Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:26])=[CH:5][CH:4]=1.P(Br)(Br)[Br:28]>C(Cl)Cl.C(Cl)Cl.CO>[Br:28][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:26])=[CH:5][CH:4]=1
Reactant: Cc1ccc(COc2ccn(CCc3ccc(CO)cc3)c(=O)c2)nc1
Reactant: BrP(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(COc2ccn(CCc3ccc(CBr)cc3)c(=O)c2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 100 mg (0.29 mmol) 1-[2-(4-hydroxymethyl-phenyl)-ethyl]-4-(5-methyl-pyridin-2-ylmethoxy)-1H-pyridin-2-one (example 13.1a) in 5.0 mL of DCM is added 21 μL (0.23 mmol) phosphorus tribromide. The mixture is stirred 2 h at RT, diluted with DCM/MeOH and extracted twice with water. The organic phase is dried over MgSO4, filtered and the solvent is evaporated to afford the product.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:24])[CH:6]([OH:23])[CH:7]([NH:15]C(=O)OC(C)(C)C)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3][CH2:2]1.[ClH:25].CO>ClCCl>[Cl-:25].[CH:1]1([NH:4][C:5](=[O:24])[CH:6]([OH:23])[CH:7]([NH3+:15])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:2][CH2:3]1
Reactant: Cl
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)C(=O)NC1CC1
Solvent: ClCCl
Solvent: CO
Product: [Cl-]
Product: [NH3+]C(Cc1ccccc1)C(O)C(=O)NC1CC1

Procedure:
tert-Butyl 4-(cyclopropylamino)-3-hydroxy-4-oxo-1-phenylbutan-2-ylcarbamate (780 mg, 2.332 mmol) in dichloromethane (30 ml) was stirred together with 2 ml of HCl (4 m solution in dioxane) for 3 h at room temperature, then 1 ml of HCl and 5 ml of methanol were added and the reaction mixture stirred over night. The mixture was concentrated under reduced pressure, co-evaporated 2× with toluene, the remainder then treated with n-pentane and dried to give 550 mg of a white solid; ESI-MS [M+H]+: 235.1.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])[C:9]=2[C:8]1=[O:28].[N:38]1([CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:42][CH2:41][CH2:40][CH2:39]1>>[F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16]([N:46]3[CH2:47][CH2:48][CH:43]([N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)[CH2:44][CH2:45]3)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])[C:9]=2[C:8]1=[O:28]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: COc1ccccc1-c1cc(Cl)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCO2
Product: COc1ccccc1-c1cc(N2CCC(N3CCCC3)CC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCO2
Yield: 38.5 %

Procedure:
In a similar manner to Example 1, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(2-methoxyphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (82.0 mg) was reacted with 4-(pyrrolidine-1-yl)piperidine (69.5 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methoxyphenyl)-6-oxo-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (38.4 mg, 39%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:30][C:29]([C:31](=[O:34])[CH2:32][CH3:33])=[N:28][N:27]=2)=[CH:22][CH:21]=1>C1COCC1>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[S:30][C:29]([C:31]([C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)([OH:34])[CH2:32][CH3:33])=[N:28][N:27]=2)=[CH:24][CH:25]=1
Reactant: Ic1ccncc1
Reactant: CCC(=O)c1nnc(-c2ccc(F)cc2)s1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(O)(c1ccncc1)c1nnc(-c2ccc(F)cc2)s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 16.5 %

