Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]=[CH:12][N:13](C)C)[C:8]([C:16]#[N:17])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20](=[O:43])[C:21]1[CH:26]=[CH:25][C:24]([S:27][C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:30][CH:29]=2)=[C:23](N)[CH:22]=1.CCOC(C)=O.C([O-])([O-])=O.[K+].[K+]>CC(O)=O.O>[CH3:18][O:19][C:20](=[O:43])[C:21]1[CH:22]=[CH:23][C:24]([S:27][C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])=[CH:30][CH:29]=2)=[C:25]([NH:17][C:16]2[C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[N:10][C:9]=3[N:11]=[CH:12][N:13]=2)[CH:26]=1
Reactant: COC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(N)c1
Reactant: CN(C)C=Nc1nc(C(C)(C)C)ccc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(Nc2ncnc3nc(C(C)(C)C)ccc23)c1
Temperature: 120 °C
Yield: 47.3 %

Procedure:
A suspension of N′-(6-tert-butyl-3-cyano-pyridin-2-yl)-N,N-dimethyl-formamidine (0.46 g, 2.0 mmol) and 3-amino-4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-benzoic acid methyl ester [prepared in Example 385C] (0.75 g, 2.0 mmol) in AcOH (10 mL) was heated at 120° C. for 30 minutes under N2. After cooling to room temperature, the reaction mixture was portioned between AcOEt and H2O, and then made basic to pH 9 with K2CO3 under stirring. The organic layer was separated, washed with 10% NaHCO3, H2O and brine, dried over MgSO4, and evaporated to give pale brown oil. The oily residue was separated by silica gel column chromatography (CH2Cl2/MeOH=98/2) to give the title compound as off-white powder (0.53 g, 47%).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=[O:8])[NH:6][CH:7]=1)[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:13]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)#[N:14]>[N+](C1C=CC=CC=1)([O-])=O>[C:13]([C:15]1[CH:23]=[CH:22][C:18]([C:19]([C:7]2[NH:6][C:5](=[O:8])[NH:4][C:3]=2[CH2:1][CH3:2])=[O:20])=[CH:17][CH:16]=1)#[N:14]
Reactant: CCc1c[nH]c(=O)[nH]1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CCc1[nH]c(=O)[nH]c1C(=O)c1ccc(C#N)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 65.8 %

Procedure:
To a stirred mixture of 3.38 grams (0.03 mole) of 1,3-dihydro-4-ethyl-2H-imidazol-2-one, 13.3 grams (0.1 mole) of anhydrous aluminum chloride and 50 ml of nitrobenzene is added 5.0 grams (0.03 mole) of 4-cyanobenzoyl chloride. The mixture is stirred at 80° C. for 6 hours, then poured on 500 grams of ice. The resulting precipitate is washed with diethyl ether and water and is recrystallized from 500 ml ethyl alcohol to give 4.76 grams of the title compound. M.P. 269-271° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH3:16][Li]>C1(C)C=CC=CC=1.C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:16])=[CH:6][CH:7]=1
Reactant: [Li]C
Reactant: Brc1ccc(N=Cc2ccccc2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(Nc1ccc(Br)cc1)c1ccccc1
Temperature: -40 °C
Reaction time: 3 h

