Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=4)=[O:20])[CH2:15]3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[C:38]#[N:39].CO>CN(C=O)C>[C:38]([NH:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:9][CH2:10][CH:11]([N:14]3[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=4)=[O:20])[CH2:15]3)[CH2:12][CH2:13]2)[CH:5]=[CH:4][CH:3]=1)#[N:39]
Reactant: N#CBr
Reactant: Nc1cccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: N#CNc1cccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of N-({1-[4-(6-amino-pyridin-2-yl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (120 mg, 0.25 mmol) in DMF (2 mL) was treated with NaH (95%, 10 mg, 0.40 mmol) at 0° C. The reaction was stirred for 20 min. and BrCN (Aldrich, 32 mg, 0.30 mmol) was slowly added. The reaction was warmed to room temperature over 2 hours. MeOH (˜0.2 mL) was added to quenched extra NaH. The reaction solution was partitioned between DCM and water. The aqueous layer was extracted with a chloroform/IPA “cocktail” (3:1 v/v). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow oil, which was purified by silica gel column on a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as white solid.
Reaction SMILES: ClC1N=NC(N(C)[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:11]=2)=C(C2C=CC(F)=CC=2OC)C=1.S(Cl)([Cl:37])=O>CN(C)C=O>[CH3:23][S:20]([C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=1)[C:9]([Cl:37])=[O:24])(=[O:22])=[O:21]
Reactant: COc1cc(F)ccc1-c1cc(Cl)nnc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cc(C(=O)Cl)cc(C(F)(F)F)c1
Yield: 102.9 %

Procedure:
To 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (1 g, 3.73 mmol, example 1, intermediate d) was added N,N-dimethylformamide (27.3 mg, 28.9 μL, 373 μmol) and thionyl chloride (8.87 g, 5.44 ml, 74.5 mmol) and the suspension was heated to reflux for 30 min. A light brown solution was formed. To remove thionyl chloride, the light brown solid was diluted with toluene, followed by complete evaporation. This procedure was repeated two times to provide the desired compound as a colorless solid (1.1 g; 99%) which was pure enough for the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:16]([OH:18])=[O:17].C(O)(=O)C.Br>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC.O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:16]([OH:18])=[O:17]
Reactant: COc1ccc(-c2ccc(O)c(C(=O)O)c2)cc1
Agent: Br
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc(-c2ccc(O)cc2)ccc1O
Yield: 48.3 %

Procedure:
A solution of 4-hydroxy-4′-methoxy-3-biphenylcarboxylic acid (5.3 g; 21.6 mmol), tetrabutylphosphonium bromide (0.8 g; 2.3 mmol), acetic acid (35 ml) and hydrobromic acid (35 ml of a 48% solution) was heated at reflux for 6 h. The reaction mixture was cooled and poured into water (400 ml). The resulting precipitate was isolated and recrystallised from ethyl acetate to give 2.4 g (47%) of 4,4′-dihydroxy-3-biphenyl-carboxylic acid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:16][OH:17])[O:11][CH2:12][C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1C=CC=CC=1.S(=O)(=O)(O)O>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:16][O:17][C:13](=[O:15])[CH2:12][O:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)COC(CO)COCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: O=C1COC(COCc2ccccc2)CO1

Procedure:
Hydroxy acid (2.34 g) obtained from Example 27 was dissolved in benzene (400 ml), and concentrated sulfuric acid (4 drops) was added thereto. The reaction mixture was stirred under reflux for 2 hours as removing water by Dean-Stark trap to complete the reaction. The reaction mixture was washed with water and saturated brine sequentially and dried over anhydrous magnesium sulfate. Upon concentrating the reaction mixture under reduced pressure, lactione (2 g) was obtain as oil.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[S:3]([C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([N+:13]([O-:15])=[O:14])[C:7]=1Cl)(=[O:5])=[O:4].[H-].[Na+].[OH2:20]>>[CH3:1][N:2]([CH3:17])[S:3]([C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([N+:13]([O-:15])=[O:14])[C:7]=1[OH:20])(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: O
Agent: [H-]
Agent: [Na+]
Product: CN(C)S(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Temperature: 35 °C
Reaction time: 16 h
Yield: 92.8 %

