Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[CH3:7][CH:8]([N:10]1[C:14]2[N:15]=[C:16]([C:24]3[CH:29]=[CH:28][C:27](SC)=[CH:26][CH:25]=3)[CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:13]=2[CH:12]=[N:11]1)[CH3:9].[CH3:32]C(C)=O>O>[CH3:7][CH:8]([N:10]1[C:14]2[N:15]=[C:16]([C:24]3[CH:25]=[CH:26][C:27]([S:3]([CH3:32])(=[O:5])=[O:2])=[CH:28][CH:29]=3)[CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:13]=2[CH:12]=[N:11]1)[CH3:9]
Reactant: CCOC(=O)c1cc(-c2ccc(SC)cc2)nc2c1cnn2C(C)C
Reactant: O=S([O-])OO
Reactant: CC(C)=O
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)nc2c1cnn2C(C)C
Reaction time: 6 h
Yield: 82 %

Procedure:
Oxone (1712 mg, 2.79 mmol) was added to a solution of ethyl 1-(1-methylethyl)-6-[4-(methylthio)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (330 mg, 0.928 mmol) in acetone (6 mL) and water (2 mL), and the reaction mixture was stirred for 6 h. The reaction mixture was quenched with water (10 mL) and then neutralized with NaHCO3 solution. The mixture was extracted with EtOAc (3×) and the combined extracts dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified using column chromatography (Silica gel, 0 to 100% EtOAc/hexanes) to give 295 mg (82%) of product. LCMS E-S (M+H)=388.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.54 (t, J=7.2 Hz, 3 H), 1.67-1.69 (d, J=6.8 Hz, 6 H), 3.14 (s, 3 H), 4.58 (q, J=7.2 Hz, 2 H), 5.48 (spt, J=6.7 Hz, 1 H), 8.06-8.18 (m, 2 H), 8.29 (s, 1 H), 8.39-8.44 (m, 2 H), 8.47 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:22]2[C:27]([F:28])=[CH:26][CH:25]=[C:24]([F:29])[C:23]=2[F:30])[C:12]2[C:13]([CH3:21])=[CH:14][C:15]([C:18]([NH2:20])=[O:19])=[N:16][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C=O.[OH-].[Na+].[C:35](OCC)(=[O:37])C>COCCOC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:22]2[C:27]([F:28])=[CH:26][CH:25]=[C:24]([F:29])[C:23]=2[F:30])[C:12]2[C:13]([CH3:21])=[CH:14][C:15]([C:18]([NH:20][CH2:35][OH:37])=[O:19])=[N:16][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: Cc1cc(C(N)=O)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: Cc1cc(C(=O)NCO)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 17 h
Yield: 56 %

Procedure:
To a solution of 5-[[(4-chlorophenyl)sulfonyl](2,3,6-trifluorophenyl)methyl]-4-methylpyridine-2-carboxamide (190 mg, 0.418 mmol) in ethylene glycol dimethyl ether (4 ml), an aqueous solution of formaldehyde (37%, 94.2 μl) and 1 N aqueous sodium hydroxide (21.0 μl) were added at room temperature, and the mixture was stirred for 17 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous ammonium chloride. Subsequently, 1 N hydrochloric acid was added to the organic layer, and the mixture was stirred for 1 hour. After the organic layer was separated, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was subjected to flash silica gel chromatography, and the fraction obtained from an elution with hexane:ethyl acetate=1:1 was concentrated under reduced pressure. The resulting residue was washed with a mixed solvent of ethyl acetate and diethyl ether, and then was collected by filtration, to obtain the title compound (113 mg, 0.233 mmol, 56%) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6](O)[CH:5]=1.O=P(Cl)(Cl)[Cl:13]>C(Cl)Cl>[Cl:13][C:6]1[CH:5]=[C:4]([CH2:3][O:2][CH3:1])[N:9]=[CH:8][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCc1cc(O)ncn1
Solvent: ClCCl
Product: COCc1cc(Cl)ncn1
Reaction time: 18 h

