Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:22](C)=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH:16](O)[CH3:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[C:24]1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:24])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH:16]=[CH2:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1cccc(CNc2cccn3c(C(C)O)c(C)nc23)c1C
Solvent: c1ccccc1
Solvent: O
Product: C=Cc1c(C)nc2c(NCc3c(C)cccc3C)cccn12
Yield: 141.8 %

Procedure:
A mixture of 1-[8-(2,3-dimethylbenzylamino)-2-methylimidazo[1,2-a]pyridine-3-yl]-1-ethanol (0.2 g, 0.65 mmol) and p-toluenesulfonic acid (0.029 g, 0.15 mmol) in benzene (40 ml) was refluxed for 20 h with Dean-Stark water separation. The solvent was evaporated under reduced pressure, the residue was solved in methylene chloride and washed with saturated sodium bicarbonate solution. The organic layer was separated, dried and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel using methylene chloride:ethyl acetate (10:1) gave 0.062 g (33%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]2[CH:15]=[C:14]([SH:16])[C:13]([Cl:17])=[CH:12][C:11]=2[F:18])=[N:4][N:5]([CH3:9])[C:6]=1[S:7][CH3:8].C([O-])([O-])=O.[K+].[K+].[CH2:25](Br)[C:26]#[CH:27]>CC(C)=O>[Cl:1][C:2]1[C:3]([C:10]2[CH:15]=[C:14]([S:16][CH2:27][C:26]#[CH:25])[C:13]([Cl:17])=[CH:12][C:11]=2[F:18])=[N:4][N:5]([CH3:9])[C:6]=1[S:7][CH3:8]
Reactant: CSc1c(Cl)c(-c2cc(S)c(Cl)cc2F)nn1C
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCSc1cc(-c2nn(C)c(SC)c2Cl)c(F)cc1Cl
Yield: 80.4 %

Procedure:
A mixture of 4-chloro-3-(4-chloro-2-fluoro-5-mercaptophenyl)-1-methyl-5-methylthio-1H-pyrazole (0.60 g, 1.86 mmoles), 30 ml acetone, a K2CO3 powder (2.04 mmoles), and propargyl bromide (2.23 mmoles), was subjected to reaction under reflux for 2 hours. Then the resulting solution was filtered to remove acetone-insoluble matter and the filtrate was concentrated and purified by silica gel column chromatography, giving crystals (0.54 g) of the title compound, m.p. 93-96° C., yield 80.5%.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)=O)#[N:2].[ClH:18].Cl.[NH2:20][O:21][CH2:22][CH2:23][NH2:24].N1C=CC=CC=1.Cl>C(O)C>[ClH:18].[NH2:24][CH2:23][CH2:22][O:21][N:20]=[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)[CH2:5][CH2:4][CH2:3][C:1]#[N:2]
Reactant: NCCON
Reactant: N#CCCCC(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: N#CCCCC(=NOCCN)c1ccc(C(F)(F)F)cc1

Procedure:
5.6 Mmol (1.35 g) of 4-cyano-4'-trifluoromethylbutyrophenone, 5.6 mmol (0.84 g) of 2 aminooxyethylamine dihydrochloride and 0.8 ml of pyridine were refluxed in 20 ml of absolute ethanol for 2.5 hours. The processing was equal to that of example 1. The resulting free base was dissolved in absolute ethanol and an equivalent quantity of 2N alcoholic hydrochloric acid was added. The ethanol was then removed in vacuo and the residue was crystallized twice from ethanol/ether (1:5). The melting point of the resulting title compound was 136°-136.5° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH3:6])=[O:4].[CH3:7][CH:8]([C:12]([OH:14])=O)[C:9]([OH:11])=O.C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:1][N:2]1[C:9](=[O:11])[CH:8]([CH3:7])[C:12](=[O:14])[N:5]([CH3:6])[C:3]1=[O:4]
Reactant: CC(C(=O)O)C(=O)O
Reactant: CNC(=O)NC
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC1C(=O)N(C)C(=O)N(C)C1=O
Temperature: 90 °C
Yield: 41.5 %