Procedure:
To a solution of 4-iodo pyridine (0.142 g, 0.635 mmol) in THF (12 mL) at −78° C. was added n-BuLi in hexane (1.6 M, 0.582 mL, 0.8474 mmol) and the mixture stirred for 30 min A solution of 1-(5-(4-fluorophenyl)-1,3,4-thiadiazole-2-yl)propan-1-one (0.1 g, 0.4237 mmol) in THF (8 mL) was added to above solution at −78° C. and the mixture stirred for 1 hour at −78° C. The reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and diluted with water (25 mL). The reaction mixture was extracted with ethyl acetate (200 mL), dried over sodium sulfate and concentrated under reduced pressure to obtain crude product. The crude compound was purified by preparative TLC (using 5% methanol and dichloromethane) to afford 1-(5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)-1-(pyridin-4-yl)propan-1-ol as white solid (22 mg, 17% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.55 (d, 2H), 8.0-7.96 (m, 2H), 7.56 (d, 2H), 7.35 (t, 2H), 7.06 (s, 1H), 2.40-2.30 (m, 2H), 0.80 (t, 3H); LC-MS m/z calculated for [M+H]+ 316.08. found 316.1.
Reaction SMILES: Cl.[NH:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]=2[CH:4]=[CH:3]1.[N:15]([O-])=O.[Na+].[OH2:19]>>[CH:3]([C:4]1[C:5]2[C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:8]=[CH:9][C:10]=2[NH:2][N:15]=1)=[O:19]
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: O=N[O-]
Reactant: O
Agent: Cl
Agent: [Na+]
Product: COC(=O)c1cccc2[nH]nc(C=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
Aqueous HCl (56.0 mL of 6N solution in water, 0.33 mol) was added dropwise over 1 hour to a stirring suspension of methyl 1H-indole-4-carboxylate (5.0 g, 28.5 mmol) in a solution of sodium nitrite (24.0 g, 0.34 mol) in water (500 mL) at ambient temperature. The mixture was stirred overnight at ambient temperature, and then extracted with ethyl acetate (5×300 mL). The combined organic layers were washed with water (2×300 mL), brine (200 mL), and dried (Na2SO4). The organics were concentrated under reduced pressure until precipitation was observed. After cooling in a dry ice bath the precipitate was collected by filtration, washed with cold ethyl acetate (50 mL), and hexanes (100 mL) and dried (Na2SO4) to afford methyl 3-formyl-1H-indazole-4-carboxylate (B1, 2.1 g, 35%) as a yellow powder: 1H NMR (300 MHz, DMSO-d6) δ 10.33 (s, 1H), 7.92 (d, J=8.1 Hz, 1H), 7.67 (d, J=7.2 Hz, 1H), 7.58 (t, J=7.2 Hz 1H), 3.96 (s, 3H); MS (ESI+) m/z 205 (M+H).
Reaction SMILES: Cl.C(O)C.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH:15]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[F:34])[CH2:16][CH2:17][CH2:18][NH:19]C(=O)OC(C)(C)C)(=[O:14])=[O:13])=[CH:8][CH:7]=1>C(O)C.C(OCC)(=O)C>[ClH:5].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([CH:15]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[F:34])[CH2:16][CH2:17][CH2:18][NH2:19])(=[O:14])=[O:13])=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)NCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: NCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 176.1 %

Procedure:
Concentrated hydrochloric acid (2 ml) was added to an ethanol solution (2 ml) of t-butyl N-[4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)butyl]carbamate (104 mg, 0.226 mmol), followed by stirring at room temperature for 2 hours. The reaction mixture was then concentrated. The residue thus obtained was recrystallized from ethanol-ethyl acetate, whereby the title compound (78.9 mg, 0.199 mmol, 88%) was obtained as colorless needle crystals.
Reaction SMILES: O[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CCN(CC)CC.[F:47][C:48]1[CH:62]=[CH:61][CH:60]=[C:59]([F:63])[C:49]=1/[CH:50]=[CH:51]/[C:52]1[CH:58]=[CH:57][C:55]([NH2:56])=[CH:54][CH:53]=1>CN(C=O)C.O>[F:47][C:48]1[CH:62]=[CH:61][CH:60]=[C:59]([F:63])[C:49]=1/[CH:50]=[CH:51]/[C:52]1[CH:53]=[CH:54][C:55]([NH:56][C:2](=[O:3])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]2[CH:16]3[CH:11]([NH:12][C:13](=[O:14])[NH:15]3)[CH2:10][S:9]2)=[CH:57][CH:58]=1
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: Nc1ccc(/C=C/c2c(F)cccc2F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCCCC1SCC2NC(=O)NC21)Nc1ccc(/C=C/c2c(F)cccc2F)cc1
Reaction time: 0.17 h
Yield: 64 %

