Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][C:3]=1[C:13]([OH:15])=[O:14].C[O-].[Na+].Cl[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].Cl(O)(=O)=O>CO.O.CN(C)C=O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:4][C:3]=1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1cc(O)c2ccccc2c1O
Reactant: CCOC(=O)CCl
Agent: C[O-]
Agent: [Na+]
Agent: [O-][Cl+2]([O-])O
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(C(=O)O)c(O)c2ccccc12
Reaction time: 0.17 h
Yield: 94.6 %

Procedure:
To 700 ml of dimethylformamide, 249 g (1.22 mol) of 1,4-dihydroxy-2-naphthoic acid was added, and the mixture was stirred under a nitrogen atmosphere. To the mixture, 490 ml (2.44 mols) of a 28% solution of sodium methoxide in methanol was added dropwise over 20 minutes. After 10 minutes, 150 g (1.22 mol) of ethyl chloroacetate was added dropwise over 30 minutes, and the mixture was stirred for 3 hours while keeping the temperature at 50° C. The reaction solution was poured into a mixture of 160 ml of concentrated chloric acid and 5 l of iced water, and the precipitated crystals were filtered off and dried to obtain 335 g (95% yield) of 1-hydroxy-4-ethoxycarbonylmethyloxy-2-naphthoic acid.
Reaction SMILES: CC([N:4]=C=NC(C)C)C.[C:10]([C:13]1[CH:45]=[CH:44][C:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]([O:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][O:39]3)[C:26]3[CH:27]=[CH:28][C:29]([O:35][CH3:36])=[C:30]([CH:34]=3)[C:31](O)=[O:32])=[CH:21][CH:20]=2)=[C:15]([CH2:46][CH2:47][CH3:48])[C:14]=1[OH:49])(=[O:12])[CH3:11].O.ON1C2C=CC=CC=2N=N1>ClCCl>[C:10]([C:13]1[CH:45]=[CH:44][C:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]([O:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][O:39]3)[C:26]3[CH:27]=[CH:28][C:29]([O:35][CH3:36])=[C:30]([CH:34]=3)[C:31]([NH2:4])=[O:32])=[CH:21][CH:20]=2)=[C:15]([CH2:46][CH2:47][CH3:48])[C:14]=1[OH:49])(=[O:12])[CH3:11]
Reactant: CC(C)N=C=NC(C)C
Reactant: CCCc1c(OCc2ccc(C(OC3CCCCO3)c3ccc(OC)c(C(=O)O)c3)cc2)ccc(C(C)=O)c1O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CCCc1c(OCc2ccc(C(OC3CCCCO3)c3ccc(OC)c(C(N)=O)c3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
Add N,N-diisopropylcarbodiimide (0.114 g, 0.902 mmol) to a solution of 5-[[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-2-methoxy-benzoic acid (0.450 g, 0.820 mmol) and 1-hydroxybenzotriazole hydrate (0.122 g, 0.902 mmol) in dichloromethane (0.2M). Stir the solution for 1 h at room temperature. Saturate the solution with ammonia gas and stir the solution for 24 h. Collect the precipitate as the title compound (0.440 g, 0.815 mmol, 98%): MS (m/z): 546 (M−1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C@H:5]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:31][N:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[N:6]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C.O>[CH2:1]([O:3][C:4](=[O:32])[C@H:5]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:31][N:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[NH2:6])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(-c2ccno2)cc1)N=C(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: CCOC(=O)[C@@H](N)Cc1ccc(-c2ccno2)cc1

Procedure:
Crude (±)-N-diphenylmethylene-3-[4-(5-isoxazolyl)-phenyl]-alanine ethyl ester (280 mg) was treated with p-toluenesulfonic acid monohydrate (100 mg) in acetonitrile (35 ml) and water (3.5 ml) at ambient temperature for 3.5 hours. After concentration the residue is extracted with ether and 1N sodium hydroxide, washed with brine, dried, and concentrated to give crude 3-[4-(5-isoxazolyl)-phenyl]-alanine ethyl ester.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([CH3:14])([CH3:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:74][CH:75]1[CH2:80][CH2:79][N:78]([CH3:81])[CH2:77][CH2:76]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([CH3:13])([CH3:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:74][CH:75]5[CH2:80][CH2:79][N:78]([CH3:81])[CH2:77][CH2:76]5)=[O:27])=[CH:24][CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(C)(C)C(=O)N4C)cc2)CC1
Reaction time: 0.25 h
Yield: 49.7 %

