Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:17]([O:19]C(C)(C)C)=[O:18])=[C:6]([CH2:9][S:10][C:11]3[S:12][C:13]([CH3:16])=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12.[C:26]([CH2:28][S:29]([CH2:32][C:33](O)=[O:34])(=[O:31])=[O:30])#[N:27].C1(N=C=NC2CCCCC2)CCCCC1>>[C:26]([CH2:28][S:29]([CH2:32][C:33]([NH:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]3[S:12][C:13]([CH3:16])=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12)=[O:34])(=[O:31])=[O:30])#[N:27]
Reactant: Cc1nnc(SCC2=C(C(=O)OC(C)(C)C)N3C(=O)C(N)[C@H]3SC2)s1
Reactant: N#CCS(=O)(=O)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)CS(=O)(=O)CC#N)[C@H]3SC2)s1
Reaction time: 2.5 h

Procedure:
t-Butyl 7-amino-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylate (8.0 g, 20 mmol), cyanomethylsulfonylacetic acid (3.3 g, 20 mmol) and dicyclohexylcarbodiimide (4.1 g. 20 mmol) were reacted by the procedure of Example 5. The crude ester was chromatographed on silica gel using ethyl acetate as eluent. The purified t-butyl ester (6.2 g) was dissolved in hot acetonitrile (40 ml) and trifluoroacetic acid (40 ml) was added. The solution was allowed to stand 2.5 hours and then was added slowly to ether (100 ml) with stirring. The precipitated title compound was collected, triturated with ether and dried.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[O:6]([CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[O:6]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][S:1](=[O:4])(=[O:3])[NH2:2])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCCCCOc1ccccc1
Reactant: NS(=O)(=O)Cl
Product: NS(=O)(=O)OCCCCOc1ccccc1
Yield: 54 %

Procedure:
The title compound was prepared by procedures of Example 16 from sulfamoyl chloride and 4-phenoxy-1-butanol in 54% yield as an off-white solid, mp 76°-77° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[NH:25][C:24](=[O:26])[O:23][C:22]([CH3:28])([CH3:27])[C:21]=3[CH:29]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH:30]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[NH:25][C:24](=[O:26])[O:23][C:22]([CH3:27])([CH3:28])[C:21]=3[CH:29]=2)=[O:30])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(SCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc1OC
Reactant: OO
Product: COc1ccc(S(=O)CCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc1OC

