Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]1([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[Cl:1][S:2]([C:9]1[CH:10]=[CH:11][C:6]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:8]=1)(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: CCOC(=O)Cc1ccccc1
Product: CCOC(=O)Cc1ccc(S(=O)(=O)Cl)cc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
Chlorosulfonic acid (87 ml) was added dropwise to ethyl phenylacetate (48 g), and the mixture was stirred at 40° C. for 30 minutes. The reaction mixture was poured into ice water (1000 ml), and the separated oily substance was extracted with methylene chloride. The methylene chloride layer was washed successively with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure gave ethyl 4-chlorosulfonylphenylacetate (42 g).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15](=[O:29])[C:16]3[C:21]([CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[N:20][N:19]([CH3:28])[C:17]=3[N:18]=2)=[C:9]([O:30][CH3:31])[CH:8]=1.[C:32](=[O:34])=[O:33].[OH-].[Na+]>O1CCCC1>[CH:22]1([C:21]2[C:16]3[C:15](=[O:29])[NH:14][C:13]([C:10]4[CH:11]=[CH:12][C:7]([C:32]([OH:34])=[O:33])=[CH:8][C:9]=4[O:30][CH3:31])=[N:18][C:17]=3[N:19]([CH3:28])[N:20]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C=O
Reactant: COc1cc(Br)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Reaction time: 0.5 h
Yield: 44 %

Procedure:
In a stream of nitrogen, 1.6 ml of n-butyl lithium (1.56M hexane solution 2.5 mmol) was added dropwise at −78° C. to a 10 ml tetrahydrofuran solution of 500 mg (1.20 mmol) of the compound obtained in Example 26. The mixture was stirred at the same temperature for 30 minutes, and then a carbon dioxide gas was blown into the reaction mixture for 45 minutes. Further, the reaction mixture was stirred at −78° C. for 2 hours, and then brought to room temperature. The reaction mixture was alkalinized by addition of a 1M aqueous solution of sodium hydroxide, and washed with dichloromethane. The aqueous layer was acidified with a 6M aqueous solution of hydrochloric acid, and precipitated solids were collected by filtration, obtaining 200 mg (44%) of the captioned compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[Li]CCCC.[O:20]1[CH2:23][C:22](=[O:24])[CH2:21]1>C1COCC1>[N:10]1([N:9]=[N:8][C:5]2[CH:6]=[CH:7][C:2]([C:22]3([OH:24])[CH2:23][O:20][CH2:21]3)=[CH:3][CH:4]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Brc1ccc(N=NN2CCCC2)cc1
Reactant: O=C1COC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ccc(N=NN3CCCC3)cc2)COC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 102.6 %

Procedure:
To a solution of 1-((4-bromophenyl)diazenyl)pyrrolidine (500 mg, 1.97 mmol) in anhydrous THF (20 mL) was added n-BuLi (1.8 mL, 4.33 mmol) dropwise at −78° C. under N2. The solution was stirred at −78° C. for 1 h, followed by the addition of oxetan-3-one (326 mg, 4.53 mmol). The resultant mixture was stirred at RT for 18 h. The reaction was quenched by saturated aqueous NH4Cl aq. (20 mL) and extracted with ethyl acetate (20 mL*3). The combined organic layers were concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (DCM:MeOH=20:1) to afford the title compound (500 mg, yield 97%) as a light yellow solid. MS (ES+) C13H17N3O2 requires: 247, found 248 [M+H]+, purity: 90%.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([CH2:11][NH2:12])=[CH:6][N:5]=1.C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>CO>[NH2:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([CH2:11][NH:12][C:20](=[O:22])[CH3:21])=[CH:6][N:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(N)ncc1CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)NCc1cnc(N)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-amino-5-aminomethyl-4-methylpyridine dihydrochloride (70 mg, 0.333 mmol) in methanol (2 mL) were added triethylamine (93 uL, 0.667 mmol) and acetic anhydride (47 uL, 0.498 mmol). The reaction mixture was stirred for 2 h at room temperature and then evaporated. The residue was chromatographed on silica gel (10% methanol/methylene chloride) to afford pure title compound.
Reaction SMILES: [Br:1][CH2:2][C:3](=[N:9][OH:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:11](Cl)(=[O:15])[C:12]([CH3:14])=[CH2:13].N1C=CC=CC=1>C(Cl)Cl>[Br:1][CH2:2][C:3](=[N:9][O:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(CBr)=NO
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=C(C)C(=O)ON=C(CBr)C(=O)OCC
Yield: 83.7 %

