Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:12]=[CH:11][O:10][CH:9]=1)(=O)=O.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K].O>CN(C)C=O>[O:10]1[CH:11]=[CH:12][C:8]([CH2:7][CH2:6][N:17]2[C:16](=[O:18])[C:15]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]3[C:13]2=[O:23])=[CH:9]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CS(=O)(=O)OCCc1ccoc1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCc1ccoc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of the 2-(3-furyl)ethyl methanesulfonate in 500 ml of N,N-dimethylformamide, 14.2 g (76.8 mmol) of potassium phthalimide was added, followed by overnight stirring at 100° C. After cooling to room temperature, the reaction mixture was added to water while being stirred vigorously. The resulting precipitate was filtered, washed with water and dried to yield N-[2-(3-furyl)ethyl]phthalimide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:38]1[N:39]=[CH:40][C:41]([C:44]#[N:45])=[N:42][CH:43]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:34])[CH3:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([C:38]4[N:39]=[CH:40][C:41]([C:44]#[N:45])=[N:42][CH:43]=4)=[CH:21][CH:22]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Reactant: N#Cc1cnc(Cl)cn1
Product: C[C@@H](c1ccc(-c2cnc(C#N)cn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 5-chloropyrazine-2-carbonitrile following a procedure analogous to that described in Example 14. LC-MS Method 1 tR=1.64 min, m/z=497 (M+Na); 1H NMR (CDCl3) 8.98 (d, 2H), 7.89 (d, 2H), 7.27 (m, 1H), 7.17 (m, 2H), 7.04 (m, 3H), 5.72 (q, 1H), 4.40 (br s, 1H), 2.98 (m, 1H), 1.59 (d, 3H), 1.13 (d, 6H).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:19]#[N:20])=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C2C=CC(I)=CC=2O[C:23]=1[C:32]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=1[Cl:41])=[O:33]>>[NH2:20][C:19]1[C:14]2[CH:13]=[C:12]3[C:17](=[CH:16][C:15]=2[O:18][C:23]=1[C:32]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=1[Cl:41])=[O:33])[N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][CH2:10][CH2:11]3
Reactant: N#Cc1cc2c(cc1O)N(Cc1ccccc1)CCC2
Reactant: Nc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(I)ccc12
Product: Nc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc3c(cc12)CCCN3Cc1ccccc1
Yield: 29 %

Procedure:
This compound was prepared from 1-benzyl-7-hydroxy-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (20 mg, 0.08 mmol) from step 4 in the manner described for [(3-amino-6-iodo-benzofuran-2-yl)-(2,4-dichloro-phenyl)-methanone, affording 10 mg (29%) of the title compound as a yellow solid. 1H-NMR (CDCl3) δ 7.44–7.40 (m, 2H), 7.33–7.22 (m, 4H), 7.18 (s, 1H), 7.15–7.13 (m, 2H), 6.25 (s, 1H), 5.96 (bs, 2H), 4.52 (s, 2H), 3.47 (t, J=6.0 Hz, 2H), 2.89 (t, J=5.9 Hz, 2H), 2.03 (m, 2H); MS LC-MS (MH+=451.3), LC MS RT: 3.81 min.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH:8]=2)[N:3]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:29][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH:8]=2)[N:3]=1
Reactant: CN1CCN(c2ccc3nc(N)c(C#N)c(Cl)c3c2)CC1
Reactant: NCc1ccccc1
Solvent: O
Product: CN1CCN(c2ccc3nc(N)c(C#N)c(NCc4ccccc4)c3c2)CC1

Procedure:
3 g of 2-amino-3-cyano-4-chloro-6-(4-methylpiperazino)quinoline and 6 mL of benzylamine are stirred at 125° C. for 3 hours. The reaction mixture is poured onto 30 mL of water. The precipitated material is filtered off, washed with 20 mL of water. After drying 2.3 g of the title compound is obtained, m.p.: 176° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.P(Cl)(Cl)(Cl)=O.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[C:21]([C:28](O)=O)=[C:22]2[CH2:27][CH2:26][CH2:25][N:23]2[N:24]=1>>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[C:21]([C:28]2[O:8][C:7]3[C:2]([N:1]=2)=[N:3][CH:4]=[CH:5][CH:6]=3)=[C:22]2[CH2:27][CH2:26][CH2:25][N:23]2[N:24]=1
Reactant: O=C(O)c1c(-c2ccccn2)nn2c1CCC2
Reactant: Nc1ncccc1O
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc(-c2nn3c(c2-c2nc4ncccc4o2)CCC3)nc1
Yield: 22.2 %

