Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:37])([Cl:36])[CH2:3][O:4][C:5](=[O:35])[O:6][CH:7]([CH:24]([CH3:34])[CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:8]([CH3:23])[C:9](=[O:22])[C:10]([CH3:21])([CH3:20])[CH:11](OC(C)C)[O:12]C(C)C.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1COCC1.O>[Cl:1][C:2]([Cl:36])([Cl:37])[CH2:3][O:4][C:5](=[O:35])[O:6][CH:7]([CH:24]([CH3:34])[CH2:25][O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH:8]([CH3:23])[C:9](=[O:22])[C:10]([CH3:21])([CH3:20])[CH:11]=[O:12]
Reactant: CC(C)OC(OC(C)C)C(C)(C)C(=O)C(C)C(OC(=O)OCC(Cl)(Cl)Cl)C(C)COCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(COCc1ccccc1)C(OC(=O)OCC(Cl)(Cl)Cl)C(C)C(=O)C(C)(C)C=O
Temperature: 70 °C
Yield: 73.2 %

Procedure:
To solution of 32a (1.28 g, 2.25 mmol) in 4:1 THF/H2O (25 mL) was added p-TsOH (111.0 mg, 0.6 mmol). After heating at 70° C. 5 h, the reaction mixture was poured into a cold (0° C.) sat. NaHCO3 aq solution (12 mL) and then extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (gradient hexane to hexane/EtOAc 84:16) to give 67 (793.2 mg, 76%) as a clear oil: 1H NMR (400 MHz, CDCl3) □ 0.90 (d, J=5.8 Hz, 3H), 1.0 (d, J=6.9 Hz, 3H), 1.24 (s, 6H), 1.97-2.04 (m, 1H), 3.24 (dd, J=4.8 and 9.2 Hz, 1H), 3.34 (m, 1H), 3.42 (dd, J=5.8 and 9.2 Hz, 1H), 4.35 (d, J=11.9 Hz, 1H), 4.39 (d, J=11.9 Hz, 1H), 4.64 (d, J=11.9 Hz, 1H), 4.69 (d, J=11.9 Hz, 1H), 4.96 (t, J=6.0 Hz, 1H), 7.19-7.28 (m, 5H), 9.49 (s, 1H); 13C NMR (100 MHz, CDCl3) −12.0, 14.8, 19.5, 19.6, 35.4, 43.3, 60.9, 71.1, 73.3, 80.37, 94.5, 127.7, 127.8, 128.3, 137.9, 154.1, 201.0, 210.1; IR (film, NaCl, cm−1) 2973, 2880, 1758, 1701, 1453, 1380, 1248; LRMS (ESI) calcd for C21H27O6Cl3Na [M+Na+] 503.0, found 503.0; [α]23D=−18.5 (c=0.8, CHCl3).
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1.C(O)C>[CH2:2]1[O:3][C:4]2([CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]2)[O:11][CH2:1]1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: OC1CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 88.5 %

Procedure:
To a solution of 1,4-cyclohexanedione monoethylene ketal (3.12 g, 20 mmol) in dioxane (25 mL) and ethanol (45 mL) was added NaBH4 (0.38 g, 10 mmol) and the resulting mixture was refluxed for 45 min. The mixture was then cooled to room temperature, acidified to pH 5 with 10% citric acid and extracted with ethyl acetate to afford crude 1-hydroxy-4-cyclohexanone ethylene ketal (2.8 g).
Reaction SMILES: CC1NC2C(C=1C1C=C(C3C4C(=CC(C)=C(C)C=4)NC=3C)OC1=O)=CC(C)=C(C)C=2.[CH2:31]([N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([CH:42]2[CH:46]=[C:45]([C:47]3[C:55]4[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=4)[N:49]([CH2:56][CH3:57])[C:48]=3[CH3:58])[O:44][C:43]2=[O:59])=[C:34]1[CH3:60])[CH3:32]>>[CH2:31]([N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([C:42]2[C:43](=[O:59])[O:44][CH:45]([C:47]3[C:55]4[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=4)[N:49]([CH2:56][CH3:57])[C:48]=3[CH3:58])[CH:46]=2)=[C:34]1[CH3:60])[CH3:32]
Reactant: CCn1c(C)c(C2=CC(c3c(C)n(CC)c4ccccc34)C(=O)O2)c2ccccc21
Agent: Cc1cc2[nH]c(C)c(C3=CC(c4c(C)[nH]c5cc(C)c(C)cc45)C(=O)O3)c2cc1C
Product: CCn1c(C)c(C2=CC(c3c(C)n(CC)c4ccccc34)OC2=O)c2ccccc21