Procedure:
Ethyl 3-bromo-2-(hydroxyimino)propanoate (4.0 g, 19 mmole) and methacryloyl chloride (2.18 g, 20.8 mmole) in methylene chloride (100 ml) were treated with dry pyridine (1.66 g, 21 mmole). After a workup as in Example 1, 4.42 g (84% yield) of ethyl 3-bromo-2-(methacryloyloximino)propanoate was obtained as an oil. NMR and IR spectra confirm the structure.
Reaction SMILES: [Cl:1]C1C=C2C(C=CN2)=CC=1.[C:11]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20](OC(F)(F)F)[CH:21]=2)[N:16]([CH2:28][C:29]([OH:31])=[O:30])[CH:15]=1)(=[O:13])[CH3:12]>>[C:11]([C:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:1])=[CH:20][CH:21]=2)[N:16]([CH2:28][C:29]([OH:31])=[O:30])[CH:15]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)c1cn(CC(=O)O)c2ccc(OC(F)(F)F)cc12
Reactant: Clc1ccc2cc[nH]c2c1
Product: CC(=O)c1cn(CC(=O)O)c2cc(Cl)ccc12

Procedure:
was prepared from 6-chloro-1H-indole in a similar manner as described in Scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl)-acetic acid. Brown solid. MS: 252 [M+H]+, 274 [M+Na]+; tR (HPLC conditions k): 2.89 min.
Reaction SMILES: [F:1][C:2]1[C:3]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[C@H:27]12[NH:34][CH2:33][C@H:32]1[CH2:31][CH2:30][N:29]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:28]2>C(Cl)Cl>[F:1][C:2]1[C:3]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([N:34]1[C@H:27]2[C@H:32]([CH2:31][CH2:30][N:29]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:28]2)[CH2:33]1)=[O:7]
Reactant: O=C(O)c1cccc(F)c1-n1nccn1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2CN[C@@H]2C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H]2CN(C(=O)c3cccc(F)c3-n3nccn3)[C@@H]2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 125.7 %

