Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][NH2:13]>CCO.O>[Cl:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[NH:13][CH3:12]
Reactant: O=[N+]([O-])c1cccc(Cl)c1F
Reactant: CN
Solvent: O
Solvent: CCO
Product: CNc1c(Cl)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
2-Fluoro-3-chloronitrobenzene (3.0 g, 17 mmol) was dissolved in EtOH (6 mL) and Methylamine 40% in Water (6 mL) was added dropwise at 0° C. and mixture was warmed up to RT overnight. Mixture went to a dark orange precipitate within 10 min. The solid was isolated by filtration, rinsed with water (2*10 mL) and dried in a desiccators under vacuum to afford 3 g of 2-chloro-N-methyl-6-nitrobenzenamine (Yield: 90%) as an orange crystalline solid.
Reaction SMILES: C([O:5][C:6]([C:8]1([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[O:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2([C:29]([O:31]CCCC)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])CCC.O[Li].O>>[C:29]([C:24]1([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:18](=[O:36])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:8]2([C:6]([OH:7])=[O:5])[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:25][CH2:26][CH2:27][CH2:28]1)([OH:31])=[O:30]
Reactant: CCCCOC(=O)C1(CCCCCC(=O)CCCCCC2(C(=O)OCCCC)CCCC2)CCCC1
Agent: [Li]O
Solvent: O
Product: O=C(CCCCCC1(C(=O)O)CCCC1)CCCCCC1(C(=O)O)CCCC1

Procedure:
Compound 107m was prepared likewise Method D starting from 106m (21.03 g, 90% pure by 1H NMR, 37.3 mmol) and LiOH.H2O (7.83 g, 187 mmol) to give, after recrystallization from iPr2O/heptane, 107m (12.15 g, 83%) as white granules. mp=78-85° C. 1H NMR: δ 2.37 (t, J=7.4 Hz, 4H), 2.18-2.10 (m, 4H), 1.65-1.45 (m, 20H), 1.29-1.25 (m, 8H). 13C NMR: δ 211.5, 184.8 (2×), 54.0 (2×), 42.4 (2×), 38.9 (2×), 35.9 (4×), 29.2 (2×), 25.5 (2×), 24.9 (4×), 23.5 (2×). Anal. calcd for C22H38O5: C, 70.02; H, 9.71. found: C, 70.37; H, 9.72.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]([CH3:12])[C:9](Cl)=[O:10].Cl.[CH2:14]([S:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:24]=1[Cl:30])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[CH3:7][N:8]([CH3:12])[C:9]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([S:22][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:24]([Cl:30])[CH:25]=1)=[O:10]
Reactant: Nc1ccc(SCCc2ccccc2)c(Cl)c1
Reactant: CN(C)C(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)Nc1ccc(SCCc2ccccc2)c(Cl)c1
Temperature: 60 °C

Procedure:
Anhydrous potassium carbonate (10 g) and dimethylcarbamyl chloride (4.0 g; 0.037 mol) are added to a solution of 2-chloro-4-aminophenyl phenethyl sulfide hydrochloride (3.0 g; 0.01 mol) in dry DMF (75 ml) at 25° C. The reaction mixture is heated at 60° C. for 15 hours and then poured into ice water (500 ml). The precipitate (74%) of title product, a white solid, m.p. 133°-134° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15].[CH2:20](N)[CH2:21][NH2:22]>>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]1[NH:22][CH2:21][CH2:20][N:15]=1
Reactant: N#Cc1ccccc1Nc1ccc([N+](=O)[O-])cc1F
Reactant: NCCN
Product: O=[N+]([O-])c1ccc(Nc2ccccc2C2=NCCN2)c(F)c1
Yield: 60 %

Procedure:
A mixture of 8.5 g (33 mmol) of 2-(2-fluoro-4-nitrophenylamino)-benzonitrile and 16.7 ml (249 mmol) of ethylenediamine was heated in an autoclave to 180° for 1 hour, and the reaction mixture was then worked up as described in Example (1a). After crystallisation from dichloromethane and ether/petroleum ether, the reaction product was obtained in a 60% yield.
Reaction SMILES: C1(O[C:8]([NH:10][C@H:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])C=CC=CC=1.[CH:26]([NH:29]C(C)C)([CH3:28])[CH3:27]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[NH:29]([CH:26]([CH3:28])[CH3:27])[C@:11]([N:10]=[C:8]=[O:9])([C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])[CH2:12][CH:13]([CH3:14])[CH3:15]
Reactant: CC(C)C[C@H](NC(=O)Oc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(C)NC(C)C
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)C[C@](N=C=O)(NC(C)C)C(=O)OCc1ccccc1
Temperature: 55 °C
Reaction time: 17 h

