Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[CH2:26]([CH:28]([CH2:34][CH3:35])[C:29]([O:31][CH2:32]I)=[O:30])[CH3:27]>C(N(CC)CC)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O:20][CH2:32][O:31][C:29](=[O:30])[CH:28]([CH2:34][CH3:35])[CH2:26][CH3:27])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CCC(CC)C(=O)OCI
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Solvent: CCN(CC)CC
Product: CCC(CC)C(=O)OCOC(=O)C1=CCS[C@@H]2C(NC(=O)C(=NOC)c3csc(N)n3)C(=O)N12

Procedure:
In the same manner as Example 8, 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn-isomer) was reacted with iodomethyl 2-ethylbutyrate in the presence of triethylamine to give 2-ethylbutyryloxymethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([OH:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[N:10]2)=[CH:5][CH:4]=1.Br[CH2:20][N:21]1[C:25](=[O:26])[C:24]2[C:27]([CH:33]([CH3:35])[CH3:34])=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:23]=2[S:22]1(=[O:37])=[O:36].[F-].[K+]>CN(C=O)C.O>[CH:33]([C:27]1[C:24]2[C:25](=[O:26])[N:21]([CH2:20][O:14][C:13]3[N:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[N:10]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:12]=3)[S:22](=[O:37])(=[O:36])[C:23]=2[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=1)([CH3:35])[CH3:34]
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Reactant: COc1ccc(-n2nc(C(F)(F)F)cc2O)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-n2nc(C(F)(F)F)cc2OCN2C(=O)c3c(C(C)C)cc(OC)cc3S2(=O)=O)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 46.2 %

Procedure:
A mixture of 1-(4-methoxyphenyl)-3-trifluoromethyl-5-hydroxy pyrazole (489 mg; 1.89 mmol), 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (600 mg, 1.72 mmol), and KF (200 mg; 3.44 mmol) in DMF (8 ml) was stirred at 20° C. for 2 hours and the mixture was diluted with water. The above mixture was extracted with ether (3×) and the organic layer was dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (silica gel; 25-50% ethyl acetate/hexane) and recrystallized from ethyl acetate/hexane to afford 418 mg (46%) of 4-isopropyl-6-methoxy-2-[1-(4-methoxyphenyl)-3-trifluoromethylpyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =4-CH3O--Ph; R2 =CF3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3) as a white solid, m.p. 111°-113° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:11](=[O:12])[CH:10]=[CH:9][C:7](=[O:8])[C:5]=2[CH:6]=1.C(O[CH:17]=[CH:18][CH:19]=[CH2:20])(=O)C.C([O-])(=O)C.[Na+].O=O>C(O)(=O)C.CN(C)C=O>[CH:17]1[C:10]2[C:11](=[O:12])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7](=[O:8])[C:9]=2[CH:20]=[CH:19][CH:18]=1
Reactant: C=CC=COC(C)=O
Reactant: O=C1C=CC(=O)c2ccccc21
Agent: CC(=O)[O-]
Agent: O=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)c2ccccc21
Temperature: 120 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
15.8 parts by weight naphthoquinone and 13.5 parts by weight of 1-acetoxybutadiene in 50 parts by volume of dimethylformamide and 1 part by volume of acetic acid are stirred for 6 hours under nitrogen at 45° - 50° C. 0.4 part by weight of sodium acetate is then added, oxygen is passed in and the batch is stirred for 2 hours at 120° C. After cooling, the anthraquinone which has precipitated is filtered off and washed with dimethylformamide. 18.2 parts by weight (91% of theory) of anthraquinone of melting point 284° C are obtained.
Reaction SMILES: [C:1]12([NH:11][C:12]#[N:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[ClH:14].[I:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18]>>[ClH:14].[C:1]12([NH:11][C:12]([NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[I:15])=[NH:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: Nc1ccccc1I
Reactant: N#CNC12CC3CC(CC(C3)C1)C2
Agent: Cl
Product: N=C(Nc1ccccc1I)NC12CC3CC(CC(C3)C1)C2
Yield: 4.2 %