Procedure:
When 3,5-bis(2,5,6-trimethyl-3-indolyl)-2(3H)-furanone is substituted for 3,5-bis(1-ethyl-2-methyl-3-indolyl)-2(3H)-furanone in part B of this example, there is obtained 3,5-bis-(2,5,6-trimethyl-3-indolyl)-2(5H)-furanone (Formula IV: R=H; R1 =CH3 ; Y=5,6-(CH3)2).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([OH:8])[CH:3]=1.[H-].[Na+].CI.[C:13]([O-])(O)=O.[Na+]>CN(C)C=O>[I:1][C:2]1[CH:7]=[CH:6][N:5]([CH3:13])[C:4](=[O:8])[CH:3]=1
Reactant: O=C([O-])O
Reactant: Oc1cc(I)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ccc(I)cc1=O
Reaction time: 0.08 h

Procedure:
To a solution of 4-iodopyridin-2-ol (450 mg, 2.0 mmol, Maybridge, Cat. No. MO07919) in N,N-dimethylformamide (7 mL) was added sodium hydride (120 mg, 3.0 mmol, 60% dispersion in mineral oil) at 0° C., the solution was stirred 5 min., then methyl iodide (250 uL, 4.1 mmol) was added. The reaction mixture was stirred at r.t. for 2 h., and then poured into aqueous NaHCO3 solution, extracted with AcOEt. The organic layer was washed by water and brine, dried over MgSO4, filtered, and concentrated to afford the desired compound which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z=235.9.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16](O)=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[CH3:34][NH:35][C:36]1[C:37]([NH2:42])=[CH:38][CH:39]=[CH:40][CH:41]=1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:16]2[N:35]([CH3:34])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[N:42]=2)[N:8]([C:6]([C:31]2[CH:30]=[CH:29][C:28]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:33][CH:32]=2)=[O:7])[CH2:12]1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CNc1ccccc1N
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: CON=C1C[C@@H](c2nc3ccccc3n2C)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 11, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4carbonyl chloride, and N1-methyl-1,2-benzenediamine, the title compound was obtained in 88% purity by HPLC. MS(ESI+): m/z=425.
Reaction SMILES: [CH2:1]1[O:12][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:13]([NH2:18])[CH2:14][CH2:15][CH2:16][NH2:17]>>[CH2:13]([NH:18][CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:14][CH2:15][CH2:16][NH:17][CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: NCCCCN
Reactant: CCCCCCCCCC1CO1
Product: CCCCCCCCCC(O)CNCCCCNCC(O)CCCCCCCCC