Procedure:
To a solution of PhOCO-Leu-OBzl (70 mg, prepared in (1)) in chloroform (2 ml) were added diisopropylamine (575 μl) and TEA (286 μl) at room temperature under argon atmosphere. The mixture was stirred at 55° C. for 17 h and cooled to room temperature. The mixture was diluted with ethyl acetate, washed with N-hydrochloric acid, sat. aq. NaHCO3 and brine successively, dried over MgSO4 and evaporated in vacuo.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[CH:4][CH:3]=1.[Br:14]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[Br:14][CH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)c2ccccc12
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)c2ccccc12
Reaction time: 8 h
Yield: 74.7 %

Procedure:
2.50 g (14.95 mmol) of 4-methyl-1-naphthonitrile are dissolved in 40 ml of tetrachloromethane and 3.19 g (17.94 mmol) of N-bromosuccinimide and 245 mg (1.50 mmol) of 2,2′-azobis-2-methyl-propanenitrile are added. The mixture is stirred at the reflux temperature overnight. After cooling, the product is filtered off. 2.75 g (74.7% of theory) of 4-(bromomethyl)-1-naphthonitrile are obtained in a purity of 90% and are reacted without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([C@@H:19]5[CH2:24][NH:23][CH2:22][CH2:21][C@@H:20]5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)=[C:5]([C:25]([F:28])([F:27])[F:26])[CH:4]=1.Br[CH2:30][CH2:31][F:32].N>>[F:32][CH2:31][CH2:30][N:23]1[CH2:22][CH2:21][C@@H:20]2[N:15]3[C:16]4[C:11](=[CH:10][C:9]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=5[C:25]([F:28])([F:26])[F:27])=[CH:18][C:17]=4[C@@H:19]2[CH2:24]1)[CH2:12][CH2:13][CH2:14]3
Reactant: FCCBr
Reactant: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCC3)c(C(F)(F)F)c1
Agent: N
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(CCF)CC[C@@H]2N4CCC3)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by the method of Example 382 as a yellow oil (32 mg, 96%) from (7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (30 mg, 0.077 mmol) and 1-bromo-2-fluoroethane (30 mg, 0.23 mmol). MS (CI, NH3): 435.1 (base, M+H).
Reaction SMILES: [F-:1].[Cs+].Cl[CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1>C(#N)C>[F:1][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1
Reactant: [F-]
Reactant: Cc1ccc(SCCl)cc1
Agent: [Cs+]
Solvent: CC#N
Product: Cc1ccc(SCF)cc1
Yield: 67.7 %