Procedure:
In a similar fashion to Example 8, react 2-amino-3-hydroxypyridine (Fluka; 144 mg, 1.3 mmol) and phosphorous oxychloride (4.4 mL) with 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid (Preparation 3; 250 mg, 1.1 mmol) to provide the title compound (74 mg, 22%) as a tan solid. Mp 182-184° C. MS ESI+ m/e 304 (M+1). 1H NMR (CDCl3) δ 8.75 (m, 1H), 8.52 (m, 1H), 8.12 (m, 1H), 7.84 (m, 1H), 7.69 (m, 1H), 7.32 (m, 1H), 7.15 (m, 1H), 4.31 (m, 2H), 7.37 (m, 2H), 2.75 (m, 2H). HPLC: 98.3%, Rt=13.95 min. TLC (SiO2): Rf0.4 (1:3 [80:18:2 chloroform/methanol/concentrated aqueous ammonium hydroxide]/dichloromethane).
Reaction SMILES: [N:1]([C:4]1([CH3:20])[CH2:8][CH2:7][CH2:6][CH:5]1[NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][C:4]1([CH3:20])[CH2:8][CH2:7][CH2:6][CH:5]1[NH:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)(=[O:12])=[O:11]
Reactant: Cc1ccc(S(=O)(=O)NC2CCCC2(C)N=[N+]=[N-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC2CCCC2(C)N)cc1

Procedure:
To a solution of N-(2-azido-2-methylcyclopentyl)-4-methylbenzene-1-sulfonamide (52.0 g, 176.87 mmol) in methanol (1100 ml) was added palladium on carbon (10% wt, 10.0 g). The reaction mixture was stirred at room temperature under a balloon of hydrogen gas for 12 hours. The reaction was filtered through diatomaceous earth (commercially sold under the trade mark “Celite”) and concentrated in vacuo to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([C:9]3[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[C:11]([O:18]CC4C=CC=CC=4)[CH:10]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([C:9]3[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[C:11]([OH:18])[CH:10]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: COC(=O)c1sc(-n2cnc3cc(Br)ccc32)cc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1sc(-n2cnc3cc(Br)ccc32)cc1O
Reaction time: 6 h
Yield: 83.3 %

Procedure:
A solution of methyl 5-(5-bromo-1H-benzimidazol-1-yl)-3-[(phenylmethyl)oxy]-2-thiophenecarboxylate (15 g, 3.4 mmol) in 10 ml of TFA was heated to 50° C. After 6 h, the reaction was concentrated. The residue was dissolved in MeOH and neutralized with 7N ammonia in MeOH. The slurry was diluted with ether and filtered. The solid was washed with water and air-dried to give 1.0 g of the title compound (85%).
Reaction SMILES: [NH:1]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22](O)=O)[CH:16]=1.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]2[N:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=2)[CH:16]=1
Reactant: O=C(O)Cc1cccnc1
Reactant: Nc1ccccc1Nc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: c1ccc(-n2c(Cc3cccnc3)nc3ccccc32)cc1
Yield: 35.1 %

Procedure:
To a solution of 2-anilinoaniline (1.84 g) and 3-pyridineacetic acid (1.37 g) in chloroform (20 ml) was dropwise added phosphorus oxychloride (1.53 g) and the mixture was refluxed for 6 hours. After removal of the solvent under reduced pressure, the resultant residue was poured into a saturated aqueous solution of sodium bicarbonate. The mixture was extracted twice with ethyl acetate. The combined extract was washed with water and a saturated aqueous solution of sodium chloride successively, and dried over magnesium sulfate. The solvent was removed under reduced pressure to give a crystalline product, which was recrystallized from a mixture of isopropyl alcohol and n-hexane (1:2) to give 2-(pyridin-3-yl)methyl-1-phenyl-1H-benzimidazole (1.0 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: OB(O)c1ccccc1
Product: NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Yield: 56.6 %

Procedure:
Using preparation method 2, 4-bromobenzenesulfonamide (472 mg, 2 mmol) was reacted with phenylboronic acid (268 mg, 2.2 mmol). Purification by washing with hot toluene followed by filtration gave 4-phenylbenzenesulfonamide as an off-white crystalline solid (264 mg, 55%). NMR 1H (ppm, CDCl3): 7.87 (d, J3=8.6 Hz, 2H), 7.83 (d, J3=8.7 Hz, 2H), 7.70 (d, J3=7.2 Hz, 2H), 7.48 (t, J3=7.3 Hz), 7.40 (t, J3=7.1 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]2[O:15][CH2:14][CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:12][O:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCOCC1>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([CH:10]2[O:11][CH2:12][CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:14][O:15]2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: CCCCCC1COC(c2ccc(F)c(C#N)c2)OC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1COCCO1
Product: CCCCCC1COC(c2ccc(F)c(CN)c2)OC1

