Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:11]2[N:12]=[C:13]([NH2:15])[S:14][C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[S:25]([N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:38](O)=[O:39])[CH:36]=2)[CH2:31][CH2:30][CH2:29]1)(=[O:27])=[O:26]>>[CH2:1]([O:3][C:4]([CH:6]1[C:11]2[N:12]=[C:13]([NH:15][C:38]([C:35]3[CH:36]=[C:37]4[C:32]([CH2:31][CH2:30][CH2:29][N:28]4[S:25]([C:19]4[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=4[O:17][CH3:16])(=[O:27])=[O:26])=[CH:33][CH:34]=3)=[O:39])[S:14][C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCc2sc(N)nc21
Reactant: COc1ccc(C)cc1S(=O)(=O)N1CCCc2ccc(C(=O)O)cc21
Product: CCOC(=O)C1CCCc2sc(NC(=O)c3ccc4c(c3)N(S(=O)(=O)c3cc(C)ccc3OC)CCC4)nc21

Procedure:
1-(2-Methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid was converted to the title compound in analogy to example 8, steps 3 and 4. Step 3 was performed using 2-amino-4,5,6,7-tetrahydro-benzothiazole-4-carboxylic acid ethyl ester and 1-(2-methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid and yielded 2-{[1-(2-methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-4,5,6,7-tetrahydro-benzothiazole-4-carboxylic acid ethyl ester, which was hydrolyzed to 2-{[1-(2-methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-4,5,6,7-tetrahydro-benzothiazole-4-carboxylic acid in step 4, MS (ISP): m/e=540.3 (M−H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH3:19])[N:11]=[C:10](S(C)(=O)=O)[N:9]=2)[CH:4]=[N:3]1.[NH2:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]1[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35].CCN(CC)CC>CC(N(C)C)=O>[C:34]([O:33][C:32]([NH:31][C@H:26]1[CH2:27][CH2:28][CH2:29][CH2:30][C@H:25]1[NH:24][C:10]1[N:9]=[C:8]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]=2[CH3:7])[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH3:19])[N:11]=1)=[O:38])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: CCOC(=O)c1c(C)nc(S(C)(=O)=O)nc1-c1cnn(C)c1C
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C)nc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1-c1cnn(C)c1C

Procedure:
A solution of ethyl 4-(1,5-dimethyl-1H-pyrazol-4-yl)-6-methyl-2-(methylsulfonyl)pyrimidine-5-carboxylate (0.07 g, 0.207 mmol), tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (0.089 g, 0.414 mmol) and Et3N (0.115 mL, 0.827 mmol) in DMA (3 mL) was heated in a sealed tube at 90° C. for 8 h. The reaction mixture was poured slowly onto ice to yield a pale yellow precipitate, which was isolated by vacuum filtration, washed with water, and dried under vacuum to give the title compound. [M+H] calc'd for C24H36N6O4, 473; found, 473.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9](=[O:17])[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O>C(Cl)Cl.C1COCC1>[C:9]([C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH:12][C:7](=[O:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:17])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1oc(-c2ccccc2)nc2ccccc12
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccccc1C(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To a solution of 2-phenyl-benzo[d][1,3]oxazin-4-one (5 mmol) in dry CH2Cl2 (20 mL) was added 1N solution of aryl magnesium bromide in THF (5 mL) at 0° C. The mixture was stirred at room temperature for 2 h and poured into water (30 mL). The aqueous layer was extracted with ethyl acetate (3×30 mL) and was washed with water (3×50 mL), brine (1×50 mL), dried (anhydrous Na2SO4) and concentrated in vacuo to afford N-(2-benzoyl-phenyl)-benzamide in 60-70% yield.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11])=O.[CH2:21]([NH2:24])[CH2:22][CH3:23].C([O-])(O)=O.[Na+]>ClCCCl>[N+:18]([C:17]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])=[CH:4][C:3]=1[CH2:1][NH:24][CH2:21][CH2:22][CH3:23])([O-:20])=[O:19]
Reactant: CCCN
Reactant: N#Cc1cccc(Oc2ccc([N+](=O)[O-])c(C=O)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCNCc1cc(Oc2cccc(C#N)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Under N2, a mixture of 3-(3-formyl-4-nitrophenoxy)-benzonitrile (0.056 mol) and propylamine (0.059 mol) in DCE (450 mL) was stirred at room temperature, and then NaBH(OAC)3 (0.063 mol) was added, and the reaction mixture was stirred overnight at room temperature. A saturated NaHCO3 solution was added, and the layers were separated. The organic layer was dried, filtered off and the solvent was evaporated. The residue was purified over silica gel filter (eluent: 99:1 CH2Cl2:CH3OH). The purest product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [CH2:1](C1C(=O)C2C=CSC=2CC1)CC.[C:14]1(=[O:24])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1.C(I)C>>[CH2:15]([CH:16]1[CH2:17][C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]1=[O:24])[CH3:1]
Reactant: O=C1CCCc2ccccc21
Reactant: CCCC1CCc2sccc2C1=O
Solvent: CCI
Product: CCC1Cc2ccccc2C1=O