Procedure:
Cesium fluoride (149.55 g, 2 eq) was added to a mixture of PEG400 (90 mL) and acetonitrile (540 mL). The mixture was stirred a few minute under an argon atmosphere and then acetonitrile (90 mL) was removed by distillation. (Chloromethyl)(p-tolyl)sulfane (102.68 g, 492.25 mmol) was added. The reaction mixture was stirred at a temperature between 80° C. and 85° C. until the reaction was complete. The suspension formed, was filtered and the filtrate was concentrated. The crude product was purified by distillation to give 52.09 g (68%) of the desired product as slightly yellow oil (bp: 57° C. at 40 Pa).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Cl:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[O:33]>C1(C)C=CC=CC=1>[Cl:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1[NH:31][C:32]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:33]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: Cc1cccc(N=C=O)c1Cl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cccc(C)c4Cl)cc3)c2cc1OC
Yield: 37 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (52 mg) was dissolved in toluene (5 ml) with heat, 2-chloro-3-methylphenyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 12 minutes. The reaction solution was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 30 mg of the title compound (yield: 37%).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:27]([O:29][CH3:30])=[O:28])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][NH:19][CH2:18][C:17]4[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31][N:32]1[CH2:39][CH2:38][CH2:37][C@@H:33]1[C:34](O)=[O:35].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:27]([O:29][CH3:30])=[O:28])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([C:34](=[O:35])[C@H:33]4[CH2:37][CH2:38][CH2:39][N:32]4[CH3:31])[CH2:18][C:17]4[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCNCc1cc(F)ccc1-3
Reactant: CN1CCC[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(C(=O)[C@H]1CCCN1C)Cc1cc(F)ccc1-3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1 eq of methyl-14-cyclohexyl-3-fluoro-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocin-11-carboxylate (prepared as described in Example 18, Step 5) in DCM (0.06 M), 1.5 eq of 1-methyl-D-proline (prepared according to literature precedent J. Org. Chem. 2003, 68, 2652) in DCM (0.2 M), 1.5 eq of DIPEA and 1.5 eq of TBTU were added and the mixture stirred at RT overnight. Volatiles were removed in vacuo and the crude was used in the next step without further purification; MS (ES+) m/z 518 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]3[CH2:29][O:28][CH2:27][CH2:26][C:11]=3[N:12]([C:14]([NH:16][C@@H:17]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:18]([NH:20][CH3:21])=[O:19])=[O:15])[N:13]=2)[CH:5]=[CH:6][C:7]=1[F:8].N[C@@H](C(C)(C)C)[C:32](NCCO)=[O:33]>>[OH:33][CH2:32][CH2:21][NH:20][C:18](=[O:19])[C@@H:17]([NH:16][C:14]([N:12]1[C:11]2[CH2:26][CH2:27][O:28][CH2:29][C:10]=2[C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)=[N:13]1)=[O:15])[C:22]([CH3:24])([CH3:25])[CH3:23]
Reactant: CC(C)(C)[C@H](N)C(=O)NCCO
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(C)(C)C
Product: CC(C)(C)[C@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(=O)NCCO

Procedure:
Compound 36 was prepared according to the procedure described for the synthesis of compound 28 by replacing tert-leucine methylamide with intermediate 23. 1H NMR (CDCl3) δ 7.89 (d, J=9.1 Hz, 1H), 7.46-7.51 (m, 1H), 7.21-7.30 (m, 2H), 4.82 (s, 2H), 4.20 (d, J=9.0 Hz, 1H), 3.94 (t, J=5.5 Hz, 2H), 3.74 (br, 2H), 3.44-3.49 (m, 2H), 3.17 (br, 2H), 1.11 (s, 9H). LCMS (+ESI) m/z=437 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9]Cl)[C:5]([CH:11]=[CH2:12])=[CH:4][N:3]=1.[C:13]([O-:21])(=[S:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[K+].O>C(O)C>[CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][S:20][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]([CH:11]=[CH2:12])=[CH:4][N:3]=1
Reactant: C=Cc1cnc(C)c(O)c1CCl
Reactant: [O-]C(=S)c1ccccc1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C=Cc1cnc(C)c(O)c1CSC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
To a stirred solution of 65 g. of 2-methyl-3-hydroxy-4-chloromethyl-5-vinylpyridine in 1 liter of ethanol under nitrogen there was added 96 g. of potassium thiobenzoate in 200 ml. of water over 30 minutes. After 1 hour, the ethanol was evaporated at 40° C. and the aqueous solution was extracted with 4 × 300 ml. of ethyl acetate. The extract was washed with 1 × 75 ml. of water, dried over magnesium sulfate and concentrated to dryness to give 2-methyl-3-hydroxy-4-benzoylthiomethyl-5-vinylpyridine.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([OH:11])[C:8]([CH3:12])=[CH:7][C:6]=1[S:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:31]([NH:35][S:36](Cl)(=[O:38])=[O:37])([CH3:34])([CH3:33])[CH3:32]>CCOCC>[C:1]([C:5]1[CH:10]=[C:9]([O:11][S:36](=[O:38])(=[O:37])[NH:35][C:31]([CH3:34])([CH3:33])[CH3:32])[C:8]([CH3:12])=[CH:7][C:6]=1[S:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:15])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(O)cc2C(C)(C)C)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Sc2cc(C)c(OS(=O)(=O)NC(C)(C)C)cc2C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a round bottom flask equipped with a magnetic stirrer were added 1.10 g (3.20 mmol) of toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxy-5-methyl-phenyl) ester (prepared in Example RRR), Et2O (50 mL), and 0.90 mL (6.40 mmol) of NEt3, in that order. The solution was cooled to 0° C. To this solution was rapidly added a solution of 1.10 g (6.40 mmol) of (tert-butyl amino)sulfonyl chloride (Matler, W. L., Comer, W. T., and Deitchman, D., Journal of Medicinal Chemistry, 1972,15 (5), 538-541) in Et2O (10 mL). A precipitate ensued and the reaction was allowed to stir for 30 minutes. Another two equivalents of (tert-butyl amino)sulfonyl chloride (1.10 g, 6.40 mmol) in Et2O (10 mL) and NEt3 (0.90 mL, 6.40 mmol) were added, and the reaction mixture was stirred for another 30 minutes. The reaction was quenched with brine and the organics extracted with Et2O. The organics were dried (MgSO4) and concentrated. The residue was submitted to flash chromatography (EtOAc:CHCl3 1:9) to yield the title compound. 1H NMR (CDCl3) δ 1.23 (s, 9 H), 1.46 (s, 9 H), 2.25 (s, 3 H), 2.42 (s, 3 H), 4.63 (br s, 1 H), 7.23 (s, 1 H), 7.26 (s, obscured by CDCl3, 1 H), 7.42 (d, 2 H), 7.46 (d, 2 H).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([F:14])[C:3]=1[C@H:4]1[O:6][CH2:5]1.[Cl-:15].[Li+].P([O-])([O-])([O-])=O>O1CCCC1>[Cl:15][CH2:5][C@@H:4]([C:3]1[C:2]([F:1])=[C:10]([F:11])[C:9]([F:12])=[C:8]([F:13])[C:7]=1[F:14])[OH:6]
Reactant: [Cl-]
Reactant: Fc1c(F)c(F)c([C@@H]2CO2)c(F)c1F
Agent: O=P([O-])([O-])[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O[C@@H](CCl)c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.3 %