Procedure:
Prepared analogously to Example 2 from 6-[4-(3,4-dimethoxy-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16](O)=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:19][C:20]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)=[O:21])[C:8]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:68][C:69]1([C:74]([NH:76][C:77]2[CH:82]=[CH:81][C:80](/[CH:83]=[CH:84]/[C:85]([O:87]CC)=[O:86])=[CH:79][CH:78]=2)=[O:75])[CH2:73][CH2:72][CH2:71][CH2:70]1.Cl>CN(C=O)C.CCOC(C)=O.C1COCC1.CO.O>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([NH:68][C:69]4([C:74]([NH:76][C:77]5[CH:78]=[CH:79][C:80](/[CH:83]=[CH:84]/[C:85]([OH:87])=[O:86])=[CH:81][CH:82]=5)=[O:75])[CH2:70][CH2:71][CH2:72][CH2:73]4)=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:19][C:20]([N:22]3[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]3)=[O:21])[C:8]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCN(C(=O)Cn2c(-c3ccccc3)c(C3CCCCC3)c3ccc(C(=O)O)cc32)CC1
Reactant: CCOC(=O)/C=C/c1ccc(NC(=O)C2(N)CCCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN1CCN(C(=O)Cn2c(-c3ccccc3)c(C3CCCCC3)c3ccc(C(=O)NC4(C(=O)Nc5ccc(/C=C/C(=O)O)cc5)CCCC4)cc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
A solution of 3-cyclohexyl-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2-phenyl-1H-indole-6-carboxylic acid (from Step 4) in DMF (0.1 M) was treated with DIPEA (4 eq.), HATU (1.5 eq.) and ethyl (2E)-3-(4-{[(1-aminocyclopentyl)carbonyl]amino}phenyl)acrylate (1.1 eq, prepared as described in Example 1, Step 7). The solution was stirred at 25° C. overnight. The mixture was diluted with EtOAc, and then washed sequentially with HCl (2×, 1N), saturated aqueous NaHCO3 (2×) and brine. The organic layer was dried over Na2SO4 and concentrated to afford an oil, which was dissolved in a mixture of THF/MeOH/H2O (0.05 M, 4:1:1, v/v/v). LiOH monohydrate (1.3 eq.) was added and the resultant mixture stirred at 40° C. for 5 h. The reaction mixture was acidified with HCl (1N) and purified by RP-HPLC (column: Waters X-terra C18, 19×150 mm, 5 micron; flow 17 mL/min) to give the title compound (20%) as a white powder after lyophilization.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([Cl:25])[CH:19]=1>ClCCl>[Cl:25][C:20]1[CH:19]=[C:18]([NH:17][C:14]([C:10]2[CH:9]=[C:8]([NH:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[N:13]=[CH:12][N:11]=2)=[O:16])[CH:23]=[CH:22][C:21]=1[OH:24]
Reactant: O=C(O)c1cc(NC2CCCCC2)ncn1
Reactant: Nc1ccc(O)c(Cl)c1
Solvent: ClCCl
Product: O=C(Nc1ccc(O)c(Cl)c1)c1cc(NC2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexylamino)pyrimidine-4-carboxylic acid (Intermediate 4) and 4-amino-2-chlorophenol (Aldrich), the title compound was obtained as a white solid after trituration in dichloromethane.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[O:21]=[S:22]1(=[O:28])[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23]1>>[O:21]=[S:22]1(=[O:28])[CH2:26][CH2:25][CH:24]([NH:27][C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[CH2:23]1
Reactant: NC1CCS(=O)(=O)C1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Product: O=C(NC1CCS(=O)(=O)C1)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and 1,1-dioxidotetrahydrothien-3-ylamine (CAN 6338-70-1) as starting materials. MS (EI): m/e=402.1 [M+H]+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[S:10](Cl)([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[OH:21][C:22]1[CH:26]=[CH:25][NH:24][C:23]=1[C:27]([O:29][CH3:30])=[O:28]>C(Cl)Cl>[S:10]([O:21][C:22]1[CH:26]=[CH:25][NH:24][C:23]=1[C:27]([O:29][CH3:30])=[O:28])([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: COC(=O)c1[nH]ccc1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1[nH]ccc1OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
Diisopropylethylamine (7.1 mL, 40.7 mmole) and then a solution of TsCl (6.46 gm, 33.9 mole) in dry DCM (20 mL) were added to an ice-cooled solution of methyl 3-hydroxy-1H-pyrrole-2-carboxylate (4.78 gm; 33.9 mmole) in dry DCM (80 mL) under a dry N2 atmosphere. After 2 hr, the reaction was removed from the bath and allowed to warm to RT. After 2 hr, this was washed with water, dried (Na2SO4), and the solvents removed to leave methyl 3-(tosyloxy)-1H-pyrrole-2-carboxylate (10 gm) as a solid. 1H NMR (CDCl3): 2.39 (s, 3H), 3.64 (s, 3H), 6.06 (m, 1H), 6.75 (m, 1H), 7.26 (m, 2H), 7.71 (m, 2H); MS: 311(M+H)+; HPLC Ret Time: 1.28 min (YMC Xterra S7 3.0×50 mm column, 2 min gradient, 5 mL/min).
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[CH3:13][CH:14]([NH2:23])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[CH3:13][CH:14]([N:23]1[CH2:10][C:5]2[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:3]1=[O:12])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: CC(N)CCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(CCc1ccccc1)N1Cc2ccccc2C1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 54.3 %

Procedure:
A mixture of 2-bromomethyl-benzoic acid methyl ester (0.115 g, 0.5 mmol), 1-methyl-3-phenyl-propylamine (0.090 g, 0.6 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (3 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(1-methyl-3-phenyl-propyl)-2,3-dihydro-isoindol-1-one (0.072 g, 54%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.32 (d, 3H), 1.92 (m, 2H), 2.64 (m, 2H), 4.34 (dd, 2H), 4.62 (m, 1H), 7.14-7.58 (m, 8H), 7.89 (d, 1H). GC-MS: m/z 265 (M)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[N:18]1([CH2:23][C:24]2[N:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:30][C:27]1[CH:28]=[N:29][C:24]([CH2:23][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:25][CH:26]=1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: Nc1ccc(CN2CCCC2)nc1
Product: O=C(c1cnc2ccc(Br)cc2c1Nc1ccc(CN2CCCC2)nc1)C1CC1
Yield: 78 %

