Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:32]=[N:33][CH:34]=[C:35]([F:37])[CH:36]=2)=[C:27]([CH3:38])[CH:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:32]=[N:33][CH:34]=[C:35]([F:37])[CH:36]=2)=[C:27]([CH3:38])[CH:26]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(Br)ccc1-c1cncc(F)c1
Product: Cc1cc(C(=O)C(NC(=O)OC(C)(C)C)c2ccc(Cl)c(Cl)c2)ccc1-c1cncc(F)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 3-(4-bromo-2-methyl-phenyl)-5-fluoro-pyridine (Intermediate 12) in analogy to Example 1a): MS (ISP): 489.2 and 491.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14](Cl)(=O)C(Cl)=O>CO.C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 63 %

Procedure:
4-fluoro-3-nitrobenzoic acid (2.5 g, 14 mmol, 1.0 eq) was dissolved in MeOH (68 mL) and heated to reflux. 2.0M oxalyl chloride in CH2Cl2 (14 mL) was added to the refluxing solution slowly and stirred for 2 h at reflux. The reaction was concentrated in vacuo, crystallized at 0° C., and filtered to give 1.7 g (63%) of crude methyl 4-fluoro-3-nitrobenzoate as a white solid. The product was confirmed by LCMS (>98% @ 220 nm and 254 nm) and carried forward without purification. Methyl 4-fluoro-3-nitrobenzoate (1.7 g, 8.4 mmol, 1.0 eq) and 5% palladium on carbon (89 mg, 0.84 mmol, 0.10 eq) were dissolved in EtOH (40 mL) and stirred under H2 atmosphere (1 atm) for 24 h. The mixture was filtered through celite and concentrated in vacuo affording 1.4 g (97%) of crude methyl 3-amino-4-fluorobenzoate as a brown solid. The product was confirmed by LCMS (>98% @ 220 nm and 254 nm) and carried forward without purification. Methyl 3-amino-4-fluorobenzoate (1.4 g, 8.2 mmol, 1.2 eq), 5-bromopyrimidine (1.1 g, 6.8 mmol, 1.0 eq), cesium carbonate (3.1 g, 9.6 mmol, 1.4 eq), Bis(dibenzylideneacetone)palladium (0.50 g, 0.55 mmol, 0.080 eq), and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.47 g, 0.82 mmol, 0.12 eq) were dissolved in Dioxane (17 mL) and stirred under argon at 100° C. overnight. The mixture cooled to rt and was filtered through celite and washed with 5% MeOH in CH2Cl2. The filtrate was collected, concentrated in vacuo, and purified by flash chromatography on silica gel afforded 1.5 g (90%) of the title compound as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.63 (s, 1H), 8.50 (s, 2H), 7.84 (dd, J=8.1, 2.1 Hz, 1H), 7.63 (ddd, J=8.5, 4.7, 2.1 Hz, 1H), 7.42 (dd, J=11.2, 8.6 Hz, 1H), 3.83 (s, 3H); ES-MS [M+1]+:248.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:18]([C:19](=[O:21])[CH3:20])=[C:11]3[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.CO[CH:24](OC)[N:25]([CH3:27])[CH3:26]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:18]([C:19](=[O:21])[CH:20]=[CH:24][N:25]([CH3:27])[CH3:26])=[C:11]3[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)c1c(-c2ccc(F)cc2)nn2cc(C#N)ccc12
Reactant: COC(OC)N(C)C
Product: CN(C)C=CC(=O)c1c(-c2ccc(F)cc2)nn2cc(C#N)ccc12
Temperature: 130 °C

