Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:15][C:16]([NH2:18])=S)[CH:4]=1.[OH-].[K+].O.O.O.C([O-])(=O)C.[Pb+2].C([O-])(=O)C>O>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:15][C:16]#[N:18])[CH:4]=1
Reactant: CSc1ccc(-c2ccccc2)c(NC(N)=S)c1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CSc1ccc(-c2ccccc2)c(NC#N)c1

Procedure:
A mixture of N-(4-methylthio-2-biphenylyl)thiourea (9.6 g), potassium hydroxide (8.5 g), lead acetate trihydrate (12.5 g) and water (165 ml) was heated at 90°-95° C. for 30 minutes to give 4-methylthio-2-biphenylylcyanamide.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@@H:14]([N:17]([C:28](=[O:54])[CH2:29][CH2:30][C@H:31]([NH:38][CH2:39][C:40]2[C:45]([NH2:46])=[CH:44][N:43]=[C:42]([O:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:41]=2)[CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH2:18][CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:56]#[N:57]>CCO>[CH2:1]([O:8][C:9]([C@H:11]1[CH2:12][CH2:13][C@@H:14]([N:17]([C:28](=[O:54])[CH2:29][CH2:30][C@H:31]([N:38]2[CH2:39][C:40]3[CH:41]=[C:42]([O:47][C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[N:43]=[CH:44][C:45]=3[N:46]=[C:56]2[NH2:57])[CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH2:18][CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CBr
Reactant: Nc1cnc(Oc2ccccc2)cc1CN[C@@H](CCC(=O)N(CCOCc1ccccc1)[C@H]1CC[C@@H](C(=O)OCc2ccccc2)CC1)C1CCOCC1
Solvent: CCO
Product: NC1=Nc2cnc(Oc3ccccc3)cc2CN1[C@@H](CCC(=O)N(CCOCc1ccccc1)[C@H]1CC[C@@H](C(=O)OCc2ccccc2)CC1)C1CCOCC1
Reaction time: 0.5 h

Procedure:
A solution of 4-[[4-[(5-amino-2-phenoxy-pyridin-4-ylmethyl)-amino]-4-(S)-(tetrahydro-pyran-4-yl)-butyryl]-(2-benzyloxy-ethyl)-amino]-cis-cyclohexanecarboxylic acid benzyl ester (0.5 g, 0.7 mmol) and BrCN (3M in CH2Cl2, 0.25 mL) in EtOH (20 mL) was stirred at room temperature overnight. The EtOH was evaporated. The resulting oil was stirred in diethyl ether (50 mL) for 30 min. 4-[[4-(2-Amino-6-phenoxy-4H-pyrido[3,4-d]pyrimidin-3-yl)-4-(S)-(tetrahydro-pyran-4-yl)-butyryl]-(2-benzyloxy-ethyl)-amino]-cis-cyclohexanecarboxylic acid benzyl ester was collected as a solid as its corresponding HBr salt.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][C:9]1([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][C:9]1([CH3:16])[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(=O)CCN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CC(O)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
Combine 1-benzyl-2,2-dimethyl-piperidin-4-one (1.0 g, 4.6 mmol) and tetrahydrofuran (20 mL) and cool to 0° C. Add lithium aluminum hydride (0.175 g, 4.6 mmol) with stirring. After 30 min., warm to ambient temperature. After 30 min., quench the reaction mixture with water (50 mL). Extract with ethyl acetate (2×75 mL), combine the organic layers and wash with aqueous NaCl solution (50 mL), dry over sodium sulfate, filter and concentrate to obtain the title compound (1.0 g, 100%). Mass spectrum (electrospray): m/z=220.1 (M+1); 1H NMR (CDCl3): 7.3 (m, 5H), 4.0 (m, 1H), 3.8 (m, 1H), 3.0 (m, 1H), 2.6 (m, 1H), 2.3 (m, 1H), 1.8 (m, 2H), 1.4 (m, 3H), 1.25 (s, 3), 1.1 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][C:7]2[NH:8][C:9]([C:12]3[C:21](O)=[C:20]4[C:15]([CH:16]=[CH:17][CH:18]=[N:19]4)=[C:14]([N:23]4[CH2:28][CH2:27][N:26]([CH2:29][C:30]([NH:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:25][CH2:24]4)[N:13]=3)=[N:10][N:11]=2)=[CH:4][CH:3]=1.C(O)=[O:39]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[NH:8][C:9]([C:12]3[CH:21]=[C:20]4[C:15]([CH:16]=[CH:17][C:18]([OH:39])=[N:19]4)=[C:14]([N:23]4[CH2:24][CH2:25][N:26]([CH2:29][C:30]([NH:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:28]4)[N:13]=3)=[N:10][N:11]=2)=[CH:36][CH:37]=1
Reactant: O=CO
Reactant: CC(C)NC(=O)CN1CCN(c2nc(-c3nnc(Cc4ccc(F)cc4)[nH]3)c(O)c3ncccc23)CC1
Product: CC(C)NC(=O)CN1CCN(c2nc(-c3nnc(Cc4ccc(F)cc4)[nH]3)cc3nc(O)ccc23)CC1

