Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:7]([CH3:10])=[CH:8][CH:9]=1)[NH2:6].[S:11](=[O:15])(=[O:14])([OH:13])N>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:6])[C:7]([CH3:10])=[CH:8][C:9]=1[S:11]([OH:15])(=[O:14])=[O:13]
Reactant: COc1ccc(C)c(N)c1
Reactant: NS(=O)(=O)O
Solvent: CC#N
Product: COc1cc(N)c(C)cc1S(=O)(=O)O
Reaction time: 2 h

Procedure:
23.1 g of 3-methoxy-6-methylaniline and 16.4 g of sulfamic acid were put into a 100 ml egg-plant type flask and the mixture was heated to temperature of from 150° to 160° C. and maintained thereat for 2 hours. Acetonitrile was added to the reaction mixture and the crystals thus deposited were collected. The crystals were dissolved in an aqueous solution of sodium hydroxide, the solution was filtered and acidified with hydrochloric acid, and the crystals thus deposited were collected by filtration.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[CH:24]([C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1B(O)O)([CH3:26])[CH3:25]>>[CH:24]([C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1)([CH3:26])[CH3:25]
Reactant: COc1ccc(B(O)O)c(C(C)C)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2N4CC3)c(C(C)C)c1

Procedure:
The title compound was prepared by the method of Example 89 step C from tert-butyl(6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)carboxylate (189 mg, 0.5 mmol) and corresponding 2-isopropyl-4-methoxyphenyl boronic acid (178 mg, 1.0 mmol) to afford after chromatographic purification the title compound (152 mg, 68%). 1H NMR (CDCl3, 300 MHz) δ 7.09 (d, 1H, J=8.4 Hz), 6.88 (d, 1H, J=2.5 Hz), 6.83 (s, 1H), 6.78 (s, 1H), 6.72 (dd, 1H, J=8.4, 2.9 Hz), 3.80–4.20 (m, 2H), 3.84 (s, 3H), 3.74–3.78 (m, 1H), 3.05–3.50 (m, 7H), 2.84–2.98 (m, 1H), 1.82–1.94 (m, 2H), 1.48 (s, 9H), 1.12–1.17 (m, 6H) ppm. MS-ApCI: 449. [M+H+].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:21]=[C:22]([CH:24]([CH3:26])[CH3:25])[CH:23]=1)[CH2:12][NH:13]C(=O)OC(C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:12][NH2:13])[CH:21]=[C:22]([CH:24]([CH3:26])[CH3:25])[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1cc(CNC(=O)OC(C)(C)C)cc(OCc2ccccc2)c1
Agent: Cl
Solvent: CO
Product: CC(C)c1cc(CN)cc(OCc2ccccc2)c1

Procedure:
A solution of tert-butyl 3-(benzyloxy)-5-isopropylbenzylcarbamate and 15.0 mL of 1.25 M HCl in MeOH was stirred at r.t. for 3.5 h. The solution was concentrated, and saturated NaHCO3 was added to a pH=7-8. The aqueous layer was extracted with the extract of (40 mL CHCl3: 5 mL MeOH: 5 mL H2O) (2×). The combined extracts were dried over Na2SO4, filtered, and concentrated to give 221 mg of crude (3-(benzyloxy)-5-isopropylphenyl)methanamine which was used for the next reaction without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([O:10][C:11](=[O:13])[CH3:12])[C:7]([CH3:15])([CH3:14])[C:6]=2[CH:16]=1.[CH3:17][N:18](C)C=O.[C-]#N.[Na+]>O>[C:17]([C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([O:10][C:11](=[O:13])[CH3:12])[C:7]([CH3:15])([CH3:14])[C:6]=2[CH:16]=1)#[N:18]
Reactant: CC(=O)OC1Oc2ccc(Br)cc2C1(C)C
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: CC(=O)OC1Oc2ccc(C#N)cc2C1(C)C
Reaction time: 3 h