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (310 mg, 1.00 mmol) was reacted with 6-(pyrrolidin-1-ylmethyl)pyridin-3-amine (280 mg, 1.50 mmol) to afford the desired product (352 mg, 78%) as a yellow foam: ESI MS m/z 451 [C23H23BrN4O+H]+.
Reaction SMILES: [CH:1]1([C:7]2[C:17]3[O:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OCC)(=O)C.[ClH:31]>C(OCC)(=O)C>[ClH:31].[CH:1]1([C:7]2[C:17]3[O:16][CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2C2CCCCC2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1cc2c(c(C3CCCCC3)c1)OCCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
A mixture of tert-butyl 9-cyclohexyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (150 mg, 0.453 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (4 ml) was stirred for 1 hr at room temperature, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (112 mg, 92.6%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:15]1[CH:20]=[CH:19][C:18](O)=[CH:17][CH:16]=1)([CH3:14])[C:6](=[O:13])[NH:7]2.C(N(CC)CC)C.[CH3:30][C@H:31]([N:38]=[C:39]=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl>[C:32]1([C@@H:31]([NH:38][C:39]([C:18]2[CH:19]=[CH:20][C:15]([C:5]3([CH3:14])[C:4](=[O:22])[C:3]4[C:8](=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=4[Cl:1])[NH:7][C:6]3=[O:13])=[CH:16][CH:17]=2)=[O:40])[CH3:30])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: C[C@H](N=C=O)c1ccccc1
Reactant: CC1(c2ccc(O)cc2)C(=O)Nc2cc(Cl)cc(Cl)c2C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)c1ccc(C2(C)C(=O)Nc3cc(Cl)cc(Cl)c3C2=O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.3 %