Procedure:
To a suspension of 0.0293 g (0.000072 mole) of 4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid (I-50a) in 3 mL of dimethylformamide was added 0.0156 g (0.00012 mole) of 1-hydroxybenzotriazole, 0.043 g (0.00011 mole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate and 0.08 mL (0.0005 mole) of ethyldiisopropylamine. The mixture was stirred for 15 minutes and then 0.0129 g (0.00011 mole) of 4-amino-1-methylpiperidine was added. The mixture was stirred for an additional 2.5 hours and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with 1 M sodium hydroxide, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (98:2-85:15) to give 0.0181 g of 4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methyl-piperidin-4-yl)-benzamide (I-50).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[H-].[Na+].I[CH2:32][CH2:33][CH3:34].CO>CN(C=O)C.O>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][CH:19]([CH2:22][O:23][CH2:32][CH2:33][CH3:34])[CH2:20][OH:21])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCCI
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(CO)CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CCCOCC(CO)NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At 0° C., 100 mg (0.26 mmol) of 8-[(2,6-difluorobenzyl)oxy]-N-(1,3-dihydroxypropan-2-yl)-2-methylimidazo[1,2-a]pyridine-3-carboxamide were initially charged in 2.4 ml of DMF, 7.1 mg (0.28 mmol) of sodium hydride (95%) were added and the mixture was stirred at 0° C. for 30 min. At 0° C., a solution of 35 mg (0.20 mmol) of iodopropane in 0.4 ml of DMF was then slowly added dropwise, and the mixture was stirred at RT overnight. Another 1.6 mg (0.064 mmol) of sodium hydride (95%) were added at room temperature, the mixture was stirred for 30 min, another 10.6 mg (0.064 mmol) of iodopropane were then added dropwise and the mixture was stirred at room temperature overnight. At RT, another 1.6 mg (0.064 mmol) of sodium hydride (95%) were then added, the mixture was stirred for 30 min and 10.6 mg (0.064 mmol) of iodopropane were then added dropwise, and the mixture was stirred at room temperature overnight. A little methanol was added, and the reaction mixture was poured into 20 ml of water and extracted twice with ethyl acetate. The combined organic phases were washed with aqueous saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The residue was purified by silica gel chromatography (mobile phase: cyclohexane:ethyl acetate=7:3, then dichloromethane:methanol=40:1). The crude product obtained was re-purified by preparative thick-layer chromatography (dichloromethane:methanol=20:1). This gave 44 mg of the target compound (38% of theory, purity 95%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:14]([OH:16])=O)=[C:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=1.C(N(C(C)C)CC)(C)C.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH2:48]([NH2:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:48]([NH:55][C:14]([C:4]1[S:3][C:2]([NH2:1])=[N:6][C:5]=1[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:16])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: Nc1nc(Cc2ccccc2)c(C(=O)O)s1
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(Cc2ccccc2)c(C(=O)NCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a solution of 2-amino-4-benzylthiazole-5-carboxylic acid (0.033 g, 0.14 mmol) and diisopropylethylamine (0.08 mL, 0.46 mmol) in N,N-dimethylformamide (5 mL) was added N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.039 g, 0.20 mmol), followed by the addition of 1-hydroxybenzotriazole (0.026 g, 0.19 mmol). After 30 minutes, benzylamine (0.02 mL, 0.18 mmol) was added. The reaction mixture was stirred at ambient temperature for 12 h, diluted with ethyl acetate, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography eluting with ethyl acetate/hexanes (5/95 to 100/0) to afford the title compound (0.029 g, 65% yield).
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10](Cl)=[N:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:15][NH2:16]>C(O)C>[C:1]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:15][NH2:16])=[N:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OCc1ccc(Cl)nc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OCc1ccc(NN)nc1

Procedure:
7.9 g (39.6 mmol) 5-(tert-butoxymethyl)-2-chloropyridine together with 19.8 g (395.6 mmol) hydrazine hydrate are divided into three portions of equal size and 15 ml ethanol are added to each portion. Each portion is reacted in a single mode microwave (CEM Explorer) at 170° C. for in each case 4 h. Thereafter, the three mixtures are combined and the solvent is removed. The residue is taken up in ethyl acetate and the mixture is washed once with saturated sodium bicarbonate solution. The aqueous phase is extracted once with ethyl acetate. The two ethyl acetate phases are combined and washed once with saturated sodium chloride solution. The mixture is dried over magnesium sulfate and the solvent is removed. The residue obtained is stirred in petroleum ether and the solid is filtered off.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[C:4]([F:18])[CH:3]=1.Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:21]=1[CH:34]=[O:35]>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:31])[CH3:32])[C:21]=2[CH:34]=[O:35])=[C:4]([F:18])[CH:3]=1
Reactant: CC1(C)OB(c2cc(F)c(Cl)cc2F)OC1(C)C
Reactant: CC(C)(C)OC(=O)Nc1nccc(Cl)c1C=O
Product: CC(C)(C)OC(=O)Nc1nccc(-c2cc(F)c(Cl)cc2F)c1C=O
Yield: 76 %