Procedure:
Adamantan-1-ylcyanamide (299 mg, 1.70 mmol) and o-iodoaniline hydrochloride (433 mg 1.70 mmol) were finely ground together and heated at 200° for 10 min. The resultant black glassy solid was pulverized, and recrystallized 5 times from EtOH/Et2O. The resultant faintly blue needles (80 mg) were dissolved in 4 ml EtOH, and passed through a short (<1 cm) column packed from bottom to top with Celite, charcoal, activated alumina, and sand. The colorless eluate was then diluted with 5ml Et2O, and allowed to stand in an Et2O diffusion chamber overnight. The white needles were collected by suction filtration, 40 mg, mp 274°-275° C. Addition of another 5 ml Et2O yielded a second crop (31 mg) of identical material. Combined yield: 21%. 1H (CD3OD) 1.779 (s, 6H), 2.090 (s, 6H), 2.164 (s, 3H), 7.168 (t, 1 H, J=8.1 Hz), 7.388 (d, 1H, J=9.1 Hz), 7.503 (t, 1H, J=7.8 Hz), 8.004 (d, 1H, J=7.8 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[CH2:19][O:20][CH2:21][C:22](O)=[O:23])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.[N:26]1([CH2:31][CH2:32][O:33][C:34]2([C:47]3[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=3)[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][CH2:35]2)[CH:30]=[CH:29][N:28]=[CH:27]1>>[N:26]1([CH2:31][CH2:32][O:33][C:34]2([C:47]3[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=3)[CH2:39][CH2:38][N:37]([C:22](=[O:23])[CH2:21][O:20][CH2:19][C@@H:14]3[CH2:15][CH2:16][CH2:17][CH2:18][N:13]3[S:10]([C:6]3[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH3:25])(=[O:11])=[O:12])[CH2:36][CH2:35]2)[CH:30]=[CH:29][N:28]=[CH:27]1
Reactant: CC(C)(C)OC(=O)N1CCC(OCCn2ccnc2)(c2cccnc2)CC1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2COCC(=O)O)c(C)c1
Product: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2COCC(=O)N2CCC(OCCn3ccnc3)(c3cccnc3)CC2)c(C)c1
Yield: 60 %

Procedure:
The desired target compound was synthesized under reaction conditions analogously to the process described for Example 61 (see below) from (S)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid [acid D] and tert-butyl 4-(2-(1H-imidazol-1-yl)ethoxy)-4-(pyridin-3-yl)piperidine-1-carboxylate [amine F]. Yield: 60%. MS, Rt=2.7 min, m/z=626.4 [MH]+
Reaction SMILES: [OH:1][C@H:2]([C:10]1[CH:19]=[CH:18][C:13]2[C:14](=[O:17])[O:15][CH2:16][C:12]=2[C:11]=1[CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH3:21][C:22]1[C:30]2[CH2:29][O:28][C:27](=[O:31])[C:26]=2[CH:25]=[CH:24][C:23]=1[C@H:32]1[CH2:34][O:33]1.C(O)C>C(Cl)Cl>[OH:1][C@H:2]([C:10]1[CH:19]=[CH:18][C:13]2[C:14](=[O:17])[O:15][CH2:16][C:12]=2[C:11]=1[CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:34][C@@H:32]([OH:33])[C:23]2[CH:24]=[CH:25][C:26]3[C:27](=[O:31])[O:28][CH2:29][C:30]=3[C:22]=2[CH3:21])[CH2:6][CH2:5]1
Reactant: Cc1c([C@@H](O)CN2CCNCC2)ccc2c1COC2=O
Reactant: Cc1c([C@H]2CO2)ccc2c1COC2=O
Solvent: ClCCl
Solvent: CCO
Product: Cc1c([C@H](O)CN2CCN(C[C@H](O)c3ccc4c(c3C)COC4=O)CC2)ccc2c1COC2=O
Temperature: 150 °C
Reaction time: 8 h