Procedure:
To 3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (390 mg, 1.9 mmol) in CH2Cl2 (18 mL) at 0° C. was added DMF (15 μL, 0.2 mmol) and oxalyl chloride (190 μL, 2.3 mmol). After 20 min, the 0° C. ice bath was removed and the reaction allowed to warm to rt. After 30 min the mixture was concentrated, diluted with CH2Cl2 (9 mL) and added to (1S,6R)-tert-butyl 3,8-diazabicyclo[4.2.0]octane-3-carboxylate (260 mg, 1.3 mmol) in CH2Cl2 (9 mL) and TEA (390 μL, 2.9 mmol). After judged complete by TLC and LC-MS, the reaction was diluted further with CH2Cl2 and washed with 1 N KHSO4. The aqueous layer was with CH2Cl2. The combined organics were dried (Na2SO4) to give a yellow foam. Purification via silica gel using 40-100% EtOAc in hexanes gave 656 mg (86%) of the title compound as a colorless oil. MS (ESI) mass calcd. C20H24FN5O3, 401.44; m/z found 346.0 [M−C(CH3)3]+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5](C(OC(C)(C)C)=O)[C@H:4]([CH2:14][OH:15])[CH2:3]1.C(Cl)Cl.[C:19]([OH:25])([C:21]([F:24])([F:23])[F:22])=[O:20]>>[C:19]([OH:25])([C:21]([F:24])([F:23])[F:22])=[O:20].[OH:15][CH2:14][C@H:4]1[NH:5][CH2:6][C@H:2]([OH:1])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC[C@@H]1C[C@@H](O)CN1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Formation of the amide bond was carried out using an adaptation of General Method A, above. A mixture of commercially available (2S,4R)-tert-butyl 4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (3.26 g, 15 mmol) in 50 mL of DCM/TFA (3:2, v/v) was stirred at rt for 4 h, concentrated in vacuo to give a brown oil as a crude TFA salt of (3R,5S)-5-(hydroxymethyl)pyrrolidin-3-ol, which was dissolved in DMF (28 mL), added with biphenyl-2-carboxylic acid (3.05 g, 15.4 mmol) and HATU (5.86 g, 15.4 mmol). The resulting solution was cooled to 0° C., added with Et3N (8.8 mL, 63 mmol) dropwise and was allowed to warm to rt gradually and stirred overnight. 2M NaOH (aq.) was added and the mixture was extracted with EtOAc (3×). The combined EtOAc solution was washed with brine, dried over MgSO4 and concentrated in vacuo to a brown oil, which was purified by column chromatography on silica gel (10% MeOH in EtOAc) to provide biphenyl-2-yl((2S,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidin-1-yl)methanone as an off-white solid (2.0 g, 45% yield over two steps). 1H NMR (CDCl3, 400 MHz) δ 7.59-7.57 (m, 2H), 7.54-7.40 (m, 7H), 4.44 (brs, 1H), 4.10 (s, 1H), 3.77-3.72 (m, 1H), 3.62 (brs, 1H), 3.32 (brs, 1H), 3.04-2.96 (m, 1H), 2.60 (brs, 1H), 2.00-1.95 (m, 1H), 1.61 (brs, 2H). MS (ESI) 298.04 (M+H).
Reaction SMILES: N1C=CC=CC=1.CS(O)(=O)=O.[CH:12]1([C:18]2[C:26]3[C:25](=[O:27])[NH:24][C:23]([C:28]4[CH:33]=[CH:32][C:31](N5CCC(O)CC5)=[CH:30][C:29]=4OC)=[N:22][C:21]=3[N:20]([CH3:43])[N:19]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[Br:44]C1C=CC(C(Cl)=O)=CC=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Br:44][C:31]1[CH:32]=[CH:33][C:28]([C:23]2[NH:24][C:25](=[O:27])[C:26]3[C:18]([CH:12]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]4)=[N:19][N:20]([CH3:43])[C:21]=3[N:22]=2)=[CH:29][CH:30]=1
Reactant: COc1cc(N2CCC(O)CC2)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cn1nc(C2CCCCC2)c2c(=O)[nH]c(-c3ccc(Br)cc3)nc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 15.2 %