Procedure:
To a solution of N-(4-bromophenyl)-N-(1-phenylmethylidene)amine (1.0 g, 0.00385 mol) in toluene (30 mL) cooled to −78° C., a 1.4M solution of methyl lithium in diethyl ether (5.5 mL) was added dropwise keeping the temperature below −75° C. The solution was warmed up to −40° C. and stirred at this temperature under an atmosphere of nitrogen for 3 hours. The reaction mixture was quenched by a dropwise addition of water and the layers were separated. The organic phase was washed with brine (50 mL), dried with magnesium sulfate and concentrated under reduced pressure to yield N-(4-bromophenyl)-N-(1-phenylethyl)amine (1.03 g, 0.00373 mol) as an off-white solid.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[NH2:6][C@@H:7]([CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:8][OH:9].[OH-].[Na+].C1COCC1>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[CH2:12]([O:11][CH2:10][C@@H:7]1[NH:6][C:3](=[O:4])[CH2:2][O:9][CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N[C@H](CO)COCc1ccccc1
Reactant: O=C(Cl)CCl
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1COC[C@H](COCc2ccccc2)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Chloroacetyl chloride (0.242 mL) was added to a mixed solution of (R)-(+)-2-amino-3-benzyloxy-1-propanol (500 g) in toluene (7 mL) and a 2 N sodium hydroxide solution (7 mL) under ice-cooling. The reaction solution was stirred at room temperature for one hour. Then, THF and brine were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Sodium iodide (82.7 mg) and potassium tert-butoxide (681 mg) were added to a solution of the resulting residue in THF (15 mL) under ice-cooling. The reaction solution was stirred at room temperature for one hour. Then, a saturated ammonium chloride solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: heptane-ethyl acetate system) to obtain 387 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[N:15]=2)[N:10]=[CH:9][CH:8]=1)(=O)=O.[O:21]=[C:22]1[CH2:27][NH:26][CH2:25][CH2:24][N:23]1[CH2:28][CH2:29][N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]1=[O:40]>CCO>[CH3:18][O:17][C:14]1[N:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[N:26]1[CH2:25][CH2:24][N:23]([CH2:28][CH2:29][N:30]2[C:31](=[O:40])[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:38]2=[O:39])[C:22](=[O:21])[CH2:27]1
Reactant: COc1ccc2nccc(OS(=O)(=O)C(F)(F)F)c2n1
Reactant: O=C1CNCCN1CCN1C(=O)c2ccccc2C1=O
Solvent: CCO
Product: COc1ccc2nccc(N3CCN(CCN4C(=O)c5ccccc5C4=O)C(=O)C3)c2n1
Reaction time: 12 h
Yield: 42.1 %

Procedure:
A solution of 6-(methyloxy)-1,5-naphthyridin-4-yl trifluoromethanesulfonate (169 mg, 0.55 mmol) and 2-[2-(2-oxo-1-piperazinyl)ethyl]-1H-isoindole-1,3(2H)-dione (150 mg, 0.55 mmol) in EtOH (2 mL) were stirred at 85° C. After 12 h, the solution was concentrated and the residue purified via column chromatography (silica, 0-8% MeOH in DCM (1% NH4OH)) yielding the title compound (100 mg, 42%) as a light yellow solid: LCMS (ES) m/e 432 (M+H)+.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].C1COCC1.Cl.Br[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.CC1(C)C(C)(C)OB([C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:37])[CH3:36])=[CH:30][CH:29]=2)O1>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:17]1[CH:18]=[CH:19][C:14]([C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:37])[CH3:36])=[CH:30][CH:29]=2)=[CH:15][CH:16]=1
Reactant: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Brc1ccncc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(-c2ccncc2)cc1
Temperature: 25 °C

Procedure:
A round bottom flask was charged with a 2 N Na2CO3 solution (4 equivalents) and THF and the mixture was sparged with N2 through a dispersion tube. 4-Bromopyridine hydrochloride (1 equivalent) and N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide (1.2 equivalents) were subsequently added, followed by Pd(dppf)2Cl2 (2.5 mol %). The reaction mixture was refluxed overnight, cooled to room temperature and diluted with EtOAc. The two phases were separated and the organic phase was washed with a 2 N Na2CO3 solution, brine, and dried (Na2SO4). Evaporation of the solvent under reduced pressure and purification by silica gel chromatography afforded the desired product as a white solid. MH+=213.1.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]/[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=2)[N:20]([CH2:28][CH2:29][CH2:30][O:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)[C:19]=1[C:42]([O:44]CC)=[O:43].[OH-:47].[Na+]>O1CCCC1.CO>[C:2]([C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:4]([NH:3][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]/[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=2)[N:20]([CH2:28][CH2:29][CH2:30][O:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)[C:19]=1[C:42]([OH:44])=[O:43])=[O:11])([OH:47])=[O:1]
Reactant: [OH-]
Reactant: CCOC(=O)c1c(/C=C/CCCCN2C(=O)c3ccccc3C2=O)c2cc(F)ccc2n1CCCOc1cccc2ccccc12
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1C(=O)NCCCC/C=C/c1c(C(=O)O)n(CCCOc2cccc3ccccc23)c2ccc(F)cc12
Temperature: 50 °C

