Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[C:17]([NH2:18])=[CH:16][N:15]=[C:14]([Cl:19])[N:13]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl>O1CCCC1>[NH2:18][C:17]1[C:12]([N:8]2[CH2:9][CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7]2)=[N:13][C:14]([Cl:19])=[N:15][CH:16]=1
Reactant: CCOC(=O)C1CCCN(c2nc(Cl)ncc2N)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1cnc(Cl)nc1N1CCCC(C(=O)O)C1
Yield: 79.1 %

Procedure:
A solution of 0.114 g (0.0004 mole) of (rac)-1-(5-amino-2-chloro-pyrimidin-4-yl)-piperidine-3-carboxylic acid ethyl ester (V-67), 1 mL of tetrahydrofuran and 1 mL of 1M sodium hydroxide was stirred at ambient temperature for 3 hours. The mixture was acidified to pH=3 by the addition of 1M hydrochloric acid. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 0.0812 g of (rac)-1-(5-amino-2-chloro-pyrimidin-4-yl)-piperidine-3-carboxylic acid. This intermediate was stirred with 0.13 g (0.00034 mole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.058 g (0.00057 mol) of triethylamine and 2 mL of dichloromethane overnight at ambient temperature. The mixture was diluted with dichloromethane, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 0.075 g of (rac)-4-chloro-1,3,5,8-tetraaza-tricyclo[8.3.1.0*2,7*]tetradeca-2,4,6-trien-9-one (VI-67).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:10]1[C:15]([O:16][CH2:17][O:18][CH3:19])=[CH:14][CH:13]=[C:12](I)[N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[CH2:27][OH:28].[Cl-].[NH4+]>C(OCC)(=O)C>[CH2:3]([C:10]1[C:15]([O:16][CH2:17][O:18][CH3:19])=[CH:14][CH:13]=[C:12]([O:28][CH2:27][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][O:21]2)[N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCC1CCCCO1
Reactant: COCOc1ccc(I)nc1Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: COCOc1ccc(OCC2CCCCO2)nc1Cc1ccccc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
Sodium hydride was added to a mixture of 456 mg of 2-benzyl-6-iodo-3-(methoxymethyloxy)pyridine, 122 mg of cuprous iodide and 3 ml of tetrahydropyran-2-methanol, followed by stirring at 90° C. for 3 hours. An aqueous ammonium chloride solution and ethyl acetate were added to the reaction solution, followed by stirring at room temperature for one hour. Then, the organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using 15% ethyl acetate/hexane, to give 383 mg of the target compound.
Reaction SMILES: C([O:4][C:5]([CH3:33])([CH2:7][CH2:8][C:9]1[N:13]2[CH:14]=[C:15]([C:18]3[N:25]4[C:21]([O:22][CH:23]=[CH:24]4)=[N:20][C:19]=3[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1)[CH3:6])(=O)C.Cl.[OH-].[Na+]>O1CCOCC1>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:19]2[N:20]=[C:21]3[N:25]([C:18]=2[C:15]2[CH:16]=[CH:17][C:12]4[N:13]([C:9]([CH2:8][CH2:7][C:5]([CH3:33])([OH:4])[CH3:6])=[N:10][N:11]=4)[CH:14]=2)[CH:24]=[CH:23][O:22]3)=[CH:27][CH:28]=1
Reactant: CC(=O)OC(C)(C)CCc1nnc2ccc(-c3c(-c4ccc(F)cc4)nc4occn34)cn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(O)CCc1nnc2ccc(-c3c(-c4ccc(F)cc4)nc4occn34)cn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.3 %