Procedure:
A mixture of N,N-dimethyl-2,6-dichloro-3-nitrobenzenesulfonamide (2.64 g, 8.83 mmol), 60% sodium hydride (1.06 g, 26.5 mmol) and water (191 mg, 10.6 mmol) was heated to 35° C. while kept under argon atmosphere for 16 hours. The solvent was evaporated. when The reaction was almost complete as indicated by 1H NMR. The residue was diluted with ethyl acetate and washed with 1N aq. HCl. The solvent was concentrated to give the crude material. Column chromatography on silica gel, eluting with ethyl acetate/hexane/acetic acid (40/58/2, v/v/v), gave the desired product (2.3 g, 93%). EI-MS (m/z)279.5 (M−).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]3[N:20]=[C:19]([CH3:21])[O:18][N:17]=3)=[CH:14][C:13]([C:22]3[CH:23]=[N:24][C:25]([N:28]4[CH2:33][CH2:32][C:31]([CH3:39])([C:34]([O:36]CC)=[O:35])[CH2:30][CH2:29]4)=[N:26][CH:27]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].[OH-].[Na+].Cl>CCO>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]3[N:20]=[C:19]([CH3:21])[O:18][N:17]=3)=[CH:14][C:13]([C:22]3[CH:27]=[N:26][C:25]([N:28]4[CH2:29][CH2:30][C:31]([CH3:39])([C:34]([OH:36])=[O:35])[CH2:32][CH2:33]4)=[N:24][CH:23]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(-c3noc(C)n3)c2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)cc(-c3noc(C)n3)c2s1
Temperature: 70 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
Ethyl 1-[5-[2-(ethylcarbamoylamino)-7-(5-methyl-1,2,4-oxadiazol-3-yl)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (192 mg, 0.349 mmol) was dissolved in EtOH (20 mL) and 2M aqueous NaOH (10 mL) added. The reaction mixture was stirred at 70° C. for 2 h then cooled to rt and 2M HCl (20 mL) added. The mixture was extracted with hot EtOAc (3×50 mL), the aqueous phase saturated with NaCl and further extracted with EtOAc (50 mL) and the combined organic fractions washed with brine, separated, dried (Na2SO4) and concentrated under reduced pressure. The solid residue was washed with MeCN then Et2O to afford Compound 213 (163 mg, 89%) as a pale-yellow solid. 1H NMR (DMSO-d6): δ10.98 (bs, 1H), 8.81 (s, 2H), 8.11 (d, J=1.8 Hz, 1H), 8.10 (d, J=1.8 Hz, 1H), 7.06 (bt, J=5.4 Hz, 1H), 4.31 (dt, J=13.9 and 4.4 Hz, 2H), 3.37 (ddd, J=13.3, 10.2 and 2.9 Hz, 2H), 3.26-3.19 (m, 2H), 2.76 (s, 3H), 2.09-2.02 (m, 2H), 1.43 (ddd, J=13.8, 10.2 and 3.9 Hz, 2H), 1.21 (s, 3H), 1.13 (t, J=7.2 Hz, 3H). MS: 523.13 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:25])[C:10](=[O:24])[C:11]([CH3:23])([CH3:22])[C@:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])([CH3:14])[N:13]=1)(C)(C)C.[N+:27]([O-])([OH:29])=[O:28].[OH-].[Na+]>S(=O)(=O)(O)O>[NH2:7][C:8]1[N:9]([CH3:25])[C:10](=[O:24])[C:11]([CH3:23])([CH3:22])[C@:12]([C:15]2[CH:20]=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=[CH:17][C:16]=2[F:21])([CH3:14])[N:13]=1
Reactant: O=[N+]([O-])O
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2ccccc2F)N=C1NC(=O)OC(C)(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc([N+](=O)[O-])ccc2F)N=C1N
Temperature: 0 °C

Procedure:
To a solution of [(S)-4-(2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate E7, 0.27 g) in sulfuric acid (98%, 3.1 ml) was added at 0° C. fuming nitric acid (0.05 ml) and the reaction mixture was allowed to warm to 22° over 30 min. The mixture was slowly added to 20 ml ice cold water, the pH was adjusted to 7 using aqueous 4N NaOH and extracted with ethyl acetate. The organic layer was washed with water, dried and evaporated to give crude (S)-2-amino-6-(2-fluoro-5-nitro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (0.19 g) as a pale orange amorphous solid. MS (ESI): m/z=309.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[OH:11].[H-].[Na+].[C:14]([O:18][C:19]([N:21]1[C@H:25]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:24]OS1(=O)=O)=[O:20])([CH3:17])([CH3:16])[CH3:15]>CN(C)C=O>[CH2:29]([O:28][C:26](=[O:27])[C@@H:25]([NH:21][C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:24][O:11][C:3]1[C:4]([N+:8]([O-:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Cc1cccc([N+](=O)[O-])c1O
Reactant: CC(C)(C)OC(=O)N1[C@H](C(=O)OCc2ccccc2)COS1(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc([N+](=O)[O-])c1OC[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 32.5 %