Procedure:
To an ice-cooled solution of 10.51 g of (R)-(+)-2,3,4,5,6-pentafluorostyrene oxide was dissolved in 100 ml of tetrahydrofuran, was added dropwise a solution of Li2CuCl4, which was prepared by adding 10.08 g of cupric chloride to a suspension of 6.36 g of lithium chloride in 150 ml of tetrahydrofuran. After completion of addition, the solution was stirred for 20 hours at room temperature. The resulted reaction mixture was poured into a 0.05 mol phosphate buffer, and was extracted with ether. The resulted extract was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 12.00 g of (R)-(-)-2-chloro-1-(pentafluorophenyl)ethanol containing 20% of (+)-2-chloro-2-(pentafluorophenyl)ethanol. This was subjected to isolation by silica gel column chromatography, thereby obtaining (R)-(-)-2-chloro-1-(pentafluorophenyl)-ethanol and (+)-2-chloro-2-(pentafluorophenyl)ethanol respectively possessing the aforementioned physical properties.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([B:9]2[O:17][C:14]([CH3:16])([CH3:15])[C:11]([CH3:13])([CH3:12])[O:10]2)[O:7][CH:8]=1)([OH:3])=[O:2].[CH3:18][Si](C=[N+]=[N-])(C)C>C(Cl)Cl.CO>[CH3:12][C:11]1([CH3:13])[C:14]([CH3:16])([CH3:15])[O:17][B:9]([C:6]2[O:7][CH:8]=[C:4]([C:1]([O:3][CH3:18])=[O:2])[CH:5]=2)[O:10]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC1(C)OB(c2cc(C(=O)O)co2)OC1(C)C
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1coc(B2OC(C)(C)C(C)(C)O2)c1
Reaction time: 0.75 h