Procedure:
The product from stage (a) (4 g), cuprous cyanide (1.8 g) and dimethylformamide (10 ml) were boiled under reflux with stirring for three hours. The mixture was then cooled, and a solution of sodium cyanide (4.5 g) in water (18 ml) was added. After stirring for 1 hour, the product was extracted into ether, the ethereal extract being washed with water (twice), dried over magnesium sulphate, and run down. Recrystallisation of the residue from ethanol gave 1.8 g of pure product, mp 140°-142° C.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH2:23]([C:27]1[C:36](=O)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([C:45]3[C:46]([C:51]([O:53][CH3:54])=[O:52])=[CH:47][CH:48]=[CH:49][CH:50]=3)=[CH:41][CH:40]=2)[CH:28]=1)[CH2:24][CH2:25][CH3:26].O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:23]([C:27]1[C:36](=[S:10])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([C:45]3[C:46]([C:51]([O:53][CH3:54])=[O:52])=[CH:47][CH:48]=[CH:49][CH:50]=3)=[CH:41][CH:40]=2)[CH:28]=1)[CH2:24][CH2:25][CH3:26]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCCCc1cn(Cc2ccc(-c3ccccc3C(=O)OC)cc2)c2ccccc2c1=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCc1cn(Cc2ccc(-c3ccccc3C(=O)OC)cc2)c2ccccc2c1=S
Yield: 26169.9 %

Procedure:
2.10 mg of Lawesson reagent were added to a solution of 400 mg of the product of Example 3 in 20 ml of toluene and the mixture was refluxed for 90 minutes. The mixture was poured into 100 ml of water and extraction was carried out with ethyl acetate. Th extracts were washed with water, dried, filtered and evaporated to dryness to obtain 0.6 g of the expected product which was chromatographed on silica (eluant: methylene chloride-acetone (98-2)) to collect 0.42 g of the desired product melting at 158° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH3:6].[CH3:7][C:8]1[CH:9]=[C:10]([SH:15])[CH:11]=[C:12]([CH3:14])[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[CH2:5]([O:4][CH2:3][CH2:2][S:15][C:10]1[CH:11]=[C:12]([CH3:14])[CH:13]=[C:8]([CH3:7])[CH:9]=1)[CH3:6]
Reactant: CCOCCCl
Reactant: Cc1cc(C)cc(S)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCCSc1cc(C)cc(C)c1
Temperature: 25 °C
Yield: 76.2 %

Procedure:
To a solution of 1-chloro-2-ethoxyethane (5.90 mL, 54.3 mmol) and 3,5-dimethylbenzenethiol (5.00 g, 36.2 mmol) in N,N-dimethylformamide (140 mL) were added potassium carbonate (5.50 g, 39.8 mmol) and potassium iodide (0.90 g, 5.43 mmol) under stirring at room temperature, and the mixture was stirred at 80° C. for 5 hr. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with diethyl ether. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane/ethyl acetate=10/1) to give the title compound (5.80 g, yield 76%) as a colorless oil.
Reaction SMILES: [ClH:1].[C:2](=[NH:6])([NH2:5])[CH2:3][CH3:4].[F:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[C:15]1[S:19][C:18](CCC#N)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:17]([C:30](=[O:35])[C@@H:31]([O:33][CH3:34])[CH3:32])[N:16]=1.Cl.N>C(O)C>[ClH:1].[F:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[C:15]1[S:19][C:18]([CH2:4][CH2:3][C:2](=[NH:5])[NH2:6])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:17]([C:30](=[O:35])[C@@H:31]([O:33][CH3:34])[CH3:32])[N:16]=1
Reactant: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCC#N)c1ccccc1
Reactant: CCC(=N)N
Agent: Cl
Agent: N
Solvent: CCO
Product: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCC(=N)N)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 15 %

Procedure:
Preparation of 345-(2,5-difluorophenyl)-3-((S)-2-methoxypropanoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propanimidamide hydrochloride: To a cooled (0° C.) solution of 3-(5-(2,5-difluorophenyl)-3-((S)-2-methoxypropanoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propanenitrile (0.053 g, 0.13 mmol) in ethanol (0.5 mL) was added a 9.8 M solution of ethanolic HCl (0.5 mL). After stirring at 0° C. for 10 minutes and then at room temperature for 4 hours, the reaction mixture was concentrated under reduced pressure. To the residue was added NH3 (1.0 mL, 7.0 mmol, 7 M solution in methanol). After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. The residue was chromatographed (dichloromethane followed by 20% MeOH and 1% aqueous NH4OH in dichloromethane) to afford the product as a mixture of diastereomers (3.4 mg, 15% yield). MS ESI (+) m/z 433 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 9.0 (br, 4H), 8.7 (br, 4H), 7.51 (m, 2H), 7.38 (m, 8H), 7.32 (m, 2H), 7.14 (m, 4H), 4.73 (m, 2H), 3.57 (m, 2H), 3.42 (s, 3H), 3.35 (s, 3H), 2.75 (m, 4H), 2.33 (m, 1H), 2.23 (m, 1H), 1.52 (d, 3H, J=6.3 Hz), 1.48 (d, 3H, J=7.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:17]([C:18]([O-:20])=O)=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.C1C=CC2N(O)N=[N:27]C=2C=1.[NH4+].[Cl-].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:17]([C:18]([NH2:27])=[O:20])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nc3cccc(C(=O)[O-])c3o2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2nc3cccc(C(N)=O)c3o2)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 3 %

