to afford the required product as a fine, pale yellow powder in 947.8 mg.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[O:28]([CH2:35][C:36](Cl)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:25]([N:24]([CH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:13]=1[C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:27])=[O:2])[CH:6]=1)[C:36](=[O:37])[CH2:35][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:26]
Reactant: O=C(Cl)COc1ccccc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)COc1ccccc1

Procedure:
(2′-{[Ethyl-(2-phenoxy-acetyl)-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (Compound 1-48) was prepared by following the procedures outlined in Example 1 and using (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and phenoxyacetyl chloride.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:8]([C:24]([F:27])([F:26])[F:25])=[CH:7][N:6]=1)(=O)=O.C(OC([NH:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]2[CH2:47][CH2:46][N:45](C(OC(C)(C)C)=O)[CH2:44][CH2:43]2)=[CH:38][C:37]=1[O:55][CH3:56])=O)(C)(C)C.FC(F)(F)C(O)=O>C(O)C(F)(F)F>[CH3:56][O:55][C:37]1[CH:38]=[C:39]([CH:42]2[CH2:43][CH2:44][NH:45][CH2:46][CH2:47]2)[CH:40]=[CH:41][C:36]=1[NH:35][C:5]1[N:10]=[C:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:8]([C:24]([F:27])([F:26])[F:25])=[CH:7][N:6]=1
Reactant: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1NC(=O)OC(C)(C)C
Reactant: COC(=O)Cc1ccccc1CCc1nc(S(C)(=O)=O)ncc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: OCC(F)(F)F
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)cc2OC)ncc1C(F)(F)F
Temperature: 100 °C

Procedure:
Methyl 2-(2-(2-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I15) (200 mg, 0.497 mmol) and tert-butyl 4-(4-((tert-butoxycarbonyl)amino)-3-methoxyphenyl)piperidine-1-carboxylate (I19) (303 mg, 0.745 mmol) were dissolved in trifluoroethanol (4 mL). Trifluoroacetic acid (200 μL) was added and the resulting mixture was heated at 100° C. under microwave irradiation for 1 hour. The crude reaction mixture was adsorbed onto silica gel and separated by silica gel chromatography (0-20% MeOH/DCM) to give the title compound (I20) (215 mg, 82%) as a light brown liquid; 1H NMR (400 MHz, d6-Acetone) δ 8.64 (s, 1H), 8.37 (dd, J=8.3, 3.7 Hz, 1H), 7.29 (ddd, J=13.2, 6.9, 1.7 Hz, 3H), 7.22 (ddd, J=8.9, 6.1, 1.7 Hz, 1H), 7.10 (d, J=1.5 Hz, 1H), 6.97 (dd, J=8.3, 1.5 Hz, 1H), 3.98 (d, J=7.4 Hz, 3H), 3.82 (s, 2H), 3.74-3.60 (m, 5H), 3.27 (t, J=11.7 Hz, 2H), 3.22-3.06 (m, 4H), 3.00 (s, 1H), 2.34-2.17 (m, 2H), 2.12 (dd, J=4.0, 3.5 Hz, 2H), 2.08 (dt, J=6.6, 2.2 Hz, 3H). LCMS Method C: rt 5.23 min; m/z 529.1 [M+1]+.
Reaction SMILES: C[P:2]([OH:11])([CH2:4][CH2:5][CH:6](N)C(O)=O)=[O:3].P(Cl)(Cl)Cl.[Cl-:16].[Cl-].[Cl-].[Cl-].[Al+3].[CH2:21]=[CH2:22]>C(O)C>[Cl:16][CH2:6][CH2:5][CH2:4][PH:2](=[O:3])[O:11][CH2:21][CH3:22]
Reactant: [Cl-]
Reactant: C=C
Reactant: CP(=O)(O)CCC(N)C(=O)O
Agent: [Al+3]
Solvent: ClP(Cl)Cl
Solvent: CCO
Product: CCO[PH](=O)CCCCl