Procedure:
A mixture of 2-(4-fluorophenyl)-3-acetyl-6-cyanopyrazolo[1,5-a]pyridine (1.6 g, 5.6 mmol) and dimethylformamide-dimethylacetal (15 mL) was stirred and heated at 130° C., under N2, overnight. The solution was cooled and the resulting solid was collected by filtration and rinsed with acetone. The filtrate was evaporated and the resulting solid was purified using chromatography. The product solids were combined to afford the title compound as a brown solid, 1.3 g (68%). 1H NMR (d6-DMSO) showed a mixture of isomers. MS (ES+) m/z 335 (M++H), 264 (M+−70).
Reaction SMILES: [OH:1][CH:2]([C:29]1[O:30][C:31]([CH2:34][O:35][CH3:36])=[N:32][N:33]=1)[CH:3]([NH:6][C:7](=[O:28])[CH:8]([CH2:17][S:18]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:20])=[O:19])[CH2:9][C:10](=[O:16])[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:4][CH3:5].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>>[CH3:36][O:35][CH2:34][C:31]1[O:30][C:29]([C:2]([CH:3]([NH:6][C:7](=[O:28])[CH:8]([CH2:17][S:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:20])=[O:19])[CH2:9][C:10](=[O:16])[N:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:4][CH3:5])=[O:1])=[N:33][N:32]=1
Reactant: CCC(NC(=O)C(CC(=O)N1CCCC1)CS(=O)(=O)Cc1ccccc1)C(O)c1nnc(COC)o1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Product: CCC(NC(=O)C(CC(=O)N1CCCC1)CS(=O)(=O)Cc1ccccc1)C(=O)c1nnc(COC)o1
Reaction time: 1 h

Procedure:
This amide was treated with Dess-Martin periodinane (114 mg, 0.153 mmol) at room temperature. After stirring for 1 hour, 5 mls of saturated Na2S2O3—NaHCO3 were added. After a further 0.5 hours, the reaction mixture was extracted with ethyl acetate, washed with brine, dried with MgSO4 and concentrated. The residue was purified with silica gel column chromatography to yield 17 mg of N-[1-(5-Methoxymethyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-4-oxo-2-benzylsulfonylmethyl-4-pyrrolidin-1-yl-butyramide; H1 NMR(CDCl3): 8.2, 8(1H, d,d, NH, diastereomeric), 7.6–7.2(5H, m), 5.3–5.1(1H, m), 4.6(2H, s, OCH2), 4.3–4.1(3H, m), 3.8–3.2(9H, m), 3–2.4(2H, m), 2.2–1.4(6H, m), 0.95(3H, t); MS:519.6(M−1), 521.6(M+1).
Reaction SMILES: C([O:8][C:9]1[CH:52]=[CH:51][C:12]([CH2:13][C@@H:14]([C:26]([O:28][CH2:29][C@H:30]2[O:34][C@@H:33]([N:35]3[CH:42]=[C:41]([F:43])[C:39](=[O:40])[NH:38][C:36]3=[O:37])[CH2:32][C@@H:31]2[O:44][CH2:45][C:46]2[O:50][CH:49]=[CH:48][CH:47]=2)=[O:27])[NH:15]C(OCC2C=CC=CC=2)=O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[F:43][C:41]1[C:39](=[O:40])[NH:38][C:36](=[O:37])[N:35]([CH:42]=1)[C@@H:33]1[O:34][C@H:30]([CH2:29][O:28][C:26](=[O:27])[C@H:14]([CH2:13][C:12]2[CH:51]=[CH:52][C:9]([OH:8])=[CH:10][CH:11]=2)[NH2:15])[C@@H:31]([O:44][CH2:45][C:46]2[O:50][CH:49]=[CH:48][CH:47]=2)[CH2:32]1
Reactant: [H][H]
Reactant: O=C(N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OCc1ccco1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OCc1ccco1
Reaction time: 2 h
Yield: 17.2 %

Procedure:
To a solution of 1.10 g of 5'-O-(O-benzyl-N- benzyloxycarbonyl-L-tyrosyl)-2'-deoxy-5-fluoro-3'-O-furfuryluridine prepared in Example 14 in 50 ml of methanol was added 0.11 g of 5% palladium-carbon, and the mixture was stirred in a hydrogen stream under ambient temperature and pressure condition for 2 hours. The catalyst was filtered off, and the solvent was evaporated off under reduced pressure. The residue was placed on silica gel column and eluted with 5% methanol-chloroform for purification, thereby giving 0.13 g of 2'-deoxy-5- fluoro-3'-O-furfuryl-5'-O-L-tyrosyluridine.
Reaction SMILES: [C:1]1([C:7]2(C3C=CC=CC=3)[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].O>CN(C=O)C.CCCCCC.C(OCC)(=O)C>[OH2:33].[C:1]1([C:7]2[C:11]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH2:35]([O:34][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][N:9]1[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:8]1)[CH3:36]
Reactant: C1=C(c2ccccc2)N=NC1(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CCCCCCCBr
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 127.7 %