Procedure:
A mixture of EXAMPLE 160A (531 mg) and potassium 1,3-dioxoisoindolin-2-ide (213 mg) in N,N-dimethylformamide (10 ml) was heated at 80° C. for 8 hours. The reaction was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and was concentrated. The residue was purified by flash chromatography, eluting with 0-100% ethyl acetate in dichloromethane to give (E)-ethyl 3-(6-(1,3-dioxoisoindolin-2-yl)hex-1-enyl)-5-fluoro-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate. This ester was dissolved in a mixture of tetrahydrofuran and methanol and 5 equivalents of aqueous NaOH (10%) was added. The mixture was heated at 50° C. for 5 hours. The reaction mixture was concentrated and the residue was dissolved in dimethyl sulfoxide and trifluoroacetic acid-methanol (3:1), and purified by RPHPLC to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 13.06 (s, 2H), 8.25 (t, J=5.52 Hz, 1H), 8.19 (dd, J=7.83, 1.38 Hz, 1H), 7.86 (dd, J=7.21, 1.99 Hz, 1H), 7.74 (dd, J=7.52, 1.38 Hz, 1H), 7.60-7.69 (m, 2H), 7.43-7.58 (m, 5H), 7.34-7.41 (m, 2H), 6.99-7.16 (m, 2H), 6.85 (d, J=7.36 Hz, 1H), 6.15-6.32 (m, 1H), 4.65-4.96 (m, 2H), 4.13 (t, J=5.68 Hz, 2H), 3.20-3.29 (m, 2H), 2.20-2.36 (m, 4H), 1.49-1.67 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8](=[O:16])[NH:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:4]C=1C.[Li+].[OH-:21]>CO.O>[C:5]([O:21][C:8]([NH:7][C:2]1[N:1]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:16])[NH:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:17][CH:18]=1)=[O:16])([CH3:17])([CH3:6])[CH3:4]
Reactant: CCOC(=O)CNC(=O)NCc1ccc(N)c(C)c1
Reactant: [OH-]
Agent: [Li+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(CNC(=O)NCC(=O)O)cn1
Temperature: 50 °C
Yield: 195.1 %

Procedure:
51 (7.5 g, 21.3 mmol) was dissolved in 50 ml of MeOH and 50 ml of water, LiOH (4 équivalent, 2.0 g) was added and the reaction mixture was heated to 50° C. for 2 h. The reaction mixture is concentrated and 200 ml of water are added, then extracted twice with AcOEt. The water is acidified to pH 5 with concentrated HCl 36%, then extracted twice with AcOEt. The combine organic phase are dried over Na2SO4, filtered and concentrated to afford 57 (6.74 g, 98%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.[BH3-]C#N.[Na+].O>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][NH:7]2
Reactant: COc1c(C)ccc2[nH]ccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1c(C)ccc2c1CCN2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To a solution of 4-methoxy-5-methylindole 27 (0.48 g, 2.98 mmol) in acetic acid (20 ml) was added NaBH3CN (0.75 g, 9 mmol) portionwise over 10 min (exothermic reaction) and the mixture was then stirred at rt for 0.5 h. Water (2-3 ml) was added and the solvent removed in vacuo. The residue was dissolved in EtOAc and washed with saturated aq. NaHCO3 and brine, dried and evaporated to give 28 as a viscous oil (449 mg, 92%) which was immediately used in the next step; δH (90 MHZ) 6.80 (1 H, d, J 9, 7-H), 6.31 (1 H, d, 6-H), 3.76 (3 H, s, OMe), 3.56 (2 H, t, J 8, 2-H), 3.12 (3 H, t, 3-H) and 2.14 (3 H, s, Me).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[NH2:46][CH2:47][C:48]1[N:49]=[CH:50][N:51]([C:53]2[CH:58]=[CH:57][C:56]([N:59]3[CH:64]=[CH:63][CH:62]=[CH:61][C:60]3=[O:65])=[CH:55][CH:54]=2)[CH:52]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:46][CH2:47][C:48]2[N:49]=[CH:50][N:51]([C:53]3[CH:54]=[CH:55][C:56]([N:59]4[CH:64]=[CH:63][CH:62]=[CH:61][C:60]4=[O:65])=[CH:57][CH:58]=3)[CH:52]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: NCc1cn(-c2ccc(-n3ccccc3=O)cc2)cn1
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1cn(-c2ccc(-n3ccccc3=O)cc2)cn1)c1ccc(Cl)cc1
Reaction time: 0.08 h
Yield: 34.3 %