Procedure:
Following the procedure for the preparation of 5-propyl-6,7-dihydro-1-benzothiophen-4(5H)-one but substituting 1-tetralone and ethyl iodide, and making non-critical variations provided the title compound as a colorless mobile oil. IR (liq.) 2963, 2933, 2875, 2860, 1712, 1610, 1588, 1475, 1464, 1327, 1296, 1278, 1205, 749, 718 cm−1; MS (EI) m/z 160 (M+); Anal. Calcd for C11H12O: C, 82.46; H, 7.55. Found: C, 82.16; H, 7.57.
Reaction SMILES: [C:1]([CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])=[CH:21][CH:20]=2)=[CH:12][CH:11]=1)[C:4](OCC)=[O:5])#[N:2].[BH4-].[Na+]>CO>[C:1]([CH:3]([CH2:4][OH:5])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])=[CH:21][CH:20]=2)=[CH:12][CH:11]=1)#[N:2]
Reactant: CCOC(=O)C(C#N)Cc1ccc(OCCc2ccc(NC(=O)C(C)C)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)C(=O)Nc1ccc(CCOc2ccc(CC(C#N)CO)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.8 %

Procedure:
Ethyl 2-cyano-3-(4-{2-[4-(isobutyrylamino)phenyl]ethoxy}phenyl)propanoate (0.5 g, 1.22 mmol) was dissolved in methanol (10 ml). Sodium borohydride (0.24 g, 6.34 mmol) was added carefully. The mixture was stirred at room temperature for 4 hours and then evaporated in vacuum to dry. Ethyl acetate and water were added into the residue. After separation, the organic phase was washed with 0.3 M hydrochloric acid, water and brine. The solvent was evaporated in vacuum. Column chromatography of the residue on silica gel using ethyl acetate/heptane as eluant gave 0.33 g desired product, yield 74%.
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[C:5]1[C:6]([I:14])=[C:7]([CH:11]=[CH:12][N:13]=1)[C:8]([OH:10])=[O:9].Cl>CO>[I:14][C:6]1[C:5]([O:2][CH3:1])=[N:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1ccnc(Br)c1I
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1nccc(C(=O)O)c1I
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a 28% methanol solution (5 g) of sodium methoxide was added 2-bromo-3-iodoisonicotinic acid (880 mg), and the mixture was stirred at 80° C. for 2 hr. To the reaction mixture was added 1N hydrochloric acid under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (780 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[C:27]3[C:22](=[C:23]([CH2:28][S:29][CH3:30])[CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH:9]2C(=O)O[C:12](C)([CH3:16])[O:11][C:10]2=[O:18])=[CH:4][CH:3]=1>N1C=CC=CC=1.C(O)C.[Cu]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:19]2[C:27]3[C:22](=[C:23]([CH2:28][S:29][CH3:30])[CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:9][C:10]([O:11][CH2:12][CH3:16])=[O:18])=[CH:6][CH:7]=1
Reactant: CSCc1cccc2c(C(c3ccc(Cl)cc3)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Agent: [Cu]
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)CC(c1ccc(Cl)cc1)c1c[nH]c2c(CSC)cccc12

Procedure:
18 mg (0.28 mmol) of copper powder were added to 12.2 g (27.5 mmol) of the compound from Example 13A in 200 ml of pyridine and 55 ml of ethanol. The reaction mixture was heated under reflux for 4 h. It was concentrated, and the residue was taken up in dichloromethane, washed with water, 1N hydrochloric acid and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient). 6.68 g (56% of theory) of the target compound were obtained.
Reaction SMILES: [C:1]([O-])(=O)[CH3:2].[Na+].[CH3:6][N:7]1[C:12](=[O:13])[CH2:11][C:10](=[S:14])[N:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:8]1=[O:19]>O>[CH3:6][N:7]1[C:12](=[O:13])[C:11]2[CH:1]=[CH:2][S:14][C:10]=2[N:9]([CH2:15][CH:16]([CH3:17])[CH3:18])[C:8]1=[O:19]
Reactant: CC(=O)[O-]
Reactant: CC(C)CN1C(=O)N(C)C(=O)CC1=S
Agent: [Na+]
Solvent: O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2ccsc21
Reaction time: 5 h
Yield: 94.7 %