Procedure:
Prepared as described in Example 17, Part C by Suzuki coupling between 2-(4-chloro-2,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane) preparation described in Example 14, Part A) and tert-butyl 4-chloro-3-formylpyridin-2-ylcarbamate (Preparation described in Example 17, Part B) to afford tert-butyl 4-(4-chloro-2,5-difluorophenyl)-3-formylpyridin-2-ylcarbamate (3.7 g, 8.91 mmol, 76% yield) as a yellow solid. LC/MS (ESI) m/e 367.1 [(m)−, calcd for C17H16ClF2N2O3 367.1] LC/MS retention time (method E): tR=1.07 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:28])[C:7]=1[NH:8][C:9]1[N:13]([CH3:14])[C:12]2[C:15]3[CH2:16][C:17]([CH3:27])([CH3:26])[O:18][C:19]=3[C:20]([C:22]([O:24]C)=O)=[CH:21][C:11]=2[N:10]=1.[CH:29]1([C:32]2[CH:33]=[CH:34][C:35]([F:39])=[C:36]([CH:38]=2)[NH2:37])[CH2:31][CH2:30]1.C[Al](C)C>C1(C)C=CC=CC=1>[CH:29]1([C:32]2[CH:33]=[CH:34][C:35]([F:39])=[C:36]([NH:37][C:22]([C:20]3[C:19]4[O:18][C:17]([CH3:27])([CH3:26])[CH2:16][C:15]=4[C:12]4[N:13]([CH3:14])[C:9]([NH:8][C:7]5[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=5[Cl:28])=[N:10][C:11]=4[CH:21]=3)=[O:24])[CH:38]=2)[CH2:31][CH2:30]1
Reactant: Nc1cc(C2CC2)ccc1F
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cncc3Cl)n(C)c2c2c1OC(C)(C)C2
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cn1c(Nc2c(Cl)cncc2Cl)nc2cc(C(=O)Nc3cc(C4CC4)ccc3F)c3c(c21)CC(C)(C)O3
Yield: 31.7 %

Procedure:
The title compound was prepared following the procedure described for Example-143 by using methyl 2-((3,5-dichloropyridin-4-yl)amino)-1,7,7-trimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate (Intermediate-60, 0.100 g, 0.245 mmol), 5-cyclopropyl-2-fluoroaniline (Intermediate-47, 0.080 g, 0.529 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL), dry toluene (5.0 mL) to afford 0.042 g of the desired product. 1HNMR (DMSO-d6): δ 0.62 (d, J=5.4 Hz, 2H), 0.94 (d, J=8.4 Hz, 2H), 1.59 (s, 6H), 1.93 (m, 1H), 3.51 (s, 2H), 3.59 (s, 3H), 6.82 (m, 1H), 7.18 (t, J=8.7 Hz, 1H), 7.29 (s, 1H), 8.18 (d, J=7.2 Hz, 1H), 8.47 (s, 2H), 9.99 (br s, 1H), 10.92 (br s, 1H); MS [M]+: 540.20.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=3)=[CH:34][CH:33]=2)[C:19](=[O:30])[C:20]([C:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=2)=[C:21]([CH3:23])[N:22]=1)[CH2:14][CH2:15][CH3:16]>O>[CH2:13]([C:17]1[N:18]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[C:44]3[NH:3][C:4](=[O:7])[O:5][N:45]=3)=[CH:34][CH:33]=2)[C:19](=[O:30])[C:20]([C:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=2)=[C:21]([CH3:23])[N:22]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)c(C2=CCCCC2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCc1nc(C)c(C2=CCCCC2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
A mixture of hydroxylammonium chloride (0.78 g), sodium hydrogen carbonate (1.11 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-[(2-butyl-5-cyclohex-1-en-1-yl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.58 g) was added, and the mixture was stirred at 90° C. for 16 hr. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitate was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (15 mL), N,N′-carbonyldiimidazole (0.33 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.30 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.33 g, 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=O)[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].P(Cl)(Cl)(Cl)(Cl)[Cl:20]>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]=[C:8]([Cl:20])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(NCc1ccc(Cl)c([N+](=O)[O-])c1)C(F)(F)F
Product: O=[N+]([O-])c1cc(CN=C(Cl)C(F)(F)F)ccc1Cl
Temperature: 100 °C