Procedure:
A 25 mL flask was charged with 4-(6-(6-(4-fluorophenyl)imidazo[2,1-b]oxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-2-methylbutan-2-yl acetate (0.196 g, 0.438 mmol; Example #K.1.1.7) in 1,4-dioxane (2 mL) to give a yellow solution. To the solution was added 5.0 M aqueous HCl (0.44 mL, 2.2 mmol) and the mixture was stirred at ambient temperature. After about 16 h, aqueous NaOH was added to the mixture and a precipitate formed. The precipitate was collected via filtration and was rinsed with water. The material was dried in a vacuum oven to furnish the title compound as an off-white solid (0.036 g, 21%): LC/MS (Table 1, Method a) Rt=1.89 min; MS m/z/z: 406.2 (M+H)+.
Reaction SMILES: Cl.Cl.C([O:5][C:6]([CH:8]([NH:19][C@@H:20]1[C:26](=[O:27])[N:25]([CH2:28][C:29]([O:31]CC)=[O:30])[C:24]2[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=2[S:22][CH2:21]1)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:7])C>CO.[OH-].[Na+]>[C:6]([CH:8]([NH:19][C@@H:20]1[C:26](=[O:27])[N:25]([CH2:28][C:29]([OH:31])=[O:30])[C:24]2[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=2[S:22][CH2:21]1)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)([OH:7])=[O:5]
Reactant: CCOC(=O)CN1C(=O)[C@@H](NC(CCCCN2CCCCC2)C(=O)OCC)CSc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CN1C(=O)[C@@H](NC(CCCCN2CCCCC2)C(=O)O)CSc2ccccc21
Reaction time: 1 h
Yield: 72.9 %

Procedure:
In a mixture of 1 ml of methanol and 1 ml of 1N aqueous sodium hydroxide solution is dissolved 30 mg of ethyl 3(R)-(1-ethoxycarbonyl-5-piperidinopentyl)amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate.dihydrochloride as obtained in Example 79, and the solution is allowed to stand at room temperature for 1 hour. After methanol is evaporated off under reduced pressure, 2 ml of water and 0.5 ml of acetic acid are added to the residue, followed by purification by Amberlite XAD-2 column chromatography (acetone:water=2:1). The eluate is concentrated under reduced pressure, and the residue is lyophilized to give 17 mg of 3(R)-(1-carboxy-5-piperidinopentyl)amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]([CH2:20][O:21][Si](C(C)(C)C)(C)C)[CH2:11][O:12][Si](C(C)(C)C)(C)C)=[CH:4][N:3]=1.Cl.C(=O)=O.CC(C)=O.N>CCO.CO>[Br:1][C:2]1[N:3]=[CH:4][C:5]([O:8][CH2:9][CH:10]([CH2:20][OH:21])[CH2:11][OH:12])=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(COc1ccc(Br)nc1)CO[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: N
Agent: O=C=O
Solvent: CC(C)=O
Solvent: CO
Solvent: CCO
Product: OCC(CO)COc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 94.3 %

Procedure:
Silyl ether 185 (11.06 g, 22.5 mmol) was treated with a solution of 1% HCl in 95% EtOH (desilylation conditions described by Cunico et al., 1980) (200 mL), and the mixture was stirred at room temperature for 13 h. The resulting solution was cooled (CO2/acetone), neutralised by dropwise addition of 7M NH3 in MeOH (10 mL) with stirring, and then concentrated to dryness and the residue was chromatographed on silica gel. Elution with 0-3% MeOH/CH2Cl2 firstly gave foreruns, and then further elution with 5% MeOH/CH2Cl2 gave 2-{[(6-bromo-3-pyridinyl)oxy]methyl}-1,3-propanediol (186) (5.56 g, 94%) as a white solid: mp (CH2Cl2) 90-91° C.; 1H NMR (CDCl3) δ 8.07 (d, J=3.1 Hz, 1H), 7.36 (d, J=8.7 Hz, 1H), 7.12 (dd, J=8.7, 3.1 Hz, 1H), 4.15 (d, J=6.1 Hz, 1H), 3.95 (dt, J=10.8, 4.9 Hz, 1H), 3.92 (dt, J=10.8, 5.3 Hz, 1H), 2.24 (m, 1H), 1.99 (t, J=5.1 Hz, 2H). Anal. (C9H12BrNO3) C, H, N.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]1[NH:12][C:10](=[O:11])[NH:9][CH2:8]1.Br[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1.C(OC(C)C)(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH3:22][O:21][C:19]([C:18]1[CH:23]=[CH:24][C:15]([CH2:14][N:9]2[CH2:8][CH2:7][NH:12][C:10]2=[O:11])=[CH:16][CH:17]=1)=[O:20]
Reactant: O=C1NCCN1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Product: COC(=O)c1ccc(CN2CCNC2=O)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 57.4 %

