Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:21]2[C:26](=[O:27])[NH:25][C:24](=[O:28])[CH:23]=[N:22]2)[CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=1.[H-].[Na+].[CH3:31][Si:32]([CH2:35][CH2:36][O:37][CH2:38]Cl)([CH3:34])[CH3:33]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:21]2[C:26](=[O:27])[N:25]([CH2:38][O:37][CH2:36][CH2:35][Si:32]([CH3:34])([CH3:33])[CH3:31])[C:24](=[O:28])[CH:23]=[N:22]2)[CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=1
Reactant: COc1ccc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1[N+](=O)[O-]
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2c(Cl)cc(-n3ncc(=O)n(COCC[Si](C)(C)C)c3=O)cc2Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 48.2 %

Procedure:
To a solution of 2-[3,5-dichloro-4-(4-methoxy-3-nitro-phenoxy)-phenyl]-2H-[1,2,4]-triazin-3,5-dione (1.32 g, 3.1 mmol) in 12 mL of DMF at 0° C. was added sodium hydride (60% dispersion in mineral oil, 0.15 g, 3.7 mmol). After stirring at 0° C. for 5 min, the mixture was stirred at room temperature for 30 min as a clear reddish brown solution. To the solution at room temperature was added SEMCl (0.63 g, 3.74 mmol). After stirring at room temperature for 20 h, the solution was diluted with H2O (30 mL) and extracted with EtOAc (2×50 mL). The combined EtOAc extracts were washed with 1N HCl (100 mL), H2O (3×50 mL), brine (100 mL), dried and concentrated. The residue was dissolved in CH2Cl2followed by addition of ether to give the title compound (0.83 g) of Step A as light brown crystals. NMR (400 Mhz, CD3OD) d 0.02 (m, 9H), 1.01 (m, 2H), 3.75 (m, 2H), 5.45 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][N:20]=1>N1C=CC=CC=1>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[S:3][C:4]([N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)=[C:5]([C:7]3[O:8][CH:9]=[CH:10][CH:11]=3)[N:6]=2)=[O:24])=[CH:21][N:20]=1
Reactant: Nc1nc(-c2ccco2)c(N2CCOCC2)s1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: c1ccncc1
Product: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 58.5 %

Procedure:
2-Amino-4-(2-furyl)-5-morpholinothiazole (2.15 g, 8.57 mmol) obtained in Step 1 of Example 29 was dissolved in pyridine (25 mL), and 6-chloronicotinoyl chloride (1.81 g, 10.3 mmol) and N,N-dimethylaminopyridine (105 mg, 0.86 mmol) were added thereto. The mixture was stirred at room temperature for 10 hours, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:1 to 1:2) to afford the entitled Compound 32 (1.96 g, 59%).
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([NH2:5])=[NH:4].[C:8]([O-])(=O)[CH2:9][C:10](C)=[O:11]>>[OH:11][C:10]1[CH:9]=[CH:8][N:5]=[C:3]([C:2]([Cl:7])([Cl:6])[Cl:1])[N:4]=1
Reactant: N=C(N)C(Cl)(Cl)Cl
Reactant: CC(=O)CC(=O)[O-]
Product: Oc1ccnc(C(Cl)(Cl)Cl)n1

Procedure:
The carboxylic ester compounds of the present invention may be prepared by reacting trichloroacetamidine with a selected acetoacetate to form the corresponding 4-hydroxy-2-trichloromethylpyrimidine, which is then reacted with a selected carboxylic acid chloride. These general reactions are illustrated below in equations (A) and (B). In equation (A), trichloroacetamidine is reacted with ethyl 2-chloroacetoacetate to form 5-chloro-4-hydroxy-6-methyl-2-trichloromethyl-pyrimidine. In equation (B), the 5-chloro-4-hydroxy-6-methyl-2-trichloromethylpyrimidine is reacted with trichloroacetyl chloride to form 5-chloro-6-methyl-4-trichloroacetoxy-2-trichloromethylpyrimidine. ##STR3##
Reaction SMILES: Cl[C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.Cl.[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[CH2:20][O:21][NH2:22].C(=O)(O)[O-].[Na+]>C(O)CC>[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[CH2:20][O:21][NH:22][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Clc1c2c(nc3ccccc13)CCCC2
Reactant: NOCc1ccccc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCO
Product: Fc1ccccc1CONc1c2c(nc3ccccc13)CCCC2

