Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+]([NH:26][C:27](N)=[O:28])([O-])=O.O>C(O)C>[NH2:26][C:27]([N:12]1[CH2:11][CH2:10][C:9]([O:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:22][CH:21]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:14][CH2:13]1)=[O:28]
Reactant: NC(=O)N[N+](=O)[O-]
Reactant: O=[N+]([O-])c1ccc(OC2(c3ccccc3)CCNCC2)cc1
Solvent: O
Solvent: CCO
Product: NC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)(c2ccccc2)CC1
Yield: 88.3 %

Procedure:
To a stirred solution of 4.0 g of 4-(4-nitrophenoxy)-4-phenylpiperidine in 50 ml of 95% ethanol was added 1.68 g of nitrourea in 50 ml of 95% ethanol. The reaction mixture was refluxed for two hours and then poured into 200 ml of water. The aqueous suspension was extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting solid was purified by high pressure liquid chromatography (silica gel; elution with 5% methanol/dichloromethane) to yield 4.04 g (91.20%) of 1-aminocarbonyl-4-(4-nitrophenoxy)-4-phenylpiperidine, m.p. 203°-206° C.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32]>C(OCC)(=O)C>[CH:10]1[C:11]2[N:12]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: OCCCCCCCl
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OCCCCCCn1c2ccccc2c2ccccc21
Temperature: 150 °C

Procedure:
To a 500 ml three-neck round bottom flask was added 25 g. carbazole, 218 g. dimethyl formamide, 45.5 g. potassium carbonate and 43 g. 6-chloro-1-hexanol. The reaction mixture was heated at 150° C. for 6 hours, and cooled to room temperature. 500 g. ethyl acetate was added, washed with 250 g water, then 250 g water with 50 g concentrated HCl, then 250 g. saturated brine. The solvent was removed on a rotary evaporator to yield 58 g of a brown semi-solid. The crude product was purified using a silica gel flash chromatography column with dichloromethane as the elutant. The concentrated product fractions yielded 33.3 g. of a white solid product; ˜90% pure by gas chromatography.
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[N:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:3]=1.[C:20](=O)([O-])[O-].[Cs+].[Cs+].CI>CC(C)=O>[CH3:20][N:3]1[C:2](=[O:1])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[N:4]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)n1nc(O)c2cc(C(=O)OC)ccc21
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)n1c2ccc(C(=O)OC)cc2c(=O)n1C