Procedure:
To a 20 mL microwave tube charged with 5-[(1R)-1-hydroxy-2-piperazin-1-ylethyl]-4-methyl-2-benzofuran-1(3H)-one (166 mg, 0.600 mmol) and a stir bar was added 4-methyl-5-[(2S)-oxiran-2-yl]-2-benzofuran-1(3H)-one (171 mg, 0.900 mmol) and ethanol (10 mL). The mixture was heated in a microwave apparatus to 150° C. for 90 minutes. After the reaction cooled down, DCM (5 mL) was added to the tube. The mixture was allowed to sit at RT overnight. A lot of solids precipitated during that time; these were collected by filtration. Chiral HPLC analysis showed the material was over 95% ee pure 5-((1R)-1-hydroxy-2-{4-[(2S)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-4-methyl-2-benzofuran-1(3H)-one. 1H-NMR (500 MHz, DMSO-d6) δ ppm 7.74 (s, 4H), 5.43 (m, 4H), 6.60-5.80 (broad, 2H), 5.33 (s, 2H), 3.40 (broad, 8H), 3.09 (broad, 4H), 2.32 (s, 6H); LCMS M+1 (calc. 467, found 467).
Reaction SMILES: Br[C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[CH:6]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[CH:6]=2)=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1c[nH]c(Br)c1
Reactant: OB(O)c1ccc(F)cc1
Product: O=[N+]([O-])c1c[nH]c(-c2ccc(F)cc2)c1
Yield: 40 %

Procedure:
2-Bromo-4-nitro-1H-pyrrole (886 mg, 4.64 mmol) synthesized in Reference Synthesis Example 244 and 4-fluorophenylboronic acid (779 mg, 5.57 mmol) were used to obtain the title compound (383 mg, yield 40%) by synthesis in a similar manner to Reference Synthesis Example 139.
Reaction SMILES: [NH2:1][C:2]1([O:11][CH3:12])[CH2:5][N:4]([S:6]([OH:9])(=[O:8])=[O:7])[C:3]1=[O:10].[Cl:13][CH2:14][C:15]([NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23](=[N:27][O:28][CH3:29])[C:24](O)=[O:25])[N:22]=1)=[O:16].C(=O)([O-])O.[Na+:34].P(=O)(O)(O)O>O.O1CCCC1>[Cl:13][CH2:14][C:15]([NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23](=[N:27][O:28][CH3:29])[C:24]([NH:1][C:2]2([O:11][CH3:12])[CH2:5][N:4]([S:6]([O-:9])(=[O:7])=[O:8])[C:3]2=[O:10])=[O:25])[N:22]=1)=[O:16].[Na+:34]
Reactant: COC1(N)CN(S(=O)(=O)O)C1=O
Reactant: CON=C(C(=O)O)c1csc(NC(=O)CCl)n1
Agent: O=C([O-])O
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CON=C(C(=O)NC1(OC)CN(S(=O)(=O)[O-])C1=O)c1csc(NC(=O)CCl)n1

Procedure:
In 1 ml of water is dissolved 30 mg of the above 3-amino-3-methoxy-2-oxoazetidine-1-sulfonic acid, and to the solution are added a solution of 89 mg of the acid chloride prepared from 2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetic acid (syn-isomer) in 1 ml of tetrahydrofuran and 36 mg of sodium hydrogen carbonate in alternate portions with ice-cooling and stirring. The mixture is further stirred at room temperature for 20 minutes and adjusted to pH 5.8 with phosphoric acid. After removal of tetrahydrofuran under reduced pressure, the water layer is washed with ethyl acetate and purified by Amberlite XAD-II chromatography. The above procedure yields 28 mg of sodium 3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-3-methoxy-2-oxoazetidine-1-sulfonate (syn-isomer) which is the same compound as the one described in Example 9.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].C(N(CC)CC)C.Cl[CH2:19][C:20](Cl)=[O:21].[H-].[Na+]>C1COCC1>[C:5]1([C@H:2]2[NH:1][C:20](=[O:21])[CH2:19][O:4][CH2:3]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: O=C(Cl)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1COC[C@@H](c2ccccc2)N1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 40.3 %