Procedure:
Potassium carbonate (7.88 g; 57 mmol) was added to a solution of 4.92 g of ethylene urea (57 mmol), 5.73 g of methyl 4-bromomethylbenzoate (25 mmol) and 1.85 g of tetra-n-butylammonium iodide (5.0 mmol) in 30 mL of DMF, and the mixture was heated with stirring at 80° C. for 5 hours. After cooling, the solid was collected by filtration and washed with ethyl acetate. The filtrate was concentrated. The residue was purified by column chromatography on silica gel (eluent:ethyl acetate:methanol=10:1). To the light yellow oil obtained was added diisopropyl ether, and the precipitated solid was collected by filtration and dried to give 3.36 g of N-(4-methoxycarbonylphenylmethyl)imidazolin-2-one (Yield: 57.4%) as a light brown solid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=1)[O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])C1C=CC=CC=1>C(O)C>[C:16]([Si:13]([CH3:15])([CH3:14])[O:12][CH:11]1[CH2:20][CH2:21][CH2:22][CH:9]([OH:8])[CH2:10]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(OCc2ccccc2)c1
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OC1CCCC(O)C1
Reaction time: 6 h

Procedure:
A mixture of 37.6 g (3-benzyloxy-phenoxy)-tert-butyl-dimethyl-silane and 3.8 g of Nishimura's catalyst in 200 ml of ethanol was hydrogenated at rt under 50 psi for 6 hours. The reaction mixture was filtered and the filtrate concentrated.
Reaction SMILES: I[C:2]1[C:3]([NH:10][C@@H:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[N:4][C:5]([NH2:9])=[N:6][C:7]=1[CH3:8].[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[CH:17]=[CH2:18].C(N(CC)CC)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:9][C:5]1[N:6]=[C:7]([CH3:8])[C:2](/[CH:18]=[CH:17]/[C:16]([O:20][CH2:21][CH3:22])=[O:19])=[C:3]([NH:10][C@@H:11]2[CH2:15][CH2:14][O:13][CH2:12]2)[N:4]=1
Reactant: Cc1nc(N)nc(N[C@@H]2CCOC2)c1I
Reactant: C=CC(=O)OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1c(C)nc(N)nc1N[C@@H]1CCOC1
Temperature: 95 °C
Yield: 94 %

Procedure:
To a solution of (R)-5-iodo-6-methyl-N4-(tetrahydrofuran-3-yl)pyrimidine-2,4-diamine (4.53 g, 14.2 mmol), ethyl acrylate (4.25 g, 42.5 mmol) and triethylamine (4.30 g, 42.5 mmol) in DMF (150 mL) was added Pd(PPh3)4 (1.635 g, 10 mol %) under nitrogen at room temperature. The resulting mixture was heated to 95° C. for 18 h under a nitrogen atmosphere. After the reaction was complete by LC/MS, the resulting mixture was concentrated under reduced pressure and directly subjected to column chromatography purification to give (R,E)-ethyl 3-(2-amino-4-methyl-6-(tetrahydrofuran-3-ylamino)pyrimidin-5-yl)acrylate (3.90 g, 94% yield). MS (EI) for C14H20N4O: 293.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][S:10](Cl)(=[O:12])=[O:11].C(N(CC)CC)C>ClCCl.O>[Cl:1][C:2]1[C:7]([NH:8][S:10]([CH3:9])(=[O:12])=[O:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccnc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccnc1Cl
Reaction time: 48 h
Yield: 93.7 %