Procedure:
1-Ethyl 5-methyl 3-hydroxy-1H-indazole-1,5-dicarboxylate (1.75 g, 6.62 mmol) was suspended in acetone (85 mL). Cesium carbonate (2.27 g, 6.95 mmol) and methyl iodide (1.3 mL, 20 mmol) were added and the reaction was stirred at reflux for 22 hours. The reaction was concentrated to dryness and the residue was partitioned between dichloromethane (60 mL) and water (100 mL). The layers were separated and the aqueous was extracted again with dichloromethane (60 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated. Purification by flash column chromatography (7-60% ethyl acetate/heptanes) gave two regioisomeric products.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([OH:18])=O)[NH:13][C:12]1=[O:19])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[SH:20][C@H:21]1[CH2:25][CH2:24][N:23]([C:26](=[N:28][C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[CH3:27])[CH2:22]1.C1(N=C=NC2CCCCC2)CCCCC1>C1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([S:20][C@H:21]2[CH2:25][CH2:24][N:23]([C:26](=[N:28][C:29]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=3)=[O:30])[CH3:27])[CH2:22]2)=[O:18])[NH:13][C:12]1=[O:19])[CH3:10])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1CC(=O)O
Reactant: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](S)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: c1ccccc1
Product: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](SC(=O)C[C@H]2NC(=O)[C@@H]2[C@@H](C)O[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
2.67 mg (0.93 mmole) of (3S, 4R)-3-[(R)-1-t-butyldimethylsilyloxyethyl]-4-carboxymethyl-2-azetidinone and 330 mg (1.02 mmole) of (S)-3-mercapto-1-[N-(p-nitrobenzyloxycarbonyl)acetimidoyl]pyrrolidine were dissolved in 5 ml of benzene. 210 mg (9.02 mmole) of dicyclohexylcarbodiimide and 5 mg (0.04 mmole) of 4-dimethylaminopyridine were added, and the mixture was stirred at room temperature for 1 hour, after which insolubles were filtered off. The filtrate was concentrated to dryness by evaporation under reduced pressure and the resulting oily residue was purified by column chromatography through 15 g of silica gel eluted with mixtures of benzene and ethyl acetate in volume ratios from 1:2 to 1:5, to give 495 mg (yield 90%) of the title product in the form of an oil.
Reaction SMILES: N1C=CC=CC=1.S(Cl)([Cl:9])=O.[CH3:11][O:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[S:21]([N:24]1[C:32]2[C:27](=[CH:28][C:29]([I:33])=[CH:30][CH:31]=2)[C:26]([C:35]2[C:36]([O:41][CH2:42][CH3:43])=[N:37][CH:38]=[CH:39][CH:40]=2)(O)[C:25]1=[O:44])(=[O:23])=[O:22]>ClCCl>[Cl:9][C:26]1([C:35]2[C:36]([O:41][CH2:42][CH3:43])=[N:37][CH:38]=[CH:39][CH:40]=2)[C:27]2[C:32](=[CH:31][CH:30]=[C:29]([I:33])[CH:28]=2)[N:24]([S:21]([C:14]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:13]=2[O:12][CH3:11])(=[O:23])=[O:22])[C:25]1=[O:44]
Reactant: O=S(Cl)Cl
Reactant: CCOc1ncccc1C1(O)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(I)cc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOc1ncccc1C1(Cl)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(I)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Pyridine (40 μl, 0.46 mmol) and thionyl chloride (35 μl, 0.46 mmol) were added successively to an ice-cooled solution of 1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypridin-3-yl)-3-hydroxy-5-iodo-1,3-dihydroindol-2-one (100 mg, 0.15 mmol) in dichloromethane (30 ml). The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. Ice-water was added to the reaction mixture, and the aqueous phase was extracted with dichloromethane. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude product (110 mg) was employed without further purification in the next stage.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[CH3:17][C:18]([O:21][C:22]([N:24]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[N:25]([C:33]1[C:38]([F:39])=[C:37](Cl)[N:36]=[C:35]([Cl:41])[N:34]=1)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:23])([CH3:20])[CH3:19]>CN(C=O)C>[CH3:20][C:18]([O:21][C:22]([N:24]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[N:25]([C:33]1[C:38]([F:39])=[C:37]([NH:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[N:36]=[C:35]([Cl:41])[N:34]=1)[C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])=[O:23])([CH3:17])[CH3:19]
Reactant: NC1CCOCC1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(Cl)c1F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(NC2CCOCC2)c1F
Reaction time: 8 h
Yield: 88.5 %

Procedure:
A solution of commercially available tetrahydro-2H-pyran-4-amine (0.122 g, 1.21 mmol) in DMF (6 mL) was cooled to 0° C. Then diisopropylethylamine (0.24 mL, 1.33 mmol) and tris(1,1-dimethylethyl)2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (0.600 g, 1.21 mmol) were added. The resulting solution was left to reach room temperature and stir overnight. The mixture was extracted with ether and washed with water, and the resulting aqueous layer was extracted once with ether. The combined ether layers were dried (Na2SO4) and concentrated in vacuo. The resulting material was purified by silica gel chromatography with (5-60% ethyl acetate in hexanes, 1% triethylamine) to provide tris(1,1-dimethylethyl)2-[2-chloro-5-fluoro-6-(tetrahydro-2H-pyran-4-ylamino)-4-pyrimidinyl]-1,1,2-hydrazinetricarboxylate as a white solid (0.602 g, 89%). LCMS: (M+H−2Boc)+=362.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:14][CH:13]=2)=[N:10][CH:11]=1)=[O:5])[CH3:2].C(N(CC)CC)C>C(OCC)(=O)C.[H][H].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[N:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:14][CH:13]=2)=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCCCOc1ccc(-c2ncc(C(=O)OCC)c(Cl)n2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCOc1ccc(-c2ncc(C(=O)OCC)cn2)cc1
Yield: 79.9 %

Procedure:
This compound (V) (3.3 g, 10 mmols) was dissolved in ethyl acetate (30 ml), followed by agitating the solution together with Pd/C (5%) (0.6 g) and triethylamine (1.0 g) in hydrogen atmosphere at room temperature for 3 hours, filtering off Pd/C, adding toluene (100 ml), washing the resulting fluid with 2N-hydrochloric acid (50 ml), washing it with water till the washing water became pH 7, drying the toluene phase over anhydrous magnesium sulfate, filtering off magnesium sulfate, concentrating under reduced pressure to obtain white crystals and recrystallizing the crystals from methanol to obtain ethyl-2-(4-butyloxyphenyl)-5-pyrimidinecarboxylate (VI) (2.4 g) (yield: 80%) having a melting point 99.1° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH:18]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[F:14][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:30][C:27]3[CH:26]=[CH:25][C:24]([O:23][C:19]4[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=4)=[CH:29][CH:28]=3)=[C:3]([C:15]#[N:16])[CH:4]=[N:5]2)=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1F
Reactant: Nc1ccc(Oc2cccnc2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2c(Nc3ccc(Oc4cccnc4)cc3)c(C#N)cnc2cc1F