Procedure:
To a solution of methyl 2-(4-methoxyphenylbenzo[d]oxazole-7-carboxylate in DMF (15 mL) was added HOBt (148 mg, 1.1 mmol), NH4Cl (54 mg, 1.0 mmol), DIPEA (387 mg, 3.0 mmol) and EDCI (211 mg, 1.1 mmol). The mixture was stirred at 25° C. for 10 hr. To the resulting mixture, water (10 mL) and aqueous hydrochloric acid (1 N) were added to pH=3, then extracted with ethyl acetate (100 mL×4). The organic phase was washed with saturated sodium bicarbonate solution and brine, concentrated, and dried in vacuum. The crude product was purified by pre-HPLC to obtain 2-(4-methoxyphenylbenzo[d]oxazole-7-carboxamide as a white solid (8 mg, yield 3% for 2 steps). 1H-NMR (400 MHz, CDCl3-d) δ 3.93 (s, 3H), 6.16 (s, 1H), 7.06-7.08 (d, J=8 Hz, 3H), 7.47 (s, 1H), 7.90-8.18 (m, 4H); LC-MS (ESI) m/z 269 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]1[C:21]([F:22])=[CH:20][N:19]=[C:18](Cl)[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][CH:25]([S:27]([CH2:30][C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34])(=[O:29])=[O:28])[CH3:26]>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]1[C:21]([F:22])=[CH:20][N:19]=[C:18]([NH:34][C:33]2[CH:35]=[CH:36][CH:37]=[C:31]([CH2:30][S:27]([CH:25]([CH3:26])[CH3:24])(=[O:29])=[O:28])[CH:32]=2)[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nc(Cl)ncc2F)c(OCc2ccccc2)c1
Reactant: CC(C)S(=O)(=O)Cc1cccc(N)c1
Product: CC(C)S(=O)(=O)Cc1cccc(Nc2ncc(F)c(-c3ccc(F)cc3OCc3ccccc3)n2)c1

Procedure:
Example 5 was prepared under similar conditions as described in the preparation of Example 3 using 4-[2-(benzyloxy)-4-fluorophenyl]-2-chloro-5-fluoropyrimidine and 3-[(propan-2-ylsulfonyl)methyl]aniline (UkrOrgSynthesis Ltd.). The batch was purified by preparative HPLC.
Reaction SMILES: [CH:1]1([C@H:4]([NH:12][C:13]([C:15]2[C:24]3[C:19](=[C:20](F)[CH:21]=[CH:22][CH:23]=3)[C:18](=[O:26])[N:17]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[C:16]=2[CH3:33])=[O:14])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=2)[CH2:3][CH2:2]1.N([O-])=[O:35].[Na+]>CN(C)C=O>[CH:1]1([C@H:4]([NH:12][C:13]([C:15]2[C:24]3[C:19](=[C:20]([OH:35])[CH:21]=[CH:22][CH:23]=3)[C:18](=[O:26])[N:17]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[C:16]=2[CH3:33])=[O:14])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(C(=O)N[C@H](c2cccc(F)c2)C2CC2)c2cccc(F)c2c(=O)n1-c1cccnc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)N[C@H](c2cccc(F)c2)C2CC2)c2cccc(O)c2c(=O)n1-c1cccnc1
Temperature: 220 °C
Reaction time: 0.33 h
Yield: 10.2 %

