Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C1COCC1.CCCCCCC.[F:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.[C:28]([O:33][CH2:34][CH3:35])(=[O:32])[C:29]([CH3:31])=[O:30].Cl>C1COCC1.O.CCOCC>[F:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[C:29]([CH3:31])([OH:30])[C:28]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: Fc1cccnc1
Reactant: CCOC(=O)C(C)=O
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: CCCCCCC
Product: CCOC(=O)C(C)(O)c1ccncc1F
Temperature: -60 °C
Yield: 54.4 %

Procedure:
A 27 ml portion of commercially-available 2.03M lithium diisopropylamide-THF/heptane solution (Lithco) was diluted with 50 mL of dry THF, cooled to -60° C. under nitrogen, and stirred while adding a solution of 4.3 mL (4.8 g, 50 mmol) of 3-fluropyridine in 10 mL of dry THF at a rate that held the mixture below -55° C. The resulting slurry was stirred at -60° C. for another 30 minutes, and then with continued cooling and stirring a solution of 6.0 mL (6.4 g, 55 mmol) of ethyl pyruvate in 30 mL of dry THF was added as quickly as possible while maintaining an internal temperature of -60° C. The resulting thin slurry was allowed to come to -10° C., then diluted with 200 mL each of water and ether. The aqueous phase was adjusted to pH 7 by addition of 1N aqueous HCl, the ether phase was separated, the aqueous phase was extracted with two 100 mL portions of ether, and the combined ether phases were washed with three 100-mL portions of water and 100 mL of brine, dried over magnesium sulfate, and evaporated to leave 5.8 g of a dark brown oil. Chromatography over silica gel, eluting with methylene chloride-methanol 99:1, provided 3.7 g (35%) of the title compound as a pale yellow solid: mp 56°-60° C.; IR (Nujol) 2600-3400, 1755, 1730 cm-1 ; NMR (CDCl3, 200 MHz) 1.2 (3H, t, J=7), 1.8 (3H, s), 3.9 (1H, s), 4.3 (2H, q, J=7), 7.5 (1H d of d, J=5,7), 8.4-8.5 (2H, m).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Cl:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([OH:18])[CH:17]=1>>[Cl:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([O:18][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH:17]=1
Reactant: Oc1cncc(Cl)c1
Reactant: O=[N+]([O-])c1ccccc1F
Product: O=[N+]([O-])c1ccccc1Oc1cncc(Cl)c1
Yield: 96.4 %

Procedure:
2-Fluoro-nitrobenzene (5.0 g) and 3-chloro-5-hydroxypyridine (4.59 g) were combined at 80° C. for 1 hr, using a method similar to that of Example 21.2 to provide 8.56 g of 2-(3-chloro-5-pyridyloxy)nitrobenzene.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[OH:29]>>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[O:29][C:15]1[CH:16]=[CH:17][C:12]([C:11]([NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:2])=[O:20])=[O:19])=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccccc1NC(=O)c1ccc(I)cc1
Reactant: Oc1ccc(F)cc1F
Product: O=C(Nc1ccccc1C(=O)O)c1ccc(Oc2ccc(F)cc2F)cc1

Procedure:
In analogy to example 2,-[4-(2,4-Difluoro-phenoxy)-benzoylamino]-benzoic acid was prepared from 2-(4-iodo-benzoylamino)-benzoic acid methyl ester [75541-84-3] and 2,4-difluoro-phenol. MS (m/e): 367.1 (M−H−, 100%).
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:9])=[C:6]([NH:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[N:5]=1)(=[NH:3])[NH2:2].[N:30]#[C:31]Br.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:31]([NH:3][C:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:9])=[C:6]([NH:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[N:5]=1)=[NH:2])#[N:30]
Reactant: N=C(N)c1ccc(C(=O)NCc2cccnc2)c(NCCc2cccc(F)c2)n1
Reactant: N#CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#CNC(=N)c1ccc(C(=O)NCc2cccnc2)c(NCCc2cccc(F)c2)n1
Yield: 40.9 %