Procedure:
A mixture of 9-chloro-1,2,3,4-tetrahydroacridine (6.18 g) and O-(2-fluorobenzyl)hydroxylamine hydrochloride (5.5 g) in 125 ml of n-propanol was heated at reflux for 20 hours. The reaction mixture was then added to an iced sodium bicarbonate solution and extracted with ethyl acetate (3×). The combined organics were washed with water and dried (saturated NaCl, MgSO4).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6]1)=[O:4].[C:15]([CH2:19][CH2:20][CH:21]([CH3:25])[C:22](Cl)=[O:23])([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>O>[CH3:1][O:2][C:3]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]1[C:22](=[O:23])[CH:21]([CH3:25])[CH2:20][CH2:19][C:15]([O:17][CH3:18])=[O:16])=[O:4]
Reactant: COC(=O)C1CCc2ccccc2N1
Reactant: COC(=O)CCC(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)CCC(C)C(=O)N1c2ccccc2CCC1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of 1.0 g of 1,2,3,4-tetrahydroquinoline-2-carboxylic acid methyl ester (Ber. 61,2377), 0.87 g of 4-carbomethoxy-2-methylbutanoyl chloride, 1.44 g of powdered potassium carbonate and 20 ml of methylene chloride is stirred at room temperature overnight. It is cooled with ice, and 50 ml of water are added. The organic layer is separated, washed with N-hydrochloric acid and water, dried and evaporated, to yield the 1-(4-carbomethoxy-2-methylbutanoyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid methyl ester, showing NMR-peaks at 0.85, 1.25, 3.35, 3.65 and 3.75 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:21])[CH2:12][NH:13][C:14]2[C:15](=[O:20])[NH:16][N:17]=[CH:18][CH:19]=2)[CH2:7][CH2:6]1.Br[CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35]>>[Cl:1][C:2]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:21])[CH2:12][NH:13][C:14]2[C:15](=[O:20])[N:16]([CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[N:17]=[CH:18][CH:19]=2)[CH2:7][CH2:6]1
Reactant: O=C(CNc1ccn[nH]c1=O)N1CCC(Oc2cc(C(F)(F)F)ccc2Cl)CC1
Reactant: CC(C)CCCBr
Product: CC(C)CCCn1nccc(NCC(=O)N2CCC(Oc3cc(C(F)(F)F)ccc3Cl)CC2)c1=O
Yield: 33 %

Procedure:
Compound 47 is prepared from intermediate 7b and from 1-bromo-4-methyl-pentane following synthesis method 6 (yield: 33%).
Reaction SMILES: [CH3:1][CH:2]([O:27][C:28](=[O:30])[CH3:29])[C:3](=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[C:18](=[O:26])[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)N1CCCCC1>C(#N)C>[CH3:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]2[C:12]=1[C:18](=[O:26])[N:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:3]([CH:2]([O:27][C:28](=[O:30])[CH3:29])[CH3:1])=[N:10]2
Reactant: CC(=O)OC(C)C(=Nc1cccc(C)c1C(=O)Nc1ccccc1)N1CCCCC1
Solvent: CC#N
Product: CC(=O)OC(C)c1nc2cccc(C)c2c(=O)n1-c1ccccc1

Procedure:
Compound 179 (0.037 g, 0.09 mmol) was dissolved in acetonitrile (10 mL) and the reaction mixture was heated at reflux for 3 h. The solvent was removed under reduced pressure and the residue dissolved in a mixture of ethyl acetate (10 mL) and 1M HCl (5 mL). After separating the aqueous layer, the organic layer was washed with additional 1M HCl (2×5 mL), saturated sodium bicarbonate solution (3×5 mL), water (2×5 mL) and saturated brine (5 mL). The solution was dried (MgSO4), filtered, and the filtrate concentrated under reduced pressure to give compound 180. ESI-MS m/z=323 (MH+). The product had nearly totally racemized at this point (chiral purity was 46:54 S:R). The reaction described above and compound 180 are shown below.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][CH:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)CCNC2=O
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc2c(=O)[nH]ccc2c1
Temperature: 100 °C
Yield: 46.1 %

