Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OC(C)=O)=O.[N+:8]1([O-])[C:9](=[CH:13][CH:14]=[C:15]([CH:19]=1)[C:16]([OH:18])=[O:17])C(O)=O.[OH-].[Na+].OC1C=CC(C(O)=O)=CN=1.C(Cl)[Cl:34]>CCN(CC)CC>[Cl:34][C:9]1[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:19][N:8]=1
Reactant: O=C(O)c1ccc(C(=O)O)[n+]([O-])c1
Reactant: ClCCl
Agent: O=C(O)c1ccc(O)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: O=C(O)c1ccc(Cl)nc1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 54.2 %

Procedure:
36.6 g of Ac2O, 60 g of Et3N and 600 g of CH2Cl2 were placed in a flask and heated at 40° C. 36.6 of isocinchomeronic acid-N-oxide was added in portions. After a further 1.5 hours, NaOH (10 percent) was added while strongly stirring until the final pH reached 13. The phases were separated. The CH2Cl2 -solution was dried with solid NaOH and was kept for the next batch. The aqueous solution was acidified with concentrated HCl (final pH was about 2). The product obtained hereby was sucked off, washed and dried. The yield was 54.2 percent of 2-chlor-5-pyridine carboxylic acid (6-chloronicotinic acid) and 37.7 percent of 2-hydroxy-5-pyridine carboxylic acid (6-hydroxynicotinic acid).
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([CH3:33])([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]([F:30])([F:29])[F:28])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:32])[C:18](=[O:31])[NH:19][N:20]=2)[CH2:9]1)=O)(C)(C)C.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>C(Cl)Cl>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[CH3:32][CH:17]1[N:16]2[C:21]([CH2:22][O:23][C:24]3[C:15]2=[CH:14][C:13]([NH:12][C:10]2([CH3:33])[CH2:11][NH:8][CH2:9]2)=[C:26]([C:27]([F:29])([F:30])[F:28])[CH:25]=3)=[N:20][NH:19][C:18]1=[O:31]
Reactant: CC1C(=O)NN=C2COc3cc(C(F)(F)F)c(NC4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1C(=O)NN=C2COc3cc(C(F)(F)F)c(NC4(C)CNC4)cc3N21
Yield: 44 %

Procedure:
A solution of 3-methyl-3-(4-methyl-3-oxo-7-trifluoromethyl-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (0.010 g, 0.021 mmol) in DCM (1 mL) and TFA (0.25 mL) was stirred for 1 h at ambient temperature. The solvent was removed in vacuo and the residue was purified by preparative HPLC (Table 3, Method 10) to give 4-methyl-6-(3-methyl-azetidin-3-ylamino)-7-trifluoromethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid as a white solid (0.0045 g, 44%). LC/MS (Table 1, Method 4) Rt=1.441 min; MS m/z: 370 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[N:6]2[CH3:11].[NH3:18]>>[CH3:11][N:6]1[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[NH2:18]
Reactant: Cn1c(-c2ccccc2)nc2c(Cl)ncnc21
Reactant: N
Product: Cn1c(-c2ccccc2)nc2c(N)ncnc21
Temperature: -196 °C

Procedure:
6-chloro-9-methyl-8-phenylpurine was added in a steel vial to ammonia cooled to −196° C. using liquid nitrogen. The reaction mixture was allowed to warm to 16° C. for 70 hours; after that, the ammonia was allowed to evaporate at room temperature and the residue was chromatographed and/or crystallized to give 9-methyl-8-phenylpurine-6-ylamine, a compound of Formula (I).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[C:11]1(=O)[CH2:14][CH2:13][CH2:12]1>C(OCC)C>[C:11]1(=[N:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: COc1ccc(CN)cc1
Reactant: O=C1CCC1
Solvent: CCOCC
Product: COc1ccc(CN=C2CCC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (4-methoxyphenyl)methanamine (9.26 mL, 71.3 mmol) and cyclobutanone (5.35 mL, 71.3 mmol) in anhydrous ethyl ether (70 mL) was treated with activated 4 angstrom molecular sieves (2.5 g). The mixture was stirred vigorously for 16 hours at ambient temperature. The reaction mixture was filtered, and the sieves were washed with ethyl ether. The filtrate was concentrated under reduced pressure with no heat. The title compound was stored under nitrogen and used without further purification. MS DCI(+) m/z 190.3 [M+H]+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][CH:15]1[CH:20]2[CH:16]1[CH2:17][N:18](C(OC(C)(C)C)=O)[CH2:19]2)(=[O:13])=[O:12].[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>C(Cl)Cl>[F:31][C:30]([F:33])([F:32])[C:28]([OH:34])=[O:29].[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][CH:15]1[CH:20]2[CH:16]1[CH2:17][NH:18][CH2:19]2)(=[O:13])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CC2C(C1)C2NS(=O)(=O)c1ccc2ccccc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(NC1C2CNCC21)c1ccc2ccccc2c1