Procedure:
Sodium hydride (0.58 g of a 50% dispersion, 12 mmol) was washed twice with hexane and covered with DMF (45 mL). 3,3,5-Triphenyl-3H-pyrazole (3 g, 10 mmol) was added and the mixture heated at 110° C. under nitrogen for 45 minutes before being cooled to room temperature. A solution of ethyl 8-bromo-octanoate (2.80 g, 11 mmol) in DMF (2 mL) was added and the mixture stirred for 10 minutes before being poured onto a mixture of water and ethyl acetate. The aqueous layer was discarded and the organic layer washed twice with water and once with saturated sodium chloride solution. The organic phase was dried over sodium sulfate and concentrated to afford an oil. Chromatography on a column of silica gel using a mixture of hexane and ethyl acetate (17:3) as eluent gave ethyl 3,4,5-triphenyl-lH-pyrazol-1-octanoate hemihydrate (4.05 g, 85%) as an oil. MS(CI): m/e =467 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].FC(F)(F)S(O[CH2:19][C:20]([F:23])([F:22])[CH3:21])(=O)=O.CCCCCCCCCCN>>[F:22][C:20]([F:23])([CH3:21])[CH2:19][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12]
Reactant: COC(=O)c1ccc(O)c(C)c1
Reactant: CC(F)(F)COS(=O)(=O)C(F)(F)F
Agent: CCCCCCCCCCN
Product: COC(=O)c1ccc(OCC(C)(F)F)c(C)c1
Yield: 76 %

Procedure:
The title compound is prepared in 76% yield (2.09 g, white solid) from methyl 4-hydroxy-3-methylbenzoate (1.86 g, 11.2 mmol) and 2,2-difluoropropyl trifluoromethanesulfonate (6.37 g, 27.9 mmol) in a similar manner to Step-1 of Amine-10.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.CCOC(C)=O>[CH3:11][O:10][C:1](=[O:9])[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[S:4][CH3:12]
Reactant: COC(=O)c1ccccc1S
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COC(=O)c1ccccc1SC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl thiosalicylate (4.0 g, 23.8 mmol) in DMF (25 mL) is added K2CO3 (4.0 g, 28.94 mmol) followed by methyl iodide (2.3 mL, 36.9 mmol). The resulting mixture is stirred at ambient temperature for 1 h. The mixture is diluted with EtOAc and washed with 1N HCl (3×) and water (1×). The organic phase is dried over MgSO4, filtered and concentrated to afford 2-methylsulfanylbenzoic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[C:9]([CH:31]=[CH:32][CH:33]=2)[O:10][C:11]2[CH:30]=[CH:29][C:14]3[O:15][CH2:16][CH2:17][N:18](C(OC(C)(C)C)=O)[S:19](=[O:21])(=[O:20])[C:13]=3[CH:12]=2)[N:3]=1>Cl.O1CCOCC1>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[C:9]([CH:31]=[CH:32][CH:33]=2)[O:10][C:11]2[CH:30]=[CH:29][C:14]3[O:15][CH2:16][CH2:17][NH:18][S:19](=[O:21])(=[O:20])[C:13]=3[CH:12]=2)[N:3]=1
Reactant: Cc1nc(-c2cccc(Oc3ccc4c(c3)S(=O)(=O)N(C(=O)OC(C)(C)C)CCO4)c2)no1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc(-c2cccc(Oc3ccc4c(c3)S(=O)(=O)NCCO4)c2)no1

Procedure:
A solution of 1.92 g (4.05 mmol) of the product obtained in Step H above is heated at 80° C. for 2 hours in 15 ml of 4N HCl solution in dioxane. The mixture is evaporated to dryness and dried in vacuo. The crude product is purified by chromatography over silica gel eluting with a mixture of CH2Cl2/AcOEt. The solid is taken up in isopropyl ether and filtered to yield the title product.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[N:13]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])[N:12]=[CH:11][C:10]=1[N+:26]([O-:28])=[O:27].C(Br)(Br)[Br:30]>>[Cl:25][C:15]1[CH:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:19]([Cl:20])[C:14]=1[N:13]1[C:9]([Br:30])=[C:10]([N+:26]([O-:28])=[O:27])[CH:11]=[N:12]1
Reactant: BrC(Br)Br
Reactant: Nc1c([N+](=O)[O-])cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: CC(C)(C)ON=O
Product: O=[N+]([O-])c1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1Br
Yield: 89 %

