Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=2[CH:31]2[CH2:40][CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[C:36]([O:41][CH3:42])[CH:37]=3)[CH2:32]2)[C:18]([CH:20]2[CH2:22][CH2:21]2)=O)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[Si](OC1C=CC(CCN(CC2CC2)C2C=C(OC)C=CC=2C2CCC3C(=CC=C(OC)C=3)C2)=CC=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH:20]1([CH2:18][N:17]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=2[CH:31]2[CH2:40][CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[C:36]([O:41][CH3:42])[CH:37]=3)[CH2:32]2)[CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[CH2:22][CH2:21]1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1N(CCc1ccc(O[Si](C)(C)C(C)(C)C)cc1)C(=O)C1CC1)C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: COc1ccc2c(c1)CCC(c1ccc(OC)cc1N(CCc1ccc(O[Si](C)(C)C(C)(C)C)cc1)CC1CC1)C2
Agent: [F-]
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1N(CCc1ccc(O)cc1)CC1CC1)C2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.6 %

Procedure:
Synthesized from cyclopropanecarboxylic acid {2-[4-(tert-butyldimethylsilyloxy)phenyl]ethyl}[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amide (2.3 g) according to an analogous synthetic method to Example 337, to a filtrate of the resulting {2-[4-(tert-butyldimethylsilyloxy)phenyl]ethyl}cyclopropylmethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine was added tetrabutylammonium fluoride (1M solution in tetrahydrofuran) (4 ml), and the solution was stirred for 20 minutes at room temperature. The reaction solution was concentrated in vacuo, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (1.7 g).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[CH2:14][C:15]1[NH:16][CH:17]=[CH:18][N:19]=1)C>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:20])=[O:3])=[C:8]([CH2:14][C:15]2[NH:19][CH:18]=[CH:17][N:16]=2)[CH:9]=1
Reactant: CCOC(=O)COc1ccc(Cl)cc1Cc1ncc[nH]1
Solvent: O
Product: O=C(O)COc1ccc(Cl)cc1Cc1ncc[nH]1

Procedure:
Hydrolysis of 4-chloro-2-(1-imidazolylmethyl)phenoxyacetic acid ethyl ester by the method of Example 14 gave 4-chloro-2-(1-imidazolylmethyl)phenoxyacetic acid, m.p. 222°-224° C. (from water). Found: C, 53.95, H, 4.10, N, 10.52. C12H11ClN2O3 requires: C, 54.04, H, 4.16, N, 10.50%.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22](O)(=[O:24])=[O:23])[C:17]=2[N:26]([C:33](=[O:37])[CH2:34][CH2:35][CH3:36])[C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[CH:12]=[C:13]([CH3:15])[CH:14]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:39].CCOCC>ClCCl>[CH3:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([Cl:39])(=[O:24])=[O:23])[C:17]=2[N:26]([C:33](=[O:37])[CH2:34][CH2:35][CH3:36])[C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[CH:12]=[C:13]([CH3:15])[CH:14]=1
Reactant: CCCC(=O)N(C(=O)C(F)(F)F)c1c(-c2cc(C)cc(C)c2)cccc1S(=O)(=O)O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCC(=O)N(C(=O)C(F)(F)F)c1c(-c2cc(C)cc(C)c2)cccc1S(=O)(=O)Cl
Temperature: 25 °C

Procedure:
To a solution of 1.8 g (3.3 mmol) of the N,N-diethylethanamine salt of 2-[(3',5'-dimethyl)-2-[(1-oxobutyl)(trifluoroacetyl)amino][1,1-biphenyl]-3-sulphonic acid in 10 ml of dichloromethane are added, at room temperature under nitrogen, 1.37 g (6.6 mmol) of phosphorus pentachloride, the mixture is heated at the reflux temperature for 4 hours and the reaction medium is then allowed to cool to room temperature, 100 ml of ether are poured in and the mixture is filtered then concentrated under reduced pressure. The residue thus obtained is purified by chromatography on a florisil™ column, eluting with dichloromethane.
Reaction SMILES: [Cl:1][C:2]1[CH2:7][C@H:6]2[C@H:4]([C@H:5]2[CH3:8])[C:3]=1[CH:9]=O.[CH2:11]([O:13][C:14]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:15])[CH3:12]>>[Cl:1][C:2]1[CH2:7][C@H:6]2[C@H:4]([C@H:5]2[CH3:8])[C:3]=1/[CH:9]=[CH:16]/[C:14]([O:13][CH2:11][CH3:12])=[O:15]
Reactant: C[C@H]1[C@H]2CC(Cl)=C(C=O)[C@@H]12
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)/C=C/C1=C(Cl)C[C@@H]2[C@H](C)[C@H]12

