Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[O:10]1[CH:14]=[CH:13][CH2:12][CH2:11]1>O1CCCC1>[O:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: C1=COCC1
Solvent: C1CCOC1
Product: O=c1[nH]c(=O)n(C2CCCO2)cc1F
Yield: 64 %

Procedure:
Into 30 ml of tetrahydrofuran were suspended 1.3 g of 5-fluorouracil. To this suspension were added 1.4 g of 2,3-dihydrofuran and the mixture was reacted in an autoclave for 5 hours at 170° C. After completion of the reaction, the reaction liquid was treated in the same manner as described in Example 1 whereby 0.30 g of the starting 5-fluorouracil was recovered as a substance insoluble in chloroform and 1.28 g of 1-(2-tetrahydrofuryl)-5-fluorouracil were obtained. The yield of the end product was 83.2% based on the consumed 5-fluorouracil.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.C([Li])CCC.[C:16](=[O:18])=[O:17].O>C1COCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:16]([OH:18])=[O:17])=[CH:3][C:4]=1[CH3:10])#[N:7]
Reactant: Cc1cc(Br)ccc1C#N
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)O)ccc1C#N
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-2-methylbenzonitrile (2.0 g, 10.2 mmol) in THF (100 ml) at −78° C. under a nitrogen atmosphere was added dropwise a 2.5M solution of n-butyl lithium (4.48 ml, 11.2 mmol). The mixture was stirred at −78° C. for 1 h and then poured onto solid carbon dioxide (5 g) in THF (50 ml). The mixture was allowed to warm to room temperature. Water was added (200 ml) and the mixture was extracted with diethyl ether (3 times). The aqueous layer was acidified by addition of concentrated HCl and extracted with chloroform (3 times). The combined chloroform extracts were washed with water, dried over MgSO4, and concentrated in vacuo to give a white solid; yield 1.2 g (73%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.[F:10][S:11]([OH:14])(=O)=[O:12].[C]=O.FC(F)(F)[C:19](O)=[O:20]>[Sb](F)(F)(F)(F)F>[CH:19]([C:3]1[C:2]([CH3:1])=[C:7]([S:11]([F:10])(=[O:14])=[O:12])[C:6]([CH3:8])=[CH:5][C:4]=1[CH3:9])=[O:20]
Reactant: Cc1cc(C)cc(C)c1
Reactant: O=S(=O)(O)F
Reactant: O=C(O)C(F)(F)F
Agent: F[Sb](F)(F)(F)F
Agent: [C]=O
Product: Cc1cc(C)c(S(=O)(=O)F)c(C)c1C=O
Yield: 30 %

Procedure:
18.9 ml of 1,3,5-trimethylbenzene was reacted with 20 ml of fluorosulfonic acid and carbon monoxide in the presence of 10 ml of antimony pentafluoride and 10 ml of trifluoroacetic acid as a solvent at 20° C. for 48 hours in substantially the same manner as that of Example 1. The molar ratio of 1,3,5-trimethylbenzene : fluorosulfonic acid : antimony pentafluoride was 1 : 3.5 : 1.4, while the consumption of carbon monoxide was 2.24 λ. The same analyses as those of Example 1 were made to confirm the formation of 6.9 g of 3-formyl-2,4,6-trimethylbenzenesulfonyl fluoride (compound No. 7) in a yield of 30 % based on 1,3,5-trimethylbenzene. mass spectrum: M+ (m/e)=230.
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[C:4]1[CH:9]=[CH:8][C:7](/[N:10]=[N:11]/[C:12]2[S:13][C:14]([CH:24]=[C:25]3[C:33](=[O:34])[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26]3=[O:35])=[C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[N:16]=2)=[CH:6][CH:5]=1)[CH3:2].[CH3:38][O:39][S:40]([O:43]C)(=[O:42])=[O:41]>C(#N)C>[CH3:38][O:39][S:40]([O-:43])(=[O:42])=[O:41].[CH2:36]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7](/[N:10]=[N:11]/[C:12]2[S:13][C:14]([CH:24]=[C:25]3[C:33](=[O:34])[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26]3=[O:35])=[C:15]([N:17]3[CH2:22][CH2:21][N+:20]([CH3:38])([CH3:23])[CH2:19][CH2:18]3)[N:16]=2)=[CH:6][CH:5]=1)[CH3:37]
Reactant: CCN(CC)c1ccc(/N=N/c2nc(N3CCN(C)CC3)c(C=C3C(=O)c4ccccc4C3=O)s2)cc1
Reactant: COS(=O)(=O)OC
Solvent: CC#N
Product: CCN(CC)c1ccc(/N=N/c2nc(N3CC[N+](C)(C)CC3)c(C=C3C(=O)c4ccccc4C3=O)s2)cc1
Product: COS(=O)(=O)[O-]
Temperature: 25 °C

Procedure:
0.93 g (1.80 mmol) 2-{[2-{(E)-[4-(diethylamino)phenyl]diazenyl}-4-(4-methyl-1-piperazinyl)-1,3-thiazol-5-yl]methylene}-1H-indene-1,3(2H)-dione was dissolved in 20 ml acetonitrile. After addition of 0.5 g (3.70 mmol) dimethylsulfate, the mixture was heated under reflux for 24 hours. After cooling to room temperature the formed precipitate was filtered off and dried in vacuum at 40° C. to obtain a dark green solid.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[CH:9]2)=[C:2]=[S:3].[OH:14][CH2:15][CH:16]1[NH:21][CH2:20][C:19]2[CH:22]=[CH:23][S:24][C:18]=2[CH2:17]1>C(O)C>[OH:14][CH2:15][CH:16]1[N:21]([C:2](=[S:3])[NH:1][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][N:8]=[CH:9]3)[CH2:20][C:19]2[CH:22]=[CH:23][S:24][C:18]=2[CH2:17]1
Reactant: S=C=Nc1cccc2cnccc12
Reactant: OCC1Cc2sccc2CN1
Solvent: CCO
Product: OCC1Cc2sccc2CN1C(=S)Nc1cccc2cnccc12
Reaction time: 48 h
Yield: 74.2 %

Procedure:
5-Isothiocyanatoisoquinoline (5.1 g) is added to a solution of (RS)-6-hydroxymethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (4.3 g) in absolute ethanol (55 cc). After 48 hours at a temperature of about 20° C., the resulting crystals are filtered off, washed with diisopropyl ether (75 cc) and then dried at 40° C. under reduced pressure (0.1 mm Hg; 0.013 kPa). (RS)-6-Hydroxymethyl-5-[(isoquinol-5-yl)thiocarbamoyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (6.7 g), melting at 185° C., is thus obtained.
Reaction SMILES: Cl[C:2](=[N:8][OH:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([C:29]3[CH:34]=[CH:33][C:32]([C:35](OC)=[CH2:36])=[CH:31][N:30]=3)([CH3:28])[CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=2)[CH:15]=[N:16][CH:17]=1.C(N(CC)CC)C.C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([C:29]3[N:30]=[CH:31][C:32]([C:35]4[O:9][N:8]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:36]=4)=[CH:33][CH:34]=3)([CH3:28])[CH:25]([CH3:26])[CH3:27])=[CH:22][CH:23]=2)[CH:15]=[N:16][CH:17]=1
Reactant: C=C(OC)c1ccc(C(C)(c2ccc(-c3cncc(OC)c3)cc2)C(C)C)nc1
Reactant: CCOC(=O)C(Cl)=NO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(-c2ccc(C(C)(c3ccc(-c4cncc(OC)c4)cc3)C(C)C)nc2)on1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Ethyl 2-chloro-2-(hydroxyimino)acetate (116 mg, 0.768 mmol) was added to a stirred solution of 3a (0.256 mmol) and triethylamine (357 μL, 2.56 mmol) in THF (10.0 mL) at rt. After approximately 1 h, the reaction mixture was acidified to ˜pH 1 by the addition of TFA, and the resulting mixture was heated to 50° C. for approximately 4.5 h. The reaction mixture was cooled to rt, neutralized with saturated aqueous sodium bicarbonate and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (gradient elution; 0%-100% EtOAc/hexanes as eluent) to afford the title compound 3b. m/z (ES) 472 (MH)+. 1HNMR (500 MHz, CDCl3): δ 9.05 (d, 1H, J=2.3 Hz), 8.46 (d, 1H, J=2.4 Hz), 8.29 (d, 1H, J=2.5 Hz), 8.00 (dd, 1H, J=2.3, 8.5 Hz), 7.51 (m, 4H), 7.41 (d, 1H, J=8.2 Hz), 7.36 (m, 1H), 6.98 (s, 1H), 4.50 (q, 2H, J=7.1 Hz), 3.92 (s, 3H), 3.71 (m, 1H), 1.78 (s, 1H), 1.47 (t, 3H, J=7.1 Hz), 0.91 (d, 3H, J=6.7 Hz), 0.88 (d, 3H, J=6.9 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[CH3:12])[NH:8][CH:7]=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]2=[O:19].[H-].[Na+].[H][H].[CH2:24](I)[CH3:25]>CN(C)C=O.O>[CH2:24]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[C:11]([CH3:12])[C:10]=2[F:13])[C:5](=[O:19])[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7]1)[CH3:25]
Reactant: CCOC(=O)c1c[nH]c2c(F)c(C)c(F)cc2c1=O
Reactant: CCI
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(CC)c2c(F)c(C)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.1 %

Procedure:
2.67 g of ethyl 6,8-difluoro-7-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate are suspended in 50 ml of dimethylformamide, and 0.46 g of 66% sodium hydride are added thereto. The suspension is stirred at room temperature until it ceases to release hydrogen gas. 3.12 g of ethyl iodide are added to the suspension, and said suspension is stirred at room temperature for 24 hours and then at 50° to 60° C. for 3 hours. The reaction mixture is condensed to dryness, and water is added to the residue. After stirring the aqueous mixture, insoluble materials are collected by filtration, washed with isopropanol and then dried. 1.95 g of ethyl 1-ethyl-6,8-difluoro-7-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate are thereby obtained as crystalline powder. Yield: 66%
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:29])[C:9]2[CH:28]=[CH:27][C:12]3[N:13]([CH3:26])[C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][S:38]([NH2:41])(=[O:40])=[O:39])=[CH:33][CH:32]=1>>[ClH:1].[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][NH:16][C:14]2[N:13]([CH3:26])[C:12]3[CH:27]=[CH:28][C:9]([N:8]([CH3:29])[C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:30][C:31]5[CH:36]=[CH:35][C:34]([CH2:37][S:38]([NH2:41])(=[O:39])=[O:40])=[CH:33][CH:32]=5)[N:7]=4)=[CH:10][C:11]=3[N:15]=2)=[CH:19][CH:20]=1
Reactant: COc1ccc(CNc2nc3cc(N(C)c4ccnc(Cl)n4)ccc3n2C)cc1
Reactant: Nc1ccc(CS(N)(=O)=O)cc1
Product: COc1ccc(CNc2nc3cc(N(C)c4ccnc(Nc5ccc(CS(N)(=O)=O)cc5)n4)ccc3n2C)cc1
Product: Cl

Procedure:
The title compound was prepared following the procedure of example two with N5-(2-chloro-pyrimidin-4-yl)-N2-(4-methoxy-benzyl)-1,N5-dimethyl-1H-benzoimidazole-2,5-diamine (82 mg, 0.20 mmol) and (4-amino-phenyl)-methanesulfonamide (37 mg, 0.20 mmol) as a white solid (49 mg, 41%). 1H NMR (300 MHz, d6-DMSO) δ 9.58 (br s, 1H), 9.00 (br s, 1H), 7.85 (d, J=6.0 Hz, 1H), 7.68 (d, J=8.1 Hz, 2H), 7.42-7.50 (M, 3H), 7.29 (s, 1H), 7.12-7.21 (m, 3H), 6.91 (d, J=8.4 Hz, 2H), 6.80 (s, 2H), 5.75 (d, J=5.7 Hz, 1H), 4.64 (d, J=5.1 Hz, 2H), 4.17 (s, 2H), 3.73 (s, 3H), 3.68 (s, 3H), 3.46 (s, 3H). MS (ESI) m/z=559 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12](=[O:15])[CH2:13]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]([NH2:22])([CH3:21])[CH3:20].[ClH:23].O>C(O)C>[ClH:23].[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:12](=[O:15])[CH2:13][NH:22][CH:19]([CH3:21])[CH3:20])[CH:16]=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N
Reactant: O=C(CBr)c1cccc(OCc2ccccc2)c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)NCC(=O)c1cccc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.01 h

Procedure:
In 425 ml of ethanol, 64 g of 3-benzyloxyphenacyl bromide and 212 ml of iso-propylamine are stirred at 5° C. under N2 atmosphere, and the temperature is allowed to rise to 12° C. After 0.75 minutes, the clear solution is poured into 2 liters of crushed ice containing 500 ml of concentrated HCl and 1.5 liters of H2O. The mixture is stirred for 20 minutes, filtered and the solid is washed with water to afford 3'-(benzyloxy)-2-isopropylamino-acetophenone hydrochloride, mp 213°-215° C. dec.. A 5 g.--sample of this material is stirred in 50 ml of methanol, and the mixture is cooled in ice and neutralized with 10% NaOH until a clear solution is obtained. To this solution, 2 g of NaBH4 is added and after 0.75 hours of stirring, the mixture is evaporated in vacuo, and the resulting solid is collected and washed with H2O. This gives, after drying, 4.4 g of m-(benzyloxy)-2-[(isopropylamino)methyl]benzyl alcohol, mp 83°-85° C.
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([CH3:22])([S:18]([CH3:21])(=[O:20])=[O:19])[C:13]([O:15]CC)=[O:14])=[CH:6][CH:5]=1.O1CCCC1CO.O.Cl>O>[Br:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([CH3:22])([S:18]([CH3:21])(=[O:20])=[O:19])[C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(C)(CCc1ccc(Br)nc1)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: OCC1CCCO1
Solvent: O
Product: CC(CCc1ccc(Br)nc1)(C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.4 %

Procedure:
A solution of lithium hydroxide (357 mg, 8.5 mmol, 4.0 equiv) and ethyl 4-(6-bromopyridin-3-yl)-2-methyl-2-(methylsulfonyl)butanoate (775 mg, 2.1 mmol, 1.0 equiv) in 1:1:1 tetrahydrofuran-methanol-water (3 mL) was allowed to stir at room temperature for 2 h. The reaction was diluted with water (150 mL), acidified (to pH=2) with 0.5 M hydrochloric acid, and then was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide the title compound (716 mg, 98%). MS (LCMS) m/z 334.1 (M−1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.56 (s, 3H) 2.03 (td, J=12.78, 5.27 Hz, 1H) 2.31 (td, J=12.68, 4.68 Hz, 1H) 2.51 (td, J=12.98, 4.49 Hz, 1H) 2.59-2.70 (m, 1H) 2.96 (s, 3H) 7.30-7.39 (m, 2H) 8.07 (d, J=1.56 Hz, 1H).
Reaction SMILES: [CH:1]1([S:6]([C:8]2[CH:9]=[C:10]([CH3:17])[CH:11]=[CH:12][C:13]=2[N+:14]([O-])=O)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=C(Cl)C=C([C:25]([O:27]O)=O)C=1.C1(S(C2C=C(C)C=CC=2N)=O)CCCC1.[NH2:44][C:45]1[S:46][CH:47]=[CH:48][N:49]=1>>[CH:1]1([S:6]([C:8]2[CH:9]=[C:10]([CH3:17])[CH:11]=[CH:12][C:13]=2[NH:14][C:25]([NH:44][C:45]2[S:46][CH:47]=[CH:48][N:49]=2)=[O:27])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Nc1nccs1
Reactant: Cc1ccc([N+](=O)[O-])c(S(=O)C2CCCC2)c1
Agent: Cc1ccc(N)c(S(=O)C2CCCC2)c1
Product: Cc1ccc(NC(=O)Nc2nccs2)c(S(=O)C2CCCC2)c1
Yield: 65 %

Procedure:
3-Cyclopentanesulfanyl-4-nitrotoluene (0.47 g, 2.0 mmol) was oxidized to 3-cyclopentanesulfinyl-4-nitrotoluene (0.46 g, 91%) following general procedure R (using one equivalent of m-CPBA). 3-Cyclopentanesulfinyl-4-nitrotoluene was reduced to 2-cyclopentanesulfinyl-4-methyl-aniline (0.33 g, 81%) following general procedure C. 1-(2-Cyclopentanesulfinyl-4-methyl-phenyl)-3-thiazol-2-yl-urea (225 mg, 65%) was prepared from 2-cyclopentanesulfinyl-4-methyl-aniline (223 mg, 1.0 mmol) and 2-aminothiazole (100 mg, 1.0 mmol) following the general procedure D.
Reaction SMILES: NN.[F:3][CH2:4][C:5]1[CH:6]=[C:7]([N:11]([CH2:13][C:14]([O:16]C)=O)[NH2:12])[CH:8]=[CH:9][CH:10]=1.[O-:18][C:19]#[N:20].[Na+].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[F:3][CH2:4][C:5]1[CH:6]=[C:7]([N:11]2[CH2:13][C:14](=[O:16])[NH:20][C:19](=[O:18])[NH:12]2)[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)CN(N)c1cccc(CF)c1
Reactant: N#C[O-]
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1CN(c2cccc(CF)c2)NC(=O)N1
Reaction time: 2.25 h
Yield: 78 %

Procedure:
The hydrazine (Intermediate 55, 1.5 g, 7.1 mmol) was dissolved in dry toluene (30 ml) under nitrogen at room temperature. Sodium cyanate (1.6 g, 24.6 mmol) was added followed by trifluoroacetic acid (1.7 ml, 22,1 mmol). The reaction was stirred for 2.25 h after which the reaction was poured into saturated sodium bicarbonate solution (100 ml) and extracted with ethyl acetate (4×(100 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give a white solid. The crude material was triturated with ether (2×100 ml) to give the title compound (Intermediate 56, 1.41 g, 78%) as a colourless powder, m.p. 169°-70°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[CH:22]1([C:25]2[O:26][C:27]([CH3:34])=[C:28]([CH2:30][C:31](O)=[O:32])[N:29]=2)[CH2:24][CH2:23]1.C(N(CC)CC)C.CCCP(=O)=O>C1COCC1>[CH:22]1([C:25]2[O:26][C:27]([CH3:34])=[C:28]([CH2:30][C:31]([NH:1][C:2]3[CH:7]=[N:6][CH:5]=[C:4]([C:8]([C:10]4[C:14]5[CH:15]=[N:16][CH:17]=[CH:18][C:13]=5[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=4)=[O:9])[CH:3]=3)=[O:32])[N:29]=2)[CH2:24][CH2:23]1
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cnccc21
Reactant: Cc1oc(C2CC2)nc1CC(=O)O
Agent: CCCP(=O)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1oc(C2CC2)nc1CC(=O)Nc1cncc(C(=O)c2cn(C(C)C)c3ccncc23)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.6 %

Procedure:
To a mixture of (5-aminopyridin-3-yl)(1-isopropyl-1H-pyrrolo[3,2-c]pyridin-3-yl)methanone (Preparation 19, 80 mg, 0.285 mmol) and (2-cyclopropyl-5-methyl-1,3-oxazol-4-yl)acetic acid (Preparation 87, 52 mg, 0.285 mmol) in THF (5 mL) was added triethylamine (138 uL, 0.997 mmol) and propylphosphonic anhydride (429 uL, 0.712 mmol). The reaction was stirred at room temperature for 18 hours. The reaction was concentrated to dryness and purified using preparative HPLC to afford the title compound as a white solid (50 mg, 39%).
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@@H:14]([CH2:27][CH:28]2[CH2:31][CH2:30][CH2:29]2)[C:15]([O:17]CC2C=CC(OC)=CC=2)=[O:16])[CH2:4]1)=O.[C:32]1([CH2:38][CH2:39][CH2:40][CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl.C(Cl)Cl.CO.[NH4+].[OH-]>>[C:32]1([CH2:38][CH2:39][CH2:40][CH:41]2[CH2:42][CH2:43][N:44]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:6][N:5]([C@@H:14]([CH2:27][CH:28]4[CH2:29][CH2:30][CH2:31]4)[C:15]([OH:17])=[O:16])[CH2:4]3)[CH2:45][CH2:46]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: c1ccc(CCCC2CCNCC2)cc1
Reactant: COc1ccc(COC(=O)[C@H](CC2CCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: O=C(O)[C@H](CC1CCC1)N1C[C@H](CN2CCC(CCCc3ccccc3)CC2)[C@@H](c2ccccc2)C1
Yield: 63.8 %

Procedure:
The title compound was prepared from 25 mg (0.059 mmol) of 2-(S)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-3-(cyclobutyl)propanoic acid, (4-methoxy)benzyl ester (from EXAMPLE 92, Step C) and 14.3 mg (0.059 mmol) of 4-(3-phenylpropyl)piperidine.HCl using a procedures analogous to those described in EXAMPLE 1, Step J and EXAMPLE 10, Step F to 18.4 mg (64%) of the title compound: RF: 0.48 (90:10:1 v/v/v CH2Cl2/MeOH/NH4OH); 1H NMR (300 MHz, CD3OD) δ 0.99-3.67 (m, 33H), 6.96-7.23 (m, 10H); ESI-MS 489 (M+H); HPLC A: 2.69 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([O:23][CH3:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[S:44]1[CH:48]=[CH:47][N:46]=[C:45]1[CH:49]([NH2:51])[CH3:50]>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:51][CH:49]([C:45]2[S:44][CH:48]=[CH:47][N:46]=2)[CH3:50])=[O:42])=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(N)c1nccs1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1NC(=O)NC(C)c1nccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 144.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methoxyaniline (816 mg) was dissolved in chloroform (40 ml) and triethylamine (2.0 ml) to prepare a solution. A solution of triphosgene (368 mg) in chloroform (1.0 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of 1-(1,3-thiazol-2-yl)-1-ethylamine (352 mg) in chloroform (1.0 ml) was added thereto, and the mixture was stirred at room temperature overnight. Water (40 ml) was added thereto, and the mixture was stirred for 10 min, followed by extraction with chloroform. The organic layer was washed with saturated brine and was dried over sodium sulfate. The solvent was removed by evaporation, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (860 mg, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[Cl:29][C:30]1[C:31](Cl)=[N:32][CH:33]=[C:34]([CH:39]=1)[C:35]([O:37][CH3:38])=[O:36].C1N2CCN(CC2)C1>>[CH3:38][O:37][C:35](=[O:36])[C:34]1[CH:39]=[C:30]([Cl:29])[C:31]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[N:32][CH:33]=1
Reactant: COC(=O)c1cnc(Cl)c(Cl)c1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Agent: C1CN2CCN1CC2
Product: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)c(Cl)c1

Procedure:
In analogy to Example 62, step 1, 6-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 56, step 4) was reacted with methyl 5,6-dichloronicotinate and DABCO (17 h, r.t.) to give the title compound as a white solid. MS (m/e)=585.0 [M+H+]
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[Na+].[I-:12].[C:13](Cl)(=[O:15])[CH3:14].C([O-])([O-])=O.[Na+].[Na+].OS([O-])=O.[Na+]>CC#N>[I:12][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:13](=[O:15])[CH3:14])[CH:9]=[CH:10][C:3]=12
Reactant: CC(=O)Cl
Reactant: [I-]
Reactant: Clc1ccnc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)n1ccc2c(I)ccnc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 4-chloro-1H-pyrrolo[2,3-b]pyridine (3.80 g, step B) and NaI (19.15 g) in CH3CN (40 mL) was added acetyl chloride (5.0 mL) slowly. The mixture was heated to reflux for overnight. After cooled to RT, 40 mL of 10% Na2CO3 and 40 mL of 10% NaHSO3 were added. After stirring for 15 min, the mixture was extracted with EtOAc 4 times. The combined organic phases were washed with brine, dried over MgSO4 and concentrated to give a brown residue as the crude compound, which was purified by chromatography through silica gel (220 g, 5 to 15% EtOAc/hexanes to afford 1-(4-iodo-pyrrolo[2,3-b]pyridin-1-yl)-ethanone as 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][CH:23]=[C:22]([CH3:26])[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][CH:23]=[C:22]([CH3:26])[CH:21]=1
Reactant: Cc1cccc(C(=O)CBr)c1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Product: CCOC(=O)n1c(C(=O)c2cccc(C)c2)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-[(ethoxycarbonyl)amino]benzonitrile (Example 1, step 1) and 2-bromo-3′-methylacetophenone (R. Yveline, G. Gerard, and M. Geroges, Chem.Pharm.Bull., 1992,40, 1170.).
Reaction SMILES: O[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=C(O)[N:3]=1.P(Cl)(Cl)([Cl:19])=O.O.[CH:23]([Cl:26])(Cl)Cl>>[Cl:19][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:23]([Cl:26])[N:3]=1
Reactant: N#Cc1c(-c2ccccc2)cc(O)nc1O
Reactant: O=P(Cl)(Cl)Cl
Reactant: ClC(Cl)Cl
Solvent: O
Product: N#Cc1c(-c2ccccc2)cc(Cl)nc1Cl
Temperature: 180 °C

Procedure:
A mixture consisting of 42.4 gm (0.2 mol) of 2,6-dihydroxy-4-phenyl-3-cyano-pyridine and 300 ml of phosphorus oxychloride was heated for 6 hours at about 180° C. in a pressure vessel made of glass, while shaking the vessel. Thereafter, the reaction mixture was allowed to cool and was then added in small portions to a mixture of ice and water (about 3 liters), while stirring. The precipitate formed thereby was collected by suction filtration, washed with water and dried, yielding 47.4 gm (95% of theory) of the raw reaction product. The raw product was dissolved in chloroform (the small amount of insoluble matter was filtered off) and purified by passing the solution through a short silicagel column with chloroform as the flow agent. The combined chloroform fractions were evaporated, leaving as a residue 37.5 gm (75% of theory) of virtually colorless crystalline 2,6-dichloro-4-phenyl-3-cyano-pyridine of the formula ##STR5## which had a melting point of 167°-169° C.