Procedure:
Condensation of 1-undecene oxide and 1,4-butanediamine affords N,N'-(1,4-butylene)-bis[2-hydroxyundecylamine] (I: R= CH3 (CH2)8, R' = H, X= (CH2)4, Z= H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[NH:5][C:4](=O)[CH:3]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:4]1[CH:3]=[C:2]([CH3:1])[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[N:5]=1
Reactant: COc1cc(Nc2nc(C)cc(=O)[nH]2)cc(OC)c1OC
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc(Nc2nc(C)cc(Cl)n2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
6-Methyl-2-(3,4,5-trimethoxyphenylamino)-4(3H)pyrimidinone (1.0 g, 3.63 mmol) was dissolved in phosphoryl chloride and heated to 100° for 2 h. The mixture was cooled to room temperature and evaporated in vacuo to a viscous oil. The oil was dissolved in CH2CH2 (50 ml) and washed twice with saturated aqueous NaHCO3, the organic phases dried (MgSO4) and concentrated in vacuo. The residue was subjected to column chromatography (silica, 2% methanol/CH2CH2) to afford the title compound as an off white solid (1.03 g). A small amount was recrystallised from ethyl acetate to give fine off-white needles. m.p. 195-196°. δH (CDCl3) 2,40 (3H, s), 3.82 (3H, s), 3.88 (6H, s), 6.64 (1H, s), 6.95 (2H, s), and 7.07 (1H, br s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([NH2:9])[C:3]=1[OH:10].[ClH:11].ClN=CC(O[CH2:18][CH3:19])=O>C(Cl)Cl>[Cl:11][CH2:18][C:19]1[O:10][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[C:5]([CH3:8])[C:4]=2[N:9]=1
Reactant: CCOC(=O)C=NCl
Reactant: Cc1ccc(C)c(O)c1N
Reactant: Cl
Solvent: ClCCl
Product: Cc1ccc(C)c2oc(CCl)nc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,5-dimethyl-6-aminophenol (0.67 g, 4.9 mmol) in methylenechloride, solid ethyl 2-chloroiminoacetate hydrochloride (0.85 g, 4.9 mmol)was added. The resultant slurry was stirred at room temperature for 18 hours, then filtered through a plug of diatomaceous earth and concentratedunder reduced pressure (15 torr). The solid residue was subjected to columnchromatography on silica gel (50 g, eluted with 1% methanol in chloroform).Collection and concentration of appropriate fractions yielded the title benzoxazole.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[S:5][C:6]=1[C:7]([NH2:9])=[O:8].CO[C:18](OC)([CH3:20])[CH3:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH3:19][C:18]1([CH3:20])[NH:1][C:2]2[N:3]=[C:4]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[S:5][C:6]=2[C:7](=[O:8])[NH:9]1
Reactant: NC(=O)c1sc(N2CCOCC2)nc1N
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)NC(=O)c2sc(N3CCOCC3)nc2N1
Temperature: 100 °C
Yield: 16 %

Procedure:
A mixture of 4-amino-2-(morpholin-4-yl)-1,3-thiazole-5-carboxamide (0.22 g, 0.98 mmol; prepared according to Liebigs Annalen der Chemie, 1986, 4, 780-4), 2,2-dimethoxypropane (3 mL, excess), acetone (2 mL, excess) and p-toluenesulfonic acid monohydrate (cat. amount) was heated to 100° C. in a sealed tube, under microwave irradiation, for 1 h. The reaction mixture was then concentrated in vacuo and purification by preparative HPLC gave the title compound (0.04 g, 16%) as an off-white solid. δH (DMSO-d6) 7.54 (1H, s), 7.01 (1H, s), 3.73-3.63 (4H, m), 3.49-3.38 (4H, m), 1.38 (6H, s). LCMS (ES+) 269.0 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][C:17]([CH2:23][CH3:24])=[N:18][C:19]=2[CH2:21][CH3:22])[N:14]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]3[N:39]=[N:40][N:41]([C:43]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[N:42]=3)=[CH:28][CH:27]=2)[C:13](=[O:62])[CH:12]=1.O>CC(N(C)C)=O>[CH2:21]([C:19]1[N:18]=[C:17]([CH2:23][CH3:24])[CH:16]=[C:15]2[C:20]=1[C:11]([S:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[CH:12][C:13](=[O:62])[N:14]2[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]2[N:39]=[N:40][N:41]([C:43]([C:56]3[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=3)([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[N:42]=2)=[CH:30][CH:31]=1)[CH3:22]
Reactant: CCc1cc2c(c(Cl)cc(=O)n2Cc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(CC)n1
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCc1cc2c(c(Sc3ccccc3)cc(=O)n2Cc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(CC)n1