Procedure:
18 ml (0.16 mole) of t-butyl nitrite are added dropwise to 17.1 g (0.05 mole) of 5-amino-4-nitro-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-pyrazole (compare DE-OS (German Published Specification) No. 3,402,308), supra, in 75 ml of bromoform in the course of 15 minutes, with stirring, whereupon the temperature of the reaction mixture rises to 50° C. When the addition has ended, the mixture is stirred at the reflux temperature for a further hour and concentrated in vacuo. 18.0 g (89% of theory) of 1-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-nitro-5-bromo-pyrazole of melting point 96° C. are obtained.
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[C:10]([O:14][C:15]([NH:17][C@@H:18]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:19](=[O:27])[CH2:20]P(=O)(OC)OC)=[O:16])([CH3:13])([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+]>C(O)C>[C:10]([O:14][C:15]([NH:17][C@@H:18]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:19](=[O:27])/[CH:20]=[CH:2]/[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])=[O:16])([CH3:11])([CH3:12])[CH3:13]
Reactant: COP(=O)(CC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)OC
Reactant: COC(=O)CCCC=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COC(=O)CCC/C=C/C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.4 %

Procedure:
A solution of aldehyde (methyl 5-oxopentanoate) (1) (3.0 g, 23.1 mmol), in absolute ethanol (100 mL) is added, under stirring, to a solution of dimethyl (3S)-3-[(tert-butoxycarbonyl)amino]-2-oxo-4-phenylbutyl-phosphonate (2) (8.58 g, 23.1 mmol) and K2CO3 (3.2 g, 23.1 mmol), dried at 75° C. for 12 hours, in absolute ethanol (200 mL). The mixture is then stirred at room temperature for 16 hours, the solid residue is filtered off and the solution neutralised with glacial acetic acid. The solvent is removed under reduced pressure and the residue partitioned between ethyl acetate and a saturated solution of NaHCO3. The aqueous phase is extracted with ethyl acetate (2×50 mL) and the pooled organic phases are washed with a saturated NaCl solution and dried over anhydrous Na2SO4. The solvent is removed by distilling under reduced pressure and the product purified by means of flash chromatography on a silica gel column by using a 1:1 mixture of ethyl ether and petroleum ether as eluant. 6.8 g (79%) of a colourless oil are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:16]([OH:18])=O)[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[NH2:19][CH2:20][C:21]1[C:22](=[O:30])[NH:23][C:24]([CH3:29])=[CH:25][C:26]=1[CH2:27][CH3:28].Cl.ON1C2N=CC=CC=2N=N1.CN1CCOCC1.C(Cl)CCl.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:16]([NH:19][CH2:20][C:21]2[C:22](=[O:30])[NH:23][C:24]([CH3:29])=[CH:25][C:26]=2[CH2:27][CH3:28])=[O:18])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15]3)[C:9]=2[CH:10]=1
Reactant: O=C(O)c1cc(Br)cc2c1cnn2C1CCCC1
Reactant: CCc1cc(C)[nH]c(=O)c1CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Product: CCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-bromo-1-cyclopentyl-1H-indazole-4-carboxylic acid (370 mg, 1.2 mmol) and 3-(aminomethyl)-4-ethyl-6-methyl-2(1H)-pyridinone.HCl (340 mg, 1.68 mmol) in DMSO (3 mL). 1-hydroxy-7-azabenzotriazole (277 mg, 2.04 mmol) was added and the resulting mixture was degassed with nitrogen for 10 minutes. N-methylmorpholine (0.55 ml, 5 mmol) and EDC (390 mg, 2 mmol) were added, the vessel was sealed, and the mixture was stirred at room temperature overnight. The mixture was poured onto 10 mL of ice-water and solids crashed out. 10% K2CO3 was added to adjust the pH˜8-9. The mixture was stirred for 4 hours and then allowed to stand for another 2 hours. Solids were filtered and air-dried. DMF along with some water was then added. Solids that precipitated were filtered and dried to afford the title compound as a light orange solid (515 mg, 91%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s, 1H) 8.63 (t, J=4.80 Hz, 1H) 8.36 (s, 1H) 8.20 (s, 1H) 7.70 (d, J=1.52 Hz, 1H) 5.93 (s, 1H) 5.23 (t, J=7.07 Hz, 1H) 4.36 (s, 1H) 4.35 (s, 1H) 2.53-2.59 (m, 2H) 2.14 (s, 3H) 2.07-2.13 (m, 2H) 1.93-2.01 (m, 2H) 1.83-1.91 (m, 2H) 1.65-1.73 (m, 2H) 1.10 (t, J=7.58 Hz, 3H); LC-MS (ES) m/z=456.9/459.1
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10](=[O:13])OC)=[CH:5][CH:4]=1.[CH3:16][C@H:17]1[CH2:22][NH:21][C@H:20]([CH3:23])[CH2:19][N:18]1[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([O:32][CH3:33])[CH:25]=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[C:28]([C:27]1[CH:30]=[CH:31][C:24]([N:18]2[C@@H:17]([CH3:16])[CH2:22][N:21]([C:10]([NH:9][C:6]3[CH:7]=[N:8][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][CH:5]=3)=[O:13])[C@H:20]([CH3:23])[CH2:19]2)=[CH:25][C:26]=1[O:32][CH3:33])#[N:29]
Reactant: COc1cc(N2C[C@@H](C)NC[C@@H]2C)ccc1C#N
Reactant: COC(=O)Nc1ccc(C(F)(F)F)nc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: COc1cc(N2C[C@@H](C)N(C(=O)Nc3ccc(C(F)(F)F)nc3)C[C@@H]2C)ccc1C#N
Temperature: 100 °C
Yield: 45.7 %