Procedure:
±(1S,5R,6S)-3-Chloro-6-methylbicyclo[3.1.0]hex-2-ene-2-carbaldehyde was olefinated with ethoxycarbonylmethylene triphenylphosphorane according to General Procedure 1.1.B to afford the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[N:11]=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:21][NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:21][N:22]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[N:11]=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cccc(-n2nc(C)cc2-c2ccnc(Cl)c2)c1
Reactant: CNCc1ccccc1
Product: Cc1cccc(-n2nc(C)cc2-c2ccnc(N(C)Cc3ccccc3)c2)c1
Temperature: 180 °C
Yield: 66 %

Procedure:
A mixture of 2-chloro-4-[1-(3-methylphenyl)-3-methyl-1H-pyrazol-5-yl]pyridine (Example 45; 1.0 g, 0.0036 mol) and N-methylbenzylamine (20 mL) was heated at 180° C. for 24 hours. The excess amine was removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was purified by chromatography on silica gel (ethyl acetate/hexane, 2:8) to give 0.88 g (66% yield) of product as a yellow oil: Anal. Calc'd. for C24H24N4: C, 78.23; H, 6.56; N, 15.20. Found: C, 78.55; H, 6.51; N, 15.21.
Reaction SMILES: O[C:2]1[N:3]=[C:4](O)[C:5]2[C:6](=[CH:8][S:9][C:10]=2[CH3:11])[N:7]=1.C([C:18]1[C:22]([NH:23]C(N)=O)=[CH:21]SC=1C)(OCC)=O.Cl>C(O)C>[CH:22]([NH:23][C:4]1[C:5]2[C:6](=[CH:8][S:9][C:10]=2[CH3:11])[N:7]=[C:2]([NH:3][CH2:4][CH2:5][CH3:10])[N:3]=1)([CH3:21])[CH3:18]
Reactant: Cc1scc2nc(O)nc(O)c12
Reactant: CCOC(=O)c1c(NC(N)=O)csc1C
Agent: Cl
Solvent: CCO
Product: CCCNc1nc(NC(C)C)c2c(C)scc2n1

Procedure:
The 2,4-dihydroxy-5-methyl-thieno[3,4-d]pyrimidine used above is also a new compound prepared from 3-carbethoxy-2-methyl-4-ureido-thiophene by heating under reflux with concentrated hydrochloric acid in absolute ethyl alcohol. Yield reaches 70%. M.P. 300°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[NH:10][C:9]2=[O:19])=[CH:4][C:3]=1[O:20][CH:21]([CH3:23])[CH3:22].S(OC)(O[CH3:28])(=O)=O.C(=O)(O)[O-].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[N:10]=[C:9]2[O:19][CH3:28])=[CH:4][C:3]=1[O:20][CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)ccc1Cl
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1nc(C(F)(F)F)cc(=O)n1-c1ccc(Cl)c(OC(C)C)c1

Procedure:
using 3-(4-chloro-3-isopropoxyphenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione with dimethyl sulphate and sodium bicarbonate in acetone there is obtained 1-(4-chloro-3-isopropoxyphenyl)-2-methoxy-4-trifluoromethyl -6(1H)-pyrimidinone. m.p. 55°-58° C.
Reaction SMILES: [ClH:1].O1CCOCC1.[CH3:8][C:9]1([CH3:38])[C:13]([CH3:15])([CH3:14])[O:12][B:11]([C:16]2[CH:17]=[C:18]([C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])[N:19](C(OC(C)(C)C)=O)[CH:20]=2)[O:10]1>C(Cl)Cl>[CH3:14][C:13]1([CH3:15])[C:9]([CH3:8])([CH3:38])[O:10][B:11]([C:16]2[CH:17]=[C:18]([C:28]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[O:29])[NH:19][CH:20]=2)[O:12]1.[ClH:1]
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cc1C(=O)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC1(C)OB(c2c[nH]c(C(=O)OCc3ccccc3)c2)OC1(C)C
Reaction time: 0.5 h