Procedure:
A solution of tert-butyl 6-[(2-napthylsulfonyl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate (27.50 g, 68.43 mmol) in 20% TFA in DCM (300 ml) was stirred at r.t. for 2 h. The reaction mixture was concentrated in vacuo and then DCM (100 ml) was added and removed in vacuo three times to remove excess TFA giving the title compound as the trifluoroacetate salt (crude yield=34.0 g). This product was used in the next step without further purification. 1H NMR (400 MHz, d6-DMSO) δ: 1.86 (2H, s), 2.20 (1H, m), 3.22 (4H, m), 7.70-7.75 (2H, m), 7.83 (1H, dd), 8.08 (1H, d), 8.18-8.23 (3H, m), 8.33 (1H, br s), 8.48 (1H, s), 9.20 (1H, br s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[C@@H:19]([NH2:21])[CH3:20])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1.CCN(C(C)C)C(C)C>CC(O)C>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[C@@H:19]([NH:21][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][N:27]3[CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH3:20])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1cc(F)cc(F)c1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)cc2n1-c1cc(F)cc(F)c1
Temperature: 90 °C
Yield: 40.2 %

Procedure:
A mixture of (S)-1-[1-(3,5-difluorophenyl)-6-fluoro-1H-benzoimidazol-2-yl]ethylamine (206 mg, 0.71 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (169 mg, 0.71 mmol) and DIPEA (0.37 mL, 2.1 mmol) in IPA (1.4 mL) was heated in a sealed tube for 20 h at 90° C. After cooling to RT, the volatiles were removed in vacuo and the resulting residue purified by column chromatography (Si—PPC, gradient 0-10% 2M NH3 in MeOH/DCM) to afford the title compound as a colourless glass (141 mg, 40%). LCMS (Method C): RT 3.38 min [M+H]+ 494. 1H NMR (CDCl3, 400 MHz): δ 8.29-8.28 (1H, m), 7.97-7.96 (1H, m), 7.72-7.68 (1H, m), 7.10-7.01 (3H, m), 6.97-6.91 (1H, m), 6.86-6.82 (1H, m), 6.37 (1H, bs), 5.79-5.67 (2H, m), 4.18-4.13 (1H, m), 3.80-3.73 (1H, m), 2.11-1.97 (3H, m), 1.80-1.63 (6H, m).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[CH:13]1[C:18](=[O:19])[N:17]([CH3:20])[C:16]2[CH:21]=[CH:22][CH:23]=[CH:24][C:15]=2[S:14]1.Br[CH2:26][CH2:27][CH2:28][Cl:29].C(OCC)(=O)C>CN(C)C=O.O>[Cl:29][CH2:28][CH2:27][CH2:26][C:13]1([C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][CH3:3])[C:18](=[O:19])[N:17]([CH3:20])[C:16]2[CH:21]=[CH:22][CH:23]=[CH:24][C:15]=2[S:14]1
Reactant: COc1ccc(OC)c(C2Sc3ccccc3N(C)C2=O)c1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(OC)c(C2(CCCCl)Sc3ccccc3N(C)C2=O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.9 %