Procedure:
2-Chloro-pyridin-3-ylamine (1.00 g, 7.75 mmol) in dichloromethane (20 mL) at 23° C. was treated with methane sulfonyl chloride (2.23 g, 19.4 mmol) and triethylamine (1.96 g, 19.4 mmol). After stirring for 48 hours, the reaction mixture was diluted with water, the layers were separated, and the aqueous phase was extracted with dichloromethane (2×). The organic layers were combined, dried over MgSO4, filtered, and the filtrate concentrated under reduced pressure. The residue was chromatographed on flash silica gel (20% ethyl acetate:hexanes), concentrated under reduced pressure, and added to a 10% aqueous sodium hydroxide solution (32 mL). The solution was stirred vigorously for about 0.5 hours until homogeneous. The solution was then neutralized to pH˜7 with 2N HCl, saturated with Na2SO4, and extracted with ethyl acetate (3×). The combined extracts were dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure to afford 1.5 g (93% yield) of the title compound. References: Tetrahedron Letters 38, 26, 4667-4670, 1997; Eur. J. Org. Chem. 2000, 1263-1270. 1H NMR (300 MHz, DMSO-d6) δ 3.12 (s, 3H), 7.46 (dd, J=4.5, 8.4 Hz, 1H), 7.89 (dd, J=1.5, 8.4 Hz, 1H), 8.27 (dd, J=1.5, 4.5 Hz, 1H), 9.72 (bs, 1H); MS (ESI) m/e 205 (M)−.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][C:7]([C:9]([F:12])([F:11])[F:10])=[O:8])=[O:5].CC(O[Na])=O.O.[Cl-].[C:20]1([N+:26]#[N:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[C:20]1([NH:26][N:27]=[C:6]([C:7](=[O:8])[C:9]([F:10])([F:11])[F:12])[C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N#[N+]c1ccccc1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: CC(=O)O[Na]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=NNc1ccccc1)C(=O)C(F)(F)F
Yield: 60 %

Procedure:
7.3 ml (0.05 mol) of ethyl 3-oxo-4,4,4-trifluoroacetoacetate, 6 g (0.073 mol) of CH3COONa, 20 ml of water, 37.5 ml of ethanol and a solution of 0.05 mol of phenyldiazonium chloride were treated as described in preparation 2. The crude product was purified by chromatography on silica gel (hexane/Et2O 0%→25%) obtaining 8.65 g of the title compound. M.p.=78°-80° C.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].C(N(C(C)C)CC)(C)C.Br[CH:18]([CH3:28])[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27])=[O:20]>O1CCCC1>[C:1]([CH:3]([CH:18]([CH3:28])[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27])=[O:20])[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: CC(Br)C(=O)c1ccccc1F
Reactant: COC(=O)CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C#N)C(C)C(=O)c1ccccc1F
Temperature: 70 °C
Reaction time: 20 h
Yield: 80 %

Procedure:
To a solution of methyl cyanoacetate (15.5 mL) and diisopropylethylamine (64 mL) in tetrahydrofuran (110 mL) was added a solution of 2-bromo-1-(2-fluorophenyl)propan-1-one (36.8 g) in tetrahydrofuran (160 mL), and the mixture was stirred at 70° C. for 20 hr. The reaction mixture was allowed to cool to room temperature, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=5:1) to give the title compound as a brown oil (yield 31.9 g, 80%).
Reaction SMILES: [CH:1]([O:4][C:5]([NH:7][C@H:8]([C:12]([OH:14])=O)[CH:9]([CH3:11])[CH3:10])=[O:6])([CH3:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:41][C:42]1[CH:53]=[CH:52][C:45]2[N:46]=[C:47]([C@H:49]([NH2:51])[CH3:50])[S:48][C:44]=2[CH:43]=1>C1(C)C=CC=CC=1.O>[F:41][C:42]1[CH:53]=[CH:52][C:45]2[N:46]=[C:47]([C@H:49]([NH:51][C:12]([C@@H:8]([NH:7][C:5](=[O:6])[O:4][CH:1]([CH3:2])[CH3:3])[CH:9]([CH3:10])[CH3:11])=[O:14])[CH3:50])[S:48][C:44]=2[CH:43]=1
Reactant: CC(C)OC(=O)N[C@H](C(=O)O)C(C)C
Reactant: C[C@@H](N)c1nc2ccc(F)cc2s1
Agent: CC(C)COC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCOCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)OC(=O)N[C@H](C(=O)N[C@H](C)c1nc2ccc(F)cc2s1)C(C)C
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 132.2 %

