Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[CH:6]([CH2:15][CH3:16])[NH:5]2.[C:17](Cl)(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[CH:6]([CH2:15][CH3:16])[N:5]2[C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1
Reactant: CCC1Nc2cc(Br)ccc2-n2cccc21
Reactant: COc1ccc(C(=O)Cl)cc1
Product: CCC1c2cccn2-c2ccc(Br)cc2N1C(=O)c1ccc(OC)cc1

Procedure:
7-Bromo-4-ethyl-5-(4-methoxybenzoyl)-4,5-dihydropyrrolo[1,2-a]quinoxaline was prepared from 7-bromo-4-ethyl-4,5-dihydropyrrolo[1,2-a]quinoxaline (see Example 42) and p-anisoyl chloride according to the procedure of Example 106, Step 2. The product was purified via Biotage Horizon® (25S, silica, gradient from 5% EtOAc/hexane to 40% EtOAc/hexane) and isolated as a white foam. MS (ESI) m/z 411/413 ([M+H]+); HRMS: calcd for C21H19BrN2O2, 410.0630; found (ESI+), 411.06959.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C:13]([F:16])([F:15])[F:14])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:17](C1C=C(C=C(OC(C)C)C=1)C(OC)=O)#[N:18]>>[C:17]([C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C:13]([F:16])([F:15])[F:14])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])#[N:18]
Reactant: COC(=O)c1cc(C#N)cc(OC(C)C)c1
Reactant: COC(=O)c1cc(Br)cc(OC(F)(F)F)c1
Product: COC(=O)c1cc(C#N)cc(OC(F)(F)F)c1

Procedure:
Prepared from methyl 3-bromo-5-(trifluoromethoxy)benzoate according to the procedure for methyl 3-cyano-5-isopropoxybenzoate. LCMS-ESI (m/z) calculated for C10H6F3NO3: 245.2; no m/z observed, tR=4.43 min. 1H NMR (400 MHz, CDCl3) δ 8.27 (t, J=1.4 Hz, 1H), 8.16-8.07 (m, 1H), 7.73-7.65 (m, 1H), 3.99 (s, 3H).
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[CH3:13][O:14][N:15]=[CH:16][C:17]1[CH:22]=[C:21]([Cl:23])[C:20]([O:24][CH2:25][C@@H:26]2[CH2:30][CH2:29][CH2:28][NH:27]2)=[C:19]([Cl:31])[CH:18]=1.C(N(CC)CC)C>ClCCl>[CH3:13][O:14][N:15]=[CH:16][C:17]1[CH:22]=[C:21]([Cl:23])[C:20]([O:24][CH2:25][C@@H:26]2[CH2:30][CH2:29][CH2:28][N:27]2[C:8]([C:7]2[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=2)=[O:9])=[C:19]([Cl:31])[CH:18]=1
Reactant: CON=Cc1cc(Cl)c(OC[C@@H]2CCCN2)c(Cl)c1
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON=Cc1cc(Cl)c(OC[C@@H]2CCCN2C(=O)c2cn(C)nc2C(F)F)c(Cl)c1
Reaction time: 4 h
Yield: 57.3 %