Procedure:
A mixture of N-(4-chloro-3-nitrobenzyl)-2,2,2-trifluoroacetamide (6.0 g, 0.0212 mol) and phosphorus pentachloride (8.9 g, 0.0427 mol) is heated to 100° C. for three hours, concentrated in vacuo to remove excess phosphorus pentachloride and triturated with methylene chloride to obtain a solution of N-(4-chloro-3-nitrobenzyl)-2,2,2-trifluoroacetimidoyl chloride in methylene chloride. The methylene chloride solution is treated with 2-chloroacrylonitrile (2.5 mL, 0.0319 mol) and triethylamine (5.9 mL, 0.0422 mol), stirred overnight at room temperature, diluted with water and extracted with ethyl acetate. The combined organic extracts are washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a residue. Chromatography of the residue using silica gel and a 4:1 hexanes/ethyl acetate solution gives the title product as a yellow solid (0.65 g, mp 258°-260° C.).
Reaction SMILES: [O:1]=[C:2]([C:13]1[S:20][C:19]([CH3:21])=[C:18]2[C:14]=1[CH2:15][C@H:16]1[C:22]([CH3:24])([CH3:23])[C@H:17]12)[CH:3]=[CH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[NH:25]1[CH2:28][CH:27]([C:29]([OH:31])=[O:30])[CH2:26]1.CO>C(#N)C.O>[O:1]=[C:2]([C:13]1[S:20][C:19]([CH3:21])=[C:18]2[C:14]=1[CH2:15][C@H:16]1[C:22]([CH3:24])([CH3:23])[C@H:17]12)[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:25]2[CH2:28][CH:27]([C:29]([OH:31])=[O:30])[CH2:26]2)=[CH:11][CH:12]=1
Reactant: Cc1sc(C(=O)C=Cc2ccc(C=O)cc2)c2c1[C@H]1[C@@H](C2)C1(C)C
Reactant: O=C(O)C1CNC1
Solvent: CC#N
Solvent: CO
Solvent: O
Product: Cc1sc(C(=O)CCc2ccc(CN3CC(C(=O)O)C3)cc2)c2c1[C@H]1[C@@H](C2)C1(C)C
Reaction time: 0.08 h
Yield: 37.8 %

Procedure:
A suspension of 4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propenyl]-benzaldehyde (50 mg, 0.15 mmol), azetidine-3-carboxylic acid (19 mg, 0.19 mmol) and NaHB(OAc)3 (94 mg, 0.45 mmol) in acetonitrile (3 mL) is stirred at rt for 4 h before methanol (1 mL) is added. The clear solution is stirred for 5 min, diluted with water and extracted four times with DCM. The combinded organic extracts are dried over MgSO4 and evaporated. The obtained resin is dissolved in ethanol (5 mL) and THF (5 mL) and treated with a suspension of Pd/C (20 mg, 10% Pd) in ethanol (2 mL). The mixture is stirred at rt for 22 h under 1.5 bar H2. The reaction mixture is filtered and the filtrate is evaporated. The crude product is purified by chromatography on prep. TLC-plates (DCM containing 20% of methanol) to give 1-{4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propyl]-benzyl}-azetidine-3-carboxylic acid (24 mg) as a beige foam; LC-MS: tR=0.87 min, [M+1]+=424.24; 1H NMR (CDCl3): δ 7.30-7.16 (m, 4H), 4.02-3.70 (m br, 7H), 3.28-3.18 (m, 1H), 3.04-2.90 (m, 3H), 2.76 (d, J=18.8 Hz, 1H), 2.36 (s, 3H), 1.90-1.84 (m, 2H), 1.10 8s, 3H), 0.68 (s, 3H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:23][C:22](=O)[O:21][C:19](=[O:20])[CH2:18]2)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]([CH2:23][C:22]2[NH:9][C:4]3[CH:3]=[C:2]([I:1])[CH:7]=[CH:6][C:5]=3[N:8]=2)[CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:16]=1.[ClH:10]
Reactant: O=C1CC(c2ccc(Cl)cc2)CC(=O)O1
Reactant: Nc1ccc(I)cc1N
Product: Cl
Product: O=C(O)CC(Cc1nc2ccc(I)cc2[nH]1)c1ccc(Cl)cc1