Procedure:
Sodium hydride (50% dispersion in oil; 100 mg) was added to a stirred solution of thiophenol (0.2 ml) in dimethylacetamide (10 ml) and the mixture was stirred until effervescence ceased. 4-Chloro-5,7-diethyl-1-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,6-naphthyridin-2(1H)-one (0.7 g) was added to the solution and the mixture was stirred at 50° C. for 4 hours. The reaction mixture was then poured into water and extracted twice with ethyl acetate. The combined extracts were washed with water, saturated sodium chloride solution and dried (MgSO4). Solvent was removed by evaporation to leave an oil which was purified by flash chromatography, eluting with ethyl acetate/petroleum ether (3:1 v/v, increasing to 2:5 v/v) to give 5,7-diethyl-4-phenylthio-1-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4yl)methyl[-1,6-naphthyridin-2(1H)-one (A) as a solid (0.53 g); m.p. 166°-168° C. (after recrystallisation from acetonitrile); NMR (d6 -DMSO): 1.07(t, 3H), 1.40(t, 3H), 2.58(q, 2H), 3.47(q, 2H), 5.40(s, 2H), 5.80(s, 1H), 6.8-7.8(complex m, 29H); mass spectrum (+ve FAB): 787 (M+H)+ ; microanalysis, found: C, 78.1; H, 5.1; N, 10.9%; C51H42N6OS requires: C, 77.8; H, 5.4; N, 10.7%.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H](COS(C)(=O)=O)C1
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride (0.48 mL) was added to a solution of (S)-tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (1.10 g) and triethylamine (1.42 mL) in DCM (20 mL) at 0° C. under nitrogen. The reaction was stirred for 2 h before being partitioned between DCM (200 mL) and water (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford the subtitle product (1.20 g) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:10]=2[OH:17])[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:24](OC(=O)C)(=[O:26])[CH3:25]>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:24]([O:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=2)=[C:10]([OH:17])[CH:11]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: OCc1ccc(Oc2cccc(F)n2)c(O)c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1ccc(Oc2cccc(F)n2)c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.4 %

Procedure:
To a solution of 2-[(6-fluoropyridin-2-yl)oxy]-5-(hydroxymethyl)phenol (0.42 mmol; 104 mg) under argon, in anhydrous DMF (0.8 mL), were added K2CO3 (0.5 mmol; 68 mg), DMAP (0.08 mmol; 12 mg), and acetic anhydride (0.41 mmol; 0.04 mL). The reaction was stirred at room temperature overnight. After dilution with ethyl acetate (4 mL), the organic phase was washed with saturated NaHCO3 (3*3 mL), dried (MgSO4), concentrated in vacuo, purified by preparative TLC (dichlorométhane) to yield the title compound as a clear oil (3 mg; 0.01 mmol; 3%).
Reaction SMILES: C(P(CC1C=CC=C(CP(C(C)(C)C)C(C)(C)C)N=1)C(C)(C)C)(C)(C)C.[C:27](#[N:31])[C:28]([CH3:30])=[CH2:29].[NH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1(C)C=CC=CC=1.C(O)(C(F)(F)F)=O.C(O)(C(F)(F)F)=O.[Pd]>[NH:32]([CH2:29][CH:28]([C:27]#[N:31])[CH3:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: C=C(C)C#N
Reactant: Nc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)P(Cc1cccc(CP(C(C)(C)C)C(C)(C)C)n1)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C#N)CNc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.6 %

Procedure:
Pd(TFA)2 (33.0 mg, 0.10 mmol) and 2,6-Bis[(di-tert-butylphosphino)methyl]pyridine (40.0 mg, 0.10 mmol) were suspended in 0.5 mL of toluene in a screw-capped vial. The vial was sealed with a cap containing a PTFE septum and removed from the dry box. Methacrylonitrile (270 mg, 4.00 mmol) and aniline (93.1 mg, 1.00 mmol) were added to the reaction mixture by syringe. The reaction mixture was stirred at room temperature for 24 h, after which time it was adsorbed onto silica gel. The product was isolated by eluting with 15% ethyl acetate/hexanes to give 142 mg (89%) of 2-anilino-1-methylethyl cyanide. 1H NMR: (CDCl3) δ 7.22 (t, J=7.6 Hz, 2H), 6.78 (t, J=7.6 Hz, 1H), 6.63 (d, J=7.6 Hz, 2H), 3.71 (brs, 1H) 3.43 (dd, J=13.8, 8.0 Hz, 1H), 3.37 (dd, J=13.8, 6.0 Hz, 1H), 2.99 (m, 1H), 1.38 (d, J=7.1 Hz, 3H). 13C{1H} NMR: (CDCl3) δ 146.52, 129.50, 121.81, 118.50, 113.04, 47.04, 25.98, 15.39. Anal. Calcd. for C10H12N2: C, 74.97; H, 7.55; N, 17.48. Found: C, 74.75; H, 7.35; N, 17.57.
Reaction SMILES: [N:1]1([C:6]2[CH:26]=[CH:25][C:9]([O:10][CH2:11][C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]#[N:24])[CH2:19][CH2:18]4)[S:15][CH:16]=3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.C([OH:29])C.O>Cl>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([NH2:24])=[O:29])[CH2:19][CH2:18]4)[S:15][CH:16]=3)=[CH:25][CH:26]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: CCO
Reactant: N#CN1CCC(c2nc(COc3ccc(-n4cnnn4)cc3)cs2)CC1
Agent: Cl
Solvent: O
Product: NC(=O)N1CCC(c2nc(COc3ccc(-n4cnnn4)cc3)cs2)CC1