Procedure:
Alternatively, another method of producing glufosinate generally comprises converting phosphorus trichloride to an adduct of methylphosphonous trichloride and aluminum tetrachloride (i.e., CH3PCl3.AlCl4). The adduct may be reacted with ethylene to form an intermediate adduct, which then may be reacted with ethanol to form ethyl 1-(2-chloroethyl)-methylphosphinate. Ethyl 1-(2-chlorethyl)-methylphosphinate may then be reacted with potassium hydroxide and ethanol to prepare the requisite ethyl vinylphosphinate precursor. The ethyl vinylphosphinate precursor is subjected to hydroformylation-aminocarbonylation, followed by hydrolysis of the hydroformylation-aminocarbonylation product in the presence of hydrochloric acid to produce glufosinate.
Reaction SMILES: Br[CH2:2][CH2:3][S:4][C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[C:11]([C:13]3[C@H:14]([CH3:37])[C@@H:15]4[C@@H:32]([C@H:33]([OH:35])[CH3:34])[C:31](=[O:36])[N:16]4[C:17]=3[C:18]([O:20]CC3C=CC([N+]([O-])=O)=CC=3)=[O:19])[S:10][C:9]=12.[NH2:38][C:39]([NH2:41])=[S:40]>C(#N)C.CN(C=O)C>[OH:35][C@@H:33]([C@H:32]1[C:31](=[O:36])[N:16]2[C:17]([C:18]([OH:20])=[O:19])=[C:13]([C:11]3[S:10][C:9]4=[C:5]([S:4][CH2:3][CH2:2][NH:41][C:39](=[NH:38])[SH:40])[N:6]=[CH:7][N:8]4[CH:12]=3)[C@H:14]([CH3:37])[C@H:15]12)[CH3:34]
Reactant: NC(N)=S
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SCCBr)c4s3)[C@H](C)[C@H]12
Solvent: CC#N
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(c3cn4cnc(SCCNC(=N)S)c4s3)[C@H](C)[C@H]12
Temperature: 50 °C
Reaction time: 18 h
Yield: 14.7 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-2-[7-(2-bromoethyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (128 mg) was dissolved in 3 ml of acetonitrile and 0.5 ml of DMF. Thiourea (222 mg) was added to the solution. The mixture was stirred at 50° C. for 18 hr. The reaction solution was concentrated under the reduced pressure. The residue was purified by column chromatography on Sephadex LH-20 (dichloromethane:methanol=1:1), followed by a reaction and purification in the same manner as in Example 1c). Thus, 14.5 mg of the title compound was prepared.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][OH:7].[H-].[Na+].F[C:11]1[N:16]=[C:15]([CH2:17][N:18]2[C:22]3=[N:23][C:24]([NH:27][C:28]4[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=4)=[N:25][CH:26]=[C:21]3[CH:20]=[N:19]2)[CH:14]=[CH:13][CH:12]=1>CN(C=O)C>[CH3:33][N:31]1[CH:32]=[C:28]([NH:27][C:24]2[N:23]=[C:22]3[N:18]([CH2:17][C:15]4[CH:14]=[CH:13][CH:12]=[C:11]([O:7][CH2:6][C@H:2]5[CH2:3][CH2:4][CH2:5][O:1]5)[N:16]=4)[N:19]=[CH:20][C:21]3=[CH:26][N:25]=2)[CH:29]=[N:30]1
Reactant: OC[C@H]1CCCO1
Reactant: Cn1cc(Nc2ncc3cnn(Cc4cccc(F)n4)c3n2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(Nc2ncc3cnn(Cc4cccc(OC[C@H]5CCCO5)n4)c3n2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(R)-(Tetrahydrofuran-2-yl)methanol (22 mg, 0.214 mmol) was added to a solution of NaH (10 mg, 0.246 mmol) in dry DMF (1 mL) in a 2-necked flask under Nitrogen. Another portion of NaH (10 mg, 0.246 mmol) was added to a stirring solution of 1-((6-fluoropyridin-2-yl)methyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine (Example 170) (50 mg, 0.154 mmol) in DMF (1 ml). This solution was added to the 2-necked flask and stirred for 16 h at rt. The reaction was quenched with NH4Cl (sat. solution, 1 mL) and diluted with Ethyl Acetate (20 mL). The organics were separated and washed with NaHCO3 (sat. solution, 20 mL). The aqueous phase was re-extracted with Ethyl Acetate (2×10 mL). The combined organics were dried over Na2SO4, filtered and the solvent evaporated to give a crude product that was purified by prep HPLC. (R)—N-(1-methyl-1H-pyrazol-4-yl)-1-((6-((tetrahydrofuran-2-yl)methoxy)pyridin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine was obtained as a white solid (24 mg, 38% yield). 1H NMR (d6-Acetone) δ 8.87 (s, 1H), 8.04 (s, 1H), 7.99 (s, 1H), 7.61 (s and t, 2H), 6.70 (d, 1H), 6.64 (d, 1H), 5.54 (s, 2H), 4.07 (m, 3H), 3.82 (s, 3H), 3.75 (m, 1H), 3.61 (m, 1H), 1.84 (m, 3H), 1.54 (m, 1H); LC-MS method B, (ES+) 407.1, RT=7.65 min.
Reaction SMILES: [C:1]([C:4]1[C:8]([S:9]([CH3:11])=[O:10])=[C:7]([NH2:12])[N:6]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[Cl:24])[N:5]=1)(=O)[CH3:2].Cl.[CH3:26][NH:27][OH:28].N1C=CC=CC=1>CO>[CH3:26][N+:27]([O-:28])=[C:1]([C:4]1[C:8]([S:9]([CH3:11])=[O:10])=[C:7]([NH2:12])[N:6]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[Cl:24])[N:5]=1)[CH3:2]
Reactant: CNO
Reactant: CC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CC(c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O)=[N+](C)[O-]
Temperature: 20 °C
Reaction time: 68 h
Yield: 36.8 %