Procedure:
A mixture of 6-carbamimidoyl-2-(3-fluorophenethylamino)-N-(pyridin-3-ylmethyl)nicotinamide (0.013 g, 0.034 mmol), CNBr (3N, 0.017 mL, 0.051 mmol), DIPEA (0.0085 mL, 0.051 mmol), in DCM (0.10 mL) was stirred at room temperature until the reaction was complete. The reaction mixture was concentrated to dryness and purified by RP-HPLC using a mixture of acetonitrile and H2O to give 6-(N-cyanocarbamimidoyl)-2-(3-fluorophenethylamino)-N-(pyridin-3-ylmethyl)nicotinamide as a solid (0.0058 g, 41%). LC/MS (M+H+) m/z 418.1.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([S:20](Cl)(=O)=O)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1>O1CCCC1>[F:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([SH:20])=[CH:16][CH:15]=2)=[CH:12][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(F)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1ccc(-c2ccc(S)cc2)cc1
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
Lithium aluminum hydride (0.95 grams, 25 mmole) was added in portions to a stirred solution of 4'-fluorobiphenyl-4-sulfonylchloride (2.7 grams, 10 mmole) in tetrahydrofuran (75 mL). The resulting mixture was heated at reflux for 4 hours, cooled in an ice bath and quenched by addition of 10% aqueous sulfuric acid solution (100 mL). After stirring for 30 minutes, the mixture was filtered through Celite™ and the tetrahydrofuran was removed under vacuum. The residue was diluted with water and extracted with diethyl ether. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated under vacuum to a solid. Trituration of the solid with diethyl ether, removal of insoluble material by filtration and concentrated of the filtrate provided the title compound as a yellow solid (1.4 grams, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]O.P(Br)(Br)[Br:11]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][Br:11]
Reactant: OCc1cccc(Cl)c1
Reactant: BrP(Br)Br
Solvent: C1CCOC1
Product: Clc1cccc(CBr)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 260 ul of 3-chlorobenzyl alcohol dissolved in 2.5 ml of dry tetrahydrofuran is cooled to 0° C. and 120 ul of PBr3 added. The reaction is stirred for 3 hours and extracted with ether. The organic layer is washed with saturated sodium bicarbonate and evaporated to give the desired product.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:10])=[C:5]([C:7]([OH:9])=O)[N:6]=1.O1CCCC1.S(Cl)(Cl)=O.[NH2:20][C:21]1[CH:22]=[C:23]([CH:40]=[CH:41][C:42]=1[CH3:43])[O:24][C:25]1[CH:26]=[CH:27][C:28]2[N:29]([N:31]=[C:32]([NH:34][C:35]([CH:37]3[CH2:39][CH2:38]3)=[O:36])[N:33]=2)[CH:30]=1>CN(C)C=O.CN(C)C(=O)C>[CH:37]1([C:35]([NH:34][C:32]2[N:33]=[C:28]3[CH:27]=[CH:26][C:25]([O:24][C:23]4[CH:40]=[CH:41][C:42]([CH3:43])=[C:21]([NH:20][C:7]([C:5]5[N:6]=[C:2]([CH3:1])[O:3][C:4]=5[CH3:10])=[O:9])[CH:22]=4)=[CH:30][N:29]3[N:31]=2)=[O:36])[CH2:38][CH2:39]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1N
Reactant: Cc1nc(C(=O)O)c(C)o1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: Cc1nc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)ccc2C)c(C)o1
Yield: 83.1 %