Procedure:
To a suspension of 100 mg (0.41 mmol 1 equiv) of biotin in 3 mL of anhydrous DMF was added 66 mg (0.49 mmol, 1.2 equiv) of 1-hydroxybenzotriazole hydrate, 94 mg (0.49 mmol, 1.2 equiv) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, and 79 mg (0.78 mmol, 1.9 equiv) of Et3N. The mixture was stirred for 10 min, and 95 mg (0.41 mmol) of 9 was added. The mixture was stirred for 24 h at 25° C. and poured into water. The precipitate was collected by filtration and chromatographed using 1:1 EtOAc-MeOH to give 120 mg (66%) of 11 as white crystals: mp 278-280° C. 1H NMR (DMSO-d6): δ 9.99 (s, 1H), 7.64 (d, 2H, J=8.8 Hz), 7.56 (d, 2H, J=8.8 Hz), 7.37-7.29 (m, 2H), 7.19-7.12 (m, 2H), 7.02 (d, 1H, J=16.4 Hz), 6.44 (s, 1H), 6.36 (s, 1H), 4.33-4.29 (m, 1H), 4.16-4.13 (m, 1H), 3.15-3.10 (m, 1H), 2.83 (dd, 1H, J1=12.8 Hz, J2=4.8 Hz), 2.58 (d, 1H, J=12.0 Hz), 2.33 (t, 2H, J=7.2 Hz), 1.70-1.33 (m, 6H). 13C NMR (DMSO-d6): δ 171.70, 163.13, 160.53 (dd, J1=247.8 Hz, J2=7.7 Hz, two C), 140.09, 135.28 (t, J=7.9 Hz), 131.77, 129.18 (t, J=10.7 Hz), 127.69 (two C), 119.54 (two C), 114.61 (t, J=15.5 Hz), 113.25, 112.45 (dd, J1=19.1 Hz, J2=6.3 Hz, two C), 61.48, 59.63, 55.82, 40.28, 36.70, 28.67, 28.53, 25.50. HRMS (EI) Calcd for C24H25F2N3O2S: 457.1636. Found: 457.1650. Anal. Calcd for C24H25F2N3O2S: C, 63.00; H, 5.51. Found: C, 62.82; H, 5.47.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][NH:7]1)=[O:5])[CH3:2].[C:12](Cl)([Cl:14])=[O:13]>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[C:12]([Cl:14])=[O:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCCCN1
Reactant: O=C(Cl)Cl
Product: CCOC(=O)N1CCCCN1C(=O)Cl

Procedure:
In the same way, 4-[2-(4-chlorobenzyloxy)-5-pyridyl]-1,2-tetramethylenetriazolidine-3,5-dione is prepared by reacting N-ethoxycarbonylhexahydropyridazine with phosgene to give N-ethoxycarbonyl-N'-chlorocarbonylhexahydropyridazine, which is then reacted with 5-amino-2-(4-chlorobenzyloxy)pyridine.
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]1[C:9]([O:11][C:12](=[O:13])[CH:2]21)=O.[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[N:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:21][CH2:20]1.[ClH:31].C(O)(C)C>N1C=CC=CC=1>[ClH:31].[N:26]1[CH:27]=[CH:28][CH:29]=[N:30][C:25]=1[N:22]1[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][CH2:16][CH2:15][N:14]2[C:12](=[O:13])[CH:2]3[CH:3]([CH:4]4[CH2:5][CH2:6][CH:1]3[CH2:8][CH2:7]4)[C:9]2=[O:11])[CH2:20][CH2:21]1
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Reactant: O=C1OC(=O)C2C3CCC(CC3)C12
Agent: Cl
Solvent: CC(C)O
Solvent: c1ccncc1
Product: O=C1C2C3CCC(CC3)C2C(=O)N1CCCCN1CCN(c2ncccn2)CC1

Procedure:
A mixture of bicyclo[2.2.2]octane-2,3-dicarboxylic anhydride (541 mg, 3 mmol), 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine (708 mg, 3 mmol) and pyridine (12.1 ml) was refluxed for 10 hours. The solvent was removed from the mixture under reduced pressure. The residue was extracted with chloroform and water. The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude crystals (1 g), which were treated with 6% hydrogen chloride/isopropanol. The solvent was removed to give N-[4-{4-(2-pyrimidinyl)-1-piperazinyl}butyl]bicyclo[2.2.2]octane-2,3-dicarboximide hydrochloride (from ethanol). M.P., 198°-200° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]1[CH2:19][N:18]([CH3:20])[C:17](=[S:21])[C:7]2[CH:8]=[C:9]([CH3:16])[C:10]3[CH:11]=[CH:12][CH:13]=[N:14][C:15]=3[C:6]=2[O:5]1.[CH3:22][NH:23][CH3:24]>>[ClH:1].[CH3:22][N:23]([CH3:24])[CH2:2][CH2:3][CH:4]1[CH2:19][N:18]([CH3:20])[C:17](=[S:21])[C:7]2[CH:8]=[C:9]([CH3:16])[C:10]3[CH:11]=[CH:12][CH:13]=[N:14][C:15]=3[C:6]=2[O:5]1
Reactant: Cc1cc2c(c3ncccc13)OC(CCCl)CN(C)C2=S
Reactant: CNC
Product: Cc1cc2c(c3ncccc13)OC(CCN(C)C)CN(C)C2=S
Product: Cl