Procedure:
4-Carboxyfuran-2-boronic acid pinacol ester (200 mg, 0.840 mmol) was dissolved in CH2Cl2 (4 mL) and MeOH (0.444 mL). Trimethylsilyldiazomethane (0.840 mL, 1.680 mmol) was added dropwise. After 45 min, the reaction was quenched with AcOH dropwise until the yellow color disappeared. The reaction was concentrated in vacuo to give methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-furoate. 1H NMR (500 MHz, CDCl3): δ 8.20 (s, 1H); 7.37 (s, 1H); 3.84 (s, 3H); 1.36 (s, 12H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14](O)[CH2:15][CH2:16][CH:17]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[OH:18])[CH:6]=[C:7]([I:13])[C:8]=1[O:9][CH2:10][CH2:11][OH:12].FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:14]2[CH2:15][CH2:16][C@H:17]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=3)[O:18]2)[CH:6]=[C:7]([I:13])[C:8]=1[O:9][CH2:10][CH2:11][OH:12]
Reactant: COc1cc(C(O)CCC(O)c2cc(OC)c(OC)c(OC)c2)cc(I)c1OCCO
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc(I)c1OCCO
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 1-(3-methoxy-4-hydroxyethoxy-5-iodophenyl)-4-(3,4,5-trimethoxyphenyl)-1,4-butanediol (11.8 g, 21.5 mmol) in chloroform (100 mL) at 0° C. was added dropwise trifluoroacetic acid (9.82 g, 86.1 mmol) in chloroform (100 mL) over 30 minutes. The solution was stirred at 0° C. for 2 hours and then at room temperature for 1 hour. The reaction mixture was quenched with 1N NaOH and chloroform (100 mL) was added. The organic layer was washed with 1N NaOH solution, water and saturated NaCl solution, and then dried over MgSO4, filtered and evaporated in vacuo to an oil which was a cis and trans mixture. The trans isomer was isolated by column chromatography (silica, 1:1 hexane/ethyl acetate) (4.7 g, 41.4%) as the faster eluting isomer. 1H NMR (CDCl3): 1.99 (m, 2H); 2.47 (m, 2H); 3.83 (t, 2H); 3.84 (s, 3H); 3.87 (s, 3H); 3.89 (s, 6H); 4.16 (t, 2H); 5.18 (m, 2H), 6.62 (s, 2H); 6.96 (d, 1H); 7.39 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[N:6])[CH3:2].[CH3:10][O-:11].[Na+]>CO>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5](=[NH:6])[O:11][CH3:10])[CH3:2]
Reactant: CCOC(C#N)OCC
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(OCC)C(=N)OC
Reaction time: 8 h
Yield: 98.6 %

Procedure:
A solution of diethoxyacetonitrile (75 g, 0.579 mol) in methanol (210 mL) was added at room temperature to a solution of sodium methoxide (28.3 g, 0.522 mol) in methanol (450 mL). The mixture was stirred overnight, and then the methanol was carefully evaporated (volatile product). The residue was diluted with dichloromethane (200 mL) and water (300 mL). The organic layer was separated, and the aqueous one was extracted with dichloromethane (2×150 mL). The combined organic layer was dried over Na2SO4 and evaporated to give 83 g of crude methyl 2,2-diethoxyethanimidoate (˜90% yield).
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=[CH:16][C:17]([OH:19])=O.C(N(CC)CC)C.[NH2:27][C:28]1[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(Cl)Cl>[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=[CH:16][C:17]([NH:27][C:28]1[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:19]
Reactant: O=C(O)C=Cc1cccs1
Reactant: CCOC(=O)c1ccccc1N
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1NC(=O)C=Cc1cccs1
Yield: 45.3 %

Procedure:
Under nitrogen stream, 2-chloro-1-methylpyridinium iodide (966 mg, 3.89 mmol) was suspended in dry methylene chloride (5 ml). To the suspension, a solution of 3-(2-thienyl)acrylic acid (500 mg, 3.24 mmol), triethylamine (1.08 ml, 7.78 mmol), and ethyl 2-aminobenzoate (0.48 ml, 3.24 mmol) in dry methylene chloride (5 ml) was added dropwise. After the addition, the mixture was heated under reflux for 39 hours. Then, the reaction mixture was diluted with methylene chloride, washed with 10% aqueous HCl, saturated aqueous sodium chloride, 1N-aqueous NaOH, and saturated aqueous sodium chloride successively, and dried. Removal of solvent gave a yellow solid, which was washed with n-hexane to give pale yellow solids of the title compound (442 mg, yield, 45%). m.p., 126°-127° C. (recrystallized from methanol)
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[CH2:25](I)[CH3:26].[H-].[Na+].O>CN(C=O)C>[C:21]([O:20][C:18]([N:17]([CH:14]1[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1)[CH2:25][CH3:26])=[O:19])([CH3:22])([CH3:23])[CH3:24]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C(=O)OC(C)(C)C)C1CCNCC1
Reaction time: 16 h
Yield: 126.1 %