Procedure:
A mixture of 8-fluoro-3-methyl-1-oxo-2-pyridin-3-yl-1,2-dihydro-isoquinoline-4-carboxylic acid [(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-amide (2a, 70.0 mg, 0.157 mmol), sodium nitrite (NaNO2, 77.0 mg, 1.12 mmol) in N,N-dimethylformamide (0.7 mL) was heated under microwave irradiation at 220° C. for 30 min. The obtained dark solution was quenched with 3M aq. HCl (5 ml), stirred for 20 min and partitioned with ethyl acetate (3×5 mL). Each organic solution was washed with 1M HCl (3×2 mL). The combined aq. solution was basified with NaHCO3 (pH=7) and extracted with ethyl acetate. The combined organic extracts were absorbed on 1 g SiO2 and flash chromatographed on 20 g silica gel with gradient heptane-ethyl acetate. The product came out with 75% ethyl acetate and only pure fractions were evaporated to give 7.1 mg of a brown residue, yield 10%. LC-MS (m/z) 444.6 (MH+); tR=1.26. 1H NMR (500 MHz, 70° C., DMSO-d6): 0.48 & 0.59 (two br. s, 2×2H, two CH2 of Cp), 1.27 (br. s, 1H, CH of Cp), 1.91 (br. s, 3H, Me), 4.51 (t, J=8.5 Hz, 1H, CHNH), 6.87 (overlapping d, J=8.1 Hz, 1H), 6.9 (overlapping br. s, 1H), 7.06 (br. T, J=8.3 Hz, 1H), 7.26 (d, J=10.5 Hz, 1H), 7.3 (d, J=7.6 Hz, 1H), 7.40 (q, J=7.2 Hz, 1H), 7.59-7.66 (br. m, 2H), 7.86 (br. m, 1H), 8.58 (s, 1H), 8.72 (s, 1H), 8.93 (br. d, J=7.8 Hz, NHCO), 12.46 (s, 1H, OH).
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41](C)[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].C([O-])(=O)C.[Na+].II.[OH-].[Na+].[OH-].[NH4+]>CO.O.O>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([NH:41][CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Agent: CC(=O)[O-]
Agent: II
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](NC)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Temperature: 47 °C
Reaction time: 3 h

Procedure:
20 g of erythromycin A (=27.2 mmole) and 11.2 g (=136.2 mmole) of sodium acetate were dissolved in 200 ml of an 8:2 methanol/water mixture. The solution was heated to 47° C. Then 6.9 g (=136.2 mmole) of iodine were added. The pH was kept at 8 to 9 by adding dilute aqueous sodium hydroxide solution. After 3 hours, the reaction mixture was worked up by pouring it into a mixture of 1 liter of water and 20 ml of ammonium hydroxide solution. The reaction mixture was extracted with ethyl acetate, and the organic extract was washed with ammonium hydroxide-containing water and concentrated. The crude product remaining after removal of the solvent was recrystallized from acetone/ammonium hydroxide solution 50:3. Melting point 143°-148° C.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:16]=[N:15][C:14]3[C:13](=[O:17])[NH:12][C:11]([NH2:18])=[N:10][C:9]2=3)C=CC=CC=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][O:42][CH2:43]Cl)=[CH:35][CH:34]=1.CCO>CN(C=O)C>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][O:42][CH2:43][N:15]2[C:14]3[C:13](=[O:17])[NH:12][C:11]([NH2:18])=[N:10][C:9]=3[N:8]=[CH:16]2)=[CH:35][CH:34]=1
Reactant: Nc1nc2c(ncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1
Reactant: COc1ccc(OCCOCCl)cc1
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1ccc(OCCOCn2cnc3nc(N)[nH]c(=O)c32)cc1
Yield: 88.6 %

Procedure:
Compound 8 (2.72 g, 8.20 mmol) was prepared in 82% yield from 6 (3.64 g, 9.25 mmol) and (2-(p-methoxyphenyloxy)ethoxy)methyl chloride (2.18 g, 10.1 mmol) in DMF (100 mL) by the method used for the synthesis of 7: mp>250° C. (dec.); Rf(hexanes/EtOAc=1:2) 0.18; UV (EtOH) λmax 290 (ε 16,500); 1H NMR (DMSO-d6) δ 3.70 (s, 3 H, OCH3), 4.02-4.10 (m, 4 H, O(CH2)2O), 5.74 (s, 2 H, H2C1′), 5.88 (s, 2 H, NH2), 6.67, 6.70 (AA′BB′, J=9.30 Hz, 4 H, C6H4), 7.50 (s, 1 H, NH), 8.85 (s, 1 H, HC8); 13C NMR (DMSO-d6) δ 56.12 (CH3), 68.74 (OCH2), 70.20 (CH2Oph), 75.31(C1′), 107.25 (C5), 144.02 (C8), 153.25 (C4), 154.48 (C2), 159.26 (C6), 115.55, 116.38, 153.51, 155.56 (C6H4); MS m/z 331 (M+). Anal (C15H17N5O4) C, H, N; calcd (%): 54.37, 5.17, 21.13; found (%): 54.26, 5.20, 21.19.
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][N:4]=1.[CH3:9][C:10]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[C:13]([CH3:26])[C:11]=1[NH2:12]>>[CH3:9][C:10]1[CH:16]=[C:15]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][N:4]=2)[CH:14]=[C:13]([CH3:26])[C:11]=1[NH2:12]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1N
Reactant: Brc1ccncn1
Agent: Cl
Product: Cc1cc(-c2ccncn2)cc(C)c1N
Temperature: 70 °C
Reaction time: 12 h