Procedure:
27.7 g of 2-(3-cyano-4-fluorophenyl)-5-pentyl-1,3-dioxane (obtainable from 3-cyano-4-fluorobenzaldehyde and 2-pentyl-1,3-propanediol) in 380 ml of dioxane are added dropwise, in the course of 2 hours, to a boiling suspension of 4.0 g of lithium aluminium hydride in 300 ml of the same solvent. When the addition is complete, heating is continued for a further hour and decomposition is then effected with water. The solution is filtered off from the precipitated hydroxide and evaporated down under reduced pressure. 2-(3-Aminomethyl-4-fluorophenyl)-5-pentyl-1,3-dioxane is obtained.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:32])[CH:12]([NH:13][C:14](=[O:31])[CH:15]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:16]C(OC(C3CC3)C)=O)[C@H:4]2[S:3]1.CCOCC>C(O)=O>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:32])[CH:12]([NH:13][C:14](=[O:31])[CH:15]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH2:16])[C@H:4]2[S:3]1
Reactant: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)C(NC(=O)OC(C)C3CC3)c3ccccc3)[C@H]2S1
Solvent: O=CO
Solvent: CCOCC
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)C(N)c3ccccc3)[C@H]2S1
Reaction time: 1.5 h
Yield: 74.7 %

Procedure:
A solution of 2-methyl-7-[N-(1-cyclopropylethoxy)carbonyl-2-phenylglycyl]amino-3-cephem-4-carboxylic acid (2.0 g) in formic acid (10 ml) was stirred for 2.5 hours at room temperature. After the reaction was completed, ether (30 ml) was added to the reaction mixture, and the supernatent was removed three times by decantation. Colorless powder was collected by filtration and washed with ether. Thus obtained powder was suspended in a mixture of acetonitrile (15 ml) and water (1 ml), and the suspension was stirred for 1.5 hours under ice-cooling. The precipitate was collected by filtration and dried to give 2-methyl-7-(2-phenylglycyl)amino-3-cephem-4-carboxylic acid (1.13 g), mp 168.5° to 171° C.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[O:26][N:25]=[C:24]([CH3:27])[C:23]=4[C:28]([O:30]C)=[O:29])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])C.[OH-].[Na+].[CH2:34]1COCC1>C(O)C.O>[CH2:1]([O:4][C:5]([C:7]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[O:26][N:25]=[C:24]([CH3:27])[C:23]=4[C:28]([OH:30])=[O:29])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)=[O:6])[CH2:3][CH3:34]
Reactant: C1CCOC1
Reactant: COC(=O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OC(C)C)CC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(=O)O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the methyl ester from Step 5 (5.2 g, 12.4 mmol) in THF (100 mL) and ethanol (20 mL) was added a solution of sodium hydroxide (1.5 g, 37.2 mmol) in water (40 mL). The solution was stirred at room temperature 3 hours. ˜50 mL solvent evaporated and 200 mL water added. The product was precipitated out of solution with dilute hydrochloric acid to pH 2. The product was isolated by filtration to yield 4.6 grams of the title compound.
Reaction SMILES: [CH2:1]([N:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3([CH2:23][O:24]C4CCCCO4)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[C:7]([Cl:31])[C:6]1=[O:32])[CH2:2][CH2:3][CH3:4].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH2:1]([N:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3([CH2:23][OH:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[C:7]([Cl:31])[C:6]1=[O:32])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1ccc(-c2ccc(C3(COC4CCCCO4)CCOCC3)cc2)c(Cl)c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CCCCn1ccc(-c2ccc(C3(CO)CCOCC3)cc2)c(Cl)c1=O
Yield: 60.5 %

Procedure:
A mixture of compound E2 (0.10 g, 0.22 mmol) and a catalytic amount of p-toluenesulfonic acid in methanol (10 ml) was stirred at room temperature for 1 hour. The solvent was evaporated in vacuo and the resulting residue was taken up with DCM, washed with an aqueous saturated solution of NaHCO3, the combined organic extracts were dried (Na2SO4) and the solvent was evaporated in vacuo. The crude residue was purified by column chromatography (silica gel; 0-30% EtOAc/DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield E3 (0.05 g, 61%) as a colourless oil. Compounds E4 to E9 (Table 1) were prepared in a similar manner. Physico-Chemical Data LCMS—General Procedure
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[OH-].[Na+].[CH2:11]([O:18][C:19](Cl)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[C:19]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])([O:18][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:20]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Yield: 95.2 %

