Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.[F:19][C:20]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:21]=1[NH2:22].[N:28]1([C:34]2[N:35]=[C:36]([CH2:41][C:42]([O-])=[O:43])[NH:37][C:38](=[O:40])[CH:39]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[Na+]>CN(C)C=O>[F:19][C:20]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:21]=1[NH:22][C:42](=[O:43])[CH2:41][C:36]1[NH:37][C:38](=[O:40])[CH:39]=[C:34]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[N:35]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1ccc(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.8 %

Procedure:
2.5 ml of pyridine, 233 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 400 mg of 2,4-difluoroaniline are added to a solution of 260 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of Example 1 in 2 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 16 hours, and then concentrated under reduced pressure. Water and ethyl acetate are added and the resulting mixture is thus stirred for 30 minutes. The precipitate formed is filtered off, and rinsed with water, ethyl ether and petroleum ether. The solid obtained is dried under vacuum. 205 mg of N-(2,4-difluorophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a pinkish solid, the characteristics of which are the following:
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([C:29]2[CH2:34][CH2:33][C:32]([CH3:40])([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31][CH:30]=2)[C:9]=1/[CH:41]=[CH:42]\OCC.C(O)(C(F)(F)F)=O.O>>[CH3:40][C:32]1([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:33][CH2:34][C:29]([C:10]2[C:9]3[CH:41]=[CH:42][NH:7][C:8]=3[N:13]3[N:14]=[CH:15][C:16]([C:17]4[CH:18]=[N:19][C:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[CH:21][CH:22]=4)=[C:12]3[N:11]=2)=[CH:30][CH2:31]1
Reactant: CCO/C=C\c1c(C2=CCC(C)(C(=O)OCC)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(C)CC=C(c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c3[nH]ccc23)CC1

Procedure:
(Z)-Ethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(2-ethoxyvinyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-methylcyclohex-3-enecarboxylate (crude Int-18h) was treated with a mixture of 50% TFA/H2O at rt overnight. The reaction mixture was evaporated to dryness and purified by Prep-LC to give ethyl 1-methyl-4-(3-(6-phenylpyridin-3-yl)-8H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidin-5-yl)cyclohex-3-enecarboxylate (Int-18i). HPLC-MS tR=1.86 min (UV254nm); mass calculated for formula C29H27N5O2 477.2, observed LCMS m/z 478.3 (M+H).
Reaction SMILES: [CH2:1]([O:9][N:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][C:13](=[O:18])[CH2:12][C:11]1([CH3:20])[CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:21][CH2:22][C:23]([CH2:27]O)([CH2:25][OH:26])[CH3:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[OH:21][CH2:22][C:23]1([CH3:27])[CH2:25][O:26][C:13]2([CH2:14][C:15]([CH3:17])([CH3:16])[N:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:11]([CH3:19])([CH3:20])[CH2:12]2)[O:18][CH2:24]1
Reactant: CC(CO)(CO)CO
Reactant: CCCCCCCCON1C(C)(C)CC(=O)CC1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCON1C(C)(C)CC2(CC1(C)C)OCC(C)(CO)CO2
Yield: 14.1 %

Procedure:
A mixture of 11.0 grams (38.5 mmol) of 1-octyloxy-2,2,6,6-tetramethylpiperidin-4-one, 10.2 grams (84.9 mmol) of 1,1,1-tris(hydroxymethyl)ethane, 1.4 grams of p-toluenesulfonic acid and 100 ml of toluene is heated at reflux for four hours. Water is collected in a Dean-Stark trap. Purification of the reaction mixture by flash chromatography on silica gel affords 2.1 grams (14% yield) of the title compound as a colorless syrup.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14](OC)[N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:22])=O>CN(C)C=O>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:22])[N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)[C@H]1CC[C@H](c2cccc(OC)n2)CC1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1CC[C@H](c2cccc(Cl)n2)CC1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of trans-4-(6-methoxy-pyridin-2-yl)-cyclohexanecarboxylic acid ethyl ester (0.55 g, 2.1 mmol) in N,N-dimethylformamide (21 ml) was added phosphorus oxychloride (0.96 ml, 10 mmol) at room temperature. Stirring for 2 h at 90° C. was followed by stirring for 24 h at 120° C. After cooling to room temperature the reaction mixture was poured onto crushed ice, stirred for 10 minutes and extracted with three 100-ml portions of ethyl acetate. The combined organic layers were washed with two 50-ml portions of water and one 50-ml portion of brine, dried over anhydrous sodium sulfate and concentrated to dryness. Purification by flash-chromatography gave the title compound (0.20 g, 36%) as light yellow oil. MS m/e: 268 ([M+H]+)
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:16]1([CH3:26])[C:17]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1.[Na+].[Cl-]>O.C1(C)C=CC=CC=1>[C:16]1([CH3:26])[C:17]([S:22]([O:13][C@H:10]2[CH2:11][CH2:12][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9]2)(=[O:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O[C@H]1CCN(Cc2ccccc2)C1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccccc1S(=O)(=O)O[C@H]1CCN(Cc2ccccc2)C1