Procedure:
To a stirred suspension of 60% sodium hydride (0.7 g) in anhydrous dimethylformamide (10 ml), 3,4-dihydro-2-(2,5-dimethoxyphenyl)-4-methyl-3-oxo-2H-1,4-benzothiazine (5.0 g) dissolved in anhydrous dimethylformamide (15 ml) is added under nitrogen atmosphere and ice-cooling, and the mixture is stirred for 20 minutes at room temperature. 1-Bromo-3-chloropropane (3.0 g) dissolved in dimethylformamide (5 ml) is added to a reaction mixture, and the mixture is stirred for 1.5 hours at 50° C. The mixture is poured into a mixture of ethyl acetate and water. The organic layer is washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography to give 5.4 g (86.9%) of the titled compound as an oily form.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]([OH:10])=O)[C:4](=[O:11])[CH2:3]1.[CH3:12][C:13]1([CH3:23])[NH:17][CH2:16][C:15](=[O:18])[N:14]1[CH2:19][C:20]([NH2:22])=[O:21].C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C=O>[CH3:12][C:13]1([CH3:23])[N:17]([C:8](=[O:10])[CH2:7][N:5]2[CH2:6][CH:2]([OH:1])[CH2:3][C:4]2=[O:11])[CH2:16][C:15](=[O:18])[N:14]1[CH2:19][C:20]([NH2:22])=[O:21]
Reactant: CC1(C)NCC(=O)N1CC(N)=O
Reactant: O=C(O)CN1CC(O)CC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CC1(C)N(CC(N)=O)C(=O)CN1C(=O)CN1CC(O)CC1=O

Procedure:
To a stirred solution of 4-hydroxy-2-oxo-1-pyrrolidine acetic acid (3.18 g) and 2,2-dimethyl-5-oxo-1-imidazolidineacetamide (3.5 g) in 100 ml of dimethylformamide at room temperature, 4.12 g of DCC were added at once. After 5 hours the solvent was evaporated under vacuum and the residue was suspended in 50 ml of stirred water. After 10 minutes the solid was filtered off and the water evaporated under reduced pressure. The residue was triturated with isopropanol and collected, affording the title product as a white powder m.p. 248°-250° C. (decomp).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].CCN(C(C)C)C(C)C.C[Al](C)C.[CH3:19][O:20][CH2:21][C:22]1[C:23](=[O:42])[C:24]([C:38](OC)=[O:39])=[N:25][N:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[CH:27]=1>C(Cl)Cl>[CH3:5][O:4][N:3]([CH3:2])[C:38]([C:24]1[C:23](=[O:42])[C:22]([CH2:21][O:20][CH3:19])=[CH:27][N:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:37])[F:36])[CH:29]=2)[N:25]=1)=[O:39]
Reactant: COCc1cn(-c2cccc(C(F)(F)F)c2)nc(C(=O)OC)c1=O
Reactant: CNOC
Agent: C[Al](C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCc1cn(-c2cccc(C(F)(F)F)c2)nc(C(=O)N(C)OC)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (2.63 g, 27 mmol) and iPr2NEt (4.70 mL, 27 mmol) in CH2Cl2 (30 mL) was added AlMe3 (1.8 M solution in toluene, 15 mL, 27 mmol) dropwise at 0° C. under Ar atmosphere. After stirring for 1 h, a solution of methyl 5-(methoxymethyl)-4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxylate (3.08 g, 9 mmol) in CH2Cl2 (30 mL) was added dropwise, and the mixture was stirred for 1 h at 0° C. The reaction mixture was poured into ice-water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt and recrystallized from hexane/AcOEt to give the title compound (1.99 g, 60% yield) as an off-white solid: mp 157-159° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.41 (3H, s), 3.53 (3H, s), 3.67 (3H, s), 4.50 (2H, d, J=1.1 Hz), 7.62-7.71 (2H, m), 7.79-7.85 (1H, m), 7.90 (1H, s), 8.39 (1H, t, J=1.1 Hz). Anal. Calcd for C16H16F3N3O4: C, 51.75; H, 4.34; N, 11.32. Found: C, 51.77; H, 4.25; N, 11.24.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[O:11].C(N(CC)CC)C.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:22])[C@@H:4]1[CH2:8][C@@H:7]([O:9][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)=[O:11]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc(OC)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
trans-1-(p-Methoxybenzyloxycarbonyl)-4-hydroxy-L-proline methyl ester (5.18 g), 3.79 g of triethylamine and 3.77 g of t-butyldimethylsilyl chloride were dissolved in 52 ml of dry dimethylformamide. The resulting mixture was stirred at room temperature for 3 hours, diluted with water, extracted with ethyl acetate, washed successively with water, dilute hydrochloric acid and water, dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue was purified by silica gel chromatography to obtain trans-1-(p-methoxybenzyloxycarbonyl)-4-t-butyldimethylsilyloxy-L-proline methyl ester.
Reaction SMILES: [C:1]([C:4]([NH:11][C:12](=O)[C:13]1[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:15](O)=[O:16])([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])(=[O:3])[NH2:2].C(C(NC(=O)C1C(=CC=CC=1)C(OC)=O)(C)C(C)(C)C)(=O)N>>[CH:5]([C:4]1([CH:8]([CH3:10])[CH3:9])[N:11]2[C:15](=[O:16])[C:14]3[C:13]([C:12]2=[N:2][C:1]1=[O:3])=[CH:21][CH:20]=[CH:19][CH:18]=3)([CH3:6])[CH3:7]
Reactant: CC(C)C(NC(=O)c1ccccc1C(=O)O)(C(N)=O)C(C)C
Agent: COC(=O)c1ccccc1C(=O)NC(C)(C(N)=O)C(C)(C)C
Product: CC(C)C1(C(C)C)C(=O)N=C2c3ccccc3C(=O)N21