Procedure:
In the same manner as in Example 55 and using 2,5-dimethyl-1,3-oxazole-4-carboxylic acid (65.0 mg, 0.462 mmol), tetrahydrofuran (5 mL), thionyl chloride (77.0 μL, 0.888 mmol), N,N-dimethylformamide (2 drops), N-[6-(3-amino-4-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (129 mg, 0.399 mmol) and N,N-dimethylacetamide (6 mL) as starting materials, the title compound (148 mg, 83%) was obtained as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:23])[CH2:3][CH2:2]1.Cl.O1CCOCC1.[C:31]([C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1)#[N:32].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO>[C:31]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37][N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[CH:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[NH:9][C:8]3=[O:23])[CH2:5][CH2:6]2)=[CH:35][CH:34]=1)#[N:32]
Reactant: O=C1Nc2ccccc2C(c2ccccc2)N1C1CCNCC1
Reactant: N#Cc1ccc(C=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CO
Solvent: C1COCCO1
Product: N#Cc1ccc(CN2CCC(N3C(=O)Nc4ccccc4C3c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of 100 mg (0.32 mmol) of 3-(piperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone in 3 ml of methanol, 0.08 ml (0.32 mmol) of 4N hydrochloric acid/dioxane, 170 mg (1.3 mmol) of 4-cyanobenzaldehyde, 82 mg (1.3 mmol) of sodium cyanoborohydride were added subsequently under ice-cooling, and stirred at room temperature for 10 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extracting with ethyl acetate, washing with water and saturated brine, and drying over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform—2% methanol/chloroform) to give the title compound as colorless oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:48]=[CH:47][CH:46]=[CH:45][C:4]=1[C:5]([O:7][C@:8]([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=1[F:44])([CH2:31][N:32]1[CH:36]=[N:35][CH:34]=[N:33]1)[C@H:9]([S:11][C@@H:12]1[CH2:17][O:16][C@@H:15](/[CH:18]=[CH:19]/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][C:23]=2[F:30])[O:14][CH2:13]1)[CH3:10])=[O:6].[CH3:49][N:50]([CH3:55])[CH2:51][C:52](O)=[O:53].[Cl-].ClC1N(C)CC[NH+]1C.CN1CCN(C)C1=O>ClCCl.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH3:49][N:50]([CH2:51][C:52]([O:1][CH2:2][C:3]1[CH:48]=[CH:47][CH:46]=[CH:45][C:4]=1[C:5]([O:7][C@:8]([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=1[F:44])([CH2:31][N:32]1[CH:36]=[N:35][CH:34]=[N:33]1)[C@H:9]([S:11][C@@H:12]1[CH2:17][O:16][C@@H:15](/[CH:18]=[CH:19]/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][C:23]=2[F:30])[O:14][CH2:13]1)[CH3:10])=[O:6])=[O:53])[CH3:55]
Reactant: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@@](Cn1cncn1)(OC(=O)c1ccccc1CO)c1ccc(F)cc1F
Reactant: CN(C)CC(=O)O
Agent: CN(C)c1ccncc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CN1CCN(C)C1=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@@](Cn1cncn1)(OC(=O)c1ccccc1COC(=O)CN(C)C)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (1R,2R)-2-[[trans-2-[(1E,3E)-4-(4-cyano-2-fluorophenyl)-1,3-butadienyl]-1,3-dioxan-5-yl]thio]-1-(2,4-difluorophenyl)-1-[(1H-1,2,4-triazol-1-yl)methyl]propyl 2-(hydroxymethyl)benzoate (640.7 mg, 0.95 mmol) obtained from Example 17-(4) in dichloromethane (20 ml) was cooled to 0° C., and then 4-(N,N-dimethylamino)pyridine (254.5 mg, 2.1 mmol), N,N-dimethylglycine (117.2 mg, 1.14 mmol), and 2-chloro-1,3-dimethylimidazolinium chloride (256.1 mg, 1.52 mmol) were added thereto. The reaction mixture was stirred at room temperature for 3 hours, diluted with ethyl acetate, and then the organic layer was washed successively with a saturated aqueous solution of ammonium chloride and with a saturated aqueous solution of sodium chloride. The solvent was evaporated under reduced pressure, and then the residue was subjected to chromatography on a silica gel (40 g) column (eluent; ethyl acetate:methanol=100:3) to give a mixture of the title compound and 1,3-dimethyl-2-imidazolidinone. The mixture was purified by recycle preparative HPLC [LC-908; Japan Analytical Industry Co., Ltd.; GPC column JAIGEL-1H (20 mm i.d. ×600 mm) and JAIGEL-2H (20 mm i.d. ×600 mm) connected in series for use; solvent, chloroform] to afford the title target compound (368.1 mg, 51% yield) as a colorless amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:12][C:13]1[NH:14][CH2:15][CH2:16][N:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[ClH:1].[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([S:8][CH2:12][C:13]2[NH:17][CH2:16][CH2:15][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(S)cccc1Cl
Reactant: ClCC1=NCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1c(Cl)cccc1SCC1=NCCN1
Reaction time: 25 h