Procedure:
To a solution of (S)-proline (25 g:0.22 mole) and sodium hydroxide (8.7 g:0.22 mole) in 150 ml of water was slowly added a solution of benzylchloroformate (43.5 g:0.26 mole) and sodium hydroxide (11.6 g:0.29 mole) in 75 ml of water with stirring under cooling on ice over 30 minutes, followed by continuing the stirring at the same temperature for 15 minutes. From the reaction mixture, excess benzylchloroformate was removed by extraction with 150 ml of chloroform. The aqueous layer was acidified with 5N hydrochloric acid, and the resulting oily product was extracted with chloroform. After drying the chloroform layer over magnesium sulfate, chloroform was removed by evaporation to give 52.2 g of (S)-1-carbobenzoxypyrrolidine-2-carboxylic acid as oil. Yield: 96%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][C:24]1=[O:28]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][C:24]1=[O:28])=[O:14]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NCCCN1CCCC1=O
Product: O=C(NCCCN1CCCC1=O)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N-[3-(2-oxopyrrolidin-1-yl)propyl]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.6 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.85 mmol of 1-(3-amino-propyl)-pyrrolidin-2-one LC/MS [8.70 min; 483 (M+1)]
Reaction SMILES: [CH:1]([S:4](Cl)(=[O:6])=[O:5])([CH3:3])[CH3:2].[CH3:8][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=2)[N:12]=[CH:11][C:10]=1[C:24]([NH:26][C:27]1[CH:28]=[N:29][C:30]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:31][CH:32]=1)=[O:25].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:8][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][N:15]=2)[N:12]=[CH:11][C:10]=1[C:24]([NH:26][C:27]1[CH:28]=[N:29][C:30]([CH:33]2[CH2:38][CH2:37][N:36]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])[CH2:35][CH2:34]2)=[CH:31][CH:32]=1)=[O:25]
Reactant: Cc1c(C(=O)Nc2ccc(C3CCNCC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Reactant: CC(C)S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(C3CCN(S(=O)(=O)C(C)C)CC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Isopropylsulfonyl chloride (167 μl) was added at room temperature to a suspension of 5-methyl-N-[6-(piperidin-4-yl)pyridin-3-yl]-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (215 mg) described in Reference Example 173 and potassium carbonate (237 mg) in N,N-dimethylformamide (1.7 ml), and stirred at room temperature for 4.5 hours. Water was added to the reaction solution, the precipitated solid was washed with ethyl acetate. The resulting solid was purified with a preparative HPLC (water:acetonitrile) to give the titled compound (44 mg) as a white solid.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])[CH3:18].C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[N:15]=[CH:14][C:13]([NH:16][S:26]([C:23]3[CH:24]=[CH:25][C:20]([CH:17]([CH3:19])[CH3:18])=[CH:21][CH:22]=3)(=[O:28])=[O:27])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)[CH:2]=[CH2:3]
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CCN1CCN(c2ccc(N)cn2)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCN1CCN(c2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.4 g (7.97 mmol) of 6-(4-allylpiperazin-1-yl)pyridin-3-ylamine from Example 1.2 and 1.74 g (7.97 mmol) of 4-isopropylbenzenesulfonyl chloride were dissolved in 30 ml of tetrahydrofuran at room temperature. 3.3 ml (23.91 mmol) of triethylamine were then added to this mixture. After that, the reaction mixture was stirred overnight at room temperature. After the solvent had been evaporated to dryness, water was added to the residue. The aqueous reaction mixture was made acid with 1N hydrochloric acid and extracted twice with diethyl ether. After that, the aqueous phase was made alkaline (pH 9-10) with a 1N aqueous solution of sodium hydroxide and then extracted twice with diethyl ether. After the combined organic phases had been dried over sodium sulfate, the drying agent had been filtered off and the solvent had been evaporated down to dryness, the resulting residue was chromatographed on silica gel using cyclohexane/ethyl acetate (45:55% to 100% ethyl acetate). The filtrate was evaporated down to dryness. The resulting residue was thoroughly stirred in 10 ml of heptane, filtered off in suction and dried, with 1.93 g (61% of theory) of the title compound being obtained.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[F:8][C@@H:9]1[C@@H](CO)[O:12][C@@H:11]([N:16]2[CH:23]=[CH:22][C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:10]1.C(O)C>N1C=CC=CC=1>[C:5]([O:4][CH2:1][C@H:2]1[O:12][C@@H:11]([N:16]2[CH:23]=[CH:22][C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:10][C@@H:9]1[F:8])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Acetic anhydride (1.2 ml, 13 mmol) was added to a solution of 2',3'-dideoxy-3'-fluorouridine (1 g, 4.34 mmol) in dry pyridine (10 ml) and the mixture was stirred at room temperature for 24 hours. Ethanol (2 ml) was added and the mixture was evaporated to dryness. Residual pyridine was removed by coevaporation with portions of ethanol and the final residue purified by silica gel column chromatography eluting with 5% MeOH/CH2Cl2 to give the title compound which was isolated following trituration with ether.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]([C:8]2[C:9](F)=[CH:10][C:11]([CH3:30])=[C:12]([C:14]([N:16]3[CH2:21][CH2:20][CH:19]([C:22]4[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)=[O:15])[CH:13]=2)=[N:6][N:7]=1)[CH3:2].Cl.[NH:33]1[CH2:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[N:33]1([C:9]2[C:8]([C:5]3[NH:4][C:3]([CH2:1][CH3:2])=[N:7][N:6]=3)=[CH:13][C:12]([C:14]([N:16]3[CH2:17][CH2:18][CH:19]([C:22]4[CH:23]=[CH:24][C:25]([C:26]#[N:27])=[CH:28][CH:29]=4)[CH2:20][CH2:21]3)=[O:15])=[C:11]([CH3:30])[CH:10]=2)[CH2:36][CH2:35][CH2:34]1
Reactant: CCc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2F)[nH]1
Reactant: C1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2N2CCC2)[nH]1
Temperature: 105 °C
Reaction time: 8 h
Yield: 19.8 %