Procedure:
In a similar manner as described in example 17, 2-(4-{7-[5-(4-fluorobenzyl)-4H-1,2,4-triazol-3-yl]-8-hydroxy-1,6-naphthyridin-5-yl}piperazin-1-yl)-N-isopropylacetamide (31 mg, 38%) was prepared as the formic acid. 1H NMR (CDCl3): δ 9.13 (d, J=4.0 Hz, 1 H), 8.42 (d, J=8.4 Hz, 1 H), 7.56(dd, J=8.4, 4.0 Hz, 1 H), 7.36 (m, 2 H), 7.02 (m, 2 H), 4.19 (s, 2 H), 4.17-4.13 (m, 1 H), 3.37 (s, 4 H), 3.13 (s, 2 H), 2.82 (s, 4 H), 1.20 (d, J=6.4 Hz, 6 H); MS m/z 505 (M+1).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23](=[O:26])[NH:24][NH2:25]>>[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23](=[O:26])[NH:24][N:25]=[C:9]1[C:10](=[O:11])[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7]1=[O:8]
Reactant: Cc1ccccc1NC(=O)NN
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: Cl
Product: Cc1ccccc1NC(=O)NN=c1c(=O)c2ccccc2c1=O

Procedure:
ninhydrin, 4-(2-methylphenyl)-semicarbazide hydrochloride
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][C:19]=1[C:28]1[NH:33][C:32](=[O:34])[N:31]2[C:35]([CH3:41])=[N:36][C:37]([CH2:38][CH2:39][CH3:40])=[C:30]2[N:29]=1)[CH3:16]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH3:14])[S:24]([C:21]2[CH:22]=[CH:23][C:18]([O:17][CH2:15][CH3:16])=[C:19]([C:28]3[NH:33][C:32](=[O:34])[N:31]4[C:35]([CH3:41])=[N:36][C:37]([CH2:38][CH2:39][CH3:40])=[C:30]4[N:29]=3)[CH:20]=2)(=[O:25])=[O:26])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nc12
Reactant: CNCCc1ccc(OC)c(OC)c1
Solvent: ClCCl
Product: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)N(C)CCc4ccc(OC)c(OC)c4)ccc3OCC)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
143 mg (0.73 mmol) of N-(3,4-dimethoxyphenylethyl)-N-methylamine are added to a solution of 100 mg (0.24 mmol) of 4-ethoxy-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-a][1,3,5]triazin-2-yl)-benzenesulfonyl chloride (example VI) in 5 ml of dichloromethane and the reaction mixture is stirred at room temperature for 2 hours. After chromatographic purification (dichloromethane/methanol=95:5), 138 mg (98%) of N-[2-(3,4-dimethoxy-phenyl)-ethyl]-4-ethoxy-N-methyl-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-a][1,3,5]triazin-2-yl)-benzene-sulfonamide are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22]N3C4C=CC=CC=4N=N3)=O)([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:43][NH:44][CH3:45]>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:13][CH2:14][C:15]([C:20]([N:44]([CH3:45])[CH3:43])=[O:22])([CH2:18][CH2:19]1)[CH2:16][CH2:17]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Solvent: C1CCOC1
Product: CN(C)C(=O)C12CCC(N(CC(=O)N3C[C@@H](F)C[C@H]3C#N)C(=O)OCc3ccccc3)(CC1)CC2