Procedure:
6-(Methoxymethyl)pyrimidin-4-ol (948 mg, 6.8 mmole) was taken up in CH2Cl2 (10 mL) and POCl3 (6 mL) at room temperature. After 18 hours, the mixture was concentrated to dryness. The residue was taken up in ice water and the pH adjusted to 7. The mixture was extracted with CHCl3 (4×). The combined organic layers were dried (MgSO4), filtered, and concentrated to give the title compound which was sufficiently pure for use in the next step without purification. 1H-NMR (500 MHz, CDCl3) δ 8.95 (s, 1H), 7.58 (s, 1H), 4.48 (s, 2H), 3.50 (s, 3H).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[C:9]1(=[O:16])[O:15][C:13](=[O:14])[CH:12]=[C:10]1[CH3:11]>CC(C)=O>[C:1]1([NH:8][C:13](=[O:14])/[CH:12]=[C:10](/[CH3:11])\[C:9]([OH:16])=[O:15])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:13](=[O:14])/[CH:12]=[C:10](/[CH3:11])\[C:9]([OH:15])=[O:16])[CH:2]=1
Reactant: CC1=CC(=O)OC1=O
Reactant: Nc1cccc(N)c1
Solvent: CC(C)=O
Product: C/C(=C/C(=O)Nc1cccc(NC(=O)/C=C(/C)C(=O)O)c1)C(=O)O
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A 3-liter, 3-neck round bottom flask was charged with 54 g (0.5 mole) of m-phenylenediamine and 500 ml of reagent acetone and flushed with nitrogen. The flask was fitted with a reflux condenser, mechanical stirrer and thermocouple. A dropping funnel containing 112 g (1.0 mole) of citraconic anhydride in 500 ml of reagent acetone was attached and the solution added dropwise over about 1 1/2 hours with stirring as the temperature was allowed to rise to reflux the acetone. The reaction mixture was refluxed for an additional hour, cooled to room temperature and suction filtered to give 166 g of N,N'-(m-phenylene)bis citraconamic acid as shown by NMR analysis, as a tan mustard-colored solid melting at 152°-156° C.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([SH:16])=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][O:11]2.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34]Cl)=[CH:30][CH:29]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][S:16][C:13]2[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:2])=[O:17])=[C:7]3[C:12]=2[O:11][CH2:10][CH2:9][CH2:8]3)=[CH:32][CH:33]=1
Reactant: ClCc1ccc(OCc2cc(Cl)ccc2Cl)cc1
Reactant: COC(=O)COc1ccc(S)c2c1CCCO2
Product: O=C(O)COc1ccc(SCc2ccc(OCc3cc(Cl)ccc3Cl)cc2)c2c1CCCO2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using (8-mercapto-chroman-5-yloxy)-acetic acid methyl ester and 1,4-Dichloro-2-(4-chloromethyl-phenoxymethyl)-benzene prepared in the manner analagous to Example 71A. m/z 519 (M+1).
Reaction SMILES: Cl.[F:2][C:3]1([F:8])[CH2:7][CH2:6][NH:5][CH2:4]1.CCN(C(C)C)C(C)C.Cl[CH2:19][CH2:20][S:21](Cl)(=[O:23])=[O:22]>CC#N.CCOCC>[F:2][C:3]1([F:8])[CH2:7][CH2:6][N:5]([S:21]([CH:20]=[CH2:19])(=[O:23])=[O:22])[CH2:4]1
Reactant: FC1(F)CCNC1
Reactant: O=S(=O)(Cl)CCCl
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: C=CS(=O)(=O)N1CCC(F)(F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.6 %