Procedure:
To a 30 ml pyridine solution of 2.2 g (10 mmol) of the compound obtained in Example 32, 2.8 g (13 mmol) of p-bromobenzoyl chloride was added, and the mixture was stirred at room temperature for 3 hours. Further, 1.0 g (4.5 mmol) of p-bromobenzoyl chloride was added, and the mixture was stirred at room temperature for 4 hours. Then, an aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate, followed by distilling off the solvent under reduced pressure. To the residue, 80 ml of ethanol and 40 ml of a 1M aqueous solution of sodium hydroxide were added, and the mixture was heated under reflux for 8 hours. Then, the reaction mixture was cooled to room temperature, and acetic acid was added. Precipitated solids were collected by filtration, the solids obtained were dissolved in chloroform, and the solution was washed with sodium hydrogen carbonate, water and a saturated aqueous solution of sodium chloride in this order. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was recrystallized (ethanol) to obtain 590 mg (15%) of the captioned compound.
Reaction SMILES: CS[C:3]1[NH:4][CH:5]=[C:6]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)[C:7](=[O:9])[N:8]=1.[F:17][C:18]1[CH:33]=[CH:32][C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH2:31])=[CH:25][CH:24]=2)=[CH:20][CH:19]=1>C(O)C>[F:17][C:18]1[CH:33]=[CH:32][C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH:31][C:3]3[NH:4][CH:5]=[C:6]([CH2:10][C:11]4[CH:12]=[N:13][CH:14]=[N:15][CH:16]=4)[C:7](=[O:9])[N:8]=3)=[CH:25][CH:24]=2)=[CH:20][CH:19]=1
Reactant: CSc1nc(=O)c(Cc2cncnc2)c[nH]1
Reactant: NCCc1ccc(Oc2ccc(F)cc2)cc1
Solvent: CCO
Product: O=c1nc(NCCc2ccc(Oc3ccc(F)cc3)cc2)[nH]cc1Cc1cncnc1
Temperature: 125 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
2-Methylsulfanyl-5-pyrimidin-5-ylmethyl-1H-pyrimidin-4-one (30 mg, 0.128 mmol, 1 eq) and 2-[4-(4-Fluoro-phenoxy)-phenyl]-ethylamine (44.4 mg, 0.192 mmol, 1.5 eq) were dissolved in dry ethanol (300 μl) and stirred at 125° C. for overnight. Reaction mixture was evaporated and crude residue was sent to HPLC/MS Purification. After HPLC/MS purification combined fractions of desired product were collected and put on lyophilisation to obtain 2-{2-[4-(4-fluoro-phenoxy)-phenyl]-ethylamino}-5-pyrimidin-5-ylmethyl-1H-pyrimidin-4-one (0.068 mmol; yield: 53.1%, HPLC-MS/UV: [M+H]+=418.45; rt: 9.78 min; purity: 98%). 1H NMR (300 MHz; DMSO-d6) δ/ppm 2.75 (t, J=7.50 Hz, 2H), 3.39-3.49 (m, 2H), 3.51 (s, 2H), 6.46 (br.s, 1H), 6.90 (d, J=8.57 Hz, 2H), 6.97-7.05 (m 2H), 7.15-7.25 (m, 4H), 7.66 (s, 1H), 8.66 (s, 2H), 8.97 (s, 1H), 10.92 (br.s., 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:12]3[C:13]([CH3:33])=[C:14]([N:19]4[CH2:24][CH2:23][N:22]([C:25]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=5)[CH2:21][CH2:20]4)[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:35])[CH3:34])=[CH:4][CH:3]=1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[C:13]([CH3:33])=[C:14]([N:19]4[CH2:24][CH2:23][N:22]([C:25]5[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=5)[CH2:21][CH2:20]4)[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:35])[CH3:34])=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)(c3ccc(Cl)cc3)C(C)(C)O4)CC2)cc1
Solvent: CCO
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(c3ccc(Cl)cc3)C(C)(C)O4)CC2)cc1
Yield: 62 %

Procedure:
Using 3-(4-chlorophenyl)-5-(4-(4-methoxyphenyl)piperazin-1-yl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol obtained in Example 62, the title compound was synthesized in the same manner as in Example 46. Yield 62%. mp. 181–183° C. (ethanol).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([CH:15]=[CH2:16])[CH:5]=1)[CH3:3].C(N(CC)CC)C.[C:24]([C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>C(Cl)Cl>[C:24]([C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:36])[NH:1][C@@H:2]([C:4]2[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([CH:15]=[CH2:16])[CH:5]=2)[CH3:3])=[CH:30][CH:29]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: C=Cc1cc(C(C)N)ccc1NS(C)(=O)=O
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=Cc1cc([C@@H](C)NC(=O)Nc2ccc(C(C)(C)C)cc2)ccc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 38 %

Procedure:
N-[4-(1-Aminoethyl)-2-vinylphenyl]methanesulfonamide (236.7 mg, 0.985 mmol, 1 eq.) and Triethylamine (274.6 μl, 1.970 mmol, 2 eq.) were added in methylene chloride. The reaction mixture was cooled down to 0° C. 4-tert-Butylphenyl isocyanate (192.5 μl, 1.083 mmol, 1.3 eq.) was added. The reaction mixture was stirred for 40 min. Methylene chloride was removed in vacuo. The residue was purified with column chromatography (n-Hx:EA=2:1) to yield title compound (155.4 mg, 38%) as white solid.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14](N2C=CN=C2)=O)[N:2]=1.[OH:21][NH:22][C:23](=[NH:26])[CH2:24][CH3:25]>C1(C)C=CC=CC=1.CN(C=O)C>[CH2:24]([C:23]1[N:26]=[C:14]([C:3]2[N:2]=[CH:1][C:13]3[NH:12][C:11]4[C:6]([C:5]=3[CH:4]=2)=[CH:7][CH:8]=[CH:9][CH:10]=4)[O:21][N:22]=1)[CH3:25]
Reactant: CCC(=N)NO
Reactant: O=C(c1cc2c(cn1)[nH]c1ccccc12)n1ccnc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCc1noc(-c2cc3c(cn2)[nH]c2ccccc23)n1
Reaction time: 72 h
Yield: 56.8 %