Procedure:
To a solution of 4-chlorobenzoic acid (40 mg, 0.26 mmol) and triethylamine (0.150 mL, 1.08 mmol) in DMF (2 mL), BOP (135 mg, 0.30 mmol) was added. After 5 min of stirring, 1-(4-(4-(aminomethyl)-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-one hydrochloride (53 mg, 0.18 mmol) was added. The mixture was stirred at room temperature for 2 h. It was then purified by HPLC to give the titled compound (25 mg). MS 405.1 and 407.1 (M+H, Cl pattern).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:19][C:20]1[CH:21]=[C:22]([C:26](=[O:28])[CH3:27])[CH:23]=[CH:24][CH:25]=1.[Cl-].[NH4+]>CN(C)C=O>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26](=[O:28])[CH3:27])[CH:21]=2)[N:3]=[CH:4][N:5]=1)[C:10]#[C:11][CH3:12]
Reactant: CC(=O)c1cccc(O)c1
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1cc(Oc2cccc(C(C)=O)c2)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 80.9 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-butynyloxy)pyrimidine, 0.23 g of potassium carbonate, and 0.18 g of 3′-hydroxyacetophenone, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.25 g of 4-(2-butynyloxy)-6-(3-acetylphenoxy)pyrimidine (the present compound (71)), m.p.: 94.0° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([SH:7])=[N:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:14]1([CH:20]([O:27][C:28]([C:30]2[N:31]3[CH:34]([CH2:35][CH2:36][C:37]=2Cl)[C@@H:33]([NH:39][C:40](=[O:70])/[C:41](/[C:63]2[N:64]=[C:65]([NH2:69])[S:66][C:67]=2[Cl:68])=[N:42]\[O:43][C:44]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:32]3=[O:71])=[O:29])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O>[C:14]1([CH:20]([O:27][C:28]([C:30]2[N:31]3[CH:34]([CH2:35][CH2:36][C:37]=2[S:7][C:5]2[S:6][C:2]([NH2:1])=[N:3][N:4]=2)[C@@H:33]([NH:39][C:40](=[O:70])/[C:41](/[C:63]2[N:64]=[C:65]([NH2:69])[S:66][C:67]=2[Cl:68])=[N:42]\[O:43][C:44]([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:32]3=[O:71])=[O:29])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1nnc(S)s1
Reactant: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(Cl)CCC23)c(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nnc(SC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@H](NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4nc(N)sc4Cl)C3CC2)s1
Reaction time: 18 h
Yield: 72 %