Procedure:
The 3,3-diisopropyl-5H-imidazo[2,1-a]isoindole-2(3H),5-dione (melting point 146°-148° C) is prepared in the manner described above, excepting that the methyl ester of N-(1-carbamoyl-1-isopropyl-2-methylpropyl)phthalamic acid is substituted for methyl N-(1-carbamoyl-1,2,2-trimethylpropyl)phthalamate, in the above reaction.
Reaction SMILES: [N+](C1C=C(S(Cl)(=O)=O)C=CC=1)([O-])=O.C(OC(=O)CN)C1C=CC=CC=1.[CH2:26]([O:33][C:34](=[O:49])[CH2:35][NH:36][S:37]([C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([N+:46]([O-])=O)[CH:41]=1)(=[O:39])=[O:38])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[Sn](Cl)(Cl)(Cl)Cl>>[CH2:26]([O:33][C:34](=[O:49])[CH2:35][NH:36][S:37]([C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([NH2:46])[CH:41]=1)(=[O:39])=[O:38])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(CNS(=O)(=O)c1cccc([N+](=O)[O-])c1)OCc1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: NCC(=O)OCc1ccccc1
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Product: Nc1cccc(S(=O)(=O)NCC(=O)OCc2ccccc2)c1

Procedure:
3-Nitro-benzenesulfonyl chloride was reacted with glycine benzyl ester and the resulting (3-nitro-benzensulfonylamino)-acetic acid benzyl ester was reduced with tin chloride to afford (3-amino-benzenesulfonylamino)-acetic acid benzyl ester. This was reacted with 5-(2-adamantan-1-yl-ethyl)-2-cyclohexyl-1H-imidazole-4-carboxylic acid (Example 252) according to the procedure of Example 20, step d. The benzyl ester was hydrolysed using the same procedure as in Example 1, step e to afford the title compound. 1H NMR (300 MHz, d6-DMSO) 12.00 (1H, br s), 9.71 (1H, br s), 8.35 (1H, s), 7.96 (2H, m), 7.45 (2H, m), 3.57 (2H, s), 2.88 (2H, m), 2.60 (1H, m), 1.94-1.32 (27H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 55.50; H, 7.88; N, 8.83%. C37H57N5O10.2.0 mols H2O requires: C, 55.55; H, 7.69; N, 8.75%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][CH2:28][NH:29][CH2:30][C:31]([O:33]CC)=[O:32])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][CH2:28][NH:29][CH2:30][C:31]([OH:33])=[O:32])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CNCCCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCCNCC(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a solution of ethyl N-{3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propyl}glycinate (D93) (50 mg) in THF (5 mL) was added aqueous NaOH (2 M, 1 mL). The reaction was stirred at 20° C. overnight. The mixture was acidified with aqueous HCl (2 M) to pH 5-6, partitioned between ethyl acetate (25 mL) and water (10 mL). The organic phase was washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulphate and evaporated to give the crude product, which was purified by Mass Directed Auto Prep to afford N-{3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propyl}glycine (E70) (45 mg, TFA salts). δH (DMSO-d6, 400 MHz): 1.37 (6H, d), 2.02 (2H, m), 2.82 (2H, t), 2.95 (2H, t), 3.69 (2H, s), 4.90 (1H, m), 7.23 (1H, t), 7.31 (1H, d), 7.45 (1H, d), 7.82 (1H, d), 7.95 (1H, d), 8.20 (1H, dd), 8.36 (1H, d), 10.85 (1H, s). MS (ES): C24H26ClN4O4 requires 468; found 469.2 (M+H+).
Reaction SMILES: CO.[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][CH:15]([CH:18]3[CH2:23][O:22][CH:21]([C:24]#[C:25][Si](C)(C)C)[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)=[C:8]([F:30])[C:7]=1[F:31])[CH3:4].[OH-].[Na+].Cl>ClCCl>[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][CH:15]([CH:18]3[CH2:23][O:22][CH:21]([C:24]#[CH:25])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)=[C:8]([F:30])[C:7]=1[F:31])[CH3:4]