Procedure:
Into 5 ml of toluene were dissolved 500 mg of methyl 6-(trifluoromethyl)pyridin-3-ylcarbamate and 557 mg of 4-[(2S,5R)-2,5-dimethylpiperazin-1-yl]-2-methoxybenzonitrile, and then 0.03 ml of DBU was added thereto, followed by heating to 100° C. and 8 hours of stirring. The reaction solution was concentrated and the residue was subjected to silica gel column chromatography to obtain 450 mg of the title compound from an eluate using chloroform-methanol (96:4, v/v).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1([C:13]#[N:14])[CH2:12][CH2:11][C:6]2([O:10]CCO2)[CH2:5][CH2:4]1.C#C.[C:18]1(C)[CH:23]=CC=[CH:20][CH:19]=1>[Co+].C1(C2CCC=CCCC=2)C=CC=C1>[CH3:15][N:2]([CH3:1])[C:3]1([C:13]2[CH:20]=[CH:19][CH:18]=[CH:23][N:14]=2)[CH2:4][CH2:5][C:6](=[O:10])[CH2:11][CH2:12]1
Reactant: Cc1ccccc1
Reactant: CN(C)C1(C#N)CCC2(CC1)OCCO2
Agent: [Co+]
Agent: C#C
Agent: C1=CC(C2=CCCC=CCC2)C=C1
Product: CN(C)C1(c2ccccn2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4.5 g 8-dimethylamino-1,4-dioxaspiro[4.5]decane-8-carbonitrile, 50 mg cyclopentadienyl cycloocta-1,5-diene cobalt (I) [cpCo(cod)] and 100 ml toluene were transferred into the reaction vessel in a protective gas/acetylene counterflow. After saturation with acetylene the reaction solution was irradiated for a period of 6 hours at a temperature of 25° C. with vigorous stirring. The reaction was interrupted by switching off the lamps and air supply, and the reaction solution was concentrated to low volume. The resulting crude product (5.47 g) was taken up in a mixture of water (8.7 ml) and concentrated hydrochloric acid (15 ml) and stirred overnight at room temperature. To recover the product it was washed with diethyl ether (3×100 ml), the phases separated, the aqueous phase alkalified with 32 percent by mass of sodium hydroxide solution, extracted with dichloromethane (3×100 ml), the combined extracts dried (Na2SO4), filtered and concentrated to low volume. 3.72 g 4-dimethylamino-4-pyridin-2-yl cyclohexanone were obtained.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.[CH2:20]([N:27]1[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH2:20]([N:27]1[CH2:32][CH2:31][C:30]([C:19]2[C:10]([Cl:9])=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)([OH:33])[CH2:29][CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Clc1ccc2ccccc2n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1(c2cc3ccccc3nc2Cl)CCN(Cc2ccccc2)CC1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
To a solution of LDA (3.4 ml of 2 M in Hept/THF) at −78° C. in THF (5 ml) was added a solution of 2-chloroquinoline (1.0 g. 6.11 mmol) in THF (10 ml) dropwise, and the reaction mixture stirred at −78° C. for 1 hour before a solution of 1-benzylpiperidin-4-one (1.22 g, 6.22 mmol) in THF (2 ml) was added dropwise. The reaction mixture was stirred from −78° C. to RT over two hours, cooled to −20° C., quenched with water and extracted with EtOAc. The organics combined, dried (Na2SO4) and evaporated to dryness. Purification by column chromatography (1 to 15% MeOH in DCM) gave the desired product. LC/MS (10% to 99%): M/Z (M+H)+ (obs)=353; tR=24.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][CH2:16][C:17]1([OH:23])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>O>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:15][CH2:16][C:17]1([OH:23])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: NCC1(O)CCOCC1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: O
Product: O=[N+]([O-])c1cnc2ccccc2c1NCC1(O)CCOCC1
Yield: 89.4 %