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazole-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2.0 M tetrahydrofuran solution of dimethylamine (65.0 μL) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(dimethylamino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (36.2 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([N+:19]([O-])=O)=[CH:17][C:6]2[CH2:7][CH2:8][N:9]([CH2:12][C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:11][C:5]=2[CH:4]=1.O.NN>CO.[Pd]>[CH3:1][O:2][C:3]1[C:18]([NH2:19])=[CH:17][C:6]2[CH2:7][CH2:8][N:9]([CH2:12][C:13]([F:14])([F:15])[F:16])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1[N+](=O)[O-])CCN(CC(F)(F)F)CC2
Agent: [Pd]
Agent: NN
Solvent: CO
Solvent: O
Product: COc1cc2c(cc1N)CCN(CC(F)(F)F)CC2
Temperature: 70 °C
Yield: 89.3 %

Procedure:
Into a 1-neck round-bottom flask was added 7-methoxy-8-nitro-3-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (310 mg, 1.0 mmol), hydrazine monohydrate (10 mL, 0.2 mol), palladium (10% wt on C, 50% wet; 100 mg, 0.9 mmol), in methanol (20 mL). The reaction mixture was heated at 70° C. for 3 hours. The reaction mixture was filtered through Celite and was concentrated. The resulting precipitate was partitioned between water and dichloromethane. The organic phase was washed with another portion of water, dried (MgSO4), and concentrated, to afford 8-methoxy-3-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (245 mg, 88%) as a waxy solid, which was used without further purification. m.p. ° C.; 1H-NMR (CDCl3) δ 6.55 (s, 1H), 6.49 (s, 1H), 3.82 (s, 3H), 3.63 (br s, 2H), 3.15 (q, J=9.5 hz, 2H), 2.88 (m, 4H), 2.77 (m, 4H); LC/MS (ESI+): 275.07 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:51][C:52]1[CH:59]=[CH:58][C:55]([CH:56]=O)=[CH:54][CH:53]=1>>[Cl:51][C:52]1[CH:59]=[CH:58][C:55]([CH2:56][NH:1][CH2:2][C:3]2[N:11]=[C:10]3[C:6]([N:7]=[CH:8][N:9]3[C@H:12]3[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]3)=[C:5]([NH:22][CH2:23][CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:4]=2)=[CH:54][CH:53]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNCc4ccc(Cl)cc4)nc32)[C@H](O)[C@@H]1O
Yield: 21.5 %

Procedure:
The title compound was prepared by a similar method to example 5 using (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino}-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (200 mg, 0.4 mmol), sodium triacetoxyborohydride (152 mg, 0.72 mmol) and 4-chlorobenzaldehyde (75 mg, 0.53 mmol). The product was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol (98:2) gradually increasing polarity to dichloromethane:methanol (90:10), which gave the title compound (53 mg) as a foam. MS: 615 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[C:6]([CH:18]=1)[C:7]([NH:9][CH2:10][C:11]1[NH:16][C:15](=[O:17])[CH:14]=[CH:13][CH:12]=1)=[O:8]>[Rh].CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][C:21]([F:24])([F:22])[F:23])=[C:6]([CH:18]=1)[C:7]([NH:9][CH2:10][CH:11]1[CH2:12][CH2:13][CH2:14][C:15](=[O:17])[NH:16]1)=[O:8]
Reactant: O=C(NCc1cccc(=O)[nH]1)c1cc(O)ccc1OCC(F)(F)F
Agent: [Rh]
Solvent: CO
Product: O=C1CCCC(CNC(=O)c2cc(O)ccc2OCC(F)(F)F)N1
Reaction time: 0.83 h