Procedure:
Following the procedure of Example 1, a mixture of 635.4 mg (2.68 mmol) 4-chloro-7-fluoro-6-methoxy-quinoline-3-carbonitrile, 500 mg (2.81 mmol) of 4-(pyridin-3-yloxy)phenylamine and 309.8 mg (2.68 mmol) of pyridine hydrochloride are refluxed in 2-ethoxyethanol (27 mL) at 100° C. for 12 hours to yield 7-fluoro-6-methoxy-4-[4-(pyridin-3-yloxy)-phenylamino]-quinoline-3-carbonitrile as an off-white solid, mp 235-236° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:21][C:22]([F:25])([F:24])[F:23])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]2.[N:26]1[CH:31]=[CH:30][C:29]([C:32]#[CH:33])=[CH:28][CH:27]=1>C1(C)C=CC=CC=1.[Cu]I>[N:26]1[CH:31]=[CH:30][C:29]([C:32]#[C:33][C:2]2[CH:3]=[C:4]([O:21][C:22]([F:24])([F:23])[F:25])[CH:5]=[C:6]3[C:11]=2[O:10][CH:9]([C:12]([F:14])([F:15])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]3)=[CH:28][CH:27]=1
Reactant: C#Cc1ccncc1
Reactant: CCOC(=O)C1=Cc2cc(OC(F)(F)F)cc(I)c2OC1C(F)(F)F
Agent: [Cu]I
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=Cc2cc(OC(F)(F)F)cc(C#Cc3ccncc3)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 120 h
Yield: 36 %

Procedure:
A mixture of ethyl 8-iodo-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 21a, Step 2 (1.00 g, 2.07 mmole), 4-pyridylacetylene (419 uL, 4.15 mmole), CuI (39 mg, 0.207 mmole), PdCI2(dppf)2-CH2Cl2 (169 mg, 0.207 mmole) and TEA (0.866 mL, 6.21 mmole) in anhydrous toluene (10 mL) was stirred at room temperature for 5 days under a N2 atmosphere. The mixture was then diluted with hexanes and purified by silica chromatography (0% to 75% EtOAc:hexanes gradient) to give 0.34 g (36% yield) of the product as a pale yellow crystalline solid: ESHRMS m/z 458.0822 (M+H, C21H14F6NO4, Calc'd 458.0822).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][C@@H:43]5[CH3:48])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:49][N:50]1[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][C@@H:43]5[CH3:48])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][N:53]3[CH2:54][CH2:55][CH2:56][N:50]([CH3:49])[CH2:51][CH2:52]3)=[CH:14][CH:15]=2)[N:9]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CN1CCCNCC1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C=O)cc4)c4ccccc43)cn12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(CN5CCCN(C)CC5)cc4)c4ccccc43)cn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To an orange solution of Intermediate 176b (0.188 mmol) and N-methyl homopiperazine (43 mg, 0.38 mmol) in DCM (3 mL) was added sodium triacetoxyborohydride (60 mg, 0.28 mmol) and the mixture stirred at RT for 1 h. Water (3 mL) was added and the mixture shaken. The aqueous was extracted with DCM (3 mL) then the combined organics passed through a hydrophobic frit and concentrated in vacuo to leave a brown gum. Flash chromatography (silica 12 g, 7-11% [2M NH3 in MeOH] in DCM) gave the title compound as a yellow solid (102 mg, 73%). LCMS (Method 3): Rt 2.84 min, m/z 745 [MH+]. 1H NMR (300 MHz, CDCl3): 0.91 (3H, d, J=6.2 Hz), 1.34 (9H, s), 1.40-1.55 (2H, m), 1.62-1.99 (7H, m), 2.15-2.02-2.14 (2H, m), 2.21-2.30 (1H, m), 2.33 (3H, s), 2.55-2.69 (8H, m), 2.90 (1H, ddd, J=12.1, 9.3, 4.1), 3.04 (1H, dt, J=12.1, 4.2 Hz), 3.23-3.32 (1H, m), 3.58 (2H, s), 5.09 (1H, td, J=8.9, 5.2 Hz), 5.19 (1H, t, J=3.9 Hz), 6.04 (1H, br d, J=8.6 Hz), 6.33 (1H, s), 6.94 (1H, dd, J=9.9, 2.1 Hz), 7.22 (1H, br s), 7.25-7.39 (7H, m), 7.43 (1H, d, J=2.2 Hz), 7.47 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[N+:12]([O-])([OH:14])=[O:13].[N+]([O-])([O-])=O.[K+]>OS(O)(=O)=O>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Clc1nccc2ccccc12
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Product: O=[N+]([O-])c1cccc2c(Cl)nccc12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A mixture of 1-chloroisoquinoline (6.0 g, 0.037 mol) in conc. H2SO4 (35 mL) was treated with a solution of fuming HNO3 (10 mL) and potassium nitrate (4.0 g, 0.040 mol) in conc. H2SO4 (35 mL) at 0-5° C. The mixture was stirred at 0° C. for a further 90 min, and then poured into ice. The precipitate was collected, washed and dried to give the product as a yellow solid. LC-MS: 3.68 min, 209.2 & 211.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH:23]([O:26][CH3:27])[O:24][CH3:25])[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:3]=1.[F-:28].[K+]>CS(C)=O.CCOC(C)=O>[C:8]([C:7]1[C:2]([F:28])=[CH:3][C:4]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH:23]([O:26][CH3:27])[O:24][CH3:25])[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[N:5][CH:6]=1)#[N:9]
Reactant: COC(OC)c1ccc2c(n1)N(C(=O)Nc1cc(Cl)c(C#N)cn1)CCC2
Reactant: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(OC)c1ccc2c(n1)N(C(=O)Nc1cc(F)c(C#N)cn1)CCC2
Temperature: 110 °C
Reaction time: 16 h