Procedure:
Following the procedure of Example 31, 2-(2-chloroethyl)-2,3-dihydro-4,7-dimethyl-1,4-oxazepino[6,7-h]quinoline-5(4H)-thione is reacted with dimethylamine to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.F[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.[C:25](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[CH:19][CH:20]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: Oc1ccc(F)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2ccnc3[nH]c(=O)c4ccccc4c23)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
1-Chloro-5H-benzo[c][1,8]naphthyridin-6-one (50 mg, 0.22 mmol), 4-fluorophenol (73 mg, 0.65 mmol), and potassium carbonate (150 mg, 1.08 mmol) were suspended in DMF (2 mL), and stirred overnight at 100° C. The reaction solution was cooled to room temperature, diluted with H2O, and the resulting precipitate was filtered. The precipitate was washed with H2O, and dried under vacuum to provide 149 (14 mg, 21% yield) as a tan solid. LC-MS (M+H=307, obsd.=307). 1H NMR (400 MHz, d6-DMSO): δ 12.15 (s, 1H), 9.05 (d, 1H), 8.42 (dd, 1H), 8.29 (d, 1H), 7.88 (dt, 1H), 7.71 (t, 1H), 7.40 (m, 4H), 6.52 (d, 1H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:22]1([CH3:30])[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=1.ClCCl>O1CCCC1.[Cl-].[Na+].O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:28]([C:25]3[CH:26]=[CH:27][C:22]([CH3:30])=[CH:23][CH:24]=3)=[NH:29])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(C#N)cc1
Reactant: Nc1ccc2c(c1)OCCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=N)Nc2ccc3c(c2)OCCO3)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 0.61 g (4.0 mmol) of 1,4-benzodioxan-6-amine in 5 mL of tetrahydrofuran at ambient temperature was added 2.2 mL (4.4 mmol) of 2.0 M (in tetrahydrofuran) sodium bis(trimethylsilyl)amide and the resulting solution was stirred for 20 min. To this reaction mixture was slowly added a solution of 0.47 g (4.0 mmol) of p-tolunitrile in 2 mL of tetrahydrofuran. The resulting mixture was stirred at ambient temperature for 5 hrs and then poured into brine (25 mL) and dichloromethane (50 mL). The organic layer was separated and the aqueous layer was extracted with 25 mL of dichloromethane (25 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as brown crystalline solid, which was used without further purification. LC/MS 269.2 (M+1).
Reaction SMILES: [CH3:1][CH:2]([NH:4][CH2:5][CH:6]([OH:19])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([NH2:18])=[O:17])=[CH:13][CH:14]=1)[CH3:3].[CH3:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([OH:29])=[O:28])=[CH:25][CH:26]=1>CC(C)=O>[CH3:3][CH:2]([NH:4][CH2:5][CH:6]([OH:19])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([NH2:18])=[O:17])=[CH:13][CH:14]=1)[CH3:1].[C:21]1([CH3:20])[CH:26]=[CH:25][C:24]([C:27]([O-:29])=[O:28])=[CH:23][CH:22]=1
Reactant: Cc1ccc(C(=O)O)cc1
Agent: CC(C)NCC(O)COc1ccc(CC(N)=O)cc1
Solvent: CC(C)=O
Product: Cc1ccc(C(=O)[O-])cc1
Reaction time: 14.5 h