Procedure:
To a solution of 5-amino-1,3,4-thiadiazole-2-thiol (0.6 g., 0.0045 mol) in dimethylformamide (25 mL) was added potassium carbonate (1.0 g, 0.0076 mol). The mixture was stirred for 1 hour at room temperature after which (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(triphenylmethoxyimino]acetamido]-3-chloro-8-oxo-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate diphenylmethyl ester (3.2 g., 0.0039 mol) was added. Stirring was continued for 18 hours. The mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was separated, washed with water (30 mL), dried over anhydrous MgSO4 and the solvent was removed with a rotary evaporator. The resultant thick oil was treated with diethyl ether (50 mL) and the solid which formed was filtered and dried to give 2.6 g of crude product.
Reaction SMILES: [O:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][C:2]21[CH:14]1[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]1)[CH2:10]2.C([O-])(=O)C.[Na+].[Br:22]Br.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[Br:22][C:8]1[CH:9]=[C:4]2[CH2:3][C:2]3([CH:14]4[CH2:13][CH2:12][N:11]([CH2:16][CH2:15]4)[CH2:10]3)[O:1][C:5]2=[N:6][CH:7]=1
Reactant: c1cnc2c(c1)CC1(CN3CCC1CC3)O2
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Brc1cnc2c(c1)CC1(CN3CCC1CC3)O2
Temperature: 25 °C
Yield: 80.1 %

Procedure:
A solution of spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] (100 mg, 0.462 mmol) and sodium acetate (410 mg, 5 mmol) in 50% aqueous acetic acid (4 mL) was heated to 60° C. Bromine (0.100 mL, 1.94 mmol) was added via a syringe over 10 minutes, and the solution was then heated under reflux for 1 hour. The mixture was allowed to cool to ambient temperature, basified to pH>10 with sodium carbonate, and extracted with chloroform (3×15 mL). The combined extracts were dried (MgSO4), filtered, and evaporated under reduced pressure to give the title compound (110 mg, 0.37 mmol, 81%) as an off-white solid: electrospray MS 295 ([MH]+, with 79Br, 100), 297 ([MH]+, with 81Br, 98).
Reaction SMILES: BrC(C1C=CC(C2C=CC=CC=2[Cl:20])=CC=1)C(OCC)=O.C(NC(=O)C(C1C=CC(C2C=CC=CC=2Cl)=CC=1)Br)(C)C.[I:42][CH:43]([C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=2Cl)=[CH:51][CH:50]=1)[C:44]([O:46][CH2:47][CH3:48])=[O:45].C(NC(=O)C(C1C=CC(C2C=CC=CC=2Cl)=CC=1)I)(C)C>>[I:42][CH:43]([C:49]1[CH:54]=[CH:53][C:52]([CH:55]2[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]2)=[C:51]([Cl:20])[CH:50]=1)[C:44]([O:46][CH2:47][CH3:48])=[O:45]
Reactant: CCOC(=O)C(I)c1ccc(-c2ccccc2Cl)cc1
Reactant: CCOC(=O)C(Br)c1ccc(-c2ccccc2Cl)cc1
Agent: CC(C)NC(=O)C(Br)c1ccc(-c2ccccc2Cl)cc1
Agent: CC(C)NC(=O)C(I)c1ccc(-c2ccccc2Cl)cc1
Product: CCOC(=O)C(I)c1ccc(C2CCCCC2)c(Cl)c1

Procedure:
When ethyl α-bromo-2'-chloro-4-biphenylylacetate in the above procedure is replaced by d ethyl α-bromo-2'-chloro-4-biphenylylacetate, l ethyl α-bromo-2'-chloro-4-biphenylylacetate of N-isopropyl α-bromo-2'-chloro-4-biphenylylacetamide, then the products prepared are d ethyl α-iodo-2'-chloro-4-biphenylylacetate, l ethyl α-iodo-2'-chloro-4-biphenylylacetate or N-isopropyl α-iodo-2'-chloro-4-biphenylylacetamide.
Reaction SMILES: [O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([NH:24]C(=O)C/C=C/C)[CH2:20][CH2:19]4)[CH2:12][CH2:11]3)[C:4]=2[CH2:3][CH2:2]1.[F:31][C:32]([F:39])([F:38])[CH:33]([OH:37])[C:34](O)=[O:35]>>[O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([NH:24][C:34](=[O:35])[CH:33]([OH:37])[C:32]([F:39])([F:38])[F:31])[CH2:20][CH2:19]4)[CH2:12][CH2:11]3)[C:4]=2[CH2:3][CH2:2]1
Reactant: O=C(O)C(O)C(F)(F)F
Reactant: C/C=C/CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)C(O)C(F)(F)F