Procedure:
To a solution of Compound 1 (1.05 g, 4 mmol) in a mixture of toluene (50 mL) and DMF (50 mL), N-hydroxypropanimidamide (0.53 g, 6 mmol) was added. The resulting mixture was heated at 140°-150° C. for 7 h, and stirring continued for 3 days at room temperture. The solvents were removed in vacuo, and the oily residue precipitated from water. The white solid (1.0 g) was dried and submitted to column chromatography on silica gel with CH2Cl2 /methanol(9:1) as eluent. This afforded the title compound (0.6 g, 56%). M.p. 146°-149° C.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=2[O:2]1.[C:13]([NH:16][CH2:17]CO)(=[O:15])[CH3:14]>>[OH:2][C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1[O:9][CH2:1][CH2:17][NH:16][C:13](=[O:15])[CH3:14]
Reactant: CC(=O)NCCO
Reactant: O=[N+]([O-])c1ccc2c(c1)OCO2
Product: CC(=O)NCCOc1ccc([N+](=O)[O-])cc1O
Temperature: 100 °C

Procedure:
0.05 mol (8.35 g) of 3,4-methylenedioxynitrobenzene is introduced into 42 ml of N-acetylethanolamine. The mixture is heated to the region of 100° C., with stirring, and 0.055 mol (3.7 ml) of 15N potassium hydroxide solution is then added. After heating for one hour, 0.050 mol (3.3 ml) of 15N potassium hydroxide solution is added and the reaction medium is stirred at 100° C. for a further 3 hours and then poured onto 120 g of crushed ice. The unreacted starting material, which is insoluble in an alkaline medium, is filtered off. The filtrate is then acidified to pH=5.6 with hydrochloric acid in order to precipitate the expected product. It is filtered off, washed with water and dried in vacuo. It melts at 165° C.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][CH:11]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[CH2:12][C:13]([O:15]CC)=[O:14].[ClH:25].C1(C)C=CC=CC=1>C(O)(=O)C>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][CH:11]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[CH2:12][C:13]([OH:15])=[O:14].[ClH:25]
Reactant: CCOC(=O)CC(Cc1nc2ccccc2[nH]1)c1ccc(Cl)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=C(O)CC(Cc1nc2ccccc2[nH]1)c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
The solution of ethyl 4-(2-benzimidazolyl)-3-(4-chlorophenyl)butanoate (200 mg) in a mixture of acetic acid (1 ml) and conc. HCl (0.25 ml) was heated at 100° C. for 1 h. Then toluene (30 ml) was added and all volatiles were removed by distillation. Distillation was repeated with further toluene (30 ml). The oily residue is treated with diethyl ether to induce crystallisation, triturated with acetone, and dried in vacuo to leave 4-(2-benzimidazolyl)-3-(4-chlorophenyl)butanoic acid•HCl (208 mg) as light red solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24]([OH:26])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.Cl.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2([NH2:41])[CH2:40][CH2:39]2)[N:33]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:26])[NH:41][C:38]5([C:34]6[N:33]=[N:32][CH:37]=[CH:36][CH:35]=6)[CH2:40][CH2:39]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: NC1(c2cccnn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5cccnn5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.04 g, 0.099 mmol, 1 eq), 1-(pyridazin-3-yl)cyclopropanamine HCl salt (0.018, 0.099 mmol, 1 eq) and Py-Bop (0.067 g, 0.13 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.026 g, 0.3 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.031 mg (60%). 1H NMR (400 MHz, CDCl3): δ 9.17 (s, 1H), 7.92-7.96 (m, 3H), 7.77-7.69 (m, 4H), 7.65 (s, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.30 (dd, J=1.6, 8.4 Hz, 1H), 7.23-7.19 (m, 2H), 5.94 (bs, 1H), 3.0 (s, 3H), 2.33 (s, 3H), 1.89-1.86 (m, 2H), 1.60-1.57 (m, 2H). 19F NMR (376.47 MHz, CDCl3): δ−75.82 (TFA), −109.29 LCMS: (ES+) m/z=521.0 (M+H)+
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14](B(O)O)[CH:13]=1>>[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:2]2[C:3]3[N:4]([N:8]=[C:9]([NH2:11])[N:10]=3)[CH:5]=[CH:6][CH:7]=2)[CH:13]=1
Reactant: OB(O)c1cccnc1
Reactant: Nc1nc2c(Br)cccn2n1
Product: Nc1nc2c(-c3cccnc3)cccn2n1