Procedure:
To a solution of 476 mg (1.42 mmol) of 1-benzyloxycarbonyl-4-(t-butoxycarbonylamino)piperidine from Step B and 0.24 mL (2.8 mmol) of ethyl iodide in 10 mL of DMF was added 85 mg (2.1 mmol) of 60% sodium hydride in mineral oil. The reaction was stirred for 16 h and was then poured into water and extracted three times with ether. The organic layers were each washed with a portion of water and brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FC eluting with 15% ethyl acetate in hexanes to afford 409 mg of title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][P:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1)(=[O:12])[O:7][CH2:8][CH2:9][O:10][CH3:11].[H][H]>CCO.[Pd]>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][P:6](=[O:12])([O:5][CH2:4][CH2:3][O:2][CH3:1])[O:7][CH2:8][CH2:9][O:10][CH3:11])=[CH:19][CH:18]=1
Reactant: [H][H]
Reactant: COCCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCCOC
Agent: [Pd]
Solvent: CCO
Product: COCCOP(=O)(Cc1ccc(N)cc1)OCCOC
Yield: 97.1 %

Procedure:
A mixture of bis(2-methoxyethyl)(4-nitrobenzyl)phosphonate (Compound 185B, 6.0 g, 18 mmol) and 5% Pd/C (0.8 g) in EtOH (150 mL) was hydrogenated under 40 psi hydrogen pressure at 40° C. for 6 h. The reaction mixture was filtered and the filtrate was concentrated to give the desired product (5.3 g, 97%). 1H NMR (CDCl3, 400 MHz): δ=3.04 (d, J=21.2 Hz, 2 H), 3.28 (s, 6 H), 3.42-3.46 (m, 4 H), 3.97-4.03 (m, 4 H), 6.55 (d, J=8.4 Hz, 2 H), 6.99-7.02 (m, 2 H).
Reaction SMILES: [H-].[Na+].[C:3]1([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br.[NH2:17][C:18]1[N:27]=[C:26]([NH2:28])[C:25]2[C:20](=[N:21][CH:22]=[C:23]([CH2:29]Br)[N:24]=2)[N:19]=1.CO>C1COCC1>[NH2:17][C:18]1[N:27]=[C:26]([NH2:28])[C:25]2[C:20](=[N:21][CH:22]=[C:23]([CH2:29][N:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:24]=2)[N:19]=1
Reactant: Nc1nc(N)c2nc(CBr)cnc2n1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(N)c2nc(CN(c3ccccc3)c3ccccc3)cnc2n1
Reaction time: 0.17 h

Procedure:
Powdered NaH (50 mg, 2.1 mmol) is added to a stirred solution of diphenylamine (1.3 g, 0.77 mmol) in dry THF (10 mL) at 0° C. under N2. After 10 min, 2,4-diamino-6-bromomethylpteridine hydrobromide (100 mg, 0.3 mmol) is added and the reaction mixture is allowed to come to room temperature and left to stir for 2 days. The excess NaH is decomposed with MeOH (1 mL) and the mixture is concentrated to dryness by rotary evaporation. Flash chromatography on silica gel with 95:5 CHCl3-MeOH as the eluent affords the product, N-(2,4-diaminopteridin-6-yl)methyl-N,N-diphenylamine, as a bright-yellow powder (56 mg, 54% yield); mp >250° C. dec.; MS (FAB) m/z (M+1)=344; IR (KBr) v 3450, 3340, 3170, 1630, 1590, 1550, 1490, 1450, 1360, 1220 cm−1; 1H NMR(d6-DMSO) δ 5.10 (s, 2H, CH2), 6.70 (m, 10H, aromatic), 8.60 (s, 1H, C7-H. Anal. Calcd for C19H17N7.0.8H2O: C, 63.73; H, 5.23; N, 27.40. Found: C, 64.15; H, 4.85; N, 27.07.