Procedure:
(S)-1-Benzyl-3-pyrrolidinol (44.32 g), 132.88 g of toluene and 166.95 g of a 30% aqueous solution of NaOH were respectively weighed and placed in a 500-mL four-necked flask. While the mixture was stirred, the flask inside temperature was lowered to 6.0° C. Then, 104.94 g of toluenesulfonyl chloride was added in divided portions at an interval of about 5 g/10 minutes over 3 hours and 10 minutes at a flask inside temperature of 5 to 10° C. Water (37 mL) was added to dissolve the NaCl which had precipitated out in the aqueous phase, and the mixture was separated into the toluene phase and aqueous phase. A toluene solution of (S)-1-benzyl-3-pyrrolidinol toluenesulfonate was thus obtained in a yield of 85.5 mole percent.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:26])[C:3]=1[OH:27].C[O:29][C:30](=[O:45])[C@@H:31](O)[CH2:32][CH2:33][N:34]1[CH2:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]1=[O:43].BrBr>>[Br:26][C:4]1[CH:5]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=[C:2]([Br:1])[C:3]=1[O:27][C@H:31]([CH2:32][CH2:33][N:34]1[CH2:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]1=[O:43])[C:30]([OH:45])=[O:29]
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Reactant: COC(=O)[C@@H](O)CCN1Cc2ccccc2C1=O
Agent: BrBr
Product: O=C(O)[C@@H](CCN1Cc2ccccc2C1=O)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br

Procedure:
Prepared from of 2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-1 1-yl)-phenol (Example 21) and (S)-(+)-α-hydroxy-1-oxo-2-isoindolinebutyric acid methyl ester (Example 106). White solid: mp 239-241° C.: NMR (CDCl3); δ8.34 (d, J =8 Hz, 1 H), 7.90 (d, J=8 Hz, 1 H), 7.80 (d, J=8 Hz, 1 H), 7.66 (ddd, J=8, 7, 1 Hz, 1 H), 7.62-7.58 (m, 4 H), 7.52-7.47 (m, 3 H), 7.39 (ddd, J=8, 7, 1 Hz, 1 H), 7.14 (ddd, J =8, 7, 1 Hz, 1 H), 6.72 (d, J=8, Hz, 1 H), 5.39 (t, J=7 Hz, 1 H), 4.59 (m, 2 H), 4.22-3.93 (m, 2 H), 2.65 (t, J=6 Hz, 2 H); MS (+FAB): [M+H]+, 3 bromine isotope pattern, 778, 780, 782, 784); Anal. Calc. for C34H22Br3NO4S: C, 52.33, H, 2.84, N, 1.79. Found: C, 52.11, H, 2.73, N, 1.79.
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1[Cl:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[N:15]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C(O)C>[Cl:12][C:11]1[C:10](=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:14])[C:2]=1[N:18]1[CH2:17][CH2:16][N:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19]1
Reactant: CCOC(=O)N1CCNCC1
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Solvent: CCO
Product: CCOC(=O)N1CCN(C2=C(Cl)C(=O)c3ccccc3C2=O)CC1
Yield: 45.9 %

Procedure:
A mixture of 11.35 g of 2,3-dichloro-1,4-naphthoquinone, 15.8 g of 1-piperazinecarboxylic acid, ethyl ester and 400 ml of absolute ethanol was heated at reflux for 3 hours and then evaporated to dryness. The residue was taken up in 300 ml of dichloromethane and filtered through silica gel. The filtrate was evaporated and the residue triturated with ether, giving 8.0 g of the desired product as red crystals, mp 120°-122° C.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH3:10]O>>[CH3:10][O:8][C:7]([C:5]1[O:6][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:9]
Reactant: CO
Reactant: O=C(O)c1ccc(Br)o1
Product: COC(=O)c1ccc(Br)o1