Procedure:
75 g (0.85 mol) of 1,3-dimethylurea and 102 g (0.86 mol) of methyl malonic acid were dissolved in 300 ml of glacial acetic acid at 65° C. To the solution was added 330 ml of acetic anhydride, the temperature was gradually raised and the mixture was refluxed by heating at 90° C. for 6 hours. The reaction solution was concentrated under reduced pressure, and benzene was added to the residue. The crystals thus-deposited were collected by filtration and recrystallized from benzene to obtain 60 g of 1,3,5-trimethylbarbituric acid. Yield: 42%, Melting Point: 83° to 85° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[N:15]=[C:14]([C:23](O)=[O:24])[CH:13]=2)[CH:5]=[C:6]([O:8][CH:9]([F:11])[F:10])[CH:7]=1.[S:26]1[CH2:30][CH2:29][NH:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[N:15]=[C:14]([C:23]([N:28]3[CH2:29][CH2:30][S:26][CH2:27]3)=[O:24])[CH:13]=2)[CH:5]=[C:6]([O:8][CH:9]([F:10])[F:11])[CH:7]=1
Reactant: C1CSCN1
Reactant: O=C(O)c1cc(-c2cc(Cl)cc(OC(F)F)c2)n(-c2cccnc2)n1
Product: O=C(c1cc(-c2cc(Cl)cc(OC(F)F)c2)n(-c2cccnc2)n1)N1CCSC1

Procedure:
95 mg (0.26 mmol) of the compound of Example 54A is reacted analogously to the synthesis of the compound of Example 3 with 25 mg (0.28 mmol) of thiazolidine for 30 minutes at room temperature. 65 mg (57% of theory) of the title compound is obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=[O:14])(=[O:9])=[O:8])[CH2:3][CH2:2]1.OS(O)(=O)=O.[CH3:24]O>>[O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([O:15][CH3:24])=[O:14])(=[O:9])=[O:8])[CH2:3][CH2:2]1
Reactant: CO
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1