Procedure:
In an inert atmosphere and under exclusion of moisture, at 0° C. a solution of 1.5 g (10 mmol) of 2-methyl-6-nitro-phenol [Ger.Offen. 3536192] in 30 ml of N,N-dimethylformamide was treated portionwise with 0.42 g (18 mmol) of sodium hydride (55% dispersion in mineral oil). After complete addition, stirring was continued for 1 hour at 0° C. Thereafter, 3.85 g (11 mmol) of (S)-2,2-dioxo-2λ6-[1,2,3]oxathiazolidine-3,4-dicarboxylic acid 4-benzyl ester 3-tert-butyl ester was added and stirring continued at 0° C. for 3 hours, then at room temperature overnight. For the working-up, the solvent was evaporated under reduced pressure, the residue treated with 100 ml of hydrochloric acid (1 N), then extracted 3 times with 150 ml of ethyl acetate. The crude product (4.0 g) was obtained as a dark brown oil which was purified by flash-chromatography on silica gel using a gradient of a 100%:0%- to 50%:50%-mixture of heptane and ethyl acetate as the eluent. There were obtained 1.4 g (33%) of the title compound as an yellow oil, [α]589=−1.45° (c=1.0% in MeOH), MS m/e (%): 431.4 (M+H+, 13).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH2:28]([N:35]([CH2:37][C:38]([N:40]([CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:41]1[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=1)=[O:39])[CH3:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:35]([CH2:37][C:38]([N:40]([C:41]1[CH:42]=[CH:43][C:44]([NH:47]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:45][CH:46]=1)[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:39])[CH3:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CN(CC(=O)N(Cc1ccccc1)c1ccc(N)cc1)Cc1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(Cc2ccccc2)C(=O)CN(C)Cc2ccccc2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-((N-benzyl-N-methyl-amino)-methylcarbonyl)-N-benzyl-p-phenylenediamine Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C40H36N4O4
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22](=O)[CH2:23][C:24]=1[CH:25]=[C:26]([S:28][C:29]1[S:33][C:32]([CH3:34])=[N:31][N:30]=1)[CH3:27])[CH:20]([NH:36][C:37](=[O:67])[C:38](=[N:64][O:65][CH3:66])[C:39]1[N:40]=[C:41]([NH:44][C:45]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[S:42][CH:43]=1)[C:19]2=[O:68])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C(=O)C.P(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O.C(OCC)(=O)C>[CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[CH:25]=[C:26]([S:28][C:29]1[S:33][C:32]([CH3:34])=[N:31][N:30]=1)[CH3:27])[CH:20]([NH:36][C:37](=[O:67])[C:38](=[N:64][O:65][CH3:66])[C:39]1[N:40]=[C:41]([NH:44][C:45]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)[C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=3)[S:42][CH:43]=1)[C:19]2=[O:68])=[O:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=C(C)Sc3nnc(C)s3)CS(=O)C12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClP(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=C(C)Sc3nnc(C)s3)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 31.1 %

Procedure:
A solution of the Z form of the syn isomer of 2-benzhydryloxycarbonyl-3-{2-[(2-methyl-1,3,4-thiadiazol-5-yl)-thio]-prop-1-en-1-yl}-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (2.52 g) in methylene chloride (40 cc) is cooled to -10° C. N,N-Dimethylacetamide (0.95 cc) and phosphorus trichloride (0.7 g) are added successively. The solution is stirred for 20 minutes at -10° C. and then poured into a saturated aqueous solution of sodium bicarbonate (50 cc). It is diluted with distilled water (200 cc) and extraction is carried out with ethyl acetate (300 cc). The organic phase is dried over sodium sulphate and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. The residue is chromatographed on a column of Merck silica gel (0.06-0.20) (25 g) (diameter of the column: 2 cm; height: 15 cm). Elution is carried out with a 50/50 (by volume) ethyl acetate/cyclohexane mixture (500 cc), 30 cc fractions being collected. Fractions 4 to 13 are concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. This yields the Z form of the syn isomer of 2-benzhydryloxycarbonyl-3-{2-[(2-methyl-1,3,4-thiadiazol-5-yl)-thio]-prop-1-en-1-yl}-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.77 g) in the form of a hard white foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][S:10]([CH2:12][C:13](O)=O)=[O:11])=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17].[CH3:19][O:20][C:21]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[C:22]=1C=O>N1C=CC=CC=1.N1CCCCC1>[CH3:1][O:2][C:3]1[C:4]([N+:16]([O-:18])=[O:17])=[CH:5][C:6]([CH2:9][S:10](/[CH:12]=[CH:13]/[C:22]2[C:25]([O:31][CH3:32])=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:21]=2[O:20][CH3:19])=[O:11])=[CH:7][N:8]=1
Reactant: COc1cc(OC)c(C=O)c(OC)c1
Reactant: COc1ncc(CS(=O)CC(=O)O)cc1[N+](=O)[O-]
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1cc(OC)c(/C=C/S(=O)Cc2cnc(OC)c([N+](=O)[O-])c2)c(OC)c1
Yield: 10 %