Procedure:
To a mixture of (2R)-2-amino-2-phenyl-ethanol (10 g, 72.90 mmol) and triethylamine (18.45 g, 25.41 mL, 182.3 mmol) in THF (207.5 mL) at 0° C., was added 2-chloroacetyl chloride (8.234 g, 5.799 mL, 72.90 mmol) over 5 mins. The reaction mixture was partitioned between EtOAc (100 mL) and water (100 mL) and the organic layer separated, washed successively with water (2×100 mL), brine (1×100 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude product was then dissolved in THF (145.2 mL) and NaH (60% in mineral oil) (3.499 g, 87.48 mmol) was added portionwise over 5 mins at rt. On complete addition, the resulting mixture was stirred at rt for 1.5 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (50 mL) and diluted with EtOAc (50 mL) and the organic layer separated, washed with sequentially with water (2×50 mL) and brine (1×50 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by ISCO column companion system (330 g column, 0-10% MeOH/CH2Cl2). Product fractions were combined and concentrated in vacuo to leave the product as a pale yellow solid (5.2 g, 41% yield); 1H NMR (400.0 MHz, DMSO) d 3.55 (1H, m), 3.96 (1H, m), 4.08 (2H, s), 4.63 (1H, m), 7.29-7.40 (5H, m) and 8.46 (1H, s) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([OH:26])[CH:19]=2)=[CH:12][CH:11]=1.Br[CH2:29][CH2:30][CH2:31][N:32]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]1=[O:42].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:27])[C:10]1[CH:11]=[CH:12][C:13]([CH2:16][NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:29][CH2:30][CH2:31][N:32]3[C:40](=[O:41])[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:33]3=[O:42])[CH:19]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(NCc2ccc(C(=O)Nc3ccccc3N)cc2)cc1O
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(NCc2ccc(C(=O)Nc3ccccc3N)cc2)cc1OCCCN1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Yield: 46.2 %

Procedure:
To a solution of N-(2-amino-phenyl)-4-[(3-hydroxy-4-methoxy-phenylamino)-methyl]-benzamide (212e) (586 mg, 0.66 mmol) in DMF (10 ml) were added 2-(3-bromo-propyl)isoindole-1,3-dione (238) (176 mg, 0.66 mmol) and K2CO3 (365 mg, 2.64 mmol) at room temperature. The reaction mixture was heated at 100° C. for 1 h then overnight at 60° C., cooled, filtered and concentrated in vacuo. The residue was purified by flash chromatography (eluent from AcOEt-hexane (40:60) to pure AcOEt) to afford 239 (168 mg, 46% yield). 1H NMR: (DMSO) δ (ppm): 9.57 (bs, 1H), 7.88 (d, J=8.0 Hz, 2H), 7.84-7.75 (m, 4H), 7.44 (d, J=8.0 Hz, 2H), 7.12 (d, J=7.2 Hz, 1H), 6.92 (t, J=8.8 Hz, 1H), 6.75 (dd, J=1.2, 7.6 Hz, 1H), 6.57 (d, J=8.4 Hz, 2H), 6.27 (d, J=2.4 Hz, 1H), 6.00-5.93 (m, 2H), 4.87 (s, 2H), 4.27 (d, J=6.0 Hz, 2H), 3.89 (dd, J=5.6, 6.0 Hz, 2H), 3.74 (dd, J=6.4, 6.8 Hz, 2H), 3.42 (s, 3H), 2.06-2.01 (m, 2H). LRMS: (calcd.) 550.4; (found.) 551.5(MH)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.C(O)C.[C].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Yield: 86.6 %

Procedure:
4-(4-Nitrophenoxy)piperidine-1-carboxylic acid tert-butyl ester (53.687 g) was hydrogenated using 7.5% palladium carbon (8.05 g) in a mixture of tetrahydrofuran (215 ml) and ethanol (215 ml) at 3 atm over 3 hours. After completion of the reaction, the reaction mixture was filtered through celite and the solvent was evaporated. Hexane was added to the obtained residue, and the obtained solid was collected by filtration and dried under reduced pressure to give the title compound (42.157 g).
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.O=[C:12]1[CH2:18][CH:17]2[N:19](C(OC(C)(C)C)=O)[CH:14]([CH2:15][CH2:16]2)[CH2:13]1.S(=O)(=O)(O)O>O1CCOCC1>[CH3:10][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:8][C:12]1[CH2:13][CH:14]3[NH:19][CH:17]([C:18]2=1)[CH2:16][CH2:15]3
Reactant: Cc1ccc(NN)cc1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: Cc1ccc2[nH]c3c(c2c1)C1CCC(C3)N1
Temperature: 80 °C