Procedure:
4-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carbonitrile (1.07 g, 2.92 mmol) was dissolved in 4 N HCl in ethanol/water (1:1). The solution was refluxed for 1 hour, cooled and the solid precipitate was filtered off. The filtrate was neutralized by the addition of excess sodium carbonate. The excess sodium carbonate was filtered off and the filtrate was diluted with EtOAc. The solution was washed with water, separated, dried (Na2SO4), filtered and concentrated. The residual oil was chromatographed on silica gel (1:1 Hexanes/EtOAc) to afford the desired compound. 1H NMR (CDCl3): δ 8.92 (1H, s), 7.60 (2H, d), 7.23 (1H, s), 7.167 (2H, d), 5.21 (2H, s), 4.25 (2H, m), 4.15 (2H, m), 3.22 (1H, m), 2.90 (2H, m), 2.18 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:17]([O:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[N:31]1[CH2:37][CH2:36][CH2:35][N:34]([CH2:38][CH2:39][C:40]2([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:44][CH2:43][NH:42][CH2:41]2)[CH2:33][CH2:32]1)[CH3:18]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:4]=1[C:5]([N:42]1[CH2:43][CH2:44][C:40]([CH2:39][CH2:38][N:34]2[CH2:35][CH2:36][CH2:37][N:31]([C:23]3[N:22]([CH2:21][CH2:20][O:19][CH2:17][CH3:18])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[N:24]=3)[CH2:32][CH2:33]2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:41]1)=[O:7]
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(S(C)(=O)=O)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-methoxy-5-methylsulfonylbenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound: Rf=0.31L (silica gel, 5% methanol/dichloromethane).
Reaction SMILES: [C:1]([C:5]([C:8](F)=[O:9])([F:7])[F:6])([F:4])([F:3])[F:2].[C:11]([O-:14])(O)=[O:12].[Na+].O[CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22]>>[C:1]([C:5]([C:11]([O:14][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][C:8]([C:5]([C:1]([F:2])([F:3])[F:4])([F:6])[F:7])=[O:9])=[O:12])([F:7])[F:6])([F:4])([F:3])[F:2]
Reactant: O=C([O-])O
Reactant: OCCOCCO
Reactant: O=C(F)C(F)(F)C(F)(F)F
Agent: [Na+]
Product: O=C(OCCOCCOC(=O)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: 30 °C
Reaction time: 2 h

Procedure:
HO(CH2)2O(CH2)2OH (40 g) was put into a flask and stirred while maintaining the internal temperature at 30° C. While maintaining the internal temperature of the flask at 30° C., nitrogen and CF3CF2COF (388 g) were supplied over a period of 1.5 hours. After completion of the reaction, while supplying nitrogen gas, stirring was continued at an internal temperature of 30° C. for 2 hours, and then the internal temperature of the flask was brought to at most 15° C., whereupon 5% NaHCO3 (300 ml) was added.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15](OCC)=[O:16])[O:12][N:11]=2)=[CH:6][CH:5]=1.S(O)(O)(=O)=O.[CH3:27][NH:28][NH2:29]>CCO>[CH3:27][NH:28][NH:29][C:15]([C:13]1[O:12][N:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:21])([F:20])[F:1])=[CH:5][CH:6]=2)[N:14]=1)=[O:16].[CH3:27][N:28]([C:15]([C:13]1[O:12][N:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:21])([F:20])[F:1])=[CH:5][CH:6]=2)[N:14]=1)=[O:16])[NH2:29]
Reactant: CCOC(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)no1
Reactant: CNN
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CN(N)C(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)no1
Product: CNNC(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %
Yield: 34 %