Procedure:
A solution of 2-((6-methoxy-5-nitropyridin-3-yl)methylsulfinyl)acetic acid (0.15 g, 0.5 mmol) in dry pyridine (20 mL) was treated with 2,4,6-trimethoxybenzaldehyde (0.20 g, 1 mmol) and piperidine (10 drops). The mixture was refluxed for 2-3 hrs. The mixture was evaporated and the residue was purified by flash chromatography; yield 10%; 1H-NMR (CDCl3): δ 3.83 (s, 6H, OCH3), 3.83 (s, 3H, OCH3), 3.89 (1H, CH), 4.07 (1H, CH), 4.09 (s, 3H, OCH3), 6.09 (s, 2H, Ph-H), 6.97 (d, 1H, J=15.2 Hz, CH), 7.28 (d, 1H, J=15.2 Hz, CH), 8.19 (d, 1H, J=2.3 Hz, Py-H), 8.29 (d, 1H, J=2.3 Hz, Py-H). HR-MS (ESI+) m/z 408.8426 C18H20N2O7S requires 408.0991.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.[CH3:7][O:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2C=[CH:19][CH:18]=[CH:17]2)=[CH:12][C:11]=1[Cl:21]>C(Cl)Cl.CN(C=O)C>[CH3:7][O:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:17]=[CH:18][CH:19]=[C:2]2[CH:1]=[O:5])=[CH:12][C:11]=1[Cl:21]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)c1ccc(-n2cccc2)cc1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(-n2cccc2C=O)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of DMF (0.1 mL) in CH2Cl2 (2 mL) was added dropwise with stirring to a solution of oxalyl chloride (0.2 mL) in CH2Cl2 (16 mL) at −30° C. under N2. The mixture was stirred for 15 min and a solution of 2-chloro-4-(1-pyrrolyl)benzoic acid methyl ester (0.5 g) in DMF (4 mL) was added. The mixture was stirred at that temperature for 3 h and allowed to warm to room temperature. The mixture was stirred overnight and evaporated. The residue was partitioned between EtOAc and 0.2 M NaOAc. The EtOAc layer was separated and the aqueous solution was extracted with EtOAc. The combined EtOAc layer was washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (silica gel; eluent: hexane/EtOAc 3/1) to yield 2-chloro-4-(2-formyl-1-pyrrolyl)benzoic acid methyl ester (0.41 g). ESMS: 264 (MH+).
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]21[CH2:25][C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:12]=1[CH2:11]2)[N:19]=[C:18]([C:22](O)=[O:23])[CH:17]=[CH:16]3.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:26]1([C:22]([C:18]2[CH:17]=[CH:16][C:15]3[C:20](=[CH:21][C:12]4[CH2:11][C:3]5([C:4]6[C:5](=[N:6][CH:7]=[CH:8][CH:9]=6)[NH:10][C:2]5=[O:1])[CH2:25][C:13]=4[CH:14]=3)[N:19]=2)=[O:23])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(O)c1ccc2cc3c(cc2n1)CC1(C3)C(=O)Nc2ncccc21
Reactant: C1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc2cc3c(cc2n1)CC1(C3)C(=O)Nc2ncccc21)N1CCCCC1