Procedure:
The atenolol having low optical purity (1 mole) and p-toluic acid (1 mole) are dissolved in acetone (5 to 50 liters) with heating and the mixture is stirred at 0° to 15° C. for 5 to 24 hours. The precipitated crystals are removed by filtration, and the mother liquor is concentrated to give an optically active atenolol p-toluate with having higher optical purity, for example a salt having an optical purity of 98% ee or more from a salt having an optical purity of 91% ee in a yield of 50 to 80%. In this method, when benzoic acid is used instead of p-toluic acid and chloroform is used instead of acetone, similar result is obtained. When p-t-butylbenzoic acid is used instead of p-toluic acid in the above method, the produced salt is hardly soluble in a solvent, and hence, it is necessary to use a solvent having higher solubility such as ethanol or 2-propanol instead of acetone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[N:16]/[OH:17])[N:6]=[C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][N:14]=2)[CH:8]=1.COC1C=C(C2N=CC=CC=2)N/C(=C\N=O)/C=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6]/[C:5](=[CH:15]/[N:16]=[O:17])/[CH:4]=1
Reactant: COc1cc(/C=N/O)nc(-c2ccccn2)c1
Agent: COC1=C/C(=C/N=O)NC(c2ccccn2)=C1
Product: COC1=C/C(=C\N=O)NC(c2ccccn2)=C1

Procedure:
Caerulomycin-A; Cerulomycin
Reaction SMILES: [OH:1][CH:2]1[CH:19]([CH2:20][CH2:21][CH:22]([O:28]C2CCCCO2)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:5]2[CH2:6][C:7]3[C:12]([CH2:13][CH:4]2[CH2:3]1)=[C:11]([O:14][CH2:15][C:16]([OH:18])=[O:17])[CH:10]=[CH:9][CH:8]=3.O[CH2:36][CH2:37][C:38]([O:40]CC1C=CC=CC=1)=[O:39].CN(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl.CC(OC)(C)C>[OH:1][CH:2]1[CH:19]([CH2:20][CH2:21][CH:22]([OH:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:5]2[CH2:6][C:7]3[C:12]([CH2:13][CH:4]2[CH2:3]1)=[C:11]([O:14][CH2:15][C:16]([O:18][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:17])[CH:10]=[CH:9][CH:8]=3
Reactant: CCCCCC(CCC1C(O)CC2Cc3c(cccc3OCC(=O)O)CC21)OC1CCCCO1
Reactant: O=C(CCO)OCc1ccccc1
Agent: CN(C)C
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: CCCCCC(O)CCC1C(O)CC2Cc3c(cccc3OCC(=O)OCCC(=O)O)CC21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Compound B (120 mg, 0.25 mmol), benzyl 3-hydroxypropionate (54 mg, 0.30 mmol) and trimethylamine (140 μL, 1.0 mmol) in DCM (4 mL) was added BOP—Cl (95 mg, 0.38 mmol). The reaction mixture was stirred at RT for 16 hr under nitrogen, diluted with MTBE, washed with brine, dried over sodium sulfate, and concentrated to an oil that was purified by silica gel chromatography. A solution of the THP-protected diester in ethanol (4 mL) was treated with PPTS (50 mg), stirred at 50° C. for 4 hr, and concentrated to an oil that was purified by silica gel chromatography. A solution of the THP-deprotected diester in dioxane (5 mL) was treated with wet 5% Pd/C (20 mg) and stirred for 24 hr under a balloon of hydrogen. The reaction mixture was filtered and concentrated to give crude Compound II-4. MS: m/z 485 [M+Na]+
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:6]([CH:13]([OH:21])[CH2:14][NH:15][C:16]([CH2:19][CH3:20])([CH3:18])[CH3:17])=[CH:5][C:4]=1[Br:22].N.[H][H]>C(OCC)(=O)C>[BrH:22].[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH:13]([OH:21])[CH2:14][NH:15][C:16]([CH2:19][CH3:20])([CH3:17])[CH3:18])=[CH:7][C:8]=1[C:9]([F:10])([F:11])[F:12]
Reactant: CCC(C)(C)NCC(O)c1cc(Br)c(N)c(C(F)(F)F)c1
Reactant: [H][H]
Agent: Cl
Agent: N
Solvent: CCOC(C)=O
Product: Br
Product: CCC(C)(C)NCC(O)c1ccc(N)c(C(F)(F)F)c1