Procedure:
Hydrogen chloride in 1,4-dioxane (4.0 M, 3.0 mL, 12 mmol) was added to a solution of 2-benzyl 1-tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1,2-dicarboxylate (0.80 g, 1.9 mmol) in methylene chloride (3.0 mL) at r.t. and the mixture was stirred for 0.5 h. The solvent was removed under reduced pressure to provide the desired product as an HCl salt. LCMS (M+H)+: m/z=328.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:21]=[CH:20][N:19]([CH2:22][CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[N:18]=4)=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:30]1[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]1>C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:21]=[CH:20][N:19]([CH2:22][CH2:23][C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:18]=4)=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:30]1[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cnc4[nH]cc(-c5ccn(CCc6ccccc6)n5)c4c3)cc2F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Fc1cc(-c2cnc3[nH]cc(-c4ccn(CCc5ccccc5)n4)c3c2)ccc1C1CCNCC1
Yield: 42.6 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(2-fluoro-4-(3-(1-phenethyl-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (66 mg, 0.116 mmol) was deprotected in TFA/toluene (5/5 mL) to afford 23 mg (34% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.82-8.81 (d, 1H), 8.58 (s, 1H), 7.87 (s, 1H), 7.58-7.45 (m, 4H), 7.23-7.11 (m, 5H), 6.577-6.570 (d, 1H), 4.48-4.44 (t, 2H), 3.56-3.52 (d, 2H), 3.24-3.15 (m, 5H), 2.15-2.03 (m, 4H). MS: m/z=466.5 (M+1), HPLC: 96.98% in method A.
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[C:3]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([NH2:25])[N:16]3[CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:12][N:11]=2)[CH:2]=1.CCN(C(C)C)C(C)C.Br[CH2:36][CH2:37][CH2:38][C:39](Cl)=[O:40]>CN(C=O)C>[N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[C:3]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([N:25]4[CH2:36][CH2:37][CH2:38][C:39]4=[O:40])[N:16]3[CH:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[CH:12][N:11]=2)[CH:2]=1
Reactant: O=C(Cl)CCCBr
Reactant: Nc1nc2cnc(-c3cnn4ccccc34)nc2n1C1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CCCN1c1nc2cnc(-c3cnn4ccccc34)nc2n1C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.6 %

Procedure:
To a suspension of example 33 (25 mg, 0.075 mmol) in DMF (1.5 mL), DIPEA (0.04 mL, 0.22 mmol) and 4-bromobutyryl chloride (0.01 mL, 0.082 mmol) were added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated to dryness and 1.7 mg of the title compound were obtained (yield 6%) after HPLC preparative purification.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[C@@H:10]([NH:20][C:21](=[O:23])[CH3:22])[CH2:11][NH:12]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:25]>C(OCC)(=O)C>[ClH:25].[CH2:1]([O:8][C:9](=[O:24])[C@@H:10]([NH:20][C:21](=[O:23])[CH3:22])[CH2:11][NH2:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)N[C@@H](CNC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](CN)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To an ice-cooled solution of N-(t-butoxycarbonyl)-2(S)-acetylamino-β-alanine benzyl ester (3.44 g) in ethyl acetate (35 ml) was added 4N HCl in ethyl acetate (25.5 ml). The mixture was stirred for 2.5 hours at an ambient temperature, then the solvent was decanted. The residue was washed with diethyl ether several times, and dried in vacuo to give 2(S)-acetylamino-β-alanine benzyl ester hydrochloride (2.31 g) as a white powder.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:13].Cl[CH2:15][O:16][CH3:17]>O1CCCC1>[Br:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:13][CH2:15][O:16][CH3:17]
Reactant: COCCl
Reactant: O=[N+]([O-])c1ccc(O)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1ccc([N+](=O)[O-])cc1Br
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 310.8 %