Procedure:
The title compound, light yellow solid (80 mg, 70%), MS (ISP) m/z=457.4 [(M+H)+], mp 204° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(6-methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate E) (110 mg, 0.25 mmol) and (RS)-3,3,3-trifluoro-2-hydroxypropanoic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][C:8]1([CH2:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[O:12][N:11]=[C:10]([C:13]2[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=2[CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(CC)C(C)C)(C)C.Cl>CN(C=O)C>[C:28]([O:27][C:26](=[O:32])[CH2:25][C:8]1([CH2:7][C:6](=[O:33])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[O:12][N:11]=[C:10]([C:13]2[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=2[CH2:20][CH2:21][C:22]([O:24][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:23])[CH2:9]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)CC1(CC(=O)OC(C)(C)C)CC(c2cc(O)ccc2CCC(=O)O)=NO1
Reactant: BrCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CC1(CC(=O)OC(C)(C)C)CC(c2cc(O)ccc2CCC(=O)OCc2ccccc2)=NO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(2-(5,5-bis(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazol-3-yl)-4-hydroxyphenyl)propanoic acid (413 mg), (bromomethyl)benzene (0.117 mL), N,N-diisopropylethylamine (0.342 mL), and DMF (4 mL) was stirred overnight at room temperature. To the reaction mixture, 0.1 M hydrochloric acid was added, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (227 mg).
Reaction SMILES: C[N:2]1[CH:6]=[N:5][N:4]=[C:3]1[S:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1.[Cl-].[Ca+2].[Cl-].[CH2:20](O)C>>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([S:7][C:3]2[N:2]=[CH:6][N:5]([CH3:20])[N:4]=2)=[CH:9][CH:10]=1
Reactant: CCO
Reactant: Cn1cnnc1Sc1ccc([N+](=O)[O-])cc1
Agent: [Ca+2]
Agent: [Cl-]
Product: Cn1cnc(Sc2ccc(N)cc2)n1
Temperature: 105 °C
Reaction time: 6 h

Procedure:
4-methyl-3-[(4-nitrophenyl)thio]-1,2,4-triazole (1.0 g), reduced iron (1.18 g) and calcium chloride (2.35 g) were added to 85% aqueous solution of ethanol (15 ml), and the mixture was stirred for 6 hours under nitrogen atmosphere at 105° C. The mixture was allowed to be at room temperature, the insolubles were filtered off, and the solvent was distilled off under reduced pressure. To the obtained residue were added water, and the mixture extracted with ethyl acetate twice. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from ethyl acetate-diisopropyl ether, to give 3-[(4-aminophenyl)thio]-1-methyl-1,2,4-triazole (418 mg) as yellow crystals.
Reaction SMILES: [Li]CCCC.[CH3:6][O:7][CH2:8][O:9][CH2:10][Sn](CCCC)(CCCC)CCCC.[CH:24]([C:26]1[S:27][CH:28]=[CH:29][N:30]=1)=[O:25]>C1COCC1.O>[OH:25][CH:24]([C:26]1[S:27][CH:28]=[CH:29][N:30]=1)[CH2:10][O:9][CH2:8][O:7][CH3:6]
Reactant: CCCC[Sn](CCCC)(CCCC)COCOC
Reactant: O=Cc1nccs1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COCOCC(O)c1nccs1
Reaction time: 8 h
Yield: 34.8 %

Procedure:
n-BuLi (2.87 mmol, 1.8 mL, 1.6M) was added dropwise to a -78° C. solution of (methoxymethoxymethyl)tributyl tin (1.05 g, 2.87 mmol) in dry THF (10 mL). After stirring for 30 minutes a solution of 2-formylthiazole (2.73 mmol, 0.31 g) in THF (2 mL) was added and the solution stirred overnight. The reaction was diluted with water and extracted with ethyl acetate, dried (MgSO4), filtered and concentrated. The residue was subjected to flash chromatography (45% ethyl acetate/hexane) to afford 0.18 g (34%) of 2-(1-hydroxy-2-(methoxymethoxy)ethyl)thiazole.