Procedure:
A mixture of (±)-2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridine]-2-carboxylic acid (15 mg, 0.045 mmol, described in Intermediate 12), piperidine (0.009 mL, 0.091 mmol), EDC (26 mg, 0.14 mmol), HOBT (21 mg, 0.14 mmol), and N,N-diisopropylethylamine (0.039 mL, 0.23 mmol) was stirred in DMF (1 mL) at ambient temperature for 18 h. The reaction mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions were combined and concentrated to give the title compound. MS: m/z=399 (M+1). HRMS: m/z=399.1817; calculated m/z—399.1816 for C24H22N4O2.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][NH:16][C:13]=4[N:14]=[CH:15][C:10]3=[N:9][N:8]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.[CH:25]1([S:28](Cl)(=[O:30])=[O:29])[CH2:27][CH2:26]1>CN(C=O)C>[CH:25]1([S:28]([N:1]2[CH2:2][CH2:3][CH:4]([C:7]3[N:11]4[C:12]5[CH:18]=[CH:17][NH:16][C:13]=5[N:14]=[CH:15][C:10]4=[N:9][N:8]=3)[CH2:5][CH2:6]2)(=[O:30])=[O:29])[CH2:27][CH2:26]1
Reactant: c1cc2c(ncc3nnc(C4CCNCC4)n32)[nH]1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=S(=O)(C1CC1)N1CCC(c2nnc3cnc4[nH]ccc4n23)CC1
Reaction time: 3 h
Yield: 6.2 %

Procedure:
To a suspension of 1-(piperidin-4-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.090 g, 0.37 mmol, Example #2) and pyridine (0.12 mL, 1.5 mmol) in DMF (5 mL) was added cyclopropanesulfonyl chloride (0.060 g, 0.41 mmol). After about 3 h at ambient temperature, the reaction mixture was quenched with MeOH (0.5 mL) and then purified by RP-HPLC (Table 2, Method b). The appropriate fractions were concentrated and lyopholized to afford 1-(1-(cyclopropylsulfonyl)piperidin-4-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine as a white solid (0.008 g, 6%): LC/MS (Table 2, Method a) Rt=1.52 min; MS m/z: 347 (M+H)+.
Reaction SMILES: [NH:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si](Cl)(Cl)(Cl)Cl.[C:20](#[N:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+]>ClCCCl.O.CO>[CH3:14][N:11]1[CH2:12][CH2:13][CH:8]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=2[C:20](=[NH:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9][CH2:10]1
Reactant: N#Cc1ccccc1
Reactant: CN1CCC(Nc2ccccc2)CC1
Agent: Cl[Si](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCCl
Solvent: O
Product: CN1CCC(Nc2ccccc2C(=N)c2ccccc2)CC1
Yield: 70.6 %

Procedure:
To a solution of 0.38 g (2 mmol) of 4-anilino-1-methyl-piperidine 1 dissolved in 10 ml of 1.2-dichloroethane are added 0.3 ml (2×1.2 mmol) of boron trifluoride ether adduct, 0.28 ml (2×1.2 mmol) of silicon tetrachloride, and 0.41 ml (2×2 mmol) of benzonitrile at room temperature with stirring, and the mixture is heated under reflux with stirring for 20 hours. The reaction mixture is cooled and a solution of 2.5 g of sodium hydroxide dissolved in 10 ml of water and 4 ml of methanol are added thereto with stirring under ice-cooling. The mixture is stirred at room temperature for 1 hour and extracted with dichloromethane; the organic layer is washed with water, dried over anhydrous magnesium sulfate, and concentrated. The resulting residue is recrystallized from ether-petroleum ether to give 414 mg of crystalline 2-(1-methyl-4-piperidinyl)aminobenzophenone imine 2.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)=O.[CH2:9]([O:11][CH2:12]CBr)[CH3:10].COCCN1CCNCC1>>[CH2:9]([O:11][CH2:12][CH2:1][N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:10]
Reactant: CCOCCBr
Reactant: O=CN1CCNCC1
Agent: COCCN1CCNCC1
Product: CCOCCN1CCNCC1

Procedure:
The title compound was prepared from formylpiperazine and 2-bromoethyl ethyl ether in the same manner as in Preparation Example 1(5) to (7). 1H NMR(CDCl3, δ ppm): 1.19(3H, t), 2.46-2.49(2H, m), 2.55-2.61(4H, m), 2.88-2.92(4H, m), 3.45-3.59(4H, m)
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=O)(=[O:3])[CH3:2].[CH2:17]([O:24][C:25](=[O:28])[CH2:26][NH2:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1.C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:17]([O:24][C:25](=[O:28])[CH2:26][NH:27][C:7](=[O:9])[CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][S:4][C:1](=[O:3])[CH3:2])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)SCC(Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
To a stirred ice-cold solution of 2.85 g (12 mmoles) 3-acetylthio-2-benzylpropanoic acid in 20 ml THF are successively added a mixture of 4.04 g (12 mmoles) glycine benzyl ester p.tosylate and 1.71 ml triethylamine in 20 ml CHCl3, a solution of 1.83 g (12 mmoles) HOBT in 15 ml THF, and a solution of 2.63 g (12.8 mmoles) DCC in 10 ml CHCl3.