Procedure:
A mixture of 2.0 grams (0.005 mole) of 3-acetyl-5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole, 0.83 gram (0.01 mole) of N-methylhydroxylamine hydrochloride, 1.21 ml (0.015 mole) of pyridine and 150 ml of methanol was stirred 68 h at 20° C. The mixture was successively evaporated, washed with CH2Cl2 and water; filtered; washed in hot acetonitrile, acetone, hot methanol; and dried so as to give 0.79 gram of Compound No. 4 (m.p. about 228° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]1([C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11]1)[CH2:5]2.[C:17]1([S:27](Cl)(=[O:29])=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C1COCC1>[C:17]1([S:27]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH2:7][C:6]2([C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11]2)[CH2:5]3)(=[O:29])=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc2c(c1)CC1(C2)NC(=O)NC1=O
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1NC(=O)C2(Cc3ccc(NS(=O)(=O)c4cccc5ccccc45)cc3C2)N1

Procedure:
To a stirred solution of 50 mg (0.23 mmol) (±)-5′-amino-spiro[imidazolidine-4,2′-indane]-2,5-dione (described in Intermediate 6) in THF (3 mL) was added 1-naphthalenesulfonyl chloride (53 mg, 0.24 mmol) and triethylamine (0.034 mL, 0.24 mmol). After 30 min the reaction mixture was concentrated to dryness. The residue was dissolved in DMF and purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound as a white solid. MS: m/z=408 (M+1). HRMS: m/z=408.1019; calculated m/z=408.1013 for C21H17N3O4S.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:20][O:21][CH:22]([C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=2)[C:23]([OH:25])=O)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[Li]CCCC.[CH2:51]([C@@H:58]1[CH2:62][O:61][C:60](=[O:63])[NH:59]1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>ClCCl.O1CCCC1.CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:20][O:21][CH:22]([C:26]2[CH:31]=[C:30]([C:32]([F:33])([F:35])[F:34])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=2)[C:23]([N:59]2[C@H:58]([CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:62][O:61][C:60]2=[O:63])=[O:25])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: CC(C)(C)OC(=O)N1CCC(COC(C(=O)O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COC(C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound of step (a) above (1.0 g, 1.7 mmol) was dissolved in anhydrous dichloromethane (50 ml). Dimethylformamide(0.05 ml) was added followed by oxalyl chloride (0.2 ml, 2.3 mmol) dropwise. After stirring at 25° C. for 0.5 hours the solvent was removed in vacuo. The resulting residue was azeotroped with toluene (2×50 ml) then, as a solution in anhydrous toluene (5 ml), added at -78° C. to the lithium anion of (4R)-4-benzyl-2-oxazolidinone (generated by adding n-BuLi (1.1 ml, 1.6M, 1.7 mmol) to a solution of (4R)-(+)-4-benzyl-2-oxazolidinone (0.301 g, 1.7 mmol) in tetrahydrofuran (5 ml) at -78° C.). The resulting colorless solution was stirred at -78° C. for a further 0.75 hours and quenched by addition of saturated ammonium chloride solution (30 ml). The product