Procedure:
To a 10-mL sealed tube was added a solution of 4-(1-[[5-(5-ethyl-4H-1,2,4-triazol-3-yl)-4-fluoro-2-methylphenyl]carbonyl]piperidin-4-yl)benzonitrile (compound 258.2, 83.5 mg, 0.200 mmol, 1.00 equiv) in 1,4-dioxane (5 mL). Azetidine hydrochloride (93.0 mg, 0.990 mmol, 5.00 equiv) was added to the reaction in portions. Potassium carbonate (276 mg, 2.00 mmol, 10.0 equiv) was also added to the above mixture. The resulting solution was stirred overnight at 105° C. behind a blast shield, then cooled to rt. The reaction was quenched with 20 mL of water. The mixture was extracted with 30 mL of ethyl acetate and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product (80 mg) was further purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 50 mL NH4CO3 and CH3CN (41.0% CH3CN up to 43.0% in 8 min, up to 100.0% in 2 min, down to 41.0% in 2 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 18.0 mg (20%) of the title compound as a white solid. m/z (ES+) 455 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 7.68 (d, J=6.3 Hz, 2H), 7.48 (d, J=5.7 Hz, 2H), 7.24 & 7.13 (2 singlets, amide rotamers, Ar—H, 1H), 6.52 (s, 1H), 4.91-7.77 (m, 1H partially obscured by water peak), 3.81-3.67 (m, 1H), 3.68 (t, J=5.6 Hz, 4H), 3.32-3.18 (m, 1H), 3.05-1.91 (m, 2H), 2.84 (q, J=5.8 Hz, 2H), 2.45-2.19 (m, 5H), 2.09-1.91 (m, 1H), 1.91-1.49 (m, 3H), 1.39 (t, J=5.7 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[NH:13][N:12]=[C:11]([C:14]([O:16]CC)=[O:15])[C:10]=2C)[CH:6]=[CH:7][CH:8]=1)#[N:2].[Li+].[OH-].O.Cl.[CH2:24]1COCC1>CO>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([C:14]([OH:16])=[O:15])[N:12]([CH3:24])[N:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)c1n[nH]c(-c2cccc(C#N)c2)c1C
Reactant: C1CCOC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1nc(-c2cccc(C#N)c2)cc1C(=O)O
Reaction time: 8 h
Yield: 52.6 %

Procedure:
To a solution of ethyl 5-(3-cyanophenyl)-4-methyl-1H-pyrazole-3-carboxylate (100 mg, 392 μmol, Eq: 1.00) in THF (5 ml) in MeOH (1.00 ml) was added LiOH 1M (2.35 ml, 2.35 mmol, Eq: 6). The mixture was stirred overnight. To the residue was added water and HCl 1N (pH:1), this aqueous phase was extracted two times with ethyl acetate, the resulting organic layers were combined and washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the desired compound (52 mg, 52.6%) as a yellow solid. MS (ISP): 228.1 (M+1).