Procedure:
3-(Morpholinosulfonyl)benzoic acid (100 mg, 0.369 mmol) was refluxed overnight in methanol in the presence of catalytic concentrated H2SO4 at 65° C. The reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and then compound was purified by column chromatography to yield the title compound as an off white solid (60 mg). 1H NMR (400 MHz, CDCl3): δ 8.38 (t, 1H, J=1.6 Hz), 8.27 (m, 1H), 7.92 (m, 1H), 7.64 (t, 1H, J=8.0 Hz), 3.95 (s, 3H), 3.73 (m, 4H), 3.00 (m, 4H). ESI-MS: 286.1 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[C:4](=[N:6][OH:7])Cl.[CH2:13]([O:15][C:16](=[O:20])[C:17]#[C:18][CH3:19])[CH3:14].CCN(CC)CC>CCOCC>[CH2:13]([O:15][C:16]([C:17]1[C:4]([C:3]2[C:8]([F:12])=[CH:9][CH:10]=[CH:11][C:2]=2[I:1])=[N:6][O:7][C:18]=1[CH3:19])=[O:20])[CH3:14]
Reactant: CC#CC(=O)OCC
Reactant: ON=C(Cl)c1c(F)cccc1I
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)c1c(-c2c(F)cccc2I)noc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of 2-iodo-6-fluorobenzoyl chloride oxime (26.6 mmol) and ethyl-2-butynoate (3.72 ml, 31.92 ml, 1.2 eq.) in Et2O (106 ml) under N2, stirring at 0-5° C. added dropwise a solution of Et3N (4.81 ml, 34.6 mmol, 1.3 eq) in Et2O (13 ml) over 1 h. The reaction was allowed to warm to room temperature and stirred overnight. Et2O was added and then washed with H2O, brine, dried (MgSO4), filtered, and concentrated. The crude residue was chromatographed on silica gel using ethyl acetate in hexanes (1-20%) to give the title compound (8.21 g, 82%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([N+:27]([O-])=O)[CH:21]=2)([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:8][C:9]=1[OH:10])([O-])=O.O.NN.NN>[Ni].CO>[NH2:27][C:22]1[CH:21]=[C:20]([C:11]([C:6]2[CH:7]=[CH:8][C:9]([OH:10])=[C:4]([NH2:1])[CH:5]=2)([C:12]([F:13])([F:14])[F:15])[C:16]([F:17])([F:18])[F:19])[CH:25]=[CH:24][C:23]=1[OH:26]
Reactant: O=[N+]([O-])c1cc(C(c2ccc(O)c([N+](=O)[O-])c2)(C(F)(F)F)C(F)(F)F)ccc1O
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1cc(C(c2ccc(O)c(N)c2)(C(F)(F)F)C(F)(F)F)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
100.0 g of 2,2-bis(3-nitro-4-hydroxyphenyl)hexafluoropropane, 300 cc of methanol, and 5.0 g of developed NDT-90 (trade name, Raney nickel catalyst, manufactured by Kawaken Fine Chemical Co.) were put into a 500-cc four-neck flask equipped with a thermometer, a Dimroth condenser and a stirrer, and heated, with stirring, up to 60° C. to completely dissolve 2,2-bis(3-nitro-4-hydroxyphenyl)hexafluoropropane in the solvent. The resulting solution was kept at 60 to 65° C., to which was dropwise added 78.3 g of an aqueous solution of 60% hydrazine monohydrate over a period of 1 hour. After the aqueous hydrazine solution was added, the mixture was stirred for further 30 minutes, and then gradually cooled to room temperature. After the catalyst was removed through filtration, the reaction mixture was concentrated to obtain a crude product of 2,2-bis(3-amino-4-hydroxy-phenyl)hexafluoropropane. The crude yield was 82.5 g (96.0%). The purity in liquid chromatography was 96.5% (area %).
Reaction SMILES: [C:1]1(C2C=CC=CC=2)[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:11]([NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[C:26]4=[N:27][C:28]([CH3:32])=[CH:29][C:30]([CH3:31])=[C:25]4[N:24]=[C:23]3[CH2:33][CH3:34])=[CH:18][CH:17]=2)=[O:12])(=[O:9])=[O:8])=CC=1.[S:41]1C=CC=C1S(N)(=O)=O>>[CH2:33]([C:23]1[N:22]([C:19]2[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][NH:13][C:11]([NH:10][S:7]([C:4]3[S:41][CH:1]=[CH:6][CH:5]=3)(=[O:9])=[O:8])=[O:12])=[CH:17][CH:18]=2)[C:26]2=[N:27][C:28]([CH3:32])=[CH:29][C:30]([CH3:31])=[C:25]2[N:24]=1)[CH3:34]