Procedure:
5.55 g (35 mmol) of 3-chloro-2-methyl-thiophenol, 5.43 g (35 mmol) of 2-chloromethyl-2-imidazoline hydrochloride and 5 g of potassium carbonate are stirred in 40 ml of ethanol at room temperature. After 25 h, the mixture is filtered and the filtrate is concentrated to dryness. The crude product is purified by column chromatography on silica gel. After the eluting agent has been stripped off, ethanolic hydrochloric acid is added to the residue and the product is precipitated by addition of ether. White crystals of melting point 208°-209° C. are obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][N:17]=1)[C:11]([O:13][CH3:14])=[O:12].[CH3:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1B(O)O.Cl>C(Cl)Cl.Cl[Pd]Cl.CO>[ClH:7].[CH3:18][C:19]1[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:20]=1[C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][N:17]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: Cc1cc(C(F)(F)F)ccc1B(O)O
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccnc(-c2ccc(C(F)(F)F)cc2C)c1
Temperature: 100 °C
Yield: 86.1 %

Procedure:
Potassium carbonate (2.66 g, 19.23 mmol), methyl 2-chloroisonicotinate (5.5 g, 32.05 mmol), 2-methyl-4-(trifluoromethyl)phenylboronic acid (8.50 g, 41.67 mmol), PdCl2 (dppf) (0.696 g, 0.96 mmol), and MeOH (50.3 mL) were split into three microwave vials and heated in a single node microwave reactor to 100° C. for 20 min. Diluted with DCM, filtered and evaporated. Purified by flash chromatography using 5% EtOAc in heptane ->20% EtOAc over 10 CV at 280 nm. The residue was dissolved in ether and hydrogen chloride (4 M in dioxane, 8.01 mL, 32.05 mmol) was added and the solvents evaporated to yield methyl 2-(2-methyl-4-(trifluoromethyl)phenyl)isonicotinate hydrochloride (9.15 g, 86%) as a white solid. 1H NMR (400 MHz, cd3od) δ 2.41 (s, 3H), 4.03 (s, 3H), 7.63-7.76 (m, 3H), 8.27 (dd, 1H), 8.33 (dd, 1H), 8.99 (dd, 1H). MS m/z 296 (M+H)+
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:46])[CH2:6][C@@H:7]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([O:44][CH3:45])[CH:37]=1)[NH:8][C:9]([C@@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17](=[O:33])/[CH:18]=[CH:19]/[CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)[CH2:12]1)=[O:10].CCO>O.O1CCCC1>[C:29]([O:28][C:26]([N:23]1[CH2:24][CH2:25][CH:20](/[CH:19]=[CH:18]/[C:17]([N:13]2[CH2:14][CH2:15][CH2:16][C@@H:11]([C:9]([NH:8][C@H:7]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([O:44][CH3:45])[CH:37]=3)[CH2:6][C:5]([OH:46])=[O:4])=[O:10])[CH2:12]2)=[O:33])[CH2:21][CH2:22]1)=[O:27])([CH3:31])([CH3:30])[CH3:32]
Reactant: COC(=O)C[C@@H](CCc1ccc(OC)c(OC)c1)NC(=O)[C@@H]1CCCN(C(=O)/C=C/C2CCN(C(=O)OC(C)(C)C)CC2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COc1ccc(CC[C@H](CC(=O)O)NC(=O)[C@@H]2CCCN(C(=O)/C=C/C3CCN(C(=O)OC(C)(C)C)CC3)C2)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
A solution of LiOH (0.11 g) in H2O (10 ml) was added to a solution of N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-3(R)-(3,4-dimethoxyphenethyl)-β-alanine methyl ester (1.83 g) in tetrahydrofuran (10 ml)-EtOH (10 ml) at 0° C. The reaction mixture was stirred for 3 hours at room temperature, and the solvent was evaporated in vacuo. The residue was resolved in ethyl acetate-water, and acidified with 10% aq. KHSO4. The whole was washed with water and brine, dried over MgSO4, and evaporated in vacuo to give N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-3(R)-(3,4-dimethoxyphenethyl)-β-alanine as a colorless oil (1.33 g, 74.4%).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:10]=[C:11]([NH2:17])[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[F:18][C:19]1[CH:20]=[C:21]([N:26]=[C:27]=[O:28])[CH:22]=[CH:23][C:24]=1[F:25]>C(Cl)Cl>[F:18][C:19]1[CH:20]=[C:21]([NH:26][C:27]([NH:17][C:11]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([C:8]3[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][CH:7]=3)[CH:10]=2)=[O:28])[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: COc1ccc(N)cc1-c1ccnn1C(C)C
Reactant: O=C=Nc1ccc(F)c(F)c1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(F)c(F)c2)cc1-c1ccnn1C(C)C
Reaction time: 8 h
Yield: 46.6 %