Procedure:
At a temperature of 0° C., a solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (0.103 g; 0.53 mmol) in dichloromethane (4 ml) was added dropwise to a stirred solution of 3,5-dichloro-4-[(S)-1-pyrrolidin-2-ylmethoxy)-benzaldehyde O-methyl-oxime (0.16 g; 0.53 mmol), which was prepared in analogy as described for example P12, and triethylamine (146 μl; 1.05 mmol) in dichloromethane (7 ml). The ice bath was removed and reaction mixture was allowed stirring for 4 hours. The reaction mixture was washed with 2M HCl (10 ml), 1M NaOH (10 ml) and saturated NaCl (30 ml) and then dried over Na2SO4. After removal of the solvent, the residue (0.20 g in the form of an oil) was purified by flash chromatography over silica gel (eluent:cyclohexane/ethyl acetate 1:1). 0.14 g (57% of theory) of 3,5-dichloro-4-[(S)-1-(3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl)-pyrrolidin-2-ylmethoxy]-benzaldehyde O-methyl-oxime was obtained in form of an oil. 1H NMR (400 MHz, CDCl3): δ 1.95 (m, 1H), 2.20 (m, 2H), 2.45 (m, 1H), 3.68 (m, 2H), 3.96 (s, 3H, NCH3), 3.98 (s, 3H, OCH3), 4.22-4.24 (m, 1H), 4.38 (m, 1H), 4.61 (m, 1H), 7.01-7.28 (t, 1H, CHF2), 7.50 (s, 2H, Ar—H), 7.61 (s, 1H), 7.89 (s, 1H). MS [M+H]+ 361/363/365.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[N:27]1([C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:37](=[O:38])[C:36]3[CH:35]=[CH:34][C:33]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[CH:41][CH:40]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)c1ccc(N2CCOCC2)cc1

Procedure:
The title compound, light yellow solid (103 mg, 80%), MS (ISP) m/z=516.3 [(M+H)+], mp 249° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-morpholin-4-yl-benzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:17](O)(=[O:24])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccncc1
Reactant: COc1ccc(N)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)c2ccncc2)cc1
Temperature: 23 °C
Reaction time: 4 h
Yield: 87.6 %

Procedure:
A solution of p-anisidine (2.46 g, 20 mmol) and triethylamine (13.9 mL, 100 mmol) in ethyl acetate (200 mL) was treated with isonicotinic acid (2.46 g, 20 mmol) followed by 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate, 15.1 mL, 24 mmol). After stirring at 23° C. for 4 h, the reaction mixture was diluted with ethyl acetate, was washed with water and with brine, and the organic layer was dried (MgSO4), was filtered, and was concentrated in vacuo. Purification by silica gel chromatography with chloroform-methanol (40:1) gave 4 g (88% yield) of the title compound; diagnostic 13C NMR signals (100 MHz, CD3OD/CDCl3) δ 164.825, 157.213, 149.758, 143.349, 130.989, 123.085, 122.068, 55.285; MS (AP/CI) 229.3 (M+H)+.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][N:18](C(OCC3C=CC=CC=3)=O)[CH2:17][CH2:16]2)(=O)=O)=CC=1.[O:31]1[CH2:35][CH2:34][CH:33]([CH2:36]O)[CH2:32]1>>[O:31]1[CH2:35][CH2:34][CH:33]([CH2:36][O:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)[CH2:32]1
Reactant: Cc1ccc(S(=O)(=O)OCCOC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Reactant: OCC1CCOC1
Product: C1CC(OCCOCC2CCOC2)CCN1
Yield: 66.6 %

Procedure:
Using benzyl 4-(2-{[(4-methylphenyl)sulfony]oxy}ethoxy)piperidine-1-carboxylate (4.00 g, 9.23 mmol) produced in Reference Example 1 (1c) and (tetrahydrofuran-3-yl)methanol (1.23 g, 12.0 mmol), the desired title compound (1.41 g, yield 67%) was obtained by the same method as in Examples 1 (1d) and 1 (1e).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH2:20])[N:19]=[C:15]3[CH:14]=[N:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)[CH:23]=4)[N:19]=[C:15]3[CH:14]=[N:13][CH:12]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CN1CCN(c2cccc(Br)c2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cncc3nc(N)nn23)cc1
Product: CN1CCN(c2cccc(Nc3nc4cncc(-c5ccc(S(C)(=O)=O)cc5)n4n3)c2)CC1
Yield: 3 %