Procedure:
A solution of 5,7-dichloro-3-(4-hydroxy-phenyl)-3-methyl-1H-quinoline-2,4-dione (0.45 g, 1.30 mmol) and triethylamine (0.18 mL) in dichloromethane (15 mL ) was added (S)-methyl benzylisocyanate (0.15 g, 1.56 mmol) at 0° C. The reaction mixture was stirred for 20 hours at room temperature, and then poured into ice water (100 mL). The reaction mixture was extracted with dichloromethane (100 mL×3), washed with brine (100 mL×2), dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by a flash column chromatography (n-hexane:EtOAc=7:1) to afford the unseparable diastereomeric 1:1 mixture (0.50 g, 80%) of the objective diastereomers: 1H NMR (500 MHz, DMSO-d6) δ 1.37 (d, J=7.0 Hz, 3H, CH3), 1.54 (s, 3H, CH3, one diastereomeric peaks), 1.64 (s, 3H, CH3, the other diastereomeric peaks), 4.65 (q, 1H, CH), 7.01-7.3 (m, 11H, ArH), 8.35 (br s, 1H, NH), 11.28 (br s, 1H, NH); m.p. 110-115° C. (diastereomeric 1:1 mixture); MS(EI) m/e 483 [M+−1], 335, 269, 120.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[C:13]([CH3:22])[CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][NH2:27]>>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([NH:27][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])=[O:18])=[C:13]([CH3:22])[CH:12]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CN(C)CCN
Reactant: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1OCC(=O)O
Product: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1OCC(=O)NCCN(C)C
Yield: 90 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)-2-methylphenoxy)acetic acid (0.2 g, 0.66 mmol), prepared from the step 4 of the example 5, and N,N-dimethylethane-1,2-diamine (0.058 g, 0.66 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)-2-methylphenoxy)-N-(2-(dimethylamino)ethyl)acetamide as a white solid (0.22 g, 89.4% yield).
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:22]([C@H:24]1[CH2:29][CH2:28][C@H:27]([CH:30]2[CH2:35][CH2:34][CH:33](O)[CH2:32][CH2:31]2)[CH2:26][CH2:25]1)[CH3:23]>C(#N)C>[Br:1][CH:33]1[CH2:34][CH2:35][CH:30]([CH:27]2[CH2:28][CH2:29][CH:24]([CH2:22][CH3:23])[CH2:25][CH2:26]2)[CH2:31][CH2:32]1
Reactant: BrBr
Reactant: CC[C@H]1CC[C@H](C2CCC(O)CC2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCC1CCC(C2CCC(Br)CC2)CC1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
102 ml of bromine are added dropwise over the course of 2 hours at 5-15° C. to 536 g of triphenylphosphine in 2000 ml of acetonitrile, the mixture is subsequently stirred at 5° C. for 1 hour, 422 g of 4-(trans-4-ethyl-cyclohexyl)cyclohexanol are added, and the mixture is stirred at RT for 24 hours. Conventional work-up gives 4′-bromo-4-ethylbicyclohexane, GC 94.7%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.OO.Cl.C(=O)([O-])[O-:13].[Na+].[Na+]>C(O)(=O)C.N1C=CC=CC=1>[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][N:6]=1)=[O:13]
Reactant: Cc1ccc(O)cn1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: O=Cc1ccc(O)cn1
Temperature: 120 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
To a stirred solution of 21.8 g of 5-hydroxy-2-picoline (0.2 mol) in 200 mL of glacial acetic acid was added 18 mL of 30% hydrogen peroxide (0.159 mol) in one portion. The mixture was heated in an oil bath at 80°-85° C. with stirring for 3 h. Then another 18 mL of hydrogen peroxide was added and the mixture was stirred for 3 h at the same temperature. Excess solvent was removed in vacuo followed by the addition of acetone, which caused the pyridine N-oxide to crystallize. Without further purification, 200 mL of acetic anhydride was added to the solid and the mixture was heated at 120° C. with stirring in an oil bath for 2 h. After cooling to room temperature, excess acetic anhydride was removed by high vacuum distillation. The oily material was again oxidized with 30% hydrogen peroxide twice and rearranged with acetic anhydride following the same procedure and amounts depicted above. The black oily material obtained was hydrolyzed with 200 mL of 1N HCl (0.2 mol) at room temperature for 3 weeks (hydrolysis at higher temperature may be harmful to the pyridine nucleus). The mixture was neutralized with anhydrous sodium carbonate, indicated by litmus paper and then extracted three times with 300 mL of diethylether. The combined ether extracts were dried (MgSO4), filtered and evaporated to leave a solid material in a small amount of oil. The pure product (7.8 g, 32%) was obtained by filtering the solid, followed by washing it with a small amount of ether. It is yellow in color and shows a sharp melting point at 186°-187° C. 1H NMR (d6 -DMSO) δ: 11.10 (br. s, 1H, OH); 9.87 (s, 1H, CHO); 8.35 (d, J=2 Hz, 1H); 7.58 (d, J=9 Hz, 1H); 7.35 (d of d, J=2 Hz, 9 Hz, 1H).
Reaction SMILES: N1C=CC=C(CNC(C2(CC3C=CC=CC=3)CCNCC2)=O)C=1.Cl.C(OC([N:32]1[CH2:37][CH2:36][C:35]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=2)([C:38]([OH:40])=O)[CH2:34][CH2:33]1)=O)(C)(C)C.[Cl:49][C:50]1[CH:57]=[CH:56][CH:55]=[CH:54][C:51]=1[CH2:52][NH2:53]>>[Cl:49][C:50]1[CH:57]=[CH:56][CH:55]=[CH:54][C:51]=1[CH2:52][NH:53][C:38]([C:35]1([CH2:41][C:42]2[CH:43]=[CH:44][C:45]([Cl:48])=[CH:46][CH:47]=2)[CH2:34][CH2:33][NH:32][CH2:37][CH2:36]1)=[O:40]
Reactant: NCc1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(Cl)cc2)(C(=O)O)CC1
Agent: Cl
Agent: O=C(NCc1cccnc1)C1(Cc2ccccc2)CCNCC1
Product: O=C(NCc1ccccc1Cl)C1(Cc2ccc(Cl)cc2)CCNCC1

Procedure:
In analogy to the procedure described for the synthesis of 4-benzyl-piperidine-4-carboxylic acid (pyridin-3-ylmethyl)-amide; hydrochloride (intermediate 1) the title compound was prepared from 4-(4-chloro-benzyl)-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (commercially available) and 2-chloro-benzylamine (commercially available) with subsequent cleavage of the protecting group under acidic conditions. The title compound was purified on silica eluting with a gradient formed from DCM and methanol and the free base was liberated under basic conditions. MS (m/e): 377.1 (MH+).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([C:20]([NH2:22])=[O:21])[CH:19]=2)[NH:16][N:15]=[C:14]3[CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:38][N:39]1[CH:43]=[C:42]([S:44](Cl)(=[O:46])=[O:45])[N:41]=[C:40]1[CH3:48]>CN(C1C=CN=CC=1)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([C:20]([NH2:22])=[O:21])[CH:19]=2)[NH:16][N:15]=[C:14]3[CH:23]2[CH2:28][CH2:27][N:26]([S:44]([C:42]3[N:41]=[C:40]([CH3:48])[N:39]([CH3:38])[CH:43]=3)(=[O:46])=[O:45])[CH2:25][CH2:24]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: Cc1nc(S(=O)(=O)Cl)cn1C
Reactant: CC(=O)Nc1ccc(-c2cc(C(N)=O)c3[nH]nc(C4CCNCC4)c3c2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(-c2cc(C(N)=O)c3[nH]nc(C4CCN(S(=O)(=O)c5cn(C)c(C)n5)CC4)c3c2)cc1
Yield: 13.3 %