Procedure:
5-Bromo-furan-2-carboxylic acid (2 g, 10.5 mmol) was esterified with MeOH using Method B to give the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[O:16][N:15]=2)=[O:13])[CH2:3]1.[CH3:23][C:24]1[S:25][C:26]([C:32]2[CH:33]=[C:34]([CH3:38])[CH:35]=[CH:36][CH:37]=2)=[C:27]([C:29](O)=[O:30])[N:28]=1>>[CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][N:6]([C:29]([C:27]3[N:28]=[C:24]([CH3:23])[S:25][C:26]=3[C:32]3[CH:33]=[C:34]([CH3:38])[CH:35]=[CH:36][CH:37]=3)=[O:30])[C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[O:16][N:15]=2)=[O:13])[CH2:3]1
Reactant: CC1C[C@H]2CN[C@H](CNC(=O)c3noc4ccccc34)[C@H]2C1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2noc3ccccc23)c1

Procedure:
prepared by reaction of benzo[d]isoxazole-3-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[O:20])[N:10]([CH2:21][CH2:22][CH2:23]Cl)[N:9]=1.[N-:34]=[N+]=[N-].[Na+]>CN(C=O)C.O>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[O:20])[N:10]([CH2:21][CH2:22][CH2:23][NH2:34])[N:9]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=c1n(CCCCl)nc(CCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1Cc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NCCCn1nc(CCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n(Cc2ccccc2)c1=O
Temperature: 80 °C

Procedure:
3-(3,5-Bis(trifluoromethyl)phenethyl)-4-benzyl-1-(3-chloropropyl)-5-oxo-1,2,4-triazole (Description 2, 2.5 g, 0.005 mol) was dissolved in DMF (30 ml) and sodium azide (0.495 g, 0.0076 mol) added and the reaction heated to 80° C. for 16 hours. The reaction was cooled, diluted with water (50 ml) and extracted into ethyl acetate (75 ml). The organic layer was washed with water (3×25 ml), brine and dried (MgSO4). The solvent was removed and the resulting azide (colourless off) was dissolved in ethanol (30 ml) and hydrogenated over palladium hydroxide (0.300 g) at 50 psi for 4 hours. The catalyst was filtered and the solvent removed in vacuo to furnish the title compound as a colourless oil. (2.4 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]([F:20])([F:19])[F:18])[CH2:13][CH2:12]2)=[CH:4][C:5]([NH:9][CH3:10])=[C:6]([CH:8]=1)[NH2:7].[N:21]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[C:32]([F:35])([F:34])[F:33])[C:27]#[N:28])=[C:22]=S.CC(C)N=C=NC(C)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]([F:19])([F:18])[F:20])[CH2:13][CH2:12]2)=[CH:4][C:5]2[N:9]([CH3:10])[C:22]([NH:21][C:24]3[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=3[C:32]([F:35])([F:34])[F:33])[C:27]#[N:28])=[N:7][C:6]=2[CH:8]=1
Reactant: CNc1cc(N2CCC(C(F)(F)F)CC2)c(Cl)cc1N
Reactant: N#Cc1ccc(C(F)(F)F)c(N=C=S)c1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2cc(C#N)ccc2C(F)(F)F)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21

Procedure:
The sub-title compound was prepared in analogy to Example 76 using 5-chloro-2-methylamino-4-(4-trifluoromethyl-piperidin-1-yl)aniline (998 mg, 3.24 mmol), 3-isothiocyanato-4-(trifluoromethyl)benzonitrile (740 mg, 3.24 mmol), DIC (409 mg, 3.24 mmol) and DMF (7 mL).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[Cl:10][C:11]1[C:16]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:22][CH:21]=2)=[O:18])=[C:15]([F:32])[C:14]([OH:33])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:10][C:11]1[C:16]([C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:24][CH:25]=2)=[O:18])=[C:15]([F:32])[C:14]([O:33][CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=2)=[CH:13][CH:12]=1
Reactant: Clc1cccc(CBr)c1
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2c(Cl)ccc(O)c2F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(NC(=O)c2c(Cl)ccc(OCc3cccc(Cl)c3)c2F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.8 %

Procedure:
3-Chlorobenzylbromide (28 μl, 0.24 mmol) was added to a suspension of ethyl (4-{[(6-chloro-2-fluoro-3-hydroxyphenyl)carbonyl]amino}phenyl)acetate (80 mg, 0.228 mmol) and potassium carbonate (38 mg, 0.273 mmol) in dimethylformamide (3 ml) and the reaction was stirred at room temperature for 4 hrs. The solvent was evaporated and the residue partitioned between water and ethyl acetate. The organic layer was separated, dried (Na2SO4) and the solvent evaporated to afford the title compound as a colourless oil (91 mg, 84%).
Reaction SMILES: [C:1]([C:9]12OC1[O:13][C:12]([C:16]([O:18]CC)=[O:17])=[CH:11][C:10]2=[O:21])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:22]>O1CCOCC1>[Cl:22][C:9]1[C:10](=[O:21])[CH:11]=[C:12]([C:16]([OH:18])=[O:17])[O:13][C:1]=1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1=CC(=O)C2(C(=O)c3ccccc3)OC2O1
Reactant: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cc(=O)c(Cl)c(-c2ccccc2)o1