Procedure:
4-Tolylhydrazine hydrochloride (1.90 g, 12.0 mmol) and tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (2.70 g, 12.0 mmol; Fluka) were heated at 50° C. in anhydrous dioxane (80 mL) for one hour. Sulfuric acid (3.2 mL) was added dropwise, and the resulting mixture was heated at 80° C. overnight. After cooling the mixture to room temperature, the dioxane phase was decanted. The remaining residue was dissolved in methanol (12 mL) and added slowly to a stirred solution of concentrated ammonium hydroxide (30 mL) kept at room temperature with a water bath. The resulting mixture was extracted with ethyl acetate (3×), and the combined organic phases were washed with brine, dried (sodium sulfate), concentrated, and purified by chromatography (silica gel, 0-5% gradient of concentrated aqueous ammonium hydroxide in acetonitrile) to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.59-1.72 (m, 1H), 1.93-2.25 (m, 3H), 2.54 (d, J=16, 1H), 3.25 (dd, J=16, 4.7, 1H), 3.91-3.99 (m, 1H), 4.49 (d, J=4.8, 1H), 6.83 (d, J=8.2, 1H), 7.12 (d, J=8.2, 1H), 7.19 (s, 1H); MS (ESI) m/z 213 (M+H)+.
Reaction SMILES: F[C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C([O-])([O-])=O.[K+].[K+].Cl.[NH:22]1[CH2:27][CH2:26][CH:25]([CH2:28][C:29]([OH:31])=[O:30])[CH2:24][CH2:23]1>CS(C)=O.CO>[C:4]([C:3]1[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:2]=1[N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][C:29]([OH:31])=[O:30])[CH2:24][CH2:23]1)(=[O:5])[NH2:6]
Reactant: NC(=O)c1ccc(C(F)(F)F)cc1F
Reactant: O=C(O)CC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CO
Product: NC(=O)c1ccc(C(F)(F)F)cc1N1CCC(CC(=O)O)CC1
Reaction time: 4 h

Procedure:
0.46 g of 2-fluoro-4-(trifluoromethyl)benzamide are added to a suspension of 1.8 g K2CO3 and 0.8 g of piperidin-4-yl acetic acid hydrochloride In 12 ml of DMSO, the mixture obtained is stirred for 4 h at 150°, solvent is evaporated, the evaporation residue obtained is suspended in MeOH and filtrated. The filtrate obtained is concentrated and subjected to chromatography on silica gel. [1-(2-Carbamoyl-5-trifluoromethyl-phenyl)-piperidin-4-yl]-acetic acid is obtained. 300 mg of EDC are added to a solution of 260 mg of [1-(2-carbamoyl-5-trifluoromethyl-phenyl)-piperidin-4-yl]-acetic acid, 230 mg of 3,5-bis-trifluoromethyl-benzenesulfonamide, 200 mg of DIEA and 90 mg of DMAP in 4 ml of DMF. The mixture obtained is stirred for 3 days at RT, solvent is evaporated in vacuo and the evaporation residue obtained is treated with EtAc. The mixture obtained is washed with 1 N HCl, saturated aqueous NaHCO3 solution and brine, dried, concentrated in vacuo and subjected to chromatography on silica gel. 2-{4-[2-(3,5-Bis-trifluoromethyl-benzenesulfonylamino)-2-oxo-ethyl]-piperidin-1-yl}-4-trifluoromethyl-benzamide is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][C:3]=1[Cl:9].[H-].[Na+].I[CH3:13]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:13])=[CH:4][C:3]=1[Cl:9]
Reactant: CI
Reactant: Sc1ccc(Br)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1ccc(Br)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 65 %