Procedure:
[5-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine and 1-(3-bromo-phenyl)-4-methyl-piperazine in a manner analogous to Step 2d and was isolated as a pale orange lyophilate (3% yield). 1H NMR (400 MHz, CDCl3, δ, ppm): 10.0 (s, 1H), 9.62 (bs, 1H), 9.14 (s, 1H), 8.42-8.40 (m, 3H), 8.20 (d, J=8.2 Hz, 2H), 7.58 (s, 1H), 7.18 (m, 1H), 7.05 (d, J=8.4 Hz, 1H), 6.60 (d, J=8.4 Hz, 1H), 3.72 (bd, 2H), 3.52 (bd, 2H), 3.39 (s, 3H), 3.17 (m, 2H), 2.93 (m, 2H), 2.87 (s, 3H). MS=464.1 (MH)+.
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].[CH:18]1([CH2:21][O:22][C:23]2[CH:33]=[CH:32][C:26]([O:27][CH:28]3[CH2:31][NH:30][CH2:29]3)=[CH:25][CH:24]=2)[CH2:20][CH2:19]1>>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([N:30]2[CH2:31][CH:28]([O:27][C:26]3[CH:25]=[CH:24][C:23]([O:22][CH2:21][CH:18]4[CH2:19][CH2:20]4)=[CH:33][CH:32]=3)[CH2:29]2)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Reactant: c1cc(OC2CNC2)ccc1OCC1CC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(N2CC(Oc3ccc(OCC4CC4)cc3)C2)cc1

Procedure:
Example 8.3 is prepared analogously to 8.1. (S)-[1-(4-Bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (1.3) and 3-(4-cyclopropylmethoxy-phenoxy)-azetidine (IX.1) are used as starting materials and the reaction temperature is 45° C.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH:12]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH:12]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)CC1CN(Cc2ccccc2)CCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CC1CN(Cc2ccccc2)CCC1O
Reaction time: 1 h

Procedure:
Sodium borohydride (0.3 g, 9.0 mmole) was added to the stirred solution of 1-benzyl-3-isobutylpiperidin-4-one (1.0 g, 4.0 mmole) in methanol (10 ml) at 0-5° C. over a period of 5 min, and stirring was continued for 1 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water (20 ml) and extracted with ethyl acetate. The ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to furnish 1-benzyl-4-hydroxy-3-isobutylpiperidine as oil. Yield 0.63 g (54%), C16H25NO, m/z 248 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:22]([O:26][C:27]([N:29]1[CH2:38][CH2:37][C:36]2[C:31](=[CH:32][C:33]([CH2:39][CH2:40]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:34][CH:35]=2)[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>CN(C=O)C>[C:22]([O:26][C:27]([N:29]1[CH2:38][CH2:37][C:36]2[C:31](=[CH:32][C:33]([CH2:39][CH2:40][N:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:10][C:11]3=[O:15])=[CH:34][CH:35]=2)[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3)cc1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(CCn3ccc(OCc4ccccc4)cc3=O)cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 450 mg (2.24 mmol) 4-benzyloxy-1H-pyridin-2-one in 2.2 mL DMF at 0° C. is added 1.46 g (4.47 mmol) cesium carbonate and after 15 min 1.00 g (2.32 mmol) 7-[2-(toluene-4-sulfonyloxy)ethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (preparation 7). The reaction mixture is stirred overnight at RT, filtered and is directly transferred to reverse HPLC chromatography (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 5:95).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13](=[O:27])[C:14]2[CH:19]=[C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:17]=[C:16]([F:26])[CH:15]=2)=[CH:4][CH:3]=1.[CH:28](B(O)O)=[CH:29][CH2:30][CH2:31][CH2:32][CH3:33].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>O1CCOCC1>[F:26][C:16]1[CH:15]=[C:14]([CH:19]=[C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:17]=1)[C:13]([NH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([CH:28]=[CH:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:3][CH:4]=1)=[O:27]
Reactant: O=C(Nc1ccc(Br)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1
Reactant: CCCCC=CB(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCCC=Cc1ccc(NC(=O)c2cc(F)cc(N3CCOCC3)c2)c2ccccc12
Yield: 107.6 %