Procedure:
8-Pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (1.0 g, 4.7 mmol) and 3-pyridylboronic acid (0.81 g, 6.6 mmol) in a manner analogous to Step 2c. The product of the reaction was isolated as a white solid (0.92 g, 93%). MP=185-187° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.28 (d, J=2.1 Hz, 1H), 8.62-8.58 (m, 2H), 8.49 (ddd, J=8.1, 1.8, 1.8 Hz, 1H), 7.82 (dd, J=7.4, 0.7 Hz, 1H), 7.53 (dd, J=8.0, 4.7 Hz, 1H), 7.01 (t, J=7.0 Hz, 1H), 6.18 (br s, 2H). MS=212 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[CH2:9]([Mg]Br)[CH3:10].[Cl-].[NH4+]>C(OCC)C.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]([OH:8])[CH2:9][CH3:10])[S:5][CH:6]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(O)c1cc(Br)cs1
Reaction time: 2 h

Procedure:
10 g (52 mmol) of 4-bromothiophene-2-carbaldehyde are dissolved in 200 mL of ethyl ether and 20 mL of THF. 26.6 mL (78 mmol) of 3.0M ethylmagnesium bromide are added slowly. After 2 hours at room temperature, the reaction medium is poured into saturated ammonium chloride solution. After extraction, a yellow oil is obtained (m=11.5 g, Y=99%).
Reaction SMILES: [CH2:1]([CH:17]1[CH2:22][C:21](=[O:23])[O:20][C:18]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:24]([C:28]1[CH:29]=[C:30]([CH2:39][CH2:40][C:41]([NH:43][NH2:44])=[O:42])[CH:31]=[C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:33]=1[OH:34])([CH3:27])([CH3:26])[CH3:25].C1(C)C=CC=CC=1>O>[C:35]([C:32]1[CH:31]=[C:30]([CH2:39][CH2:40][C:41]([NH:43][N:44]2[C:21](=[O:23])[CH2:22][CH:17]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:18]2=[O:20])=[O:42])[CH:29]=[C:28]([C:24]([CH3:25])([CH3:26])[CH3:27])[C:33]=1[OH:34])([CH3:36])([CH3:37])[CH3:38]
Reactant: CC(C)(C)c1cc(CCC(=O)NN)cc(C(C)(C)C)c1O
Reactant: CCCCCCCCCCCCCCCCC1CC(=O)OC1=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCC1CC(=O)N(NC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 101.4 %

Procedure:
2-Hexadecylsuccinic anhydride (10.5 g, 31.3 mmol), 3-(3,5-di-t-butyl-4-hydroxyphenyl)propanoic acid hydrazide (9.2 g, 31.3 mmol) and 10 ml of toluene were combined and refluxed for one hour under a nitrogen atmosphere with the azeotropic removal of water. Solvent was then removed under vacuum as the mixture was warmed to about 130° C. After 20 minutes, the reaction mixture was cooled and the vacuum was removed. The resulting viscous yellow mass was further chilled in an acetone/dry ice bath causing the mass to harden for facile removal from the reaction vessel. About 19 g of a viscous yellow gum was obtained that solidified to a translucent white solid upon standing for several days at room temperature.