Procedure:
To a solution of 3-(2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.1 g, 0.433 mmol) in CH2Cl2, was added 3,4-difluoro phenyl isocyanate (0.067 g, 0.476 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 46 as a colorless solid (0.078 g, 42%). LCMS m/z (%)=387 M+H+, (100), 1H NMR (400 MHz, acetone-d6) δ: 8.45 (bs, 1H), 8.27 (bs, 1H), 7.65-7.59 (m, 3H), 7.485 (d, J=2.56 Hz, 1H), 7.228-7.009 (m, 4H), 6.245 (d, J=1.73 Hz, 1H), 4.36 (m, 1H), 3.82 (s, 3H), 1.418 (d, J=6.61 Hz, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([C:13]([O:15]CC2C=CC=CC=2)=[O:14])=[C:11]([Cl:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+]>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([C:13]([OH:15])=[O:14])=[C:11]([Cl:25])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)c1ccc(OCc2ccccc2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Product: O=C(O)c1ccc(OCc2ccccc2)cc1Cl
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 97.1 %

Procedure:
To benzyl 4-benzyloxy-2-chlorobenzoate (1.12 g) were added ethanol (8.8 ml), 1,4-dioxane (2.2 ml) and 1N aqueous sodium hydroxide solution (4.7 ml) and the mixture was stirred at 70° C. for 1.5 hr. The solvent was evaporated and water was added to the residue for dissolution, which was washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and the precipitate was collected by filtration to give 4-benzyloxy-2-chlorobenzoic acid (810 mg) as a pale-yellow powder.
Reaction SMILES: [CH:1]1([C:4]([NH:6][CH:7]([CH2:13][SH:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=O)[CH2:3][CH2:2]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[S:14][CH:13]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(CS)NC(=O)C1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1csc(C2CC2)n1

Procedure:
A solution of ethyl 2-(cyclopropanecarboxamido)-3-mercaptopropanoate (example 57, step a) (5 g) and tosic acid (0.875 g) in toluene (100 mL) was heated at reflux under Dean and Stark conditions overnight. The reaction was allowed to cool and the toluene solution was washed with saturated sodium hydrogen carbonate solution (3×100 mL) dried over sodium sulphate, filtered and evaporated. The resulting brown gum was redissolved in acetonitrile (100 mL). Manganese dioxide (40 g) was added and the mixture heated at reflux overnight. The reaction was filtered through Celite and the filter pad washed with MeCN (3×100 mL). The combined filtrate and washings were evaporated and the residue purified by silica gel chromatography eluting with 9:1 to 4:1 isohexane:ethyl acetate gradient. The fractions containing product were combined and evaporated to give the subtitled compound as a clear oil. Yield 0.15 g.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH:14]([OH:16])[CH:13]([CH:17]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:18][CH:19]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:12]1)=O)C1C=CC=CC=1>CO>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH:19]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)[O:18][CH:17]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:13]2[CH2:12][NH:11][CH2:15][CH:14]2[OH:16])=[CH:25][CH:24]=1
Reactant: COc1ccc(C(OC(c2ccccc2)C2CN(C(=O)OCc3ccccc3)CC2O)c2ccc(OC)cc2)cc1
Solvent: CO
Product: COc1ccc(C(OC(c2ccccc2)C2CNCC2O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
Compound 75 (8.25 g, 14.9 mmol) was dissolved in methanol (20 mL) and purged with argon. To the solution was added 10% palladium on carbon (0.825 g). The flask was purged with hydrogen 2 times and stirred further at room temperature under hydrogen atmosphere for 3 h. The disappearance of the starting material was confirmed by the TLC. The reaction mixture was filtered through a pad of Celite and washed with methanol. The combined organic layer was concentrated under reduced pressure to afford amine 76 (6.12 g, 98%) as white solid. This was used as such for the next step.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:9](=[CH2:10])[NH:8][CH:7]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:6]=1)=[O:4].[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>O1CCCC1>[CH3:10][C:9]1[NH:8][C:7]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:6][C:5]=1[C:3](=[O:4])[CH2:2][N:26]1[CH2:27][CH2:28][N:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:24][CH2:25]1
Reactant: C=C1NC(c2cccnc2)N=C1C(=O)CBr
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1[nH]c(-c2cccnc2)nc1C(=O)CN1CCN(c2ccccc2)CC1
Reaction time: 1 h
Yield: 50.7 %