Procedure:
4-Chloro-3-nitroquinoline (12.0 g, 57.5 mmol) and was reacted with 4-(aminomethyl)tetrahydro-2H-pyran-4-ol (11.3 g, 86.3 mmol) according to the method described in Part C of Example 9. The crude yellow solid was stirred in water (100 mL) and was isolated by filtration, dried under vacuum, and recrystallized from 1,2-dichloroethane to yield 4-{[(3-nitroquinolin-4-yl)amino]methyl}tetrahydro-2H-pyran-4-ol as bright yellow crystals (15.6 g, 90%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH:6]=[C:5]2[N:19]([CH3:21])[CH3:20].C(=O)([O-])[O-].[Ca+2]>C(O)C.[Pd]>[F:18][C:14]1[CH:13]=[C:12]([C:7]2[CH:6]=[C:5]([N:19]([CH3:21])[CH3:20])[C:4]3[C:9](=[CH:10][CH:11]=[CH:2][CH:3]=3)[N:8]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CN(C)c1cc(-c2cccc(F)c2)nc2ccc(Br)cc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Product: CN(C)c1cc(-c2cccc(F)c2)nc2ccccc12
Reaction time: 48 h
Yield: 34.8 %

Procedure:
N-[6-bromo-2-(3-fluorophenyl)-4-quinolinyl]-N,N-dimethylamine (2.5 g, 7.55 mmoles) and 300 mg of a catalyst consisting of 5% palladium on a calcium carbonate support in 200 mL of ethanol was placed under a hydrogen atmosphere at 50 psi and shaken for 48 hrs. At the end of this time the atmosphere was replaced by nitrogen and the mixture concentrated. Solids containing insoluble quinoline hydrobromide salts were washed with ethyl acetate and 5% sodium hydroxide solution and residual solids removed by filtration. Filtrates were combined, the layers were separated, and the organic layer was recovered, dried over Na2SO4, filtered and concentrated. The extracted material was recrystallized from methylene chloride and hexane to provide 700 mg (37%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[S:4][CH:5]=[C:6]([CH2:8]O)[CH:7]=1)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:29]C(Br)(Br)Br>C1COCC1>[Br:29][CH2:8][C:6]1[CH:7]=[C:3]([C:1]#[N:2])[S:4][CH:5]=1
Reactant: BrC(Br)(Br)Br
Reactant: N#Cc1cc(CO)cs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1cc(CBr)cs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 110.7 %

Procedure:
11.7 g (84.07 mmol) of 2-cyano-4-hydroxymethylthiophene together with 24.1 g (91.87 mmol) of triphenylphosphine were dissolved in 100 ml of-THF at room temperature, and 30.47 g (91.87 mmol) of tetrabromomethane were added, a little at a time, with cooling (ice bath). After stirring for 3 hours at room temperature, the mixture was concentrated in vacuo and purified by chromatography over silica gel (methylene chloride/petroleum ether). 18.8 g of crystalline pale yellow product which still contained petroleum ether resulted.