Procedure:
Following the general procedure of Example 11, 5-[4-(acetylamino)phenyl]-3-(4-piperidinyl)-1H-indazole-7-carboxamide (Example 71) (0.07 mmol), diisopropylethylamine (100 uL, 0.56 mmol), DMAP (25 mg, 0.014 mmol) and 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride (33 mg, 0.17 mmol) were reacted to give the title compound (5 mg, 13% for 3 steps).
Reaction SMILES: Cl.Cl.[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])([NH:16][NH2:17])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.C(=N)(OC)C.[CH2:29]([N:31](CC)[CH2:32]C)[CH3:30]>CO>[CH2:3]([N:10]1[CH2:11][CH2:12][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])([N:16]2[CH:32]=[N:31][C:29]([CH3:30])=[N:17]2)[CH2:14][CH2:15]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)C1(NN)CCN(Cc2ccccc2)CC1
Agent: COC(C)=N
Agent: Cl
Solvent: CO
Product: CCOC(=O)C1(n2cnc(C)n2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 15.2 %

Procedure:
A solution of ethyl 1-benzyl-4-hydrazino-piperidin-4-ylcarboxylate dihydrochloride salt (D27, 3.0 g, 0.0086 mol) in methanol (100 ml) under nitrogen was treated with methyl acetimidate hydrochloride (940 mg, 0.0086 mol) and triethylamine (3.7 ml, 0.026 mol) and stirred at room temperature for 3 h. The solution was concentrated in vacuo at below 30° C. and the residue treated with triethylorthoformate (50 ml) and pyridine (5 ml) and the heterogenous mixture stirred for 18 h at room temperature, followed by heating under reflux for 1.5 h. The mixture was concentrated in vacuo and the residue treated with potassium carbonate solution (30 ml) and extracted with ethyl acetate (2×40 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuo to leave a dark red oil, which was chromatographed on silica gel eluting initially with ether, then with 1:1 ethyl acetate/ether to afford the title compound (D30) as a yellow oil (430 mg, 15%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)([O-])=O.CO.[H][H]>CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2
Reactant: [H][H]
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2N1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)CC(=O)N2
Reaction time: 2 h
Yield: 98 %

Procedure:
A mixture of 1.5 g (8.4 mmol) of 5-nitro-1,3-dihydro-indol-2-one, 150 mg of Pd/C 10%, and 50 ml MeOH in 100 ml of EtOAc was placed on Parr® hydrogenator and charged with 45 psi of Hydrogen gas. The mixture was shaken for 2 hrs. The mixture was filtered and the solvent was removed in vacuo to yield 5-amino 1,3-dihydro-indol-2-one (1.22 g, 98%): 1H NMR (DMSO-d6): δ3.27 (s, 2H), 4.6 (s, 2H), 6.34 (dd, J1=2 Hz, J2=8.1 Hz, 1H), 6.45 (m, 2H), 9.88 (s, 1 H). APCI-MS: m/z 147 (m−H)−.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12]([NH2:14])=[O:13])=[CH:7][CH:6]=1)=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>C(O)C>[N:16]1[C:3]([C:5]2[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12]([NH2:14])=[O:13])=[CH:7][CH:6]=2)=[CH:2][N:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=12
Reactant: CC(C(N)=O)c1ccc(C(=O)CCl)cc1
Reactant: Nc1ccccn1
Solvent: CCO
Product: CC(C(N)=O)c1ccc(-c2cn3ccccc3n2)cc1
Yield: 65.2 %

Procedure:
A mixture of 9 g of 2-[4-(chloroacetyl)phenyl]propionamide, 30 ml of ethanol and 7.6 g of 2-aminopyridine is heated under reflux for 2 hours. The ethanol is distilled off under reduced pressure, and water is added to the residue. The crystalline precipitate is filtered off and recrystallized from aqueous dimethylformamide to give 6.9 g of 2-[4-(imidazo[1,2-a]pyridin-2-yl)phenyl]propionamide as colorless scales melting at 219°-220°C.