Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][N:8]2[C:13]([C:15]1[N:20]=[CH:19][N:18]=[C:17]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]3[C:35]4[C:30](=[N:31][CH:32]=[CH:33][CH:34]=4)[NH:29][C:28]3=[O:36])[CH2:23][CH2:22]2)[CH:16]=1)=[O:14])([O-])=O.CO.[H][H]>[Pd].C1COCC1>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][N:8]2[C:13]([C:15]1[N:20]=[CH:19][N:18]=[C:17]([N:21]2[CH2:22][CH2:23][CH:24]([N:27]3[C:35]4[C:30](=[N:31][CH:32]=[CH:33][CH:34]=4)[NH:29][C:28]3=[O:36])[CH2:25][CH2:26]2)[CH:16]=1)=[O:14]
Reactant: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)N1CCc2c1cccc2[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cccc2c1CCN2C(=O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1

Procedure:
Under a hydrogen atmosphere 130 mg (0.27 mmol) 1-{1-[6-(4-nitro-2,3-dihydroindole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydroimidazo[4,5-b]pyridin-2-one and 25 mg palladium on charcoal (10%) were hydrogenated in a 1:1 mixture methanol:THF (15 mL of each) at RT and 3 bar hydrogen pressure. Then the catalyst was eliminated by suction filtering and the residue was washed with 50 mL DMF. The filtrate was evaporated down i. vac., the residue was stirred with methanol and suction filtered. The solid was dried at 50° C. in the CAD.
Reaction SMILES: [C:1](=[NH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18](=[O:22])[C@H:19]([CH3:21])N)[CH3:16]>C(Cl)Cl>[C:2]1([C:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:14][C@H:19]([C:18]([O:17][CH2:15][CH3:16])=[O:22])[CH3:21])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)[C@H](C)N
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 89.6 %

Procedure:
Benzophenone imine (53.4 g, 286 mmol) was dissolved in methylene chloride (400 mL) and stirred at room temperature. To the solution was added L-alanine ethyl ester (43.9 g, 286 mmol) and the reaction stirred at room temperature for 48 hours. The reaction was washed 3 times with water (200 mL). The organic layer was separated, dried (MgSO4), and the filtrate was concentrated in vacuo to give a clear oil. The oil was crystallized from pentane to give the title compound (72.1 g, 90%), FAB-MS 282 (MH+).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([Cl:20])[C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.ClC1C(F)=C(C=C(F)C=1F)C(CC(OCC)=O)=O.[NH2:41][C:42]1[C:47]([F:48])=[CH:46][C:45]([F:49])=[C:44]([NH:50][CH3:51])[N:43]=1>C(Cl)(Cl)Cl>[Cl:20][C:14]1[C:15]([F:19])=[C:16]([F:18])[CH:17]=[C:12]2[C:13]=1[N:41]([C:42]1[C:47]([F:48])=[CH:46][C:45]([F:49])=[C:44]([NH:50][CH3:51])[N:43]=1)[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]2=[O:22]
Reactant: CNc1nc(N)c(F)cc1F
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1F
Agent: CCOC(=O)CC(=O)c1cc(F)c(F)c(Cl)c1F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(-c2nc(NC)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
To 5 ml of chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 0.70 g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process was added 430 mg of 2-amino-3,5-difluoro-6-(methylamino)pyridine. The solution was concentrated under reduced pressure. To the residue were added 0.3 g of anhydrous potassium carbonate and 2 ml of N,N-dimethyl-formamide, and the mixture was stirred at 90° C. for 10 minutes and allowed to cool. The solution was separated by adding 30 ml of chloroform and 300 ml of distilled water, and the chloroform layer was washed twice with 300 ml distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and allowed to stand. The precipitate was collected by filtration, washed with ethanol and diisopropylether successively to obtain 784 mg of the title compound as a colorless powder.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[CH2:10][CH2:11][C@H:12]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([NH:28][NH2:29])(=O)[CH3:26]>O1CCCC1>[CH2:1]([O:8][C:9](=[O:24])[CH2:10][CH2:11][C@H:12]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:13]1[O:15][C:25]([CH3:26])=[N:28][N:29]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(=O)NN
Solvent: C1CCOC1
Product: Cc1nnc([C@H](CCC(=O)OCc2ccccc2)NC(=O)OC(C)(C)C)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
674 mg (2 mmol) of (S)-5-(benzyloxy)-2-(tert-butoxycarbonylamino)-5-oxopentanoic acid (Boc-Glu (OBzl)-OH) and 148 mg (2 mmol) of acetohydrazide were added with 5 ml of tetrahydrofuran, added with 356 mg of N,N-carbonyl diimidazole and stirred at room temperature overnight. The solvent was distilled away, and the resultant was purified using purified purification step A to obtain a crude purified substance of (4S)-4-(N′-acetylhydrazinecarbonyl)-4-{[(tert-butoxy)carbonyl]amino}butanoic acid benzyl ester. The obtained crude purified substance was dissolved in 2 ml of methylene chloride, which was added with 72 mg of Burgess reagent and stirred at room temperature overnight. Another 72 mg of Burgess reagent was added and stirred for two days. After distilling the solvent away, purification was carried out using purification step A to obtain the title compound.
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.[Br:17][CH2:18][CH2:19]Br.C(OCC)(=O)C>CS(C)=O>[Br:17][CH2:18][CH2:19][N:8]([N:6]1[CH:5]=[N:4][N:3]=[CH:7]1)[C:9]1[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=1
Reactant: BrCCBr
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(CCBr)n2cnnc2)cc1
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 240 mg, 6.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMSO (25 mL) at r.t. The mixture was stirred for 1 hour at this temperature and 1,2-dibromethane (5 mL) was added. The reaction mixture was stirred overnight and ethyl acetate (100 mL) was added. The mixture was transferred into a separation funnel and extracted with water (twice 100 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure (water bath temperature <30° C.). The resulting orange oil was mixed with diethyl ether (100 mL) and filtered through a layer of silica (ca. 5 cm). The silica was washed with more diethyl ether (ca. 100 mL) to remove the excess of 1,2-dibromoethane; the crude product was washed from the silica with acetone (120 mL). The acetone solution was concentrated under reduced pressure and the residue was purified by column-chromatography (eluent: ethyl acetate) to give the title compound as a white solid. Yield: 628 mg (43%). 1H-NMR (400 MHz, d6-DMSO) δ=3.61 (t; J=6.2 Hz, 2H), 4.30 (t, J=6.4 Hz, 2H), 6.64 (d, J=9.0 Hz), 7.74 (d, 9.0 Hz, 2H), 8.97 (s, 2H). LRMS (FAB+):292.0 (100, [M+H]+).
Reaction SMILES: [Br:1]Br.C([NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:21]([CH3:22])=[CH:20][S:19][C:18]=2[C:23]([O:25][CH3:26])=[O:24])=[CH:13][C:12]=1[CH3:27])(=[O:10])=[O:9])(C)(C)C>C(Cl)Cl>[Br:1][C:20]1[S:19][C:18]([C:23]([O:25][CH3:26])=[O:24])=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([S:8](=[O:10])(=[O:9])[NH2:7])=[C:12]([CH3:27])[CH:13]=2)[C:21]=1[CH3:22]
Reactant: BrBr
Reactant: COC(=O)c1scc(C)c1-c1ccc(S(=O)(=O)NC(C)(C)C)c(C)c1
Solvent: ClCCl
Product: COC(=O)c1sc(Br)c(C)c1-c1ccc(S(N)(=O)=O)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.2 %

Procedure:
Bromine (0.35 g, 0.11 ml, 2.2 mmol) was added drop wise to a stirred suspension of methyl 3-(4-(N-(tert-butyl)sulfamoyl)-3-methylphenyl)-4-methylthiophene-2-carboxylate (41a, 0.70 g, 1.83 mmol) in DCM (15 ml) at 0° C. The reaction mixture was then stirred at 25° C. for 3 hours. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated. DCM (50 ml) was added to the residue. The mixture so obtained was washed with water (2×20 ml), brine (lx 20 ml) and dried over sodium sulfate. The dried organic layer was then concentrated under reduced pressure to obtain a crude product as semi-solid (0.7 g), which was then purified by flash column chromatography using 40% ethyl acetate in hexanes as an eluent to obtain the title compound (0.63 g, 85.13%).
Reaction SMILES: C([O-])=O.[NH4+].C([O:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17]([O:23][C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[NH:29][C:28]([CH3:33])=[CH:27]4)=[N:18][CH:19]=[N:20]2)=[CH:15][CH:14]=1)C1C=CC=CC=1>[Pd].CN(C=O)C>[OH:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17]([O:23][C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[NH:29][C:28]([CH3:33])=[CH:27]4)=[N:18][CH:19]=[N:20]2)=[CH:15][CH:14]=1
Reactant: Cc1cc2cc(Oc3ncnc4cc(OCc5ccccc5)ccc34)ccc2[nH]1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1cc2cc(Oc3ncnc4cc(O)ccc34)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
10% Palladium on charcoal (200 mg) followed by ammonium formate (4.34 g, 69 mmol) were added to a solution of 7-benzyloxy-4-(2-methylindol-5-yloxy)quinazoline (1.75 g, 4.58 mmol) in DMF (60 ml). After stirring for 1 hour at ambient temperature, the mixture was filtered. The filtrate was evaporated. The residue was triturated with water, filtered, washed with ethyl acetate, and dried under vacuum to give 7-hydroxy-4-(2-methylindol-5-yloxy)quinazoline (1.24 g, 93%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].CC1(C)C(C)(C)OB([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[N:33]=[CH:32][CH:31]=[CH:30]3)O1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][CH:36]=3)[N:33]=[CH:32][CH:31]=[CH:30]4)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: CC1(C)OB(c2ccc3ncccc3c2)OC1(C)C
Product: CCCNC(=O)c1nnc2c(-c3ccc4ncccc4c3)cccc2c1N
Yield: 89 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.33 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolane-2-yl)quinoline (247 mg, 0.97 mmol) were reacted to afford the title compound (105 mg, 91.9% yield) as a pale-yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.96 (dd, J=4.2 Hz, J′=1.7 Hz, 1H), 8.56 (br, 1H), 8.23 (d, J=8.4 Hz, 2H), 8.05-8.15 (m, 2H), 7.88-7.96 (m, 2H), 7.78 (t, J=7.7 Hz, 1H), 7.44 (dd, J=8.2 Hz, J′=4.2 Hz, 1H), 3.47 (q, J=6.7 Hz, 2H), 1.67 (m, J=7.2 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H) MS APCI, m/z=358 (M+H) HPLC 1.47 min.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:8][OH:9])[S:6][CH:7]=1)#[CH:2].C(N(CC)CC)C.[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18].O>ClCCl.CN(C)C1C=CN=CC=1>[C:17]([Si:21]([O:9][CH2:8][C:5]1[S:6][CH:7]=[C:3]([C:1]#[CH:2])[CH:4]=1)([CH3:24])[CH3:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#Cc1csc(CO)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C#Cc1csc(CO[Si](C)(C)C(C)(C)C)c1
Yield: 94 %

Procedure:
To a solution of (4-ethynyl-2-thienyl)methanol (0.88 g, 6.4 mmol) that was obtained in Example 9 (9c) in dichloromethane (20 ml) were added successively triethylamine (1.3 ml, 9.6 mmol), t-butyldimethylchlorosilane (1.2 g, 7.6 mmol), and 4-dimethylaminopyridine (78 mg, 0.64 mmol) with stirring, and the resulting mixture was stirred at room temperature for 1 hour. After stirring, water (50 ml) was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (0:1 to 1:9) as the eluent to afford the title compound (1.5 g) in a yield of 94% as a brown oily product.
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:7](O)=[O:8])=[CH:5][N:4]([CH2:10][C:11]([F:14])([F:13])[F:12])[N:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH2:21][C:22]1[CH:43]=[CH:42][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]3[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]4[CH2:41][CH2:40]4)=[O:38])[N:35]=3)[CH:32]=2)=[C:24]([F:44])[CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH:39]1([C:37]([NH:36][C:34]2[N:35]=[C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]4[CH:42]=[CH:43][C:22]([NH:21][C:7]([C:6]5[C:2](=[O:1])[N:3]([C:15]6[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=6)[N:4]([CH2:10][C:11]([F:12])([F:13])[F:14])[CH:5]=5)=[O:8])=[CH:23][C:24]=4[F:44])=[CH:32][N:31]3[CH:33]=2)=[O:38])[CH2:40][CH2:41]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: O=C(O)c1cn(CC(F)(F)F)n(-c2ccccc2)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1)c1cn(CC(F)(F)F)n(-c2ccccc2)c1=O
Yield: 77.6 %

Procedure:
Using 3-oxo-2-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-pyrazole-4-carboxylic acid (210 mg, 0.72 mmol), N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (170 mg, 0.52 mmol), HATU (280 mg, 0.72 mmol), diisopropylethylamine (200 mg, 1.6 mmol) and N,N-dimethylformamide (6 mL) as starting materials and in the same manner as in Example 35, the title compound (240 mg, 77%) was obtained as a white solid.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:33])[C@H:11]([N:16]([P@:24]([CH3:32])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:12][CH:13]([CH3:15])[CH3:14])C1C=CC=CC=1.[H][H]>[Pd].CO>[OH:8][NH:9][C:10](=[O:33])[C@H:11]([N:16]([P@@:24]([CH3:32])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:25])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)C[C@H](C(=O)NOCc1ccccc1)N(Cc1ccccc1)[P@@](C)(=O)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@H](C(=O)NO)N(Cc1ccccc1)[P@](C)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-Benzyloxy-2(R)-[[(S)-methylphenylphosphinyl]benzylamino]-4-methylpentanamide (460 mg, 0.99 mmol) and 10% Pd/C (100 mg) are evacuated in a flask. To this is added methanol (10 mL) and a hydrogen atmosphere is introduced. The reaction is allowed to stir at room temperature for 2 hours at which time the reaction appears complete by TLC. The mixture is filtered through celite; the filtrate is collected and evaporated to give a white glassy solid. The hydroxamic acid is crystallized by dissolving in ethyl acetate and adding hexane dropwise until the solution becomes cloudy. N-Hydroxy-2(R)-[[(R)-methylphenyl-phosphinyl]benzylamino]-4-methylpentanamide is obtained as a white crystalline solid: MS-IS m/z 375 [M+H]+, 397 [M+Na]+, 413 [M+K]+. (R2 =isobutyl, R1 =benzyl, R3 =methyl, R4 =phenyl).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(O[CH:12]=[C:13]([C:19]#[N:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.O>C(O)(=O)C>[NH2:20][C:19]1[N:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=[CH:12][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: NNc1ccccn1
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cnn(-c2ccccn2)c1N
Temperature: 25 °C
Yield: 50.8 %

Procedure:
A solution of 21.83 g of 2-hydrazinopyridine and 38.2 g of ethyl (ethoxymethylene)cyanoacetate dissolved in 150 ml of acetic acid and 50 ml of water was heated on a steam bath for approximately 16 hours. The reaction mixture was allowed to cool to room temperature and placed in a refrigerator whereupon crystals slowly formed. The precipitated solid was collected by filtration and washed with cold 50% aqueous ethanol to provide 23.6 g of 5-amino-1-(2-pyridinyl)-1H-pyrazole-4-carboxylic acid, ethyl ester. Yield 50.9%. mp=89°-91° C.
Reaction SMILES: F[C:2]1[CH:23]=[C:22]([C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[CH:19]=[CH:18][C:10]([C:11]([O:13]C(C)(C)C)=[O:12])=[CH:9][CH:8]=1)=[O:5].[F:31][C:32](F)(F)[C:33]([OH:35])=O>ClCCl>[F:31][C:32]1[CH:25]=[C:24]([F:29])[CH:22]=[CH:21][C:33]=1[O:35][C:2]1[CH:23]=[C:22]([C:24]([F:29])([F:30])[C:25]([F:27])([F:28])[F:26])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[CH:19]=[CH:18][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)c2ccc(C(F)(F)C(F)(F)F)cc2F)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(NC(=O)c2ccc(C(F)(F)C(F)(F)F)cc2Oc2ccc(F)cc2F)cc1
Temperature: 40 °C
Reaction time: 18 h
Yield: 22 %

Procedure:
The ester obtained in the previous step was dissolved in dichloromethane (1 mL). 2,2,2-Trifluoroacetic acid (4 mL, 52.50 mmol) was added and the reaction was stirred at 40° C. for 18 hours. The excess TFA and dichloromethane was evaporated under reduced pressure. The crude product was filtered and purified by reverse phase preparative chromatography utilizing a gradient of 30-99% acetonitrile in water containing HCl as a modifier to yield 4-(2-(2,4-difluorophenoxy)-4-(perfluoroethyl)benzamido)benzoic acid (2) (31.8 mg, 22%). ESI-MS m/z calc. 487.07, found 488.5 (M+1)+; Retention time: 2.01 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 10.92 (s, 1H), 7.98-7.87 (m, 3H), 7.87-7.75 (m, 2H), 7.68-7.59 (m, 1H), 7.57-7.45 (m, 1H), 7.44-7.31 (m, 1H), 7.22-7.13 (m, 1H), 7.11 (s, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15](=[S:24])[NH:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][C:28]=1[Cl:37]>>[Cl:37][C:28]1[CH:29]=[C:30]([S:33]([NH2:36])(=[O:34])=[O:35])[CH:31]=[CH:32][C:27]=1[CH2:26][S:24][C:15]1[N:16]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[C:12]([C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)([CH3:11])[CH3:10])=[CH:13][N:14]=1
Reactant: CC(C)(c1ccc(Cl)c(Cl)c1)c1c[nH]c(=S)n1-c1ccc(F)cc1
Reactant: NS(=O)(=O)c1ccc(CBr)c(Cl)c1
Product: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(SCc2ccc(S(N)(=O)=O)cc2Cl)n1-c1ccc(F)cc1

Procedure:
Similarly the title compound was prepared from 5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2(3H)-thione and 4-(bromomethyl)-3-chlorobenzenesulfonamide. MS (EI) m/z 584 (MH)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]1[C:9](OC)([O:10]C)[CH2:8][CH2:7][N:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:5]1)[CH3:2].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:1]([O:3][CH:4]1[C:9](=[O:10])[CH2:8][CH2:7][N:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:5]1)[CH3:2]
Reactant: CCOC(=O)N1CCC(OC)(OC)C(OCC)C1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)N1CCC(=O)C(OCC)C1

Procedure:
A mixture of 34.1 parts of ethyl 3-ethoxy-4,4-dimethoxy-1-piperidinecarboxylate and 1110 parts of a sulfuric acid solution 1% in water was stirred and refluxed for 3 hours. The reaction mixture was cooled and saturated with sodium carbonate. The product was extracted with dichloromethane. The extract was washed with a small amount of water, dried, filtered and evaporated. The residue was stirred in petroleum ether. The product was separated and distilled, yielding 21.1 parts of ethyl 3-ethoxy-4-oxo-1-piperidinecarboxylate bp. ±95° C. at 0.05 mm. pressure (intermediate 68).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1)=[O:5].[Br:18][CH2:19][C:20](Br)=[O:21]>O1CCCC1.C(N(C(C)C)CC)(C)C.C(OCC)(=O)C.O>[Br:18][CH2:19][C:20]([NH:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1)=[O:5])=[O:21]
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Reactant: O=C(Br)CBr
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CBr)Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a stirred solution of 2-amino-N-(5-chloropyridin-2-yl)benzamide (1.65 g, 6.66 mmol) in tetrahydrofuran (60 mL)and diisopropylethyl amine (1.28 mL) was added bromoacetyl bromide (0.64 mL, 7.32 mmol) dropwise at 0° C. The reaction mixture was warmed to room temperature and stirred overnight. Diluted the reaction mixture with ethyl acetate (120 mL) and water (50 mL). Separated the organic layer and washed with water (25 mL), saturated sodium bicarbonate (50 mL), 0.2 N hydrochloric acid (25 mL), water (50 mL). Dried over sodium sulfate and remove the solvent to get crude product (2.2 g), which was used as such in the following step.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:9][CH:8]=[C:7]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]4)=[N:21][CH:22]=3)[N:6]2[CH:36]=1.Cl[C:38]1[N:43]=[CH:42][CH:41]=[CH:40][N:39]=1>>[O:14]1[CH2:13][CH2:12][N:11]([C:10]2[C:5]3[N:6]([CH:36]=[C:3]([CH2:2][O:1][C:38]4[N:43]=[CH:42][CH:41]=[CH:40][N:39]=4)[N:4]=3)[C:7]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:27][CH2:28]4)=[N:21][CH:22]=3)=[CH:8][N:9]=2)[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(N4CCOCC4)c4nc(CO)cn34)cn2)CC1
Reactant: Clc1ncccn1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(N4CCOCC4)c4nc(COc5ncccn5)cn34)cn2)CC1

Procedure:
Following the procedures described in Example 22, Step A, the title compound was prepared from compound 23a and 2-chloropyrimidine. Mass Spectrum (LCMS, ESI pos.) Calcd. for C29H35N9O4: 574.3 (M+H). Found 574.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][C:8](=[CH:13]N(C)C)[C:7](=O)[C:6]=2[CH:18]=1.Cl.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([NH2:31])=[NH:30])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][C:8]3[CH:13]=[N:30][C:29]([CH2:28][C:25]4[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=4)=[N:31][C:7]=3[C:6]=2[CH:18]=1
Reactant: COc1ccc(CC(=N)N)cc1
Reactant: CN(C)C=C1CC(=O)Nc2ccc(Cl)cc2C1=O
Agent: Cl
Product: COc1ccc(Cc2ncc3c(n2)-c2cc(Cl)ccc2NC(=O)C3)cc1
Yield: 87 %

Procedure:
Analogous to Scheme 1, from 7-chloro-4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepine-2,5-dione and 2-(4-methoxyphenyl)-acetamidine hydrochloride. Yield: 87%. White solid, m/z (ISP) 366 (MH).
Reaction SMILES: [C:1]([CH:3]=[CH:4][C:5]1[C:6]([O:15][CH3:16])=[N:7][CH:8]=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])#[N:2].C(O)(=O)C>[C].[Pd].CO>[C:1]([CH2:3][CH2:4][C:5]1[C:6]([O:15][CH3:16])=[N:7][CH:8]=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])#[N:2]
Reactant: COC(=O)c1cnc(OC)c(C=CC#N)c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cnc(OC)c(CCC#N)c1
Temperature: 70 °C
Reaction time: 40 h
Yield: 57.2 %

Procedure:
To a mixture of methyl 5-(2-cyanovinyl)-6-methoxynicotinate (1.02 g), acetic acid (20 ml) and methanol (20 mL) was added 10% palladium-carbon (504 mg), and the mixture was stirred under a hydrogen atmosphere at 70° C. for 40 hr. The reaction mixture was filtered, and the filtrate was diluted with THF and ethyl acetate. The diluted solution was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (589 mg) as white crystals.