Procedure:
N-(4-chloro-5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 2J, 106 mg, 0.273 mmol) and KF (159 mg, 2.73 mmol) were dissolved in DMSO (3 ml). The mixture was stirred at 110° C. for 16 h. The mixture was cooled to room temperature, diluted in EtOAc and washed with sat. aq. NaHCO3 (2×) and brine. The org. layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, heptanes/EtOAc 100:0 to 60:40) to give the title compound as a white solid. (UPLC-MS 3) tR 1.20 min; ESI-MS 372.1 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:25]1[CH:29]=[C:28]([CH:30]=[O:31])[CH:27]=[N:26]1>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:25]3[CH:29]=[C:28]([CH:30]=[O:31])[CH:27]=[N:26]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1cn[nH]c1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C=O)cn3)ccc2n1CC1CCOCC1
Yield: 29.6 %

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (3.26 g, 8.8 mmol), 1H-pyrazole-4-carbaldehyde (1.01 g, 10.5 mmol) and DMAP (2.15 g, 17.6 mmol) in MeCN (70 mL). The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 1.12 g (30%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.39-1.56 (m, 4 H), 1.58 (s, 9 H), 2.21-2.36 (m, 1 H), 3.29-3.33 (m, 2 H), 3.88 (m, 2 H), 4.40 (d, J=7.42 Hz, 2 H), 5.41 (s, 1 H), 7.69 (s, 1 H), 7.84-7.90 (m, 1 H), 7.92-7.97 (m, 1 H), 8.25 (t, J=0.68 Hz, 1 H), 8.29 (d, J=1.76 Hz, 1 H); MS (ESI) (M+H)+=430.7; Anal. Calcd for C21H26N4O4S+0.80 TFA+0.30 CH3CN+0.20H2O (537.67): C, 51.83; H, 5.27; N, 11.20. Found: C, 51.79; H, 5.20; N, 11.16.
Reaction SMILES: [ClH:1].[N:2]1(C2C=CC(CC3CCNCC3)=CC=2)[CH:6]=N[N:4]=[N:3]1.[N+:20]([C:23]1[CH:41]=[CH:40][CH:39]=[CH:38][C:24]=1[CH2:25][CH:26]1[CH2:31][CH2:30][N:29](C(=O)C(F)(F)F)[CH2:28][CH2:27]1)([O-])=O>>[ClH:1].[N:20]1([C:23]2[CH:41]=[CH:40][CH:39]=[CH:38][C:24]=2[CH2:25][CH:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]2)[CH:6]=[N:2][N:3]=[N:4]1
Reactant: c1cc(-n2cnnn2)ccc1CC1CCNCC1
Reactant: O=C(N1CCC(Cc2ccccc2[N+](=O)[O-])CC1)C(F)(F)F
Agent: Cl
Product: c1ccc(-n2cnnn2)c(CC2CCNCC2)c1