Procedure:
6-tert-Butyl-3,4-dihydro-2H-isoquinolin-1-one (1.709 g, 8.4 mmol) and 2,3-5,6-dicyano-p-benzoquinone (DDQ) (3.85 g, 2 eq) were taken up in dioxane (130 mL) and the resulting mixture was heated to 100° C. for four days. After allowing to cool to room temperature, most of the dioxane was removed under reduced pressure at 55° C. Ethyl acetate (300 mL) and 2N NaOH (100 mL) were added to the residue and the mixture was partitioned and the layers were sepearated. Subsequently washed again with 2N NaOH (3×100 mL), water (1×125 mL) and finally with brine (1×125 mL). The ethyl acetate layer was dried over magnesium sulfate, filtered and concentrated to give the crude product (1.783 G). Purification on silica gel eluting with 30% ethyl acetate in hexanes afforded the title compound (779 mg) as a light tan powder. MS (ESI) 202.0 (M+H)+.
Reaction SMILES: C(N[C@H](C(O)=O)CC(C)C)(OC(C)(C)C)=[O:2].[CH2:17]([O:24][C:25](=[O:42])[CH:26]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[N:27]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:28][CH:29]=[CH2:30])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(Br)C=C>C1COCC1>[CH2:17]([O:24][C:25](=[O:42])[CH:26]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[N:27]([C:31]([CH3:32])([CH3:33])[CH3:34])[CH2:28][CH2:29][CH2:30][OH:2])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C=CCN(C(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(C)(C)C
Solvent: C1CCOC1
Solvent: C=CCBr
Product: CC(C)(C)OC(=O)C(C(=O)OCc1ccccc1)N(CCCO)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
BOC-L-leucine is converted to racemic BOC-(2-isobutyl)-allyl glycine benzyl ester using essentially the procedures of Example 20, Steps A and B, substituting allyl bromide in the alkylation step. The benzyl ester (2.07 g, 5.73 mmol) is dissolved in THF (40 ml), under nitrogen, 0.5M 9-borabicyclo[3.3.1]-nonane (9-BBN)in hexanes (46 ml, 23 mmol) is added and mixture stirred at room temperature for 16 hours. The reaction mixture is quenched with water (1 ml) and a mixture of 1N aqueous sodium hydroxide solution (51 ml) and 30% hydrogen peroxide solution (18 ml) is added dropwise. The mixture is stirred for 1 hour at room temperature, saturated with solid sodium chloride, then extracted with ether. The organic layer is washed with saturated sodium bicarbonate solution, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product is purified by flash chromatography, eluting with 20% ethyl acetate/hexanes to give BOC-(2-isobutyl)-3-hydroxypropyl glycine benzyl ester.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[SH:19][CH2:20][C@:21]12[C:27]([CH3:29])([CH3:28])[C@H:24]([CH2:25][CH2:26]1)[CH2:23][C@@:22]2([C:31]#[C:32][Si](C)(C)C)[OH:30].O>O1CCCC1>[CH3:28][C:27]1([CH3:29])[C@@H:24]2[CH2:25][CH2:26][C@:21]31[C@:22]([OH:30])([CH2:23]2)[C:31](=[CH2:32])[S:19][CH2:20]3
Reactant: CC1(C)[C@@H]2CC[C@@]1(CS)[C@@](O)(C#C[Si](C)(C)C)C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C=C1SC[C@]23CC[C@H](C[C@]12O)C3(C)C
Yield: 64.1 %