Procedure:
The title compound is prepared from 4-bromopyrimidine hydrochloride and 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline following a procedure analogous to that described in Step 2 of Intermediate 62. The mixture is stirred for 12 hours at 70° C. LC (method 9): tR=0.74 min; Mass spectrum (ESI+): m/z=200 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[C:25]4[C:21]([C:22]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[CH:23][NH:24]4)=[CH:20][C:19]=3[F:34])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+].Cl>C(O)(C)C.O>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[C:25]4[C:21]([C:22]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:23][NH:24]4)=[CH:20][C:19]=3[F:34])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: CCOC(=O)CCc1c[nH]c2cc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)c(F)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(C)Oc1ccc(-c2nc(-c3cc4[nH]cc(CCC(=O)O)c4cc3F)no2)cc1C#N
Temperature: 20 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a solution of ethyl 3-[6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-fluoro-1H-indol-3-yl]propanoate (D157) (180 mg) in isopropanol (25 mL) and water (5 mL) was added 0.8 mL 20% aqueous NaOH solution. The reaction mixture was stirred at 20° C. overnight. Afterwards, the mixture was adjusted to pH 3 by addion of 6 M HCl and evaporated. The residue was treated with 6 mL DMF and filtered. The filtrate was purified by MDAP to give the designed product 3-[6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-fluoro-1H-indol-3-yl]propanoic acid (E110) (115 mg). δH (DMSO-d6, 400 MHz): 1.32 (6H, d), 2.55 (2H, t), 2.88 (2H, t), 4.92 (1H, m), 7.37 (1H, s), 7.47 (1H, d), 7.50 (1H, d), 8.05 (1H, d), 8.35 (1H, dd), 8.44 (1H, d), 11.23 (1H, s), 12.05 (1H, s); δF (DMSO-d6, 376 MHz): −121.7; MS (ES): C23H19FN4O4 requires 434; found 435.2 (M+H+).
Reaction SMILES: C(OC(=O)N[C@H]1CC[C@H](O)C1)(C)(C)C.C(OC(=O)N[C@H]1CC[C@@H](N)C1)(C)(C)C.C(OC(=O)[NH:35][C@H:36]1[CH2:40][CH2:39][C@@H:38]([N:41]2[C:45]3[CH:46]=[CH:47][C:48]([CH3:50])=[CH:49][C:44]=3[N:43]=[C:42]2[CH3:51])[CH2:37]1)(C)(C)C.CC1N([C@H]2CC[C@H](N)C2)C2C=CC(C)=CC=2N=1>>[CH3:51][C:42]1[N:41]([C@@H:38]2[CH2:39][CH2:40][C@H:36]([NH2:35])[CH2:37]2)[C:45]2[CH:46]=[CH:47][C:48]([CH3:50])=[CH:49][C:44]=2[N:43]=1
Reactant: Cc1ccc2c(c1)nc(C)n2[C@@H]1CC[C@H](NC(=O)OC(C)(C)C)C1
Agent: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)C1
Agent: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)C1
Agent: Cc1ccc2c(c1)nc(C)n2[C@H]1CC[C@H](N)C1
Product: Cc1ccc2c(c1)nc(C)n2[C@@H]1CC[C@H](N)C1