Procedure:
N-(4-Bromo-naphthalen-1-yl)-3-fluoro-5-morpholin-4-yl-benzamide (2.5 g, 5.8 mmol), 1-hexenyl boronic acid (1.06 g, 8.3 mmol), cesium carbonate (3.04 g, 9.34 mmol) and tetrakis triphenylphosphine palladium(0) (100 mg) in dioxane (22 ml) are heated to 100° C. under nitrogen for 24 hours. The mixture is then poured into ethyl acetate (200 ml) and washed with water (2×100 ml). The organic layer is dried over anhydrous sodium sulfate and evaporated to dryness to give 3-fluoro-N-(4-hex-1-enyl-naphthalen-1-yl)-5-morpholin-4-yl-benzamide as a brown solid (2.7 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][N:7]=1.[CH2:21]([CH:28]1[CH2:32][C:31](=[O:33])[O:30][C:29]1=[O:34])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[CH2:21]([CH:28]([CH2:32][C:31]([NH:1][C:2]1[CH:3]=[C:4]([CH2:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[NH:8][N:7]=2)[CH:17]=[CH:18][C:19]=1[F:20])=[O:33])[C:29]([OH:34])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: O=C1CC(Cc2ccccc2)C(=O)O1
Solvent: Cc1ccccc1
Product: O=C(CC(Cc1ccccc1)C(=O)O)Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred mixture of 4-(3-amino-4-fluorobenzyl)-2H-phthalazin-1-one (0.135 g, 0.5 mmol; prepared in a manner similar to that described in Example 23), 3-benzyldihydrofuran-2,5-dione (0.095 g, 0.5 mmol) and toluene (8 ml) was heated under reflux for 1 hour, allowed to stand at ambient overnight, then heated under reflux for a further 6.5 hours and allowed to cool to ambient temperature. The resulting solid was collected by filtration, washed with hexane (10 ml) and dried in vacuo to give 2-benzyl-N-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]succinamic acid (0.156 g) as an off white solid, 250 MHz 1H-nmr (d6-DMSO) δ (ppm): 2.2–2.95 (m 5H) (—CH2CH(CO2H)CH2Ph), 4.2 (s, 2H) (ArCH2—), 6.9–7.25 (m, 7H) (7×ArH), 7.6–7.9 (m, 4H) (4×ArH), 8.15 (d, 1H) (ArH), 9.65 (s, 1H) (chain CONH), 12.2 (s, 1H) (—CO2H), 12.5 (s, 1H) (ring CONH).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:32]1([CH3:41])[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>COCCOC>[C:18]1([N:13]2[C:12]([C:35]3[CH:36]=[CH:37][C:32]([CH3:41])=[CH:33][CH:34]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1ccccc1B(O)O
Reactant: CC(C)(C)OC(=O)N1CCc2nn(-c3ccccc3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Solvent: COCCOC
Product: Cc1ccc(-c2c3c(nn2-c2ccccc2)CCNCC3)cc1

Procedure:
The title compound (17.5 mg) was prepared from 188.9 mg of 2-phenyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 176, Step B) and 93.3 mg of p tolylboronic acid as in Example 199, using DME as the solvent. MS (ESI): exact mass calculated for C20H21N3, 303.17; found, m/z 304.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.26-7.23 (m, 2H), 7.21-7.16 (m, 3H), 7.15-7.12 (m, 2H), 7.04-7.01 (m, 2H), 3.11-3.07 (m, 2H), 3.04-3.00 (m, 2H), 2.98-2.96 (m, 2H), 2.68-2.65 (m, 2H), 2.35 (s, 3H).
Reaction SMILES: COC1C=CC(N2C[C@H](C[N:15]3[CH2:20][CH2:19][CH:18]([O:21][C:22]4[CH:27]=[CH:26][C:25]([NH:28][CH:29]=[O:30])=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)OC2=O)=CC=1>CS(C)=O>[CH:29]([NH:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][CH:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)=[CH:27][CH:26]=1)=[O:30]
Reactant: COc1ccc(N2C[C@H](CN3CCC(Oc4ccc(NC=O)cc4)CC3)OC2=O)cc1
Solvent: CS(C)=O
Product: O=CNc1ccc(OC2CCNCC2)cc1