Procedure:
Tetrabutylammonium fluoride (0.5 mL of a 1.0M solution in tetrahydrofuran) was added to a solution of alcohol 2 (65 mg, 0.23 mmol) in tetrahydrofuran (5 mL) under nitrogen. After two hours water was added to the solution and the resulting mixture extracted with dichloromethane. The combined organic extracts were washed with brine and dried over MgSO4. After filtration and removal of the solvents under reduced pressure, chromatography with 5% ethyl acetate in petrol gave sulfide 3 (31 mg, 64%), [a]20D−90.5 (c 2.10 in CHCl3); umax (thin film)/cm−1 3483 (OH), 2942 (CH), 1701 (C═C), 1627 (C═C); dH (250 MHz; CDCl3) 0.97 (3H, s, CH3), 1.01-1.16 (1H, m), 1.27 (3H, s, CH3), 1.50-1.83 (4H, m), 1.96-2.10 (2H, m), 2.14 (1H, br s, OH), 2.52 (1H, d, J 9.0, CHHS), 3.22 (1H, d, J 9.0, CHHS), 4.93 (1H, d, J 1.0, ═CHH), 5.12 (1H, d, J 1.0, ═CHH); dC (63 MHz; CDCl3) 22.02 (CH3), 22.05 (CH3), 26.89 (CH2), 31.95 (CH2), 32.07 (CH2), 37.38 (CH2), 46.25 (C), 50.79 (CH), 61.68 (C), 93.20 (C), 101.39 (CH2), 151.81 (C); m/z (EI) 210 (M+, 30%), 108 (57), 95 (100), 81 (27), (Found; M+, 210.1085. C12H18OS requires 210.1078).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10]C)[CH:7]=[CH:6][C:4]=1[NH2:5].[F:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22]C)C(O)=O>>[F:12][C:13]1[CH:14]=[C:15]([C:1]2[O:2][C:3]3[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:4]=3[N:5]=2)[CH:19]=[CH:20][C:21]=1[OH:22]
Reactant: COc1ccc(N)c(OC)c1
Reactant: COc1ccc(C(=O)O)cc1F
Product: Oc1ccc2nc(-c3ccc(O)c(F)c3)oc2c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, from 2,4-dimethoxyaniline, and 3-fluoro-4-methoxybenzoic acid and was obtained as a white solid, m.p. 269-271° C.; MS m/e 244 (M−H)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[C:22]([O:26][C:27]([N:29]1[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1CCN2C(=NCCC2)CC1.[H-].[Na+]>CN(C=O)C>[C:22]([O:26][C:27]([N:29]1[CH2:33][CH2:32][CH:31]([O:34][C:11]2[CH:12]=[C:13]3[C:8]([C:7](=[O:16])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:15])[CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cn(C2CC2)c2cc(OC3CCN(C(=O)OC(C)(C)C)C3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 11 h
Yield: 40.5 %

Procedure:
To a mixture of 220 mg of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate, 280 mg of 1-t-butoxycarbonyl-3-hydroxypyrrolidine, 170 mg of DBU and 5 ml of DMF was added 65 mg of 55% sodium hydride while the former was stirred at room temperature. The resultant mixture was stirred for 2 hours at room temperature and then at 45° C. for 11 hours. The reaction mixture was concentrated to dryness under reduced pressure. Chloroform was added to the residue to dissolve the latter. The resultant solution was washed successively with a 10% aqueous solution of citric acid, a 5% aqueous solution of sodium hydrogencarbonate and saturated saline. The resulting chloroform layer was dried over anhydrous sodium sulfate and then concentrated. The residue was purified by chromatography on silica gel (chloroform/methanol: 100/1), whereby 140 mg of ethyl 7-(1-t-butoxycarbonyl-3-pyrrolidinyloxy)-1-cyclopropyl-6-fluoro1,4-dihydro-4-oxoquinoline-3-carboxylate was obtained.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C(N(CC)CC)C.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[C:14]([N:4]1[CH:3]=[C:2]([I:1])[CH:6]=[N:5]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Ic1cn[nH]c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)n1cc(I)cn1
Temperature: 100 °C
Reaction time: 4 h
Yield: 87.2 %

Procedure:
To a stirred solution of 4-iodopyrazole (10.30 g, 53.1 mmol) in toluene (50 mL) at r.t. was added triethylamine (8.10 mL, 58.1 mmol), followed by benzoyl chloride (8.20 g, 58.3 mmol). The reaction mixture was then heated to 100° C. and stirred for 4 h. The solid was filtered and washed with toluene (50 mL). The organic filtrate was diluted with EtOAc (100 mL), washed with water (3×50 ml), then brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. Recrystallisation from hexanes gave the title compound (13.80 g, 87%) as a white solid. δH (DMSO-d6) 8.77 (1H, s), 8.05 (1H, s), 8.02-7.95 (2H, m), 7.74-7.67 (1H, m), 7.61-7.53 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.[K+].[CH3:14][O:15][C:16](=[O:21])[CH2:17]C([O-])=O>>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](=[O:12])[CH2:17][C:16]([O:15][CH3:14])=[O:21]
Reactant: COC(=O)CC(=O)[O-]
Reactant: Cc1ccc(CC(=O)O)c(F)c1
Agent: [K+]
Product: COC(=O)CC(=O)Cc1ccc(C)cc1F