Procedure:
The trans-(3-hydroxy-cyclopentyl)-carbamic acid tert-butyl ester was converted to cis-(3-amino-cyclopentyl)-carbamic acid tert-butyl ester using the same method described previously. The resulting compound was further converted to cis-[3-(2,5-dimethyl-benzoimidazol-1-yl)-cyclopentyl]-carbamic acid tert-butyl ester using the same method described in the preparation of the hydrochloride salt of trans-3-(2,5-dimethyl-benzoimidazol-1-yl)-cyclopentylamine. After the acid cleavage of the carbamic acid tert-butyl ester and base extraction, cis-3-(2,5-dimethyl-benzoimidazol-1-yl)-cyclopentylamine was obtained as pale brown oil. LR-MS calcd for C14H19N3 (m/e) 229.1579, obsd 230.2 (M+H).
Reaction SMILES: [NH2:1][CH:2]([F:21])[C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)=[O:4].BrC(F)C(NC1C=CC(Cl)=CC=1C(C1C=CC=CC=1)=O)=O.N>N1C=CC=CC=1>[F:21][CH:2]1[N:1]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:6]=2[NH:5][C:3]1=[O:4]
Reactant: NC(F)C(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: N
Agent: O=C(c1ccccc1)c1cc(Cl)ccc1NC(=O)C(F)Br
Solvent: c1ccncc1
Product: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=NC1F

Procedure:
A solution of 3.07 g. of 2-(α-amino-α-fluoroacetamido)-5-chlorobenzophenone, obtainable from 2-(α-bromo-α-fluoroacetamido)-5-chlorobenzophenone and liquid NH3, in 35 ml. of pyridine is boiled for 2 hours and evaporated. Working up in the customary manner gives 3-fluoro-5-phenyl-7-chloro-2,3-dihydro-1H-1,4-benzodiazepin-2-one, m.p. 235° (decomposition).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:18])([CH3:17])[CH3:16])[O:11][C:10]([CH3:31])([CH2:19][O:20][C:21]1[CH:26]=[C:25]([N+:27]([O-])=O)[CH:24]=[CH:23][C:22]=1[CH3:30])[CH2:9][C:8]2=[O:32])(=[O:3])[CH3:2]>[Pd].C(O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:18])([CH3:17])[CH3:16])[O:11][C:10]([CH2:19][O:20][C:21]1[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][C:22]=1[CH3:30])([CH3:31])[CH2:9][C:8]2=[O:32])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc2c(cc1C(C)(C)C)OC(C)(COc1cc([N+](=O)[O-])ccc1C)CC2=O
Agent: [Pd]
Solvent: CCO
Product: CC(=O)Oc1cc2c(cc1C(C)(C)C)OC(C)(COc1cc(N)ccc1C)CC2=O

Procedure:
Following the same procedure as described in Preparation 24, hydrogenation of 7.3 g of 6-acetoxy-7-t-butyl-2-methyl-2-(2-methyl-5-nitrophenoxymethyl)chroman-4-one (prepared as described in Preparation 40) in the presence of 1 g of 10% w/w palladium-on-carbon and 100 ml of ethanol gave the title compound as a slightly red, foamy substance.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]([CH2:9][C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=2)[CH:6]=[CH:7][N:8]=1.[C:18]1([CH:25]=[CH:24][CH:23]=[C:21]([OH:22])[CH:20]=1)[OH:19].C([O-])([O-])=O.[K+].[K+].Cl>O.CS(C)=O>[Cl:17][C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([Cl:16])[CH:13]=1)[CH2:9][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[CH2:3][O:19][C:18]1[CH:20]=[C:21]([OH:22])[CH:23]=[CH:24][CH:25]=1
Reactant: ClCc1nccn1Cc1cc(Cl)cc(Cl)c1
Reactant: Oc1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Oc1cccc(OCc2nccn2Cc2cc(Cl)cc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 64.7 %

Procedure:
To a mixture of 2-chloromethyl-1-(3,5-dichlorobenzyl)-1H-imidazole hydrochloride (156 mg, 0.5 mmol), resorcinol (330 mg, 3.0 mmol) and DMSO (1 mL) was added K2CO3 (691 mg, 5.0 mmol). The reaction was stirred at ambient temperature for 14 h before diluting with water (20 mL). A solution of 1N HCl was added until the mixture was made only slightly basic (pH 8) before extracting with EtOAc (30 mL). The EtOAc phase was washed with water (10 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 1:2 to 1:3 hexane/EtOAc then 100% EtOAc) to provide the title compound (113 mg, 65%) as an off-white solid: ESI MS m/z 349 [C17H14Cl2N2O2+H]+.