Procedure:
A mixture of 0.16 g (0.468 mmole) of 6-[5-hydroxy-2-(2,2,2-trifluoroethoxy)benzamidomethyl]-2(1H)-pyridone, 0.05 g of 5% rhodium on alumina and 50 ml of methanol was hydrogenated on a Parr apparatus for 50 minutes. The mixture was filtered, the filtrate was evaporated, and the residue was dried to provide 5-hydroxy-N-(6-oxo-2-piperidylmethyl)-2-(2,2,2-trifluoroethoxy)benzamide. The structural assignment was confirmed by comparison of infrared and nuclear magnetic resonance spectra to those of the same compound prepared by an alternative synthetic procedure which is described in U.S. Pat. No. 4,496,734.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[CH:18]2)(=[O:11])=[O:10].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[F:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[C:14]1[C:13](=[C:22]3[C:17](=[CH:16][CH:15]=1)[CH:18]=[CH:19][CH:20]=[N:21]3)[NH:12][S:9]2(=[O:11])=[O:10]
Reactant: Nc1ccc(F)cc1S(=O)(=O)Nc1cccc2cccnc12
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=S1(=O)Nc2c(ccc3cccnc23)-c2ccc(F)cc21
Yield: 9 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-5-fluoro-N-quinolin-8-yl-benzenesulfonamide (Intermediate 297) (250 mg, 0.78 mmol), t-butyl nitrite (121 mg, 1.18 mmol), AcOH (2.5 ml) and THF (2.5 ml) gave the title compound (21 mg, 8%) after purification by column chromatography (×2) with n-hexane/DCM (50:50) as the eluent followed by recrystallisation.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[F:24][C:25]([F:40])([F:39])[C:26]1[N:31]=[N:30][C:29]([C:32]2[CH:37]=[CH:36][NH:35][C:34](=[O:38])[CH:33]=2)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[CH3:11][N:8]1[C:9]2[CH:10]=[C:2]([N:35]3[CH:36]=[CH:37][C:32]([C:29]4[N:30]=[N:31][C:26]([C:25]([F:39])([F:24])[F:40])=[CH:27][CH:28]=4)=[CH:33][C:34]3=[O:38])[CH:3]=[CH:4][C:5]=2[C:6]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]1=2
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CCC2
Reactant: O=c1cc(-c2ccc(C(F)(F)F)nn2)cc[nH]1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nn5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CCC2
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 36.4 %

Procedure:
tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.21 g, 0.56 mmol), 4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one (0.16 g, 0.68 mmol) and Cs2CO3 (0.20 g, 0.61 mmol) were suspended in DMSO (2.0 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (24 mg, 0.17 mmol) and copper iodide (0.14 g, 0.72 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N2. The mixture was cooled, diluted with 5:1 MeOH/NH4OH (20 mL), and the resulting solution was stirred at ambient temperature for 30 min. The reaction was further diluted with CH2Cl2 (75 mL). The resulting solution was filtered through silica gel and the filtrate was concentrated under reduced pressure. The residue was diluted with CH2Cl2 and washed with brine (3×20 mL). The organic solution was dried over Na2SO4, filtered and concentrated to dryness. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 5 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes and held for 5 column volumes) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA) gave the title compound (110 mg, 37%) as a yellow film: 1H NMR (500 MHz, DMSO-d6) δ 8.70 (d, J=9.0 Hz, 1H), 8.45 (d, J=9.0 Hz, 1H), 7.91 (d, J=7.0 Hz, 1H), 7.55-7.54 (m, 2H), 7.37 (d, J=1.5 Hz, 1H), 7.16 (dd, J=7.0, 1.5 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 4.60 (s, 2H), 3.70-3.66 (m, 5H), 3.01-3.00 (m, 2H), 1.95-1.91 (m, 2H), 1.36-1.30 (m, 9H); ESI MS m/z 540 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].C([O-])([O-])=O.[K+].[K+].Br[CH2:17][CH2:18][O:19][CH3:20]>CN(C=O)C.O.CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH2:18][O:19][CH3:20])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(O)ccc1Cl
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: COCCOc1ccc(Cl)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-chloro-3-methylphenol (1 eq.) in DMF (0.7 M) was added K2CO3 (1.2 eq.). The mixture was stirred at 50° C. for 5 min before 1-bromo-2-methoxyethane (1.5 eq.) was added. After 2 h at 70° C., the reaction mixture was cooled down to RT and then diluted with water and ether. The organic phase was separated and washed sequentially with 2 N aq. NaOH, water and brine. The organic extract was dried over Na2SO4, filtered and the filtrate concentrated in vacuo to afford the title compound as a yellowish oil.
Reaction SMILES: [N:1]1([C:27]([O:29]C(C)(C)C)=O)[CH2:26][CH2:25][CH2:24][C@H:2]1[C:3]([NH:5][C@H:6]([C:17]([NH:19][CH2:20][C:21]([NH2:23])=[O:22])=[O:18])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:16])[NH:12][N+:13]([O-:15])=[O:14])=[O:4].Cl.CCOC(C)=O.[NH:41]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[C@H:42](C(ON1C(=O)CCC1=O)=O)[CH2:43][O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CCN(CC)CC>[NH:41]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[C@H:42]([C:27]([N:1]1[CH2:26][CH2:25][CH2:24][C@H:2]1[C:3]([NH:5][C@H:6]([C:17]([NH:19][CH2:20][C:21]([NH2:23])=[O:22])=[O:18])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:16])[NH:12][N+:13]([O-:15])=[O:14])=[O:4])=[O:29])[CH2:43][O:44][CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)NCC(N)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)NCC(N)=O