Procedure:
A solution of 3,3-difluoropyrrolidine hydrochloride (0.3 g, 2.1 mmol, Matrix) and DIEA (0.37 mL, 2.1 mmol) in MeCN (5 mL) was stirred at about 50° C. for about 30 min. The reaction was cooled to ambient temperature and concd under reduced pressure. The solid was dissolved in MeCN (2 mL) and a solution of 2-chloroethanesulfonyl chloride (0.22 mL, 2.1 mmol) in Et2O (3 mL) was added at about −78° C. and stirred for about 2 h. To the reaction mixture was added DIEA (0.6 mL, 3.4 mmol) and stirred for about 1 h. The reaction was warmed to ambient temperature and the solvent was removed under reduced pressure. The residue was partitioned between DCM (5 mL) and water (2×2 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concd under reduced pressure to give crude 3,3-difluoro-1-(vinylsulfonyl)pyrrolidine (0.11 g, 27%) which was used without further purification: LC/MS (Table 1, Method b) Rt=2.04 min; MS m/z: 198 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:8][N:7]([CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])[C:6]2=[O:24])[CH2:3][CH2:2]1>C(Cl)Cl.C(C(O)=O)(F)(F)F>[CH:1]1([CH2:4][N:5]2[C:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:8][N:7]([CH2:16][C:17]([OH:19])=[O:18])[C:6]2=[O:24])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)Cn1cc(-c2ccccc2)n(CC2CC2)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cn1cc(-c2ccccc2)n(CC2CC2)c1=O

Procedure:
A solution of tert-butyl [3-(cyclopropylmethyl)-2-oxo-4-phenyl-2,3-dihydro-1H-imidazol-1-yl]acetate from Step C (41 mg, 0.125 mmol) in CH2Cl2 (2 mL) and CF3CO2H (1 mL) was stirred at ambient temperature for 3 h. The mixture was concentrated in vacuo to afford the title compound. MS: m/z=273 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[C:8](=[NH:15])(OC)[CH2:9][CH2:10][CH2:11][CH3:12]>CO.O.C1(C)C=CC=CC=1>[C:8]([NH:1][CH2:2][C:3]([OH:5])=[O:4])(=[NH:15])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: NCC(=O)O
Reactant: CCCCC(=N)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCC(=N)NCC(=O)O
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A stirred suspension of glycine (18.77 g, 0.25 mol) in methanol (80 ml) and water (4.5 ml) was cooled to 0° C. and adjusted to pH 9.6 by adding 30 percent strength sodium hydroxide solution. Methyl pentanimidate (67.12 g of a 42.9 percent strength solution in toluene=0.25 mol) was added to this suspension over the course of 7 minutes. The reaction mixture was stirred for 5 hours at room temperature. Methanol and water were then distilled off at a reduced pressure of 30 mbar to 150 mbar. In total, 250 ml of toluene was added during this distillation. The mixture was then filtered, and the filter cake washed with toluene (75 ml) and dried. The yield of the title compound was 39.61 g (purity approximately 90 percent by H-NMR), 90 percent based on glycine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]#[C:13][C:14]([OH:16])=O.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH2:36])[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH:31]([O:34][CH3:35])[CH2:30][CH2:29]1>ClCCl.CO>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:36][C:14](=[O:16])[C:13]#[C:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[Cl:1])[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH:31]([O:34][CH3:35])[CH2:30][CH2:29]1
Reactant: COc1cc(N)ccc1OCCN1CCC(OC)CC1
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Solvent: ClCCl
Solvent: CO
Product: COc1cc(NC(=O)C#Cc2ccc(C(F)(F)F)cc2Cl)ccc1OCCN1CCC(OC)CC1

Procedure:
Prepared analogously to Example 2.3.f. from 150 mg (0.6 mmol) of (2-chloro-4-trifluoromethylphenyl)propynoic acid and 186 mg (0.66 mmol) of 3-methoxy-4-[2-(4-methoxypiperidin-1-yl)ethoxy]phenylamine. Yield: 20 mg (7% of theory); melting point: 195° C.-197° C.; C25H26ClF3N2O4 (M=510.93); calc.: molecular ion peak (M+H)+: 511/513 (Cl); found: molecular ion peak (M+H)+: (M+H)+: 511/513 (Cl); Rf value: 0.3 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.Cl.[F:14][C:15]([F:25])([F:24])[CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1.[C@H:26]1([NH:35][C:36]2[CH:45]=[CH:44][C:43]3[C:38](=[CH:39][CH:40]=[C:41]([NH2:46])[CH:42]=3)[N:37]=2)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27]1>>[C@H:26]1([NH:35][C:36]2[CH:45]=[CH:44][C:43]3[C:38](=[CH:39][CH:40]=[C:41]([NH:46][C:1]([NH:23][CH:20]4[CH2:21][CH2:22][N:17]([CH2:16][C:15]([F:14])([F:24])[F:25])[CH2:18][CH2:19]4)=[O:12])[CH:42]=3)[N:37]=2)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: NC1CCN(CC(F)(F)F)CC1
Agent: Cl
Product: O=C(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)NC1CCN(CC(F)(F)F)CC1