Procedure:
4-Bromo-3-chloro-benzenethiol (0.94 g, 4.21 mmol) was dissolved in tetrahydrofuran (10 ml) and cooled to 0° C. under argon. Sodium hydride (0.19 g, 4.63 mmol) was added and the mixture was stirred for 5 minutes, then iodomethane (0.28 ml, 4.42 mmol) was added. The mixture was allowed to warm, stirring for 30 minutes, then the reaction was quenched with saturated aqueous ammonium chloride. The mixture was extracted with dichloromethane (×2) and the combined organic layers were dried (MgSO4) and concentrated. Purification of the resultant residue by flash chromatography (Si-PCC, pentane) afforded the title compound as a colourless oil (0.65 g, 65%). 1H NMR (CDCl3 400 MHz) 2.47 (3H, s), 6.99 (1H, dd, J=8.45, 2.26 Hz), 7.30 (1H, d, J=2.25 Hz), 7.48 (1H, d, J=8.45 Hz).
Reaction SMILES: I[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[C-:15]#[N:16].[K+].C(=O)([O-])O.[Na+]>CN(C)P(=O)(N(C)C)N(C)C>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:6]2[O:5][CH2:4][CH:3]([CH2:2][C:15]#[N:16])[O:8][C:7]=2[CH:9]=1
Reactant: [C-]#N
Reactant: COc1ccc2c(c1)OC(CI)CO2
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1ccc2c(c1)OC(CC#N)CO2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1.35 g (4.43 mmol) of the iodinated compound obtained in Step C and 1.37 g (26.6 mmol) of potassium cyanide are dissolved in 15 ml of anhydrous hexamethylphosphoric triamide; the reaction mixture is then stirred for 2 days under argon and at ambient temperature. The solution is then hydrolysed with a solution of sodium hydrogen carbonate; the aqueous phase is then extracted with dichloromethane. The organic phase, dried over magnesium sulphate acid then filtered, is concentrated under reduced pressure. The title nitrile is obtained pure in the form of a clear oil after chromatography on silica gel (eluant:PE then AcOEt/PE:15/85).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[N:9]=[C:8]([NH2:17])[CH2:7]1)=[O:5])[CH3:2].[N+]([C:21]1C=CC=CC=1CN(CC#N)C(=O)OCC)([O-])=O>>[NH2:17][C:8]1[CH2:7][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:12]([CH3:21])[C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[N:9]=1
Reactant: CCOC(=O)N(CC#N)Cc1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)N1CC(N)=Nc2ccccc2C1
Product: CCOC(=O)N1CC(N)=Nc2ccccc2C1C
Yield: 13 %

Procedure:
This compound was prepared in a similar manner to (E)-ethyl-2-amino-3H-benzo[e][1,4]diazepine-4(5H)-carboxylate (3), substituting ethyl cyanomethyl(1-(2-nitrophenyl)ethyl)carbamate (8) for ethyl-2-nitrobenzyl-(cyanomethyl)carbamate (2), to provide 2.6 mg (0.011 mmol, 13% yield), of the desired product. 1H NMR (400 MHz, CDCl3) δ 1.26 (br s, 3H), 1.40 (d, 3H), 3.45-3.58 (br s, 1H), 4.15-4.29 (m, 2H), 4.44 (br s, 1H), 4.97 (br s, 1H), 7.03-7.06 (m, 2H), 7.18-7.31 (m, 2H).
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH3:6][C:7]1[N:8]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][S:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11](OC3C=CC=CC=3)[C:10]=2[N:24]=1.[OH-].[Na+]>O>[CH3:6][C:7]1[N:8]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][S:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH2:5])[C:10]=2[N:24]=1
Reactant: Cc1nc(Oc2ccccc2)c2nc(C)n(CCCCCSc3ccccc3)c2c1C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc(N)c2nc(C)n(CCCCCSc3ccccc3)c2c1C
Temperature: 160 °C

Procedure:
Ammonium acetate (25 g) and 2,6,7-trimethyl-4-phenoxy-1-[5-(phenylthio)pentyl]-1H-imidazo[4,5-c]pyridine (2.50 g, 5.80 mmol) were combined and heated at 160° C. in a sealed tube for 2 days. The reaction mixture was cooled to ambient temperature and diluted with water (100 mL). Sodium hydroxide (15%) was added and the mixture was extracted with chloroform (2×150 mL). The combined extracts were dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel eluting with 2% methanol in chloroform) followed by recrystallization from methanol/dichloromethane/hexanes to provide 2,6,7-trimethyl-1-[5-(phenylthio)pentyl]-1H-imidazo[4,5-c]pyridin-4-amine as an off white powder, m.p. 181-183° C.