Procedure:
The desired compound was prepared from 6.0 g of Boc-Pro-Arg(NO2)-Gly-NH2, 35 ml of 4 N HCl-AcOEt, 1.8 ml of Et3N and 5.1 g of Boc-Ser(Bzl)-OSu in the same manner as in Example 26-(4).
Reaction SMILES: [C:1]([N:4]([CH2:6][C:7]1[CH:20]=[CH:19][C:10]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:9][CH:8]=1)C)(=O)C.Cl.O>>[CH3:1][NH:4][CH2:6][C:7]1[CH:20]=[CH:19][C:10]([C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:12])=[CH:9][CH:8]=1
Reactant: CC(=O)N(C)Cc1ccc(C(=O)c2ccccc2)cc1
Agent: Cl
Solvent: O
Product: CNCc1ccc(C(=O)c2ccccc2)cc1
Yield: 86.3 %

Procedure:
22 g of 4-(N-acetyl-N-methylaminomethyl)benzophenone are refluxed in 100 mL of 1:1 -HCl/water mixture (by volume) for 7 hours. From the reaction mixture there are isolated 16 g of 4-(N-methylaminomethyl)benzophenone. HNMR: δ=1.7 (1H, NH), 2.5 (3H, NCH3), 3.9 (2H, NCH2), 7.1-7.4 (9H, aromatics).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:19]([O:23][C:24](=[O:48])[NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33](=[O:47])[CH2:34]/[CH:35]=[CH:36]/[CH2:37][CH2:38][O:39][Si](C(C)(C)C)(C)C)([CH3:22])([CH3:21])[CH3:20]>C1COCC1.CCOCC>[OH:39][CH2:38][CH2:37]/[CH:36]=[CH:35]/[CH2:34][C:33]([NH:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[NH:25][C:24](=[O:48])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:47]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)C/C=C/CCO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)C/C=C/CCO
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.3 %

Procedure:
A TBAF (4.46 g, 17.06 mmol) in THF was added to a solution of (E)-tert-butyl2-(6-(tert-butyldimethylsilyloxy)hex-3-enamido)phenylcarbamate (6.17 g, 14.2 mmol) in THF (180 mL) at 0° C. for 0.5 hour, then the mixture was stirred at RT for 12 hours. The reaction mixture was diluted with ether (500 mL) and washed with brine (3×200 mL), the organic layer was dried over Na2SO4, filtered and concentrated to give the desired compound of (E)-tert-butyl 2-(6-hydroxyhex-3-enamido)phenylcarbamate (10) (2.38 g, 52%) as a yellow oil after purification by column chromatography on silica gel (eluent: PE:EA=1:1). 1H NMR (300 MHz, CDCl3): δ 1.475 (S, 9H), 2.292 (q, 2H), 3.096 (d, 2H), 3.652 (t, 2H), 5.655-5.701 (m, 2H), 6.996-7.124 (m, 2H), 7.310-7.380 (m, 2H), 7.482 (d, J=7.8 Hz, 1H), 8.652 (s, 1H); LC-MS found 321 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:32]=O)[CH:27]=[N:28][C:29]=1[CH2:30][OH:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>ClCCl.CO>[Cl:23][C:24]1[CH:25]=[C:26]([CH2:32][NH:1][CH:2]2[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=4)[CH:13]=[CH:12][C:11]3=[O:22])[CH2:6][CH2:7]2)[CH:27]=[N:28][C:29]=1[CH2:30][OH:31]
Reactant: COc1cnc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: O=Cc1cnc(CO)c(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cnc2ccc(=O)n(CCN3CCC(NCc4cnc(CO)c(Cl)c4)CC3)c2c1
Reaction time: 3 h
Yield: 29.7 %