Procedure:
By a similar manner to the production of 4-[4-(1H-tetrazol-1-yl)benzyl]piperidine hydrochloride (Reference Example 95), the titled compound was synthesized by using 4-(2-nitrobenzyl)-1-(trifluoroacetyl)piperidine as a starting compound.
Reaction SMILES: [C:1]1([C:7]([OH:12])([CH3:11])[C:8](=[O:10])[CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C[O:14][C:15](=[O:23])[C:16](OC)(OC)OC.[H-].[Na+]>C1COCC1>[C:1]1([C:7]2([CH3:11])[O:12][C:16]([C:15]([OH:23])=[O:14])=[CH:9][C:8]2=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: COC(=O)C(OC)(OC)OC
Reactant: CC(=O)C(C)(O)C1=CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C2=CCCCC2)OC(C(=O)O)=CC1=O
Temperature: 65 °C

Procedure:
To an oven-dried 10 mL vial was added 3-cyclohex-1-enyl-3-hydroxy-butan-2-one (0.80 g, 4.80 mmol), THF (4 mL) and trimethoxy-acetic acid methyl ester (0.94 g, 5.76 mmol). The vial was capped with a septum and flushed with Ar. In a dried round-bottom flask with stirring bar was added sodium hydride (60% dispersion in mineral oil, 0.57 g, 14.4 mmol) and THF (20 mL). The flask was capped with a septum and flushed with Ar. The contents of the vial were added dropwise via syringe to the round-bottom flask. The round-bottom flask was equipped with a condenser and septum and heated to 65° C. under Ar for 12 h. The reaction was quenched with sat'd NH4Cl (20 mL) and the layers were separated. The organic extract was concentrated and dissolved in 1,4-dioxane (4 mL). The solution was mixed with conc. HCl (0.5 mL) and stirred overnight at rt. Saturated NaHCO3 solution (20 mL) was added and the reaction was extracted with EtOAc (3×50 mL). The extracts were dried (Na2SO4), filtered and concentrated. The crude product was purified with a Biotage 25+M silica gel column using a gradient of 0-10% EtOAc in hexanes providing 0.37 g (32%) of racemic 5-cyclohex-1-enyl-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid methyl ester: LC-MS) m/z 235 (M−1); 1H NMR (400 MHz, CDCl3) 6.20 (s, 1H), 5.90-5.88 (m, 1H), 3.96 (s, 3H), 2.14-2.04 (m, 3H), 1.87-1.78 (m, 1H), 1.63-1.52 (m, 4H), 1.54 (s, 3H).
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:6]([CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)COc1ccc(-c2ccc(C#N)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(-c2ccc(OCC(=O)O)cc2)cc1
Reaction time: 3 h

Procedure:
32.9 g of 4-(tert.butyloxycarbonylmethyloxy)-4'-cyano-biphenyl dissolved in 250 ml of methylene chloride is mixed slowly with 137 ml of trifluoroacetic acid. After stirring for 3 hours, the reaction mixture is evaporated to dryness and the solid residue is triturated with water.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][CH:14]=2)=[CH:6][CH:5]=1.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([NH:15][S:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:25])=[O:24])[S:13][CH:14]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(-c2csc(N)n2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2csc(NS(=O)(=O)c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-(2-amino-thiazol-4-yl)-benzoic acid methyl ester (1.17 g, 5 mmol), benzenesulfonyl chloride (1.06 g, 6 mmol) and 4-dimethylaminopyridine (2.20 g, 18 mmol) in CH2Cl2 (50 mL) was stirred at room temp for 18 h. A white solid was provided as 4-(2-benzenesulfonylamino-thiazol-4-yl)-benzoic acid methyl ester.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][CH:14]=2)[N:4]=[C:3]1[C:24]([O:26][CH2:27][CH3:28])=[O:25].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>C1(C)C=CC=CC=1>[N:19]1([C:16]2[CH:15]=[CH:14][C:13]([CH2:12][N:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:2](=[S:38])[C:3]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:4]3)=[CH:18][CH:17]=2)[CH:23]=[CH:22][CH:21]=[N:20]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)c1nn(Cc2ccc(-n3cccn3)cc2)c2ccccc2c1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nn(Cc2ccc(-n3cccn3)cc2)c2ccccc2c1=S
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 4-oxo-1-[4-(1H-pyrazol-1-yl)benzyl]-1,4-dihydrocinnoline-3-carboxylate (750 mg, 2.00 mmol) was dissolved in toluene (9 mL), sparged under nitrogen and treated with Lawesson's Reagent (486 mg, 1.20 mmol, 0.6 equiv). The mixture was placed into an oil bath preheated to 105° C. for 1 hour, cooled to ambient temperature and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 60:40; hexanes:ethyl acetate) to provide the titled compound as a dark green solid.