Procedure:
To a stirred suspension of 4 g of 2-bromo-1-[5-methyyl-2-(3-pyridinyl)-1H-imidazol-4-yl]ethanone in 50 ml of dry tetrahydrofuran was added rapidly a mixture of 2.3 g of 1-phenylpiperazine and 1.4 g of triethylamine in 5 ml of dry tetrahydrofuran. This mixture was stirred for one hour and then filtered. Evaporation of the filtrate left a gummy foam which became amorphous upon trituration with 200 ml of ether. This solid was collected, washed with ether, suspended in 6 ml of acetone and stirred for 15 minutes. The solid was collected, washed repeatedly with acetone and then dried, giving 2.6 g of the desired intermediate, mp 141°-152° C. (dec.).
Reaction SMILES: [NH2:1]N.C[N:4](/[CH:6]=[C:7]1/[CH2:8][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][C:11]/1=O)C>C(O)C>[N:1]1[NH:4][CH:6]=[C:7]2[CH2:8][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][C:11]=12
Reactant: NN
Reactant: CN(C)/C=C1/CN(C(=O)OC(C)(C)C)CC1=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1Cc2c[nH]nc2C1

Procedure:
A solution of hydrazine (3 mL) and tert-butyl(3Z)-3-[(dimethylamino)methylene]-4-oxopyrrolidine-1-carboxylate (19.22 g) in ethanol (40 mL) was heated at 85° C. in a sealed tube for 4 h. Solvent was removed under reduced pressure, and the residue was triturated with dichloromethane (160 mL) and ethyl acetate (15 mL). The resulting solid was filtered. The filtrate was concentrated and the resulting solid was triturated again and filtered. The combined solids were used without further purification. LC/MS: 210.1 (M+1).
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:20]=[CH:19][C:10]([CH2:11][CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[CH:9][CH:8]=1)([O:3]C)=[O:2].[OH-].[Na+].Cl>O>[C:1]([CH2:5][O:6][C:7]1[CH:20]=[CH:19][C:10]([CH2:11][CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[CH:9][CH:8]=1)([OH:3])=[O:2]
Reactant: COC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 12.5 °C
Reaction time: 2.5 h

Procedure:
A suspension of 5-[4-[(carbomethoxy)methoxy]benzyl]thiazolidine-2,4-dione obtained by following a procedure described in any of Examples 23-24 (135 g, 0.46 M) and water (540 ml, 4 times w/v) was taken in a round bottom flask fitted with a mechanical stirrer. Aq. sodium hydroxide solution (37 g of NaOH in 135 ml of water) was added slowly over a period of 5-10 minutes at 20-25° C. Stirring was continued at ambient temperature for a period of 2-3 h, while monitoring the reaction by TLC. After the completion of the reaction, the pH of the reaction mixture was adjusted to 2 using conc. HCl (temp. raises to 40-45° C.) and allowed to attain room temperature. The mass was cooled to 10-15° C. and the solid thus obtained was filtered and dried at 60-70° C. under 1-2 mm Hg of vacuum to afford 5-[4-[(carboxy)methoxy]benzyl]thiazolidine-2,4-dione (121 g, Y=99%, P=99.2%).