Procedure:
In 500 ml of toluene, 18.9 g (0.093 mol) of N-isopropoxycarbonyl-L-valine was dissolved. The solution was cooled to −5° C. Thereto were dropwise added, at −5° C., 23.0 g (0.233 mol) of N-methylmorpholine and 12.7 g (0.093 mol) of isobutyl chlorocarbonate. Thereto was added, at −5° C., 17.4 g (0.047 mol) of (R)-1-(6-fluoro-2-benzothiazolyl)ethylamine p-toluenesulfonate in one portion. The mixture was stirred at the same temperature for 0.5 hour and then at room temperature for 2 hours. To the reaction mixture was added 300 ml of water. The mixture was heated to 70° C. to dissolve the solid. The toluene layer was separated, washed with hot water, and then cooled, whereby a solid was precipitated. The solid was collected by filtration and dried to obtain 23.7 g (yield: 70%) of isopropyl {(S)-1-[(R)-1-(6-fluorobenzothiazol-2-yl)ethylcarbamoyl]-2-methylpropyl}carbamate. The compound obtained was confirmed for the structure by IR analysis and NMR analysis in comparison with its authentic material and identified.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:5][CH:4]=1.[CH3:30][NH:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([N:31]([CH3:30])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:26])=[CH:23][CH:22]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCNC
Reactant: COc1ccc(-c2cc(C(CC(C)C)Nc3ccc(C(=O)O)cc3)c(C)s2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(C(CC(C)C)Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)c(C)s2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
A solution of 4-({1-[5-(6-methoxypyridin-3-yl)-2-methylthiophen-3-yl]-3-methylbutyl}amino)benzoic acid (328 mg), ethyl 3-(methylamino)propanoate (131 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (192 mg), hydroxybenzotriazole monohydrate (154 mg) and triethylamine (139 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. To the residue were added ethanol (3 mL), tetrahydrofuran (3 mL) and 1N lithium hydroxide (1.5 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (329 mg, 83%).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][O:6][C:7]1[C:12]([Cl:13])=[CH:11][C:10]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=2)=[S:16])=[CH:9][C:8]=1[Cl:28])C.O1CCCC1.[OH-].[Na+].Cl>CO>[C:25]([NH:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:15](=[S:16])[NH:14][C:10]2[CH:11]=[C:12]([Cl:13])[C:7]([O:6][CH2:5][C:4]([OH:29])=[O:3])=[C:8]([Cl:28])[CH:9]=2)=[CH:19][CH:20]=1)(=[O:27])[CH3:26]
Reactant: CCOC(=O)COc1c(Cl)cc(NC(=S)Nc2ccc(NC(C)=O)cc2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(NC(=S)Nc2cc(Cl)c(OCC(=O)O)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of {4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-acetic acid ethyl ester (0.29 g) in a 1:1 mixture of tetrahydrofuran and methanol (4 mL) is added 1N aqueous sodium hydroxide (2 mL) and the mixture is stirred for approximately 2 hours at room temperature. The solution is then poured into 2 M aqueous hydrochloric acid (5 mL), extracted into ethyl acetate, and the extracts are dried over anhydrous sodium sulfate. The solvent is removed by evaporation under reduced pressure and the residue is triturated with diethyl ether to provide the desired product as a white solid.
Reaction SMILES: [C:1]([N:9]1[CH2:12][CH:11]([CH2:13][O:14][C:15]2[C:24]([CH:25]3[CH2:27][CH2:26]3)=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[C:17]([F:28])[CH:16]=2)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.O>[C:1]([N:9]1[CH2:10][CH:11]([CH2:13][O:14][C:15]2[C:24]([CH:25]3[CH2:26][CH2:27]3)=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[C:17]([F:28])[CH:16]=2)[CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(C2CC2)c(OCC2CN(C(=O)c3ccccc3)C2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(C2CC2)c(OCC2CN(C(=O)c3ccccc3)C2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.2 %

Procedure:
A mixture of methyl 4-((1-benzoylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate (70 mg, 0.18 mmol) and lithium hydroxide (22 mg, 0.91 mmol) in THF (5 mL) and H2O (10 ml) was stirred at room temperature for 18 h. The mixture was quenched with HCl (1N, 2 mL) and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to get the target compound (50 mg, 74%) as a yellow solid. LCMS (ESI) m/z: 370.1 [M+H].
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[N:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[C:24]([O:23][C:22](=[O:28])[NH:21][N:15]1[CH2:20][CH2:19][N:18]([CH2:13][C:11]([OH:12])([CH3:14])[CH2:10][N:3]2[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=[C:2]2[Cl:1])[CH2:17][CH2:16]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: CC(C)(C)OC(=O)NN1CCNCC1
Product: CC(O)(CN1CCN(NC(=O)OC(C)(C)C)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Yield: 72.6 %