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(-c3ccccc3)cc2)cc1
Reactant: NS(=O)(=O)c1cccs1
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2cccs2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from phenyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of Example 18) and 2-thiophenesulfonamide (Huang, H. C.; Reinhard, E. J.; Reitz, D. B. Tetrahedron Lett., 1994, 35, 7201.; Graham, S. L.; Scholz, T. H. Synthesis, 1986, 1031).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:48]([CH3:49])=[CH:47][C:39]([O:40][CH2:41][CH:42]2[CH2:46][CH2:45][CH2:44][O:43]2)=[CH:38][C:37]=1[CH3:50]>>[CH3:50][C:37]1[CH:38]=[C:39]([O:40][CH2:41][CH:42]2[CH2:46][CH2:45][CH2:44][O:43]2)[CH:47]=[C:48]([CH3:49])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: Cc1cc(OCC2CCCO2)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCC6CCCO6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 2-((4-bromo-3,5-dimethylphenoxy)methyl)-tetrahydrofuran following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 1): tR=1.48 min; Mass spectrum (ESI+): m/z=569 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([F:38])[CH:37]=1)[C:32](Cl)=[O:33]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[C:32](=[O:33])[C:31]2[CH:30]=[C:29]([F:28])[CH:37]=[C:36]([F:38])[CH:35]=2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Product: O=C1OC2(CCN(C(=O)c3cn(C(=O)c4cc(F)cc(F)c4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure VII as described above, the acylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16) with commercially available 3,5-difluorobenzoyl chloride gave the title compound.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([CH:18](O)[CH:19]([CH3:21])[CH3:20])=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH2:1]([C:8]1[C:9]([CH:18]([N:27]2[C:23](=[O:33])[C:24]3[C:25](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:26]2=[O:28])[CH:19]([CH3:21])[CH3:20])=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(O)c1nc2ccccc2cc1Cc1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)C(c1nc2ccccc2cc1Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
To a solution of 1-(3-benzylquinolin-2-yl)-2-methylpropan-1-ol 13 (102 mg, 1 eq.) in dry tetrahydrofuran (3 ml) at 0° C., was added phthalimide (154 mg, 3 eq), triphenylphosphine (138 mg, 1.5 eq.), and DIAD (1.5 eq., 104 μl). The reaction was allowed to warm to room temperature and stirred overnight. The solvent was evaporated. The residue was dissolved in ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The material was purified by flash chromatography to yield 91 mg of 2-[1-(3-benzylquinolin-2-yl)-2-methylpropyl]-1H-isoindole-1,3(2H)-dione 14 as yellow oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:6][NH2:7].[C:16]([C:20]1[N:25]=[CH:24][C:23]([O:26][CH2:27][C:28](O)=[O:29])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].CCN(CC)CC>C1COCC1>[C:16]([C:20]1[N:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:3]([F:2])[CH:4]=2)=[O:29])=[CH:22][CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(OCC(=O)NCc2ccc(NS(C)(=O)=O)c(F)c2)cn1
Yield: 65 %