Procedure:
By a procedure similar to that of example 1.4, starting from 4-iodo-1,2-phenylenediamine and 3-(4-chlorophenyl)glutaric anhydride, 3-(4-chlorophenyl)-4-(5-iodo-2-benzimidazolyl)butanoic acid•HCl was obtained as light red solid. 1H-NMR (500 MHz, DMSO-d6): δ (ppm)=2.72 (dd, J=16.3, 8.6 Hz, 1H), 2.83 (dd, J=16.3, 6.2 Hz, 1H), 3.43 (dd, J=14.9, 9.3 Hz, 1H), 3.55 (dd, J=14.9, 6.9 Hz, 1H), 3.86 (m, 1H), 7.29 (d, J=8.5 Hz, 2H), 7.35 (d, J=8.5 Hz, 2H), 7.53 (d, J=8.6 Hz, 1H), 7.74 (dd, J=8.6, 1.4 Hz, 1H), 8.07 (d, J=1.3 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:24]=1[CH2:25]Cl.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:25][C:24]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:23]=2[Cl:22])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(OCc2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 168 h
Yield: 57.5 %

Procedure:
To a 25 mL vial which contained a solution of the product from step 1 (150 mg, 0.5 mmol) and 2,4-dichloro-benzyl chloride (180 mg, 0.8 mmol) in anhydrous DMF (15 mL) was added dry Cs2CO3 (150 mg, 0.75 mmol) at rt. The reaction mixture which resulted was allowed to stir at rt for 7 d. The mixture was poured onto 50 mL ice-water solution and extracted with EtOAc (3×30 mL) allowed). The combined organic layers were washed with water (30 mL) and brine (30 mL) and dried over anhy. Na2SO4. The solvent was removed under vacuo to obtain the crude product which was purified by silica gel flash chromatography to afford the title product (130 mg, 55%); 1H NMR (400 MHz, CDCl3); δ 1.47 (s, 9H), 1.80-2.10 (m, 4H), 3.26-3.45 (m, 2H), 3.69-3.91 (m, 1H), 4.01-4.18 (m, 2H), 5.07 (s, 2H), 6.84-6.90 (m, 4H), 7.25-7.28 (m, 1H), 7.41 (d, J=2.0 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H),
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]([C@@H:12]([OH:23])[CH2:13][C@@H:14]([NH2:22])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1(B(O)O)C=CC=CC=1.O.[N+](C1C=CC([O:43][C:44]([O:46][CH2:47][C:48]2[S:52][CH:51]=[N:50][CH:49]=2)=O)=CC=1)([O-])=O>C1(C)C=CC=CC=1.CN(C=O)C.Cl>[NH2:22][C@@H:14]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:13][C@H:12]([OH:23])[C@@H:4]([NH:3][C:44]([O:46][CH2:47][C:48]1[S:52][CH:51]=[N:50][CH:49]=1)=[O:43])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: O=C(OCc1cncs1)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: OB(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Temperature: -60 °C
Reaction time: 8 h

Procedure:
The product of Example 66F (9.5 g, 33.4 mmol) and phenylboronic acid (4.1 g, 33.6 mmol) were combined in toluene (150 mL) and refluxed for 2.5 hours with azeotropic water removal (Dean-Stark trap). Toluene (100 mL) was distilled out at atmospheric pressure, then the remaining toluene was removed under vacuum, to provide a yellow syrup which was dissolved in DMF (50 mL) and cooled to -60° C. A solution of 5-(p-nitrophenyloxycarbonyloxy-methyl)thiazole (9.5 g, 33.5 mmol) in DMF (50 mL) was added over 45 minutes. The resulting mixture was stirred for 8 hours at -55°±5° C., then 14 hours at -25° C., then was allowed to warm to room temperature. The reaction mixture was diluted with 1N HCl (250 mL) and washed with CH2Cl2 (2×80 mL). The combined organic layers were back-extracted with 1N HCl (60 mL). The combined aqueous HCl layers were cooled in an ice-bath to 2° C., and conc. (37%) HCL (30 mL) was added over 5 minutes. The desired product (bis HCl salt) began to precipitate within 30 minutes. The slurry was stirred 3 hours at 2°-5° C., then the product (bis HCl salt) was collected by filtration and dried in a vacuum oven at 55°-60° C. Yield 11.4 g (68%).