Procedure:
A solution of ethyl 6-benzoyl-5-oxo-2,7-dioxabicyclo[4.1.0]-hept-3-ene-3-carboxylate (2.9 g) prepared as in Example 44, in dioxan (30 ml) and concentrated hydrochloric acid (10 mol) was heated under reflux for 2 hours. The solution was evaporated under vacuum and the solid residue was crystallised from ethyl acetate-petroleum ether 60°-80° C. and then from dioxan-water to give the title product (mp 216°-218° C. with decomposition).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:12]=2[O:13][CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.Cl.[CH:32](I)([CH3:34])[CH3:33]>CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>[CH:32]([N:10]([S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:8])=[O:9])[C:11]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:12]=1[O:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)([CH3:34])[CH3:33]
Reactant: COC(=O)c1ccc(COc2ccc(Cl)cc2NS(=O)(=O)c2ccccc2)cc1
Reactant: CC(C)I
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(COc2ccc(Cl)cc2N(C(C)C)S(=O)(=O)c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 9 h

Procedure:
To a solution of methyl 4-(2-phenylsulfonylamino-4-chlorophenoxy-methyl)benzoate (402 mg; prepared in Example 7(a)) in DMF (4 ml), potassium carbonate 256 (mg) and isopropyl iodide (185 μl) were added. The mixture was stirred overnight at room temperature and for 9 hours at 50° C. To the reaction solution, iced water and 2N HCl were added. The mixture was extracted with ethyl acetate. The organic layer was washed, dried over, concentrated after filtration, solidified with ethanol and washed to give the title compound (411 mg) having the following physical data.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:17]([CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:21][CH2:20]1)=[O:18]>C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:17]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH2:21][CH2:20]2)=[O:18])=[CH:3][CH:4]=1
Reactant: CON(C)C(=O)C1CCN(c2ccccn2)CC1
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)cc1)C1CCN(c2ccccn2)CC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 71.1 %

Procedure:
A solution of 1,4-dibromobenzene (0.223 g, 0.944 mmol) in anhydrous THF (3.0 ml) was cooled to −78° C. To the cooled solution, n-butyllithium (1.6 M in hexanes, 0.47 ml, 0.746 mmol) was added dropwise, and the reaction stirred at −78° C. for 45 minutes. A solution of the 3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid methoxy-methyl-amide (0.124 g, 0.497 mmol) in anhydrous THF (3.0 ml) was then added dropwise to the reaction. The reaction stirred at −78° C. for 3 hours and at 0° C. until complete. The reaction was quenched at 0° C. by the addition of 1 N HCl (5 ml) and saturated NaHCO3 (7.5 ml). The mixture was extracted with ethyl acetate, washed with brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel chromatography using 3-10% acetone in hexanes, yielding the product (0.1220 g, 71%) as a colorless oi: 1H NMR (400 MHz, CDCl3) δ 8.16 (dd, J=4.9, 1.2 Hz, 1H), 7.81 (m, 2H), 7.61 (m, 2H), 7.46 (m, 1H), 6.67 (d, J=8.7 Hz, 1H), 6.59 (dd, J=6.7, 5.1 Hz, 1H). 4.33 (dt, J=13.1, 3.1 Hz, 2H), 3.42 (m, 1H), 3.14 (m, 2H), 1.93 (d, J=13.2, 2.2 Hz, 2H), 1.82 (m, 2H); 13C NMR (100 MHz, CDCl3) 201.20, 159.20, 147.87, 137.53, 134.57, 132.28, 129.80, 128.20, 113.09, 107.34, 45.01, 43.76, 28.01; m/z calcd. for C17H17BrN2O: 344.05 found: (M+H)+347.1; HPLC retention time=3.205 min (wavelength 254 nm), purity=100%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[C:3]=1[CH3:27].[O:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[C:36]3[NH:42][CH2:41][C:40]4([CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[C:37]3=[N:38][CH:39]=2)[CH2:30][CH2:29]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([N:42]1[C:36]3[C:37](=[N:38][CH:39]=[C:34]([N:31]4[CH2:32][CH2:33][O:28][CH2:29][CH2:30]4)[CH:35]=3)[C:40]3([CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)[CH2:41]1)=[C:3]([CH3:27])[C:4]([N:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:18][CH2:19]1)=[N:5]2
Reactant: Cc1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cc(F)cc(F)c2c1Cl
Reactant: c1nc2c(cc1N1CCOCC1)NCC21CCOCC1
Solvent: Cc1ccccc1
Product: Cc1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cc(F)cc(F)c2c1N1CC2(CCOCC2)c2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y using tert-butyl 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)piperazine-1-carboxylate (690.0 mg, 1.70 mmol) and 6′-morpholino-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] in toluene to give tert-butyl 4-(5,7-difluoro-3-methyl-4-(6′-(4-morpholinyl)-2,3,5,6-tetrahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridin]-1′(2′H)-yl)-2-quinolinyl)-1-piperazinecarboxylate. 1H NMR (400 MHz, chloroform-d) δ ppm 7.56 (1H, d, J=2.3 Hz), 7.35 (1H, ddd, J=9.8, 2.4, 1.1 Hz), 6.75 (1H, ddd, J=11.8, 8.9, 2.5 Hz), 5.66 (1H, d, J=2.3 Hz), 4.05-4.22 (2H, m), 3.80-3.98 (2H, m), 3.71-3.79 (4H, m), 3.48-3.71 (6H, m), 3.24-3.44 (4H, m), 2.89-3.06 (4H, m), 2.26-2.43 (2H, m), 2.25 (3H, s), 1.64-1.87 (3H, m), 1.51 (9H, s). Mass Spectrum (ESI) m/e=637.5 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][N:5]2[CH3:13].[N+:14]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)([O-:16])=[O:15]>>[N+:14]([C:17]1[CH:22]=[C:21]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH2:6][N:5]3[CH3:13])[CH:20]=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: CN1CC(=O)Nc2ccc(Br)cc21
Product: CN1CC(=O)Nc2ccc(-c3cccc([N+](=O)[O-])c3)cc21