Procedure:
3-Fluoro-4-methanesulfonylaminobenzylamine hydrochloride (158 mg, 0.62 mmol) was reacted with (6-tert-butyl-pyridin-3-yloxy)-acetic acid (130 mg) DMTMM (1.2 eq, 206 mg) and NEt3(2.5 eq, 220 μl) in THF to give the title compound (165 mg, 65%) after purification by column chromatography (Hex/EtOAc=1/3).
Reaction SMILES: [CH3:1][CH:2]([CH3:29])[C@@H:3]([O:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:4]([NH:6][C@H:7]([C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=1)[CH3:8])=[O:5].[OH-].[Na+].Cl>CO.C1COCC1>[CH3:1][CH:2]([CH3:29])[C@@H:3]([O:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:4]([NH:6][C@H:7]([C:9]1[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[CH3:8])=[O:5]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H](OCCOc2ccccc2)C(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)[C@@H](OCCOc1ccccc1)C(=O)N[C@@H](C)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 47.9 %

Procedure:
To a solution of methyl 4-[(1S)-1-[[(2R)-3-methyl-2-(2-phenoxyethoxy)butanoyl]amino]ethyl]benzoate (2.0 g, 5.01 mmol) in MeOH (25 mL) and THF (25 mL) is added 5N NaOH (10 mL, 50 mmol). The mixture is stirred at room temperature for 1.5 h, treated with 5N HCl (10 mL), and concentrated to remove organic solvents. The aqueous residue is extracted with ethyl acetate (3×30 mL). The combined ethyl acetate layers are dried with MgSO4, filtered, and concentrated. The crude material (1.36 g) is dissolved in ethyl acetate and washed with 1N NaOH (25 mL). The aqueous layer is extracted with ethyl acetate (25 mL), acidified with 1N HCl (25 mL), and extracted with ethyl acetate (3×25 mL). The combined ethyl acetate layers are dried with MgSO4, filtered, and concentrated to a waxy solid. This material is co-evaporated with MeOH (3×) to provide the title compound as a white solid (925 mg, 48%). MS (m/z): 386.2 (M+1).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[C:13]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:18]=CC=C[CH:14]=1.CC(O)C.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH:13]([O:1][N:2]1[C:3](=[O:12])[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:7])([CH3:18])[CH3:14]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(C)ON1C(=O)c2ccccc2C1=O
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a suspension of N-hydroxyphthalimide (2.52 g, 15.45 mmol) in THF (60 ml) was added triphenylphosphine (4.10 g, 15.63 mmol), 2-propanol (1.2 ml, 15.67 mmol) and diethyl azodicarboxylate (2.68 ml, 17.0 mmol) and the reaction stirred overnight. The mixture was concentrated and purified by column chromatography on silica gel (Hexanes/EtOAc, 4:1) to afford 2-isopropoxy-isoindole-1,3-dione (2.59 g, 82%) as a white solid. 1H NMR (CDCl3) δ 1.38 (d, 6H, J=6 Hz), 4.52-4.58 (m, 1H), 7.73-7.76 (m, 2H), 7.83-7.85 (m, 2H).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC1(C)O[C@H]2[C@@H]3OC(C)(C)O[C@]3(C(O)=O)O[C@H]2C[O:11]1.O.OO.NC(N)=O>ClCCl>[C:3]1([CH:2]2[CH2:1][O:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: CC1(C)OC[C@@H]2O[C@@]3(C(=O)O)OC(C)(C)O[C@H]3[C@@H]2O1
Agent: NC(N)=O
Agent: OO
Solvent: ClCCl
Solvent: O
Product: c1ccc(C2CO2)cc1
Temperature: 25 °C
Yield: 70 %

Procedure:
Styrene (1 g, 9.6 mmol) was taken with 100 mg Immobilized lipase and 2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid monohydrate (0.3 g, 1.03 mmol) in dry dichloromethane (15 mL) and stirred at 25° C. and added urea hydrogen peroxide (3 g, 32 mmol) portion-wise at a pH 5 for 20 hours. The reaction was monitored occasionally on TLC. The mixture was filtered and washed the residue with dichloromethane and the filtrate was reduced its volume under reduced pressure using vacuum flash evaporator. The product was purified by preparative TLC with 40% CH2Cl2/hexane. Yield: 70%; oil (Found: C, 79.91; H, 6.65. C8H8O requires C, 79.97; H, 6.71%); Rf (40% CH2Cl2/hexane) 0.55. The enantiomeric excess was determined by HPLC analysis using a Chiralcel OD column [iPrOH:hexane=0.2:99.8, flow rate 0.2 cm3 min−1], [α]D22+21.6 (c 0.7, PhH) 48% ee; {lit., [α]D22+44.8 (c 1.00, PhH), R}; νmax (neat/cm−1) 1496, 1476, 1452, 1390; δH (300 MHz; CDCl3) 2.80 (1H, dd, J 2.6 and 5.5, HCOCHH), 3.13 (1H, dd, J 4.1 and 5.5, HCOCHH), 3.85 (1H, dd, J 2.6 and 4.0, PhCHOCH2), 7.26-7.36 (5H, m, 5×CH, arom.); δC (300 MHz; CDCl3) 51.7 (CH2), 52.8 (CH), 125.9, 126.3, 128.6, 128.9 and 138.0 (6×C-Ph). MS m/z (rel. intensity %): 122 (M+2, 15), 121 (M+1, 43), 120 (M+, 20), 105(100), 91(68), 77 (88).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:20])(C)(C)C.CC1(C)O[C:27]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)[C:32]#[N:33])=[CH:26][C:25](=[O:37])O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:37]=[C:25]1[CH2:26][C:27]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)[C:32]#[N:33])=[N:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[NH:20]1
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccncc2)cc1N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(C2=Nc3ccc(-c4ccncc4)cc3NC(=O)C2)c1