was extracted into ethyl acetate (2×30 ml) then the organic layer was dried over MgSO4 and filtered. The clear oil obtained after removal of solvent in vacuo was purified by chromatography on silica gel eluting first with 20% ethyl acetate/hexane to obtain the title compound, diastereomer A (0.350 g), and then with 30% ethyl acetate/hexane to obtain the title compound, diastereomer B (0.380 g). Diastereomer A was converted to a mixture (1:2) of diastereomer A and diastereomer B by treating a solution in dichloromethane with anhydrous triethylamine for 16 hours. The solvents were evaporated and the mixture separated by chromatography as described above to obtain diastereomer B: 1H NMR (250 MHz, CDCl3) δ 7.78 (s, 1H), 7.70 (s, 2H), 7.10-7.30 (m, 8H), 6.88 (m, 2H), 5.86 (s, 1H), 4.62 (m, 1H), 4.06-4.12 (m, 2H), 3.68 (m, 2H), 3.54 (d, J=7 Hz, 1 H), 3.22 (d, J=7 Hz, 1 H), 2.96 (m, 3H), 2.54 (dd, J=7, 2 Hz, 1H), 2.1 (m, 2H), 1.8 (m, 2H), 1.34 (s, 9H).
Reaction SMILES: O[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[CH2:11]=[O:12].[Cl-:13].[Ca+2].[Cl-].Cl>C(Cl)Cl>[Cl:13][CH2:11][O:12][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1
Reactant: [Cl-]
Reactant: OC1Cc2ccccc2C1
Reactant: C=O
Agent: Cl
Agent: [Ca+2]
Solvent: ClCCl
Product: ClCOC1Cc2ccccc2C1
Yield: 100.3 %

Procedure:
A mixture of 134 g of 2-hydroxyindane, 36.1 g of paraformaldehyde, 200 g of calcium chloride, and 1200 g of methylene chloride was agitated. Into the mixture was dropped 239 g of a concentrated hydrochloric acid at room temperature for 3 hours, and then the reaction mixture was agitated for 16 hours. After separated an organic layer from the mixture, the solvent was removed by distillation to obtain 183 g of chloromethyl(2-indanyl)ether as an oily matter.
Reaction SMILES: [CH3:1][CH:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][CH:7]=1)[CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[C:19]([O:22][CH2:23][CH2:24]Br)(=[O:21])[CH3:20].O>CN(C=O)C>[C:19]([O:22][CH2:23][CH2:24][S:12][C:9]1[CH:8]=[CH:7][C:6]([S:5][CH:2]([CH3:1])[CH2:3][CH3:4])=[CH:11][CH:10]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OCCBr
Reactant: CCC(C)Sc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)Sc1ccc(SCCOC(C)=O)cc1

Procedure:
To a mixture of 4-(1-methylpropylthio)benzenethiol (53.7 g, 271.0 mmol) and potassium carbonate (49.4 g, 358.0 mmol) in DMF under N2 and with stirring is added dropwise 2-bromoethyl acetate (34.0 ml, 298.0 mmol). The mixture is stirred at RT overnight, after which water is added and the mixture is extracted with ether. The combined organic layers are washed with water and brine, dried, the solvent removed and the residue purified by distillation to give 2[4-(1-methylpropylthio)phenylthio]ethyl acetate. To the acetate (60.9 g, 214.0 mmol) in 200 ml of ethanol is added 50% sodium hydroxide (20 ml). The reaction mixture is stirred at RT for 7 hours and is then neutralized by addition of 10% sulfuric acid and extracted with ether. The organic layer is washed with water and brine, dried and the solvent removed to give 2-[4-(1-methylpropylthio)phenylthio]ethanol.