Procedure:
Sodium acetate (38.9 g) was added to a stirred suspension of 3-methyl-1-(2-methylpropyl)-6-thioxo-pyrimidine-2,4(1H,3H)-dione (25.42 g) in water (1 l). After 5 hours, the mixture was filtered. Aqueous chloroacetaldehyde solution (50 wt. %, 142 ml) was added to the filtrate and the mixture was stirred for 16 hours. The mixture was acidified with concentrated hydrochloric acid and extracted with ethyl acetate (3×500 ml). The combined organic extracts were washed with saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residual oil was purified by column chromatography over silica, eluting with isohexane:ether (1:1) to give the title compound (26.78 g) as a solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:16]1([C@@H:22]([CH2:24][OH:25])[NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(O)(C)C>[OH:25][CH2:24][C@@H:22]([NH:23][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N[C@H](CO)c1ccccc1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(N[C@H](CO)c3ccccc3)c2cc1OC
Yield: 70 %

Procedure:
A solution of 4-chloro-6,7-dimethoxyquinazoline (225 mg, 1 mmol), (S)-2-phenylglycinol (137.2 mg, 1 mmol) and triethylamine (304 mg, 3 mmol) in isopropanol (7 ml) was heated to reflux for about 8 h. Then the mixture was evaporated under vacuum to dryness and the residue purified by gradient elution chromatography on silica gel using as eluant dichloromethane/ethanol 2-6%. Thus pure title compound was obtained in 70% yield (228 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:13])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[OH:14][C@:15]1([C:22]2[CH:27]=[CH:26][CH:25]=[C:24](I)[CH:23]=2)[CH2:20][CH2:19][O:18][C@@H:17]([CH3:21])[CH2:16]1>>[Cl:1][C:2]1[CH:3]=[C:4]([S:13][C:26]2[CH:27]=[C:22]([C@@:15]3([OH:14])[CH2:20][CH2:19][O:18][C@@H:17]([CH3:21])[CH2:16]3)[CH:23]=[CH:24][CH:25]=2)[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2
Reactant: O=C1CCc2cc(S)cc(Cl)c2N1
Reactant: C[C@H]1C[C@@](O)(c2cccc(I)c2)CCO1
Product: C[C@H]1C[C@@](O)(c2cccc(Sc3cc(Cl)c4c(c3)CCC(=O)N4)c2)CCO1
Yield: 69 %

Procedure:
Using an analogous procedure to that described in Example 6, 8-chloro-6-mercapto-1,2,3,4-tetrahydroquinolin-2-one was reacted with (2S,4R)-4-hydroxy-4-(3-iodophenyl)-2-methyltetrahydropyran to give (2S,4R)-4-[3-(8-chloro-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)phenyl]-4-hydroxy-2-methyltetrahydropyran in 69% yield as a gum;
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:10]=2[CH:11]=[O:12])[CH2:3]1.C[C@H]1O[C@H](C)CN(C2C=CC(F)=CC=2C=O)C1>>[CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:10]=2[CH:11]=[O:12])[CH2:3]1
Reactant: C[C@@H]1CN(c2ccc(F)cc2C=O)C[C@H](C)O1
Agent: C[C@@H]1CN(c2ccc(F)cc2C=O)C[C@@H](C)O1
Product: CC1CN(c2ccc(F)cc2C=O)CC(C)O1

Procedure:
In a manner similar to that described in Example 1 (Step 1) cis-2-(2,6-dimethylmorpholin-4-yl)-5-fluorobenzaldehyde and trans-2-(2,6-dimethylmorpholin-4-yl)-5-fluorobenzaldehyde are obtained in 24% and 6% yields as a yellow solid and a yellow oil, respectively. Cis-isomer: 1H NMR (400 MHz, CDCl3) δ 10.37, 7.50, 7.31-7.24, 7.14, 7.12, 3.97-3.86, 3.00, 2.64, 1.24; and trans-isomer: 1H NMR (400 MHz, CDCl3) δ 10.45, 7.50, 7.14, 7.12, 4.27-4.17, 3.07, 2.76, 2.74, 1.35.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:14][C:15]1[CH:16]=[C:17]([N:21]=[C:22]=[O:23])[CH:18]=[CH:19][CH:20]=1>CN(C)C=O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:22](=[O:23])[NH:21][C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([Br:14])[CH:16]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1cccc(Br)c1
Reactant: Oc1ccc2ncccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Br)c1)Oc1ccc2ncccc2c1
Reaction time: 0.5 h

Procedure:
A solution of quinolin-6-ol (0.29 g., 2 mmol) in dry dimethylformamide (3 ml) was added to a stirred suspension of sodium hydride (0.048 g., 2 mmol) in dry dimethylformamide (2 ml) at −10° C. during 5 min. The reaction mixture was stirred for ½ hours. Then 3-bromo-phenyl isocyanate (0.475 g., 2.4 mmol) was added to the stirring reaction mixture. Stirring was continued for additional 1 hr. during which the temperature was allowed to rise to room temperature (21° C.). The reaction mixture was quenched with water (0.2 ml), diluted with water (2 ml), extracted with ethyl acetate (2×5 ml) and dried over sodium sulphate. The combined fractions of ethyl acetate were concentrated under vaccum. The residue was washed with methanol (2×2 ml) to give 1d; yield: 0.35 g. (51.01%), m.p. 260° C., C16H11BrN2O2; 1H NMR δ ppm (pyridine d5): 7.09-7.58 (m, 9H), 8.28 (bs, 2H), 9.58 (bs, 1H); IR vmax (KBr) (cm−1). 522, 645, 743, 782, 877, 928, 992, 1069, 1227, 1286, 1406, 1470, 1581, 1637, 1875, 1946, 2374, 3290, 3753, 3872, 3952.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18]3[CH:17]=[CH:16][C:15]4[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=4[C:13]=3[NH:12][C:11](=[O:23])[C:10]2=[O:24])=[CH:5][CH:4]=1.[N+:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35])([O-:27])=[O:26]>>[O:23]=[C:11]1[NH:12][C:13]2[C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[CH:16]=[CH:17][C:18]=2[N:9]([C:6]2[CH:7]=[CH:8][C:3]([NH:2][S:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[N+:25]([O-:27])=[O:26])(=[O:35])=[O:36])=[CH:4][CH:5]=2)[C:10]1=[O:24]
Reactant: Nc1ccc(-n2c(=O)c(=O)[nH]c3c4ccccc4ccc32)cc1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: Cl
Product: O=c1[nH]c2c3ccccc3ccc2n(-c2ccc(NS(=O)(=O)c3ccccc3[N+](=O)[O-])cc2)c1=O
Yield: 45.2 %

Procedure:
4-(4-Aminophenyl)-1,4-dihydrobenzo[f]quinoxaline-2,3-dione hydrochloride (80 mg, 0.24 mmol) and 2-nitrobenzenesulfonyl chloride (78 mg, 0.35 mmol) were used in a process similar to Example 9 to give the titled compound (53 mg, yield 46%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:28])([F:29])[F:30])=[CH:22][CH:21]=1
Reactant: O=C(CBr)c1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Product: CCOC(=O)n1c(C(=O)c2ccc(OC(F)(F)F)cc2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-bromo-4′-trifluoromethoxyacetophenone.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[C:15]([F:21])[CH:14]=2)[CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.B(Br)(Br)Br>>[F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:21])[CH:14]=2)[CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2
Reactant: COc1ccc(-c2cc(F)c3cc(O)ccc3c2)cc1F
Agent: BrB(Br)Br
Product: Oc1ccc2cc(-c3ccc(O)c(F)c3)cc(F)c2c1

Procedure:
The title compound was prepared by reacting 8-fluoro-6-(3-fluoro-4-methoxyphenyl)-2-naphthol (0.10 g, 0.35 mmol) with boron tribromide (0.7 mL of 1N solution, 0.7 mmol) according to method D to yield 0.020 g (21%) of a white solid: mp 218–220° C. d; 1H NMR (DMSO-d6): δ 7.01–7.07 (1H, m), 7.16–7.19 (2H, m), 7.46 (1H, dd, J=1.74 Hz, J=8.40 Hz), 7.56–7.65 (2H, m), 7.88 (1H, d, J=8.31 Hz), 7.93 (1H, bs), 10.04 (1H, s), 10.11 (1H, s); MS (ESI) m/z 271 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][C:42]([CH2:46][N:47]2[CH:51]=[CH:50][C:49]([NH2:52])=[N:48]2)([OH:45])[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:32]([O:36][C:37]([N:39]1[CH2:40][CH2:41][C:42]([CH2:46][N:47]2[CH:51]=[CH:50][C:49]([NH:52][C:28]([C@H:9]3[C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:31])[C@:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10]3)=[O:30])=[N:48]2)([OH:45])[CH2:43][CH2:44]1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(Cn2ccc(N)n2)CC1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccn(CC3(O)CCN(C(=O)OC(C)(C)C)CC3)n2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (500 mg, 1.0 mmol), 4-(3-amino-pyrazol-1-ylmethyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (592 mg, 2.0 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 593 mg, 1.5 mmol) and iPr2NEt (0.718 mL, 4 mmol) in CH2Cl2 (50 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, dried over Na2SO4 and filtered. The mixture was then concentrated and purified flash column chromatography (1-100% ethyl acetate/heptane) to afford rac-4-(3-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-pyrazol-1-ylmethyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester as a white powder (480 mg, 64.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10]C)=[O:9])=[C:4]([NH:14][C:15](OCC)=O)[CH:3]=1.Br.BrC[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:24]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6]([CH2:7][C:8]([OH:10])=[O:9])=[C:15]([C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[O:24])[NH:14]2)=[CH:12][CH:13]=1
Reactant: O=C(CBr)c1ccccn1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1/C=C/C(=O)OC
Agent: Br
Product: O=C(O)Cc1c(C(=O)c2ccccn2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound were prepared according the procedure described in step 2 of Example 31 from methyl trans-4-chloro-2-(ethoxycarbonylamino)cinnamate (Example 31, step 1) and 2-bromoacetylpyridine hydrobromide (H. McKennis et al., J. Org. Chem., 1963, 387.).
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([NH:9][S:10]([CH2:13][CH2:14][NH:15]C(=O)OC(C)(C)C)(=[O:12])=[O:11])=[CH:5][C:4]=1[NH:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[N:25]=1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[NH2:15][CH2:14][CH2:13][S:10]([NH:9][C:6]1[CH:7]=[N:8][C:3]([C:1]#[N:2])=[C:4]([NH:23][C:24]2[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[N:25]=2)[CH:5]=1)(=[O:12])=[O:11]
Reactant: Cc1cc(C)nc(Nc2cc(NS(=O)(=O)CCNC(=O)OC(C)(C)C)cnc2C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)nc(Nc2cc(NS(=O)(=O)CCN)cnc2C#N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl [2-({6-cyano-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl}sulfamoyl)ethyl]carbamate (100 mg, 0.22 mmol) in dichloromethane (1.8 mL) was added trifluoroacetic acid (0.26 mL, 3.4 mmol). The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure to afford 2-amino-N-{6-cyano-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl}ethanesulfonamide, which was used without further purification. MS ESI calc'd. for C15H19N6O2S [M+H]+ 347. found 347.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:10][O-:11].[Na+]>CO>[Br:1][C:2]1[C:3]([O:11][CH3:10])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(Cl)c(Br)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ncc(C)cc1Br
Temperature: 65 °C
Reaction time: 32 h

Procedure:
To a solution of 3-bromo-2-chloro-5-methylpyridine (5 g, 24.2 mmol) in MeOH (80 mL) was added a solution of sodium methoxide 5.4M in MeOH (25 mL, 135 mmol) and the mixture was stirred at 65° C. for 32 h. The resulting suspension was filtered and the mother liquor was concentrated. Et2O and H2O were added and the phases were separated. The organic layer was washed with H2O and brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (heptane/EtOAc: 90:10→0:100) to afford the title compound. tR: 1.03 min (LC-MS 2).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[C:5]([F:19])=[C:6]([NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:8][CH:9]=1.S(OC)(O[CH3:24])(=O)=O>C1(C)C=CC=CC=1>[Cl:3][C:4]1[C:5]([F:19])=[C:6]([N:10]([CH3:24])[C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Nc1cccc(Cl)c1F)c1ccccc1
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CN(C(=O)c1ccccc1)c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
Into toluene (60 g) were added 85% potassium hydroxide (2.8 g, 0.05 mol) and 10.0 g (0.40 mol) of N-(3-chloro-2-fluorophenyl)benzamide obtained above. While the reaction mixture was heated at reflux, 6.1 g (0.05 mol) of dimethyl sulfate was added dropwise. The reaction was conducted with a dean stark trap to remove the water generated. After the dropwise addition was completed, the mixture was stirred for 1 hour and allowed to cool to room temperature. The resultant was mixed with 20 g of a 5% aqueous sodium hydroxide solution and stirred for 1 hour. The mixture was allowed to separate to give a toluene layer, which was washed with 40 g of water. The toluene layer was concentrated under reduced pressure, and the resultant residue was washed with n-hexane to obtain 9.97 g of the title compound (yield: 94%) as a white solid.