Procedure:
3-p-methoxyphenyl-5(S)-[(4-p-formamido-phenoxypiperidino)methyl]-2-oxazolidinone, m.p. 102°-103°; [α]D =-31.2° (DMSO);
Reaction SMILES: C[O-].[Na+].I.[NH:5]=[C:6]1[N:10]([CH3:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[N:7]1[CH3:16].[C:17]1([N:23]=[C:24]=[S:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C.C1(C)C=CC=CC=1>[CH3:11][N:10]1[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[N:7]([CH3:16])[C:6]1=[N:5][C:24]([NH:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[S:25]
Reactant: S=C=Nc1ccccc1
Reactant: Cn1c(=N)n(C)c2ccccc21
Agent: C[O-]
Agent: I
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cn1c(=NC(=S)Nc2ccccc2)n(C)c2ccccc21

Procedure:
Sodium methoxide (0.54 g) was added to a mixture of 2-imino-1,3-dimethylbenzimidazole hydroiodide (3.135 g) in ethanol (10 ml) and brought to reflux, with stirring. Phenylisothiocyanate (1.635 g) in toluene (5 ml) was added to the mixture over 10 minutes and the resulting mixture heated under reflux, with stirring, for 1 hour then cooled in ice. Filtration, washing with ethanol and water and drying gave analytically pure product, mpt 245° C.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:18][CH2:19][O:20]CC1C=CC(OC)=CC=1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C([O-])(O)=O.[Na+]>ClCCl.O>[Si:1]([O:8][C@@H:9]([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:18][CH2:19][OH:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(COCC[C@H](CCc2ccccc2)O[Si](C)(C)C(C)(C)C)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H](CCO)CCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
(S)-3-(t-butyldimethylsilyloxy)-5-(4-methoxy-benzyloxy)-1-phenyl pentane (15 g, 36.2 mmol) was dissolved in a solvent mixture of dichloromethane-water (20:1) (252 ml) DDQ (8.2 g, 36.2 mmol) was added thereto and the mixture was stirred for 30 minutes at room temperature. After completion of the reaction, saturated aqueous NaHCO3 solution (100 ml) was added to the reaction solution to stop the reaction. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=15:1) to give (S)-3-(t-butyldimethylsilyloxy)-5-phenyl-pentan-1-ol (10.6 g, Yield 99%) of a yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][O:37][CH2:38][C:39]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)=[O:40]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:44]3[CH2:43][CH2:42][N:41]([C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:46][CH2:45]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COCC(=O)N1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)COC)CC1

Procedure:
1-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-2-methoxy-ethanone was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and 2-methoxy-1-piperazin-1-yl-ethanone in an analogous manner as described in example 25. LR-MS: 651.4 [(M+H)]
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:24]([C:29]2[C:34]([C:35]4[CH:40]=[CH:39][C:38](F)=[CH:37][CH:36]=4)=[CH:33][CH:32]=[C:31]([C:42]([N:44]4[CH2:48][CH2:47][CH2:46][CH2:45]4)=[O:43])[CH:30]=2)[CH:23]=[CH:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:49]([O:51]C(C1C=CC2N(C3CCCCC3)C(C3C=C4C(=CC=3)N=C(C3C(C5C=CC(F)=CC=5)=CC=C(C(N5CCCC5)=O)C=3)C=C4)=NC=2C=1)=O)C>>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:24]([C:29]2[C:34]([C:35]4[CH:40]=[CH:39][C:38]([O:51][CH3:49])=[CH:37][CH:36]=4)=[CH:33][CH:32]=[C:31]([C:42]([N:44]4[CH2:48][CH2:47][CH2:46][CH2:45]4)=[O:43])[CH:30]=2)[CH:23]=[CH:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4-c4ccc(F)cc4)ccc3c1)n2C1CCCCC1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4-c4ccc(F)cc4)ccc3c1)n2C1CCCCC1
Product: COc1ccc(-c2ccc(C(=O)N3CCCC3)cc2-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)cc1