Procedure:
Prepared according to the procedure for Example 5 from 6-bromo-4-methyl-3,4-dihydro-1H-quinoxalin-2-one (4.8 g, 20 mmol), and 3-nitrophenylboronic acid (4.8 g, 30 mmol). A red powder (0.95 g, 16%): mp 237-243° C. 1H-NMR (DMSO-d6) δ 2.88 (s, 3H), 6.9 (d, J=7.9 Hz, 1H), 7.01 (d, J=2 Hz, 1H), 7.11 (dd, J=7.9, 2.0 Hz, 1H), 7.7 (t, J=7.9 Hz, 1H), 8.1 (m, 2H), 8.37 (t, J=0.7 Hz), MS (ESI) m/z 283 (M)+.
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].[Cl:19][C:20]([C:22]([F:25])([F:24])[F:23])=[CH2:21].Cl>[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[Cl:19][CH:20]([C:22]([F:25])([F:24])[F:23])[CH2:21][C:4]([CH2:3][C:2]([F:18])([F:1])[C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])([C:7]#[N:8])[C:5]#[N:6]
Reactant: C=C(Cl)C(F)(F)F
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: N#CC(C#N)(CC(Cl)C(F)(F)F)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile was dissolved in 10 ml of a solution (1 mol/L) of tetrabutylammonium fluoride in tetrahydrofuran and thereto 5 ml of 2-chloro-3,3,3-trifluoropropene was added at 0° C. The mixture was then stirred at room temperature for 3 days. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.03 g of 2-(2-chloro-3,3,3-trifluoropropyl)-2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile (hereinafter, referred to as the present compound (69)).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[CH:11][C:10]=1[O:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[B:23](OOC(C)C)([O:29]OC(C)C)[O:24]OC(C)C.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH2:1]([O:8][CH:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1([O:16][CH3:17])[B:23]([OH:29])[OH:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OOB(OOC(C)C)OOC(C)C
Reactant: COc1ccc(Br)cc1OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC1(B(O)O)C=CC=CC1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
4.86 g of 2-Benzyloxy-4-bromo-1-methoxybenzene was dissolved in 100 ml of anhydrous tetrahydrofuran and cooled to −78° C. in a nitrogen atmosphere. 15 ml of 1.6 M n-butyl lithium in hexane was added dropwise, and the mixture was stirred for 30 minutes. 6 ml of Triisopropoxy borate was added all at once, and the mixture was allowed to warm overnight at room temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated. The residue was dissolved in 1N aqueous sodium hydroxide and extracted with diethyl ether. The aqueous layer was neutralized with 5N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated to give 1.76 of the title compound.