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 1-(2,2,2-trifluoro-ethyl)-piperidin-4-ylamine hydrochloride (CAS no: 180869-49-2) and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=484.8 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([NH:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[C:3]=1[N+:21]([O-:23])=[O:22].[NH3:24]>>[ClH:1].[NH2:24][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([NH:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[C:3]=1[N+:21]([O-:23])=[O:22]
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1NCCCN(C)C
Reactant: N
Product: CCOC(=O)c1c(C)nc(N)c([N+](=O)[O-])c1NCCCN(C)C
Product: Cl

Procedure:
6-Chloro-4-[[3-(dimethylamino)propyl]amino]-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester is treated with ammonia according to the procedure of Example 1 c and 6-amino-4-[[3-(dimethylamino)propyl]amino]-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester, hydrochloride is obtained, m.p. 182° (dec.), (methanol). The aqueous solution of this hydrochloride is made alkaline with sodium hydroxide and extracted with ether to obtain the free base, m.p. 52°-53° (methanol).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4]1([CH2:16][O:15][C:14]3[CH:17]=[C:18]4[C:22](=[CH:23][C:13]1=3)[CH2:21][CH2:20][O:19]4)[C:5](=[O:12])[NH:6]2.N1C2C(=CC=CC=2)[C:26]2([C:36]3=CC4OCOC=4[CH:43]=[C:35]3[O:34][CH2:33]2)C1=O.CC1C=CC(S(OC[C@H]2CCCO2)(=O)=O)=CC=1.CC1C=CC(S(OC[C@H]2COCCO2)(=O)=O)=CC=1>>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4]1([CH2:16][O:15][C:14]3[CH:17]=[C:18]4[C:22](=[CH:23][C:13]1=3)[CH2:21][CH2:20][O:19]4)[C:5](=[O:12])[N:6]2[CH2:43][C@H:35]1[CH2:36][CH2:26][CH2:33][O:34]1
Reactant: Cc1ccc(F)c2c1NC(=O)C21COc2cc3c(cc21)CCO3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2COCCO2)cc1
Product: Cc1ccc(F)c2c1N(C[C@H]1CCCO1)C(=O)C21COc2cc3c(cc21)CCO3