Procedure:
Prepared as described for Compound 549 using Compound 561a instead Compound 549a.
Reaction SMILES: [Si](OCC[N:11]1[C:23]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:16]([O-])=[CH:15][C:14]=2[N:13]=[C:12]1[CH2:25][O:26][CH2:27][CH3:28])(C(C)(C)C)(C)C.[NH4+:29].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl>[CH2:27]([O:26][CH2:25][C:12]1[NH:11][C:23]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH2:29])[C:14]=2[N:13]=1)[CH3:28]
Reactant: CCOCc1nc2c[n+]([O-])c3cccnc3c2n1CCO[Si](C)(C)C(C)(C)C
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cccnc3c2[nH]1
Reaction time: 1.5 h

Procedure:
1-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridine 5-oxide (2.40 g, 5.97 mmol) was dissolved in 60 mL of CH2Cl2 and treated with 6 mL of concentrated aqueous NH4OH solution. The mixture was stirred rapidly and then p-toluenesulfonyl chloride (1.19 g, 6.27 mmol) was carefully added. Rapid stirring was continued for 1.5 hours. The reaction mixture was then treated with 50 mL of CH2Cl2 and 25 mL of H2O. The layers were separated and the organic portion was washed successively with 2% Na2CO3 solution (2×25 mL), H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 10-15% CMA/CHCl3) gave 1-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (1.93 g) as a light-brown foam.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[CH:3]=1.[Cl:10]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:10][C:3]1[C:4](=[O:9])[NH:5][C:6]([CH3:8])=[CH:7][C:2]=1[OH:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(O)cc(=O)[nH]1
Solvent: CC(=O)O
Product: Cc1cc(O)c(Cl)c(=O)[nH]1
Temperature: 115 °C
Yield: 60.2 %

Procedure:
4-Hydroxy-6-methyl-1H-pyridin-2-one (25 g, 0.2 mol) and N-chlorosuccinimide (29.4 g, 0.22 mol) were dissolved in 200 mL of acetic acid. The reaction was heated at 115° C. for 6 hours. The reaction was cooled to room temperature, the solid was filtered, and washed with acetic acid and hexanes. The solid was dried in a vacuum oven overnight to give a white solid (19.2 g, 60%): 1H NMR (300 MHz, DMSO-d6) δ 11.46 (br s, 1H), 11.04 (s, 1H), 5.79 (s, 1H), 2.09 (s, 3H).
Reaction SMILES: [B:1]([C@@H:4]([NH:16][C:17]([C:19]1[C:27]2[CH2:26][CH2:25][NH:24][CH2:23][C:22]=2[S:21][CH:20]=1)=[O:18])[CH2:5][C:6]1[C:7](O)=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])([OH:3])[OH:2].[CH2:28]=O>CO.[Pd]>[OH:2][B:1]1[C@@H:4]([NH:16][C:17]([C:19]2[C:27]3[CH2:26][CH2:25][N:24]([CH3:28])[CH2:23][C:22]=3[S:21][CH:20]=2)=[O:18])[CH2:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:8]([C:9]([OH:11])=[O:10])[C:7]=2[O:3]1
Reactant: O=C(O)c1cccc(C[C@H](NC(=O)c2csc3c2CCNC3)B(O)O)c1O
Reactant: C=O
Agent: [Pd]
Solvent: CO
Product: CN1CCc2c(C(=O)N[C@H]3Cc4cccc(C(=O)O)c4OB3O)csc2C1

Procedure:
To (R)-3-(2-borono-2-(4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamido)ethyl)-2-hydroxybenzoic acid (10.0 mg from Example 4) in MeOH (5 mL) was added formaldehyde (1.0 mL, 37% solution), followed by 10% Pd/C (20 mg). The reaction mixture was hydrogenated under H2 balloon for 3 hr. The reaction mixture was filtrated and the solvent was removed under vacuum. The final product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 387 (MH)+.