Procedure:
Using 2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 6 (4.36 g, 20.0 mmol) and tert-butyl piperazin-1-ylcarbamate (4.44 g, 22.0 mmol) gave tert-butyl{4-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]piperazin-1-yl}carbamate (6.08 g, yield 72%) as a white powder in the same manner as in Example 365.
Reaction SMILES: C(OC(N1C(C=CC2C=C(C)C=CC=2)CCC1C(N1CCC[C@H]1C#N)=O)=O)(C)(C)C.C(OC([N:38]1[CH:42]([CH:43]=[CH:44][C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=2)[CH2:41][CH2:40][CH:39]1[C:52]([N:54]1[CH2:58][CH2:57][CH2:56][C@H:55]1[C:59]#[N:60])=[O:53])=O)(C)(C)C>>[Cl:51][C:48]1[CH:49]=[CH:50][C:45]([CH2:44][CH2:43][CH:42]2[NH:38][C@H:39]([C:52]([N:54]3[CH2:58][CH2:57][CH2:56][C@H:55]3[C:59]#[N:60])=[O:53])[CH2:40][CH2:41]2)=[CH:46][CH:47]=1
Reactant: CC(C)(C)OC(=O)N1C(C=Cc2ccc(Cl)cc2)CCC1C(=O)N1CCC[C@H]1C#N
Agent: Cc1cccc(C=CC2CCC(C(=O)N3CCC[C@H]3C#N)N2C(=O)OC(C)(C)C)c1
Product: N#C[C@@H]1CCCN1C(=O)[C@@H]1CCC(CCc2ccc(Cl)cc2)N1

Procedure:
The title compound was synthesized by substituting 2-(2-(S)-cyano-pyrrolidine-1-carbonyl)-5-(R/S)-(2-m-tolyl-vinyl)-pyrrolidine-1-carboxylic acid tert-butyl ester in Example 36 with 2-(2-(S)-cyano-pyrrolidine-1-carbonyl)-5-(R/S)-(2-p-chlorophenyl-vinyl)-pyrrolidine-1-carboxylic acid tert-butyl ester. 1H NMR (400 MHz, MeOH-d4) δ 1.83 (m, 1H), 1.98 (m, 2H), 2.24 (m, 6H), 2.71 (m, 4H), 3.64 (t, J=6.60 Hz, 2H), 3.73 (m, 1H), 4.59 (t, J=8.29 Hz, 1H), 7.25 (d, J=8.29 Hz, 2H), 7.31 (d, J=8.29 Hz, 2H) ppm. MS (ESI) m/z 332, 334 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[C:5]#[N:6].[H-].[Na+].F[C:14]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[CH:16][C:15]=1[N+:22]([O-:24])=[O:23].Cl>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:14]2[C:15]([N+:22]([O-:24])=[O:23])=[CH:16][CH:17]=[C:18]([F:21])[C:19]=2[F:20])[CH:9]=1)[C:5]#[N:6]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: N#Cc1cc(O)cc(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1cc(Cl)cc(Oc2c([N+](=O)[O-])ccc(F)c2F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
3-Chloro-5-hydroxybenzonitrile (20.0 g, 130 mmol) was dissolved in anhydrous THF (500 mL) and cooled to 0° C. Sodium hydride (60% dispersion in oil, 4.81 g, 125 mmol) was added and stirred for 30 minutes. 2,3,4-Trifluoronitrobenzene (23.06 g, 130 mmol) was added and the reaction was allowed to warm to RT. Stirring was continued until TLC showed no remaining starting material. The reaction mixture was poured into a mixture of 10% HCl and ice. Ethyl acetate was added and the organic layer was separated, dried over MgSO4, filtered and evaporated. The resulting oil was triturated with hexanes and Et2O to afford a solid. The washing were collected, evaporated and triturated with hexanes. The materials were combined to afford the title compound (30 g, 74%) as a solid. 1H NMR (400 MHz, CDCl3): δ ppm 7.98 (ddd, 1H), 7.43 (t, 1H), 7.34 (ddd, 1H), 7.21 (t, 1H), 7.08 (dd, 1H).