Reactant: CCOc1ccc(C2CCC(C3CCC(C#C[Si](C)(C)C)OC3)CC2)c(F)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: C#CC1CCC(C2CCC(c3ccc(OCC)c(F)c3F)CC2)CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
40 mL of methanol and 30 mL of dichloromethane were added to 3.7 g of (5-[4-(4-ethoxy-2,3-difluorophenyl)cyclohexyl]-tetrahydropyran-2-ylethynyl) trimethylsilane obtained in the seventh step, and the mixture was cooled to 0° C., to which 5 mL of a sodium hydroxide aqueous solution (1M) was added. The temperature of the reaction solution was increased to room temperature, and the reaction solution was stirred for 2 hours, neutralized with hydrochloric acid, and the solvent was concentrated to about 30 mL under reduced pressure. The residue was extracted three times with 20 mL of diethyl ether, and the mixture including the organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by distilling off the solvent. The residue was purified by silica gel column chromatography to provide 2.6 g of 5-[4-(4-ethoxy-2,3-difluorophenyl)cyclohexyl]-2-ethynyltetrahydropyran.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[NH2:12][CH:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1.CCN(C(C)C)C(C)C>CS(C)=O.O.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:12][CH:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Br)ccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.4 %

Procedure:
To a solution of 4-bromo-2-fluoro-1-nitrobenzene (500 mg, 2.27 mmol) and tert-butyl 3-aminopyrrolidine-1-carboxylate (390 mg, 2.27 mmol) in DMSO (5 mL) was added DIPEA (351 mg, 2.72 mmol) and the solution stirred in a sealed bottle at room temperature for 16 h. After LCMS analysis indicated completion of the reaction, the solution was diluted with water (100 mL) and DCM (100 mL). The organic layer was washed by water (30 mL×2) and brine (30 mL) and dried over anhydrous Na2SO4 before being filtered and concentrated to yield the desired product (670 mg Yield 80%). The material was used in the next step without further purification. LCMS (m/z): 386.1 (M+1).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([CH:6]=O)=O.[NH2:8][CH:9]([C:13]([NH2:15])=[O:14])[C:10]([NH2:12])=[O:11].Cl>O>[OH:11][C:10]1[C:9]([C:13]([NH2:15])=[O:14])=[N:8][C:4]([CH3:6])=[CH:3][N:12]=1
Reactant: NC(=O)C(N)C(N)=O
Reactant: CC(=O)C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cnc(O)c(C(N)=O)n1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
An aqueous solution of NaOH (10.6 mL, 12.5N, 0.133mol) is added dropwise to a 40% water solution of pyruvic aldehyde (24 g, 9.6 g, 0.133mol) and 2-amino-malonamide (16 g, 0.136mol) at −20° C., keeping the temperature bellow 0° C. The reaction mixture is mechanically stirred overnight at r.t and then the reaction mixture is cooled to −20° C. and HCl conc. (16 mL, 0.16 mol) is slowly added keeping the temperature bellow 0° C. and stirred at r.t. for 48 h. The reaction mixture is cooled in an ice bath and the crystals formed filtered off, washed with a little water and dried with air, to give 3-hydroxy-6-methyl-pyrazine-2-carboxylic acid amide as a brown solid, (5.7 g, 28%).
Reaction SMILES: [N:1]1([C@H:7]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[N:22]=[CH:21]4)=[CH:16][CH:15]=3)=O)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[N:1]1([C@H:7]2[CH2:11][CH2:10][N:9]([CH2:12][C:14]3[CH:15]=[CH:16][C:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[N:22]=[CH:21]4)=[CH:18][CH:19]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc(-n2cnc3ccccc32)cc1)N1CC[C@H](N2CCCCC2)C1
Agent: O=C(O)/C=C/C(=O)O
Product: c1ccc2c(c1)ncn2-c1ccc(CN2CC[C@H](N3CCCCC3)C2)cc1

