Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](Cl)=[N:7][CH:6]=1)[CH3:2].[CH2:13]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([N:30]2[CH2:35][CH2:34][NH:33][C@H:32]([CH3:36])[CH2:31]2)=[N:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:33]2[CH2:34][CH2:35][N:30]([C:23]3[C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:20]([CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[N:21][N:22]=3)[CH2:31][C@H:32]2[CH3:36])=[N:7][CH:6]=1)[CH3:2]
Reactant: C[C@@H]1CN(c2nnc(Cc3ccccc3)c3ccccc23)CCN1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Product: CCOC(=O)c1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)C[C@H]2C)nc1
Yield: 71.1 %

Procedure:
Following the above procedure, 6-chloronicotinic acid ethyl ester (100 mg, 0.54 mmol, 1.7 eq) and 1-benzyl-4-((R)-3-methyl-piperazin-1-yl)-phthalazine (100 mg, 0.31 mmol, 1.0 eq) afford the title compound as a white solid (103 mg, 71% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][Si](C(C)(C)C)(C)C)[N:13]=2)=[O:9])[CH:5]=[C:4]([C:27]2[O:28][C:29]([CH3:32])=[CH:30][CH:31]=2)[N:3]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C.C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][OH:19])[N:13]=2)=[O:9])[CH:5]=[C:4]([C:27]2[O:28][C:29]([CH3:32])=[CH:30][CH:31]=2)[N:3]=1
Reactant: Cc1ccc(-c2cc(C(=O)NCc3cccc(CO[Si](C)(C)C(C)(C)C)n3)nc(N)n2)o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(C(=O)NCc3cccc(CO)n3)nc(N)n2)o1
Yield: 116.1 %

Procedure:
A solution of 2-amino-6-(5-methyl-2-furyl)-N-(6-(tert-butyldimethylsilyloxymethyl)pyridin-2-ylmethyl)pyrimidine-4-carboxamide (614 mg, 1.36 mmol) in acetic acid (9 mL) water (3 mL) and THF (3 mL) was stirred at room temperature for 4 days, neutralised with saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic phase was dried (MgSO4), concentrated in vacuo, and the resulting solid triturated with MeOH and filtered to give the title compound (536 mg, 49%) as a cream solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.Br[CH2:12][CH2:13]Cl>[OH-].[Na+].[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2([C:8]([OH:10])=[O:9])[CH2:13][CH2:12]2)=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccncc1
Reactant: ClCCBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: O=C(O)C1(c2ccncc2)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a mixture of pyridin-4-yl-acetic acid (930 mg, 6.0 mmol) and 1-bromo-2-chloroethane (750 mg, 9.0 mmol) in 50% NaOH aq. solution (5 mL) is added benzyltriethylammonium chloride (680 mg, 3 mmol). The solution is heated to 60° C. and stirred at the temperature for 2 hours. After cooling down to rt, the aqueous layer is removed and the organic layer is neutralized with sat. NH4Cl aq. and extracted with Et2O. The combined organic phases are washed with H2O and dried over Na2SO4. Concentration under reduced pressure gives the title compound. The material is used in a next step without purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1([CH2:23]O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:20]1[CH2:21][CH2:22][CH:17]([CH2:23][O:15][C:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)=[O:16])[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: OCC1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)OCC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (66.94 mmol; 15.35 g) in dichloromethane (100 mL) was added cyclohexylmethanol (55.79 mmol; 6.37 g), dimethylaminopyridine (1.12 mmol; 0.14 g) and dicyclohexylcarbodiimide (66.94 mmol; 12.83 g) and the resulting mixture was stirred for 3 hours at room temperature. The resulting solution was evaporated and the residue was dissolved in ethyl acetate (200 mL). The resulting solution was washed with a 1N hydrochloric acid solution (2×50 mL) and brine (50 mL), and dried over magnesium sulfate. After filtration and evaporation, the residue was purified via flash column chromatography ((eluent gradient: 0 to 5% EtOAc in heptane) to yield piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-cyclohexylmethyl ester after evaporation. MS (ESI) m/z 326.29 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[O:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21].O>CC(C)=O>[OH:1][C:2]1[C:3]([C:9](=[O:11])[CH3:10])=[C:4]([O:8][CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1c(O)cccc1O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)COc1cccc(O)c1C(C)=O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a mixture of 2′,6′-dihydroxyacetophenone (6 g) and potassium carbonate (5.72 g) in acetone (20 mL) was added methyl bromoacetate (3.73 mL), and the mixture was stirred at room temperature for 5 days. To the reaction mixture was added water, and the precipitated crystals were collected by filtration. The crystals were washed with water and dried under reduced pressure to give the title compound (7.89 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:14]([C:15](=O)[NH:16][CH2:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)=O)[CH2:13][C:10]2([CH2:12][CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+:32]>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH:14]([C:15]2[NH:32][C:18]([C:20]3[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=3)=[CH:17][N:16]=2)[CH2:13][C:10]2([CH2:12][CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC2(CC2)CC1C(=O)NCC(=O)c1ccc(Br)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(Br)cc2)[nH]1
Temperature: 140 °C
Yield: 61.4 %

Procedure:
15 mL Xylenes was added to 6-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester (424 mg, 0.97 mmol) and ammonium acetate (20 eq., 1.5 g). The mixture was heated in microwave at 140° C. for 60 minutes. The mixture was diluted with EtOAc and washed with sat. NaHCO3 aqueous solution. The organic layer was concentrated down and purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexane) to give 6-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester (249 mg, yield 61%). LCMS-ESI−: calc'd for C20H24BrN3O2: 418.33; Found: 418. (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:6][CH2:5]2.[CH3:18][O:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[N:24][CH:25]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH:7]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:6][CH2:5]3)[CH:23]=[N:24][CH:25]=1
Reactant: CC(C)S(=O)(=O)NC1CCc2cc(O)ccc21
Reactant: COc1cncc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cncc(Oc2ccc3c(c2)CCC3NS(=O)(=O)C(C)C)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of N-(5-hydroxy-2,3-dihydro-1H-inden-1-yl)propane-2-sulfonamide (50.0 mg, 0.196 mmol), 5-methoxypyridin-3-ylboronic acid (90 mg, 0.587 mmol), Copper(II)acetate (35.6 mg, 0.196 mmol), triethylamine (0.136 mL, 0.979 mmol), and crushed 4 Å molecular sieves (150 mg) in Dichloromethane (2 mL) was stirred at rt for 3 days. After this time the reaction