Procedure:
Following the procedure as described in EXAMPLE 8 and making non-critical variations using 4′-fluoro-7′-methyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate, 4′-fluoro-7′-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (76%) as a colorless solid: mp 175-176° C. (diethyl ether); 1H NMR (300 MHz, CD3OD) δ7.14-7.06 (m, 1H), 6.71-6.52 (m, 2H), 6.25 (d, J=2.3 Hz, 1H), 4.80-4.78 (m, 2H), 4.51 (t, J=8.6 Hz, 2H), 4.26-3.69 (m, 5H), 3.00 (t, J=8.6 Hz, 2H), 2.56 (s, 3H), 2.16-1.87 (m, 3H), 1.78-1.69 (m, 1H); MS (ES+) m/z 396.0 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25](Br)=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([N:3]2[CH:4]=[C:5]([C:8]([F:9])([F:11])[F:10])[CH:6]=[CH:7][C:2]2=[O:1])=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Reactant: Oc1ccc(C(F)(F)F)cn1
Product: Cc1nc(-n2cc(C(F)(F)F)ccc2=O)sc1C(=O)NCc1ccccc1
Yield: 60 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 2-hydroxy-5-(trifluoromethyl)pyridine in place of 4-aminopyridin-2(1H)-one to react with N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 60% yield: mp 148-149° C.; 1H NMR (300 MHz, CDCl3) δ 9.19 (br s, 1H), 7.53 (dd, J=9.6, 2.7 Hz, 1H), 7.37-7.25 (m, 5H), 6.78 (d, J=9.6 Hz, 1H), 6.27 (t, J=5.7 Hz, 1H), 4.58 (d, J=5.7 Hz, 2H), 2.69 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.7, 159.6, 152.4, 151.9, 137.6, 135.2, 131.1, 128.8, 127.9, 124.6, 124.5, 122.1, 121.1, 111.8, 44.2, 17.2; MS (ES+) m/z 394.2 (M+1).
Reaction SMILES: [NH:1]([C:3]1[N:4]=[C:5]2[CH:11]=[CH:10][N:9]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]2=[N:7][CH:8]=1)[NH2:2].[C:22]([O:26][C:27]([NH:29][C:30]12[CH2:37][CH2:36][C:33]([C:38](O)=[O:39])([CH2:34][CH2:35]1)[CH2:32][CH2:31]2)=[O:28])([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(Cl)Cl>O>[S:12]([N:9]1[C:6]2=[N:7][CH:8]=[C:3]([NH:1][NH:2][C:38]([C:33]34[CH2:34][CH2:35][C:30]([NH:29][C:27](=[O:28])[O:26][C:22]([CH3:24])([CH3:23])[CH3:25])([CH2:31][CH2:32]3)[CH2:37][CH2:36]4)=[O:39])[N:4]=[C:5]2[CH:11]=[CH:10]1)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: CC(C)(C)OC(=O)NC12CCC(C(=O)O)(CC1)CC2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(NNC(=O)C45CCC(NC(=O)OC(C)(C)C)(CC4)CC5)cnc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
A round bottom flask was charged with 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (3.75 g, 11.1 mmol, Preparation #9), 4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid (3.0 g, 11 mmol, Prime Organics), HATU (4.23 g, 11.1 mmol), TEA (6.2 mL, 44 mmol), and DCM (65 mL). The reaction mixture was stirred at ambient temperature for about 16 h. The reaction mixture was diluted with water (30 mL) and the layers were separated. The reaction mixture was filtered through Celite® and washed with DCM (60 mL). The organic layer was washed with water (3×50 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-100% EtOAc in DCM to afford tert-butyl 4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)bicyclo[2.2.2]octan-1-ylcarbamate as a brown amorphous solid (5.38 g, 87%): LC/MS (Table 2, Method a) Rt=2.40 min; MS m/z 555 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si](C)(C)C)=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([Li])CCC.Cl[C:38]([O:40][CH3:41])=[O:39]>C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:38]([O:40][CH3:41])=[O:39])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#Cc1ccc(F)cc1
Reactant: COC(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: COC(=O)C#Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-(4-fluorophenyl)-2-trimethylsilylacetylene (64 g, 0.33 mol) in dry diethyl ether (400 mL) was cooled to 0° C. under a nitrogen atmosphere. To this solution was added, dropwise over 45 minutes, a solution of tetrabutylammonium fluoride (1M in tetrahydrofuran, 330 mL, 0.33 mol) via a dropping funnel maintaining the internal temperature below 2° C. The mixture was allowed to warm to room temperature over about 1 hour. Diethyl ether (300 mL) was added to the mixture and the organic solution was washed with water, saturated brine and then dried over anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration and the filtrate was cooled to about −78° C. n-Butyl lithium (1.6M in hexanes, 450 mL, 0.72 mol) was added dropwise via a dropping funnel over about 1 hour while the temperature was maintained below −66° C. After complete addition the mixture was stirred at −78° C. for about 1 hour and then a precooled solution of methyl chloroformate (110 mL, 1.4 mol) in dry diethyl ether (200 mL) was added in a continuous stream as fast as possible. The mixture was allowed to cool to −78° C. and the allowed to warm to room temperature over 1.5 h. The organic reaction mixture was washed with water and saturated brine and then dried over anhydrous magnesium sulfate. The solvents are remove under reduced pressure and the residue dried under reduced pressure to give the title compound as a brown solid, 36.5 g (61%). 1H NMR (CDCl3) δ 7.58 (dd, 2H, J=9, 5.4 Hz), 7.07 (t, 2H, J=8.5 Hz), 3.84 (s, 3H). MS (+ve ion electrospray) 178 (30), (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].C([N:13](CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19]>C(OCC)(=O)C>[C:18]([O:10][C:3]1[C:4]([CH3:9])=[C:5]([C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])[NH2:13])(=[O:20])[CH3:19]
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: CC(=O)Cl
Reactant: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)Oc1c(C)cc(C)c(N)c1C
Reaction time: 8 h