Procedure:
5 gm of 1-(4'-amino-3'-bromo-5'-trifluoromethyl-phenyl)-2-tert.pentylamino-ethanol hydrochloride were distributed between ethyl acetate and 2N ammonia. The organic layer was dried and evaporated in vacuo, the residual base was dissolved in 100 ml of methanol in a hydrogenation vessel. 2.5 gm of palladium oxide/barium sulfate catalyst (5%) were added, and the mixture was hydrogenated until 1 mol of hydrogen had been absorbed. After the catalyst had been removed by filtration, the filtrate was evaporated in vacuo, and the solid residue was recrystallized from isopropanol. The obtained hydrobromide melted at 174°-175° C. (decomp.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[C:4]([F:15])[CH:3]=1.[Na+].[CH3:17][S:18]([O-:20])=[O:19].[OH-].[Na+]>CS(C)=O>[F:15][C:4]1[CH:3]=[C:2]([S:18]([CH3:17])(=[O:20])=[O:19])[CH:7]=[CH:6][C:5]=1[C:8]1[N:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1
Reactant: CS(=O)[O-]
Reactant: Oc1ccc(-c2ccc(Br)cc2F)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(-c2ccc(O)cn2)c(F)c1
Temperature: 120 °C
Yield: 68.3 %

Procedure:
A mixture of 6-(4-bromo-2-fluorophenyl)-3-pyridinol (0.245 g, 0.91 mmol), methanesulfinic acid sodium salt (0.47 g, 80%, 3.66 mmol), Cul (0.70 g, 3.66 mmol) and NaOH (44 mg, 1.10 mmol) in DMSO (20 mL) was degassed with N2 three times and heated at 120° C. overnight. After the mixture was cooled to ambient temperature, 1N HCl was added to adjust the aqueous pH to about 8. The mixture was extracted with EtOAc. The combined organic extract was washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a light brown viscous oil. The crude product was purified by chromatography on a silica gel column eluted with 2:4:0.1 EtOAc/CH2Cl2/MeOH to give 0.166 g (68%) of 6-[2-fluoro-4-(methylsulfonyl)phenyl]-3-pyridinol as a white solid. 1H NMR (400 MHz, CD3OD): δ 8.26 (d, 1H, J=2.7 Hz), 8.15-8.05 (m, 1H), 7.90-7.75 (m, 2H), 7.74 (dd, 1H, Ja=8.6 Hz, Jb=2.1 Hz), 7.32 (dd, 1H, Ja=8.6 Hz, Jb=2.8 Hz), 3.18 (s, 3H); LRMS (ESI), m/z 268 (M+H).
Reaction SMILES: O=[C:2]([CH2:7][CH2:8][C:9]([O:11]C)=O)[C:3]([O:5][CH3:6])=[O:4].[C:13]1([NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19]>CO>[OH:11][C:9]1[C:8]([CH2:7][CH2:2][C:3]([O:5][CH3:6])=[O:4])=[N:19][C:14]2[C:13]([N:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: Nc1ccccc1N
Reactant: COC(=O)CCC(=O)C(=O)OC
Solvent: CO
Product: COC(=O)CCc1nc2ccccc2nc1O
Reaction time: 8 h
Yield: 101.2 %

Procedure:
Dimethyl 2-ketoglutarate (3.75 g) and o-phenylenediamine (2.5 g) were dissolved in methanol (30 ml), and the mixture was stirred overnight. The precipitated crystals were recovered by filtration and washed with water and methanol to obtain 5.06 g of methyl 3-(3-hydroxyquinoxaline-2-yl)propanoate Yield: 94%.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH2:19][O:20][CH3:21])=[C:8]([CH2:22][OH:23])[N:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4]>C1(C)C=CC=CC=1.[O-2].[Mn+2]>[CH2:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH2:19][O:20][CH3:21])=[C:8]([CH:22]=[O:23])[N:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cnc(CO)c1-c1ccc(OC)cc1OCOC
Agent: [Mn+2]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCCCn1cnc(C=O)c1-c1ccc(OC)cc1OCOC
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.2 %

Procedure:
To a solution 1-n-butyl-4-hydroxymethyl-5-(2-methoxymethoxy-4-methoxy-phenyl)-1H-imidazole (0.05 g, 0.16 mmol) in toluene (5 mL) was added manganese oxide (0.04 g, 0.47 mmol). The mixture was stirred for 5 h at room temperature. The mixture was filtered and the filtrate was evaporated to dryness. Flash column chromatography (1:4 ethyl acetate/hexane) of the residue afforded the title compound as an oil (0.05 g, 94%). 1H NMR (250 MHz, CDCl3) δ 9.65 (s, 1H), 7.58 (s, 1H), 7.13 (d, 1H), 6.80 (d, 1H), 6.65 (dd, 1H), 5.05 (s, 2H), 3.90 (s, 3H) 3.80 (t, 2H), 3.35 (s, 3H), 1.55 (quintet, 2H), 1.25 (quintet, 2H), 0.83 (t, 3H).