Procedure:
To a solution of ethyl 3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carboxylate (3.5 g, 11.5 mmol) in EtOH (25 mL), methylhydrazine sulfate salt (2.5 g, 17.2 mmol) and TEA (7.5 mL) were added at RT. The mixture was stirred at RT overnight, concentrated and purified by Combiflash reverse phase chromatography (50%˜60% MeCN/H2O containing 0.01% TFA) to give N′-methyl-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carbohydrazide (1.1 g, 32%) and N-methyl-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carbohydrazide as white solids (1.2 g, 34%). MS (ES+) C11H9F3N4O3 requires: 302, found: 303[M+H]+.
Reaction SMILES: Cl.[F:2][C:3]([F:22])([F:21])[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]3[CH2:17][NH:18][CH2:19][CH:13]3[C:12]2=[O:20])=[CH:7][CH:6]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1.CCN(CC)CC.ClCCl>CO>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:18]2[CH2:17][CH:14]3[CH:13]([C:12](=[O:20])[N:11]([C:8]4[CH:9]=[CH:10][C:5]([O:4][C:3]([F:2])([F:21])[F:22])=[CH:6][CH:7]=4)[CH2:16][CH2:15]3)[CH2:19]2)=[CH:26][CH:27]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C1C2CNCC2CCN1c1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1C2CN(Cc3ccc(F)cc3)CC2CCN1c1ccc(OC(F)(F)F)cc1
Reaction time: 12 h
Yield: 30.6 %

Procedure:
5-(4-Trifluoromethoxy-phenyl)-octahydro-pyrrolo[3,4-c]pyridin-4-one, hydrochloride (80 mg, 0.24 mmol), 1-(bromomethyl)-4-fluorobenzene (90 mg, 0.48 mmol) and Et3N (0.12 g, 1.2 mmol) were added to dichloromethane (2 mL), and the mixture was stirred for 12 h. The product (30 mg, 31%) was obtained by prep-TLC (eluting with dichloromethane: MeOH=25:1). 1H NMR (300 MHz, CDCl3): δ 7.48-7.44 (m, 2H), 7.29-7.09 (m, 6H), 4.23-4.19 (m, 2H), 3.85-3.25 (m, 7H), 2.50-2.48 (m, 1H), 2.28-2.24 (m, 1H), 1.25-1.23 (m, 1H); LC-MS: [M+1]+ 409.1.
Reaction SMILES: C1OC1.P(Cl)(Cl)Cl.[Cl:8][CH2:9][CH2:10]O.[P:12]([O:21][CH2:22][CH2:23][Cl:24])([O:17][CH2:18][CH2:19][Cl:20])[O:13]CCCl.C(O)(=O)C=C.COC1C=CC(O)=CC=1>>[Cl:8][CH2:9][CH2:10][P:12](=[O:13])([O:17][CH2:18][CH2:19][Cl:20])[O:21][CH2:22][CH2:23][Cl:24]
Reactant: OCCCl
Reactant: ClCCOP(OCCCl)OCCCl
Agent: C=CC(=O)O
Agent: COc1ccc(O)cc1
Solvent: ClP(Cl)Cl
Solvent: C1CO1
Product: O=P(CCCl)(OCCCl)OCCCl
Reaction time: 3.25 h

Procedure:
Ethylene oxide, 816 g. (18.5 m) is added subsurface to a stirred solution of 824 g. (6.0 m) of phosphorus trichloride and 8.2 g. of 2-chloroethanol in 2.75 hr with cooling at 15°-20° C. The resulting reaction mixture consists of about 90% tris(2-chloroethyl) phosphite, the remainder being a mixture of phosphonates, is warmed to 80°, and 389 g. (5.4 m.) of acrylic acid containing 100 ppm of hydroquinone monomethyl ether is added in 1.2 hr with cooling at 80°-85°. The reaction mixture is warmed to 130° in 0.5 hr and kept at 130°-140° for 3.25 hr. Stripping to 165°/1 mm leaves 1881 g. of yellow liquid which is a mixture of 2-chloroethyl phosphonates, acidity 9.7 meq/100 g. Washing of a 622 g. portion with 5% sodium carbonate solution, followed by stripping at reduced pressure, gives 590 g. acidity 3.7 meq./100 g. Distillation of a portion of the washed material gives bis(2-chloroethyl) 2-chloroethylphosphonate, b.p. 148°-151°/0.5 mm., and 2-chloroethyl 3-[bis(2-chloroethoxy)phosphinyl]propionate, b.p. 189°-191°/0.1 mm, leaving a mixture containing higher molecular weight 2-chloroethyl phosphonates as undistilled residue.