Procedure:
To a solution of 2,4,6-trimethylphenol (10 g, 73.5 mmol) and triethylamine (11.1 g, 110.3 mmol) in ethyl acetate (200 mL) was added acetyl chloride (7.5 g, 95.6 mmol) dropwise at 0° C. The mixture was stirred overnight. The reaction was quenched with water and the organic layer was washed with 1 N HCl. The organic layer was dried and concentrated as usual. The residue was nitrated Example 14 (procedure B) and reduced as demonstrated for Example 14 (procedure C) to give 3-acetoxy-2,4,6-trimethylaniline.
Reaction SMILES: [F:1][CH2:2][CH:3]([NH2:8])[CH2:4][C:5]([CH3:7])=[CH2:6].C(N1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])(OCC)=O>C1C=CC=CC=1>[F:1][CH2:2][CH:3]([N:8]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])[CH2:4][C:5]([CH3:7])=[CH2:6]
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: C=C(C)CC(N)CF
Solvent: c1ccccc1
Product: C=C(C)CC(CF)N1C(=O)c2ccccc2C1=O
Yield: 84.5 %

Procedure:
A mixture of 1-fluoro-2-amino-4-methyl-4-pentene (52.5 g, 450 mmoles) prepared as in step A above, N-carbethoxyphthalimide (98.55 g, 450 mmoles), and benzene (600 mL) is kept overnight at room temperature. The solution is concentrated under vacuum, the oily residue is dissolved in methylene chloride (500 mL) and treated with 50 g of triethylamine during 4 hours at room temperature. After extraction with 2 N hydrochloric acid (6×500 mL), the organic layer is dried over sodium sulfate and discoloured by filtration through a layer of silica gel and another of carbon black. The oily residue obtained after concentration (110 g) is extracted several times with petroleum ether to remove some insoluble N-carbethoxyphthalimide. Evaporation of the petroleum ether affords a yellow oil (94 g) which is crystallized from pentane at low temperature (85 g, 77%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[CH2:11](O)[CH3:12]>[Ni]>[CH2:11]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1)[CH3:12]
Reactant: CCO
Reactant: Nc1ccc2c(c1)CCO2
Agent: [Ni]
Product: CCNc1ccc2c(c1)CCO2
Temperature: 25 °C

Procedure:
A mixture of 148 g. (1.09 moles) of 5-amino-2,3-dihydrobenzofuran and 93 g. of W2 Raney nickel in 850 ml. of ethanol was heated to reflux for 24 hours. The reaction was cooled to 25° C., filtered and evaporated to give a quantitative yield of the desired intermediate.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1.C(N(CC)CC)C.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:32][C:23]1[CH:28]=[CH:27][C:26]([C:29]([O:11][CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][C:3]3[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=3[F:1])[CH2:6][CH2:7]2)=[O:30])=[CH:25][CH:24]=1
Reactant: OC1CCN(Cc2ccccc2F)CC1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)OC2CCN(Cc3ccccc3F)CC2)cc1
Yield: 80.3 %

Procedure:
0.382 g (0.001825 mol) of 1-(2-fluoro-benzyl)-piperidin-4-ol and 0.512 ml (0.00365 mol) of triethylamine were dissolved in 10 ml of toluene, treated with 0.483 ml (0.00365 mol) of p-toluoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 0.48 g (80%) of 1-(2-fluoro-benzyl)-piperidin-4-yl 4-methyl-benzoate was obtained as a yellow oil. MS: me/e=328 (C20H23 FN02+).