Procedure:
1-[2-(4-amino-1-piperidinyl)ethyl]-7-(methyloxy)-1,5-naphthyridin-2(1H)-one (Intermediate 29: 100 mg, 0.331 mmol) was dissolved in a mixture of Dichloromethane (DCM) (4 mL) and Methanol (0.444 mL). Aldehyde 5-chloro-6-(hydroxymethyl)-3-pyridinecarbaldehyde (Intermediate 39: 56.7 mg, 0.331 mmol) was added and the mixture was left at room temp. for 3 hours. Then sodium triacetoxy borohydride (210 mg, 0.992 mmol) was added and after 2 hours 2 more eq. of triacetoxy borohydride were added leaving the reaction under stirring overnight. LCMS overnight showed still imine remaining so 3 eq more of sodium triacetoxy borohydride were added and 2 eq more after 3 hours leaving the reaction overnight. Next morning 2 more eq. of sodium triacetoxy borohydride were added and after 3H reaction was stopped. Volatiles were removed under vacuum and the corresponding crude was diluted with DCM and washed with NaHCO3 several times. Organic layers were dried over Na2SO4, filtered and volatiles removed under vacuum. Corresponding crude was purified by flash master chromatography. Si II, 5 g. DCM/MeOH (0-30%), to obtain a solid which was left in the oven overnight to afford 45 mg of the final compound as a pale yellow solid.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:18]2[B:19]([OH:26])[O:20][CH:21]([CH2:22][N+:23]([O-:25])=[O:24])[C:17]=2[CH:16]=[C:15]([Cl:27])[CH:14]=1)C1C=CC=CC=1.Cl.[H][H]>CO.[OH-].[OH-].[Pd+2]>[Cl:27][C:15]1[CH:14]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][OH:8])[C:18]2[B:19]([OH:26])[O:20][CH:21]([CH2:22][N+:23]([O-:25])=[O:24])[C:17]=2[CH:16]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])CC1OB(O)c2c(OCCCOCc3ccccc3)cc(Cl)cc21
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: O=[N+]([O-])CC1OB(O)c2c(OCCCO)cc(Cl)cc21
Yield: 29.2 %

Procedure:
7-(3-Benzyloxy-propoxy)-5-chloro-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol (0.3 g, 0.91 mmol) in MeOH (30 mL) was added conc HCl (1 mL) and Pd(OH)2 (10% w/w on carbon, 0.2 g) and the reaction vessel was pressurized to 40 psi with hydrogen for 30 minutes at room temperature. The mixture was filtered through a pad of Celite® and washed with EtOAc. The filtrate was concentrated in vacuo and the product was purified by prep. HPLC(C18 column, using acetonitrile and 0.1% AcOH/water solution gradient) provided the title compound (80 mg, 33%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.19 (s, 1H), 7.22 (s, 1H), 6.97 (s, 1H), 5.71 (dd, J=8.9, 2.3 Hz, 1H), 5.32 (dd, J=13.2, 2.7 Hz, 1H), 4.64 (dd, J=13.6, 8.9 Hz, 1H), 4.53 (t, J=4.8 Hz, 1H), 4.12 (t, J=6.0 Hz, 2H), 3.57 (q, J=5.5 Hz, 2H), 1.86 (t, J=6.2 Hz, 2H).