Procedure:
Prepared from (2-amino-4-pyridin-4-yl-phenyl)-carbamic acid tert.-butyl ester (Example G28) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a red-brown solid (25 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]=[O:30].O>O1CCCC1>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:29]([OH:30])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1ccccn1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(O)c2ccccn2)cc1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
500 mg of the compound [1-1] was dissolved in 10 mL of tetrahydrofuran and cooled to −78° C. Thereafter, 2.33 mL of n-butyllithium (1.57M hexane solution) was added thereto. After the 1 hour stirring at the same temperature, 193 μL of picolinaldehyde was added to the resulting white suspension, and the suspension was stirred overnight while heating back to room temperature. 50 mL of water was added to the reaction mixture, and the mixture was extracted with 200 mL of ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Then, the insolubles were filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=100/0-30/70) to obtain 212 mg of tert-butyl((1S)-1-{4-[hydroxy (pyridin-2-yl)methyl]phenyl}ethyl)carbamate [12-1] (hereinafter, referred to as the compound [12-1]) as a light brown oily product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:7][CH:6]=1.[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:23][CH:4]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[CH:9][CH:10]=1)[C:3]([O:2][CH3:1])=[O:22]
Reactant: COC(=O)Cc1ccc(OCCOc2ccc(Cl)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc(OCCOc2ccc(Cl)cc2)cc1
Yield: 62 %

Procedure:
A mixture of 64 g of methyl{p-[2-(p-chlorophenoxy)ethoxy]phenyl}acetate and 37.4 g of N-bromosuccinimide in 800 ml of carbon tetrachloride is stirred and refluxed for 72 hours or until the reaction is complete. The solution is filtered and the filtrate passed through a silica gel column with carbon tetrachloride as eluent to give 49.4 g of white crystals, mp 76°-80° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:10]=1)=[N:7][O:8][N:9]=2.C(=O)([O-])[O-].[Na+].[Na+].[CH3:17][N:18]([CH3:28])[C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>COCCOC.O>[N:9]1[O:8][N:7]=[C:6]2[CH:10]=[C:2]([C:22]3[CH:23]=[CH:24][C:19]([N:18]([CH3:28])[CH3:17])=[CH:20][CH:21]=3)[CH:3]=[CH:4][C:5]=12
Reactant: Brc1ccc2nonc2c1
Reactant: CN(C)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN(C)c1ccc(-c2ccc3nonc3c2)cc1
Temperature: 25 °C

Procedure:
500 mg (2.5 mmol) 5-bromo-benzo[1,2,5]oxadiazole and 313 mg (0.1 eq.) tetrakis-(triphenylphosphine)palladium are stirred for 30 minutes at room temperature in 10 mL 1,2-dimethoxyethane. 533 mg (2 eq.) sodium carbonate are dissolved in 1.8 mL water and added to the reaction mixture, followed by 663 mg (1.6 eq.) 4-(dimethylamino)phenylboronic acid. After stirring at reflux for 18 h, the reaction mixture is cooled to room temperature and extracted with ethyl acetate and water. The organic phases are combined, dried with magnesium sulfate, filtered and evaporated. The residue is column chromatographed (hexane, then hexane/ethyl acetate 8:1 then 5:1) to yield the desired product as a yellow solid. MS(ES+): 240 (M+1).
Reaction SMILES: C([N:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:12]=1)[CH2:9][CH3:10])(OC(C)(C)C)=O.Cl.O1CCOCC1>>[CH2:9]([NH:8][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:12]=1)[CH3:10]
Reactant: CCOC(=O)Cc1cccc(N(CC)C(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: C1COCCO1
Product: CCNc1cccc(CC(=O)OCC)n1

Procedure:
A solution of ethyl 2-(N-Boc-N-ethylamino)-6-pyridylacetate (1.5 g, 4.87 mmol) and 4M HCl/dioxane (5 mL, 20 mol) was stirred at RT overnight, then was concentrated. Reconcentration from toluene gave the title compound as white solid: MS (ES) m/e 209 (M+H)+.