Procedure:
Using essentially the same procedure described in Example 14 and employing 1-(4-{[(3S)-3-piperidin-1-ylpyrrolidin-1-yl]carbonyl}phenyl)-1H-benzimidazole as starting material and fumaric acid, the title compound was obtained and identified by NMR and mass spectral analyses. MS [361.2 m/e (M+H)].
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCCCCCCCCCCC.NC(N)=[O:23].C(=O)([O-])[O-].[Na+].[Na+].OO>O.C([O-])(=O)C.[Mn+2].C([O-])(=O)C>[CH2:1]1[O:23][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: NC(N)=O
Agent: [Mn+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCCCCCCCCCCC
Product: c1ccc(C2CO2)cc1
Yield: 87 %

Procedure:
To a mechanically stirred solution of styrene (0.01 mol), dodecane (0.001 mol), urea (0.208 mol), sodium carbonate (0.004 mol) and manganese (II) acetate (0.2 mmol) in 10.0 ml of water at 30° C. is added 30% aqueous hydrogen peroxide (0.45 mol) in three equal portions over a period of 3 hours. After 8 hours the reaction mixture was extracted with 4×5 ml diethyl ether. The combined organic layer was dried over anhydrous sodium sulphate. Removal of solvent yielded styrene oxide in 87% yield with selectivity 82%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]=[C:14]([CH2:18][OH:19])[CH2:13]1.C(N(CC)CC)C>C(Cl)Cl.O>[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]=[C:14]([CH:18]=[O:19])[CH2:13]1
Reactant: CN1CCC=C(CO)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCC=C(C=O)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 109.7 %

Procedure:
2.88 mL oxalyl chloride (2.4 equiv.) was dissolved in 20 mL DCM. The mixture was cooled to −78° C. and a solution of 3.37 mL DMSO (2.0 equiv.) in 10 mL DCM was added dropwise. The mixture was stirred for 15 minutes at −78° C. A solution of 3.0 g (1-Methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-methanol in 10 mL DCM was added dropwise while keeping the temperature below −65° C. The mixture was stirred for 15 minutes at −78° C. 9.81 mL Triethylamine (3.0 equiv.) was added dropwise and subsequently the mixture was allowed to warm to room temperature. 50 mL DCM was added to keep the mixture stirrable. The mixture was stirred for 1 hour at room temperature. H2O was added, the organic layer was separated and the aqueous layer again extracted with DCM. The combined organic layers were dried over Na2SO4, filtrated and concentrated to yield 3.24 g of an orange oil (85% pure) which was used without further purification in the subsequent step. 1H NMR (400 MHz, CDCl3) δ 2.43 (s, 3H), 2.48-2.60 (m, 4H), 3.11-3.15 (m, 2H), 6.85 (m, 1H), 9.43 (s, 1H).