Procedure:
4.2 g (140 mmol) of a sodium hydride dispersion (55% in oil) are added portion-wise at 0° C. to a solution of 15.3 g 2-bromo-4-nitrophenol (70 mmol) in 250 ml tetrahydrofuran. Subsequently the reaction mixture is stirred for 50 minutes at 0° C. and then mixed with 1.83 g of chloromethyl-methyl ether (19.4 mmol). The mixture is stirred for an additional hour at 0° C. and then poured into ice, extracted with ethyl acetate and the organic phase is washed with a saturated aqueous salt solution, dried over Na2SO4, filtered and concentrated. The residue so obtained is concentrated over silica gel with petroleum ether/ethyl acetate (9:1). 15.8 g (80% theoretical yield) of 2-bromo-1-methoxymethoxy-4-nitrobenzene are obtained.
Reaction SMILES: N1C=CC=CC=1.[Cr](O)(O)(=O)=O.[OH:12][CH:13]1[CH2:17][CH2:16][CH:15](/[CH:18]=[CH:19]/[C:20]([OH:27])([CH3:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:14]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35]>C(Cl)Cl>[OH:27][C:20]([CH3:26])([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:19]=[CH:18][C@@H:15]1[CH2:16][CH2:17][C:13](=[O:12])[C@H:14]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35]
Reactant: CCCCCC(C)(O)/C=C/C1CCC(O)C1CCCCCCC(=O)OC
Agent: O=[Cr](=O)(O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCC(C)(O)C=C[C@@H]1CCC(=O)[C@H]1CCCCCCC(=O)OC
Reaction time: 0.33 h

Procedure:
To a solution of dry pyridine (5.85 ml) in methylene chloride (135 ml, purified by shaking with H2SO4, and dried over CaO, and distilled) is added chromic acid (4 g) at 15° C. The mixture is stirred for 20 min. To this mixture is added a solution of the compound of formula 1 in which R2 is methyl, methyl trans-7-[2-hydroxy-5-(3-hydroxy-3-methyl-1-octenyl)cyclopentyl]heptanoate, described in Example 92, in methylene chloride (50 ml). The mixture is stirred for one hour. The reaction mixture is filtered and the collected slurry on the filter pad is washed with more methylene chloride. The organic phase of the filtrate and washing are combined and washed with water, dried (Na2SO4) and the solvent concentrated, to yield the crude product. Chromatography of the product on a silica gel column affords the title compound, identical to the product of the same name described in Example 91.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])(=[O:16])=[O:15])[CH2:11][NH:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH2:25]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([N:36]2[CH2:39][CH2:38][CH:37]2[C:40]([O-])=[O:41])[CH2:32][CH2:31]1)=[O:29])[CH3:26].[Li+]>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])(=[O:16])=[O:15])[CH2:11][N:10]2[C:40]([CH:37]2[CH2:38][CH2:39][N:36]2[CH:33]2[CH2:32][CH2:31][N:30]([C:28]([O:27][CH2:25][CH3:26])=[O:29])[CH2:35][CH2:34]2)=[O:41])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: CCOC(=O)N1CCC(N2CCC2C(=O)[O-])CC1
Reactant: COc1ccccc1S(=O)(=O)[C@H]1CN[C@H](C(=O)NC2(C#N)CC2)C1
Agent: [Li+]
Product: CCOC(=O)N1CCC(N2CCC2C(=O)N2C[C@H](S(=O)(=O)c3ccccc3OC)C[C@H]2C(=O)NC2(C#N)CC2)CC1

Procedure:
The reaction of (2S,4R)-N-(1-cyanocyclopropyl)-4-(2-methoxyphenylsulfonyl)pyrrolidine-2-carboxamide 7C and lithium 1-(1-(ethoxycarbonyl)piperidin-4-yl)azetidine-2-carboxylate 20J carried out according to the general procedure L yielded ethyl 4-(2-((2S,4R)-2-(1-cyanocyclopropylcarbamoyl)-4-(2-methoxyphenylsulfonyl)pyrrolidine-1-carbonyl)azetidin-1-yl)piperidine-1-carboxylate 1:1 epimers as a white solid (76%). MS ISP (m/e): 588.2 (100) [(M+H)]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[C:5]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[N:4]=1.ClC1C=CC=C(C(OO)=[O:26])C=1>C(Cl)(Cl)Cl>[CH3:1][S:2]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[C:5]([C:12](=[O:17])[C:13]([F:16])([F:14])[F:15])[N:4]=1)=[O:26]
Reactant: CSc1nc(C(=O)C(F)(F)F)c2ccccn12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1nc(C(=O)C(F)(F)F)c2ccccn12

Procedure:
A solution of 15.6 g (0.06 mole) of 3-methylthio-1-trifluoroacetylimidazo[1,5-a]pyridine (J. Bourdais et al. J. Het. Chem. 17, 1351, 1980) in 750 ml of chloroform is cooled to 5° C. 30.6 g (0.132 mole) of m-chloroperbenzoic acid is added in the course of approximately 1 h.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([O:21][C:22]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[O:23])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:30])=[N:9]2)=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[F:46][C:47]([F:52])([F:51])[C:48](O)=[O:49]>C(Cl)Cl>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([O:21][C:22]([N:24]4[CH2:25][CH2:26][N:27]([C:48](=[O:49])[C:47]([F:52])([F:51])[F:46])[CH2:28][CH2:29]4)=[O:23])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:30])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1)N1CCNCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1)N1CCN(C(=O)C(F)(F)F)CC1
Yield: 35 %

Procedure:
The procedure of Example 14 is followed but starting with 2-(7-chloro-1,8-naphthyridin-2-yl)-3-(piperazin-1-yl)carbonyloxy-isoindolin-1-one (2.12 g.), N,N'-dicyclohexylcarbodiimide (2.05 g.) in anhydrous methylene chloride (50 cc.) and trifluoroacetic acid (1.71 g.). The crude product, after it has been filtered off, is washed with diethyl ether (50 cc.). The product is then dissolved in methylene chloride (110 cc.). The solution is filtered and concentrated to dryness and the residue is washed again with diethyl ether (45 cc.). 2-(7-Chloro-1,8-naphthyridin-2-yl)-3-(4-trifluoroacetylpiperazin-1-yl)carbonyloxy-isoindolin-1-one (0.91 g.), which melts at 218° C., is thus obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:6][N:5]([C:7](=[N:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21]C(=O)C)=[CH:17][CH:16]=2)(=[O:14])=[O:13])[NH:8][CH2:9][CH3:10])[N:4]=[CH:3]1.Cl.[OH-].[Na+]>CO>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([N:11]=[C:7]([N:5]2[CH2:6][C:2]([CH3:1])([CH3:25])[CH:3]=[N:4]2)[NH:8][CH2:9][CH3:10])(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: CCNC(=NS(=O)(=O)c1ccc(NC(C)=O)cc1)N1CC(C)(C)C=N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCNC(=NS(=O)(=O)c1ccc(N)cc1)N1CC(C)(C)C=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
900 mg N-(4-{[(4,4-Dimethyl-4,5-dihydro-pyrazol-1-yl)-ethylamino-methylene]-sulfamoyl}-phenyl)acetamide was dissolved in 5 mL MeOH, and 5 mL of concentrated HCl was added. The mixture was stirred overnight at room temperature. The mixture was basified with 2M NaOH, and extracted twice with DCM. The combined organic layers were dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (DCM/MeOH 99:1) to give 400 mg (50%) of 4-Amino-N-[(4,4-dimethyl-4,5-dihydro-pyrazol-1-yl)-ethylamino-methylene]-benzenesulfonamide as an amorphous solid. 1H NMR (400 MHz, CDCl3) δ 1.15 (t, J=7 Hz, 3H), 1.20 (s, 6H), 3.42-3.51 (m, 2H), 3.74 (br.s., 2H), 4.00 (br.s., 2H), 6.62-6.68 (m, 2H), 6.71 (s, 1H), 6.90 (br.s., 1H), 7.67-7.73 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.CN.C[CH2:21][N:22]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>O1CCCC1.C(N(CC)CC)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH:22][CH3:21])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)c1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask was placed a solution of 4-(4-hydroxyphenyl)benzoic acid (1 g, 4.7 mmol, 1 equiv) in tetrahydrofuran (20 mL), methylamine hydrochloride, (0.409 g 6 mmol, 1.3 equiv), EDCl (1.18 g, 6.2 mmol, 1.3 equiv), HOBt (0.74 g, 5.5 mmol, 1.2 equiv), and triethylamine (2 mL). The resulting solution was stirred overnight at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluting with 15:2 ethyl acetate/petroleum ether) to give 4-(4-hydroxyphenyl)-N-methylbenzamide as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH3:10])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].C([Li])CCC.Br[CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[O:6]=[C:5]([CH:7]=[CH:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:4][C:3]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)CC(C)=O
Reactant: BrCCCc1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CC(=O)C=CCCc1ccccc1
Temperature: -25 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
To a suspension of 60% NaH (2.76 g, 69 mmol) in anhydrous DMF (50 mL) at 0° C. is added a solution of methyl acetoacetate (8 g) in DMF (50 mL) dropwise over 10 minutes. The mixture is cooled to -25° C. and 2.5M n-butyllithium (27.6 mL, 69 mmol) is added dropwise over 5 minutes. The mixture is stirred for 5 minutes and 1-bromo-3-phenylpropane (10.48 mL, 69 mmol) is added dropwise over 5 minutes. The cooling bath is removed and the mixture is stirred at room temperature for 2 hours. The mixture is poured into water and is extracted with ether. The organic layer is washed with water and is dried over MgSO4. The solvent is removed in vacuo and the residue is chromatographed on silica gel (6:1 hexane:ethyl acetate) to produce methyl 3-keto-7-phenylheptenoate as an oil (8 g, 50% ): 1H-NMR (300 MHz, CDCl3) δ (TMS) 1.50-1.68 (m, 4H), 2.42-2.62 (m, 4H), 3.40 (s, 2H), 3.70 (s, 3H), 7.10-7.18 (m, 2H), 7.18-7.30 (m, 3H).
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[NH:5]2.[C:16](Cl)(=[O:18])[CH3:17]>C1C=CC=CC=1>[C:16]([N:5]1[C:6]2[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=2[NH:8][C:9](=[O:11])[C:10]2=[CH:1][S:2][CH:3]=[C:4]12)(=[O:18])[CH3:17]
Reactant: O=C1Nc2ccccc2Nc2cscc21
Reactant: CC(=O)Cl
Solvent: c1ccccc1
Product: CC(=O)N1c2ccccc2NC(=O)c2cscc21
Reaction time: 8 h

Procedure:
A reaction mixture comprising 9.9 g. of 4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 4 g. (3.7 ml.) of acetyl chloride in 100 ml. of benzene is refluxed for 3 hours and then allowed to stand at room temperature overnight. The precipitate is collected, washed with benzene and dried. The solid is crystallized twice from hot methanol with cooling giving the desired product, mp. 228°-230° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=C)=[CH:6][N:5]=[C:4]([NH:10][C:11](=[O:13])[CH3:12])[CH:3]=1.N1C(C)=CC=CC=1C.CC([OH:26])(C)C.I([O-])(=O)(=O)=O.[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[C:7]([CH:8]=[O:26])=[CH:6][N:5]=[C:4]([NH:10][C:11](=[O:13])[CH3:12])[CH:3]=1
Reactant: C=Cc1cnc(NC(C)=O)cc1Cl
Reactant: CC(C)(C)O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: Cc1cccc(C)n1
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(Cl)c(C=O)cn1
Reaction time: 4 h
Yield: 92.1 %

Procedure:
To a stirred solution of N-(4-chloro-5-vinylpyridin-2-yl)acetamide (6 g, 30.5 mmol) and 2,6-lutidine (7.11 mL, 61.0 mmol) in a mixture of dioxane (110 mL) and water (25 mL) at 0° C. was added osmium tetroxide, 2.5 wt % solution in 2-methyl-2-propanol (9.58 mL, 30.5 mmol) followed by the addition of sodium periodate (19.58 g, 92 mmol) and the reaction was stirred for 4 h. The reaction mixture was diluted with water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine solution, dried over sodium sulphate, concentrated under reduced pressure. The residue was purified by silica column using hexane/Ethyl acetate to yield N-(4-chloro-5-formylpyridin-2-yl)acetamide as an off-white solid (5.8 g, 28.1 mmol, 92% yield). LCMS (ESI) m/e 197.0 [(M)−, calcd for C8H6ClN2O2197.04] LC/MS retention time (method A): tR=1.21 min; 1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 10.18 (s, 1H), 8.76 (s, 1H), 8.27 (s, 1H), 2.16 (s, 3H).