Procedure:
The title compound was prepared from 2-(2-fluoro-4-methylphenyl)acetic acid and 3-methoxy-3-oxopropanoic acid potassium salt according to the procedure for the preparation of Example 170, part A. 1H NMR (300 MHz, CDCl3): δ 2.35 (3H, s), 3.52 (2H, s), 3.74 (3H, s), 3.83 (2H, s), 6.89-6.95 (2H, m), 7.05-7.08 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9]3([C:16]=2[CH:17]=1)[C:13](=[O:14])NC(=O)[NH:10]3.[OH-].[Ba+2].[OH-].C(=O)([O-])[O-:22].[NH4+].[NH4+]>O>[NH2:10][C:9]1([C:13]([OH:14])=[O:22])[CH2:8][CH2:7][CH2:6][C:5]2[N:4]=[CH:3][C:2]([Cl:1])=[CH:17][C:16]1=2
Reactant: O=C1NC(=O)C2(CCCc3ncc(Cl)cc32)N1
Reactant: O=C([O-])[O-]
Agent: [Ba+2]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: NC1(C(=O)O)CCCc2ncc(Cl)cc21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
3-Chlorospiro-[5,6,7,8-tetrahydroquinolin-5,4'-imidazolidine]-2',5'-dione, (20 grams, 0.0795 mol) and barium hydroxide (50 grams, 0.159 mol) in water (300 ml) were heated at reflux for 48 hours. The solution was cooled to 50° C. and ammonium carbonate (16 grams, 0.167 mol) was added in portions. After 0.5 hours, the aqueous suspension was filtered and the solids washed with warm water. The filtrate was evaporated in vacuo to a solid. This was slurried in isopropanol (200 ml) was the solvent was again evaporated. The residual solid was suspended in isopropanol (125 ml) and ether (125 ml), granulated for 1 hour, and collected by filtration. The amino acid was dried in vacuo; 13.68 grams, 75% yield. mp 213°-14.5° C. (dec.) NMR (DMSO-d6, 300 MHz) δ8.46 (d, 1), 7.88 (d, 1), 3.5 (br s, NH3), 2.80 (t, 2), 2.27 (m, 1), 2.10 (m, 1), 1.88 (m, 2).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[C:19](Cl)(=[O:21])[CH3:20]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH:12][C:19](=[O:21])[CH3:20])=[N:9][C:8]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: Cc1nc(-c2sc(N)nc2-c2ccccc2)no1
Reactant: CC(=O)Cl
Product: CC(=O)Nc1nc(-c2ccccc2)c(-c2noc(C)n2)s1

Procedure:
Prepared from 5-(5-methyl-[1,2,4]oxadiazol-3-yl)-4-phenyl-thiazol-2-ylamine and acetyl chloride.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:17])[C@@H:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH3:8])[CH:2]=[CH2:3].[C:18]([O:22][C:23]([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](Br)=[CH:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[C:12]([O:11][C:10]([NH:9][C@@H:6]([CH2:7][CH3:8])[C:5]([NH:4][CH2:1]/[CH:2]=[CH:3]/[C:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:25]([C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[CH:26]=1)=[O:17])=[O:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: C=CCNC(=O)[C@H](CC)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)n1cc(Br)c2ccccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)NC/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 90 °C

Procedure:
A 50 mL sealed tube was charged with (S)-tert-butyl 1-(allylamino)-1-oxobutan-2-ylcarbamate (500 mg, 2.07 mmol), 3-bromo-indole-1-carboxylic acid tert-butyl ester (620 mg, 2.09 mmol), palladium (II) acetate (59 mg, 0.263 mmol), tri-o-tolylphosphine (180 mg, 0.591), acetonitrile (10 mL), and triethylamine (0.6 mL, 4.30 mmol). The tube was flushed with argon and sealed, then stirred and heated to 90° C. for 24 h. The resulting mixture was concentrated in vacuo and the resulting residue purified via flash silica gel chromatography (Analogix IF-280, SF65-150 g column, gradient 90:10-50:50 Heptane:EtOAc) to yield (S,E)-tert-butyl 3-(3-(2-(tert-butoxycarbonylamino)butanamido)prop-1-enyl)-1H-indole-1-carboxylate. 1H NMR (300 MHz, CDCl3) δ 7.58 (s, 1H), 7.23-7.36 (m, 4H), 6.60-6.66 (m, 1H), 6.20-6.51 (m, 1H), 4.05-4.11 (m, 1H), 3.86-3.91 (m, 2H), 1.83-1.93 (m, 1H), 1.59-1.72 (m, 1H), 1.44 (s, 18H), and 0.95 (t, J=7.4 Hz, 3H).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7](B(O)O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:12][C:13]1[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=1>>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:7]2[S:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=2)=[CH:15][CH:14]=1
Reactant: Brc1ccc(I)cc1
Reactant: CC(=O)c1ccc(B(O)O)s1
Product: CC(=O)c1ccc(-c2ccc(Br)cc2)s1

Procedure:
1-(5-(4-Bromophenyl)thien-2-yl)ethanone is prepared from 5-acetyl-2-thiopheneboronic acid and 1-bromo-4-iodobenzene according to general procedure A.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([NH:16][CH2:17][C:18]([N:20]([C:22]2[C:23]([Cl:43])=[C:24]([C:39]([Cl:42])=[CH:40][CH:41]=2)[CH2:25][O:26][C:27]2[C:35]3[N:34]=[C:33]([O:36][CH3:37])[N:32]([CH3:38])[C:31]=3[CH:30]=[CH:29][CH:28]=2)[CH3:21])=[O:19])=[O:15])=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[C:4]([C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([NH:16][CH2:17][C:18]([N:20]([C:22]2[C:23]([Cl:43])=[C:24]([C:39]([Cl:42])=[CH:40][CH:41]=2)[CH2:25][O:26][C:27]2[C:35]3[N:34]=[C:33]([O:36][CH3:37])[N:32]([CH3:38])[C:31]=3[CH:30]=[CH:29][CH:28]=2)[CH3:21])=[O:19])=[O:15])=[CH:8][CH:7]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(/C=C/C(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4C)c2Cl)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(C(=O)O)nc4)c3Cl)cccc2n1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.2 %

Procedure:
To a solution of 4-[3-[N-[(E)-3-(6-ethoxycarbonylpyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1-methyl-1H-benzimidazole (304 mg) in ethanol was added 1N sodium hydroxide solution (0.5 ml), and the mixture was stirred for 1.5 hours at ambient temperature. The solvent was removed, water was added to the residue. The mixture was adjusted to pH 4 with 1N hydrochloric acid and extracted with chloroform. The extract was dried and evaporated in vacuo. Acetonitrile was added to the residue, and the residue was collected by filtration to give 4-[3-[N-[(E)-3-(6-carboxypyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1-methyl-1H-benzimidazole (195 mg).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:11][CH:5]2[C:6](=[O:10])O[C:8](=[O:9])[CH:4]2[CH2:3]1.[F:12][C:13]([F:23])([F:22])[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1>>[CH2:1]=[C:2]1[CH2:3][CH:4]2[C:8](=[O:9])[N:21]([C:18]3[CH:19]=[CH:20][C:15]([O:14][C:13]([F:12])([F:22])[F:23])=[CH:16][CH:17]=3)[C:6](=[O:10])[CH:5]2[CH2:11]1
Reactant: C=C1CC2C(=O)OC(=O)C2C1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Product: C=C1CC2C(=O)N(c3ccc(OC(F)(F)F)cc3)C(=O)C2C1
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
A mixture of 5-Methylene-tetrahydro-cyclopenta[c]furan-1,3-dione (2.8 g, 18.4 mmol) and 4-(trifluoromethoxy)benzenamine (2.6 g, 14.7 mmol) was stirred at 180° C. for 0.5 h. The mixture was cooled to room temperature and purified by silica gel column (petroleum/ethyl acetate=5/1) to yield the title compound (3.0 g, 66%). 1H NMR (300 MHz, CDCl3): δ 7.33-7.26 (m, 4H), 4.99 (s, 2H), 3.44-3.41 (m, 2H), 2.84-2.78 (m, 4H); LC-MS: [M+1]+ 312.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([F:10])=[CH:8][C:7]([OH:11])=[CH:6][C:5]=1[F:12].Br.Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[CH3:1][O:2][C:3](=[O:13])[C:4]1[C:5]([F:12])=[CH:6][C:7]([O:11][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:8][C:9]=1[F:10]
Reactant: BrCc1ccccn1
Reactant: COC(=O)c1c(F)cc(O)cc1F
Agent: Br
Product: COC(=O)c1c(F)cc(OCc2ccccn2)cc1F

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure E from 2,6-Difluoro-4-hydroxy-benzoic acid methyl ester and 2-(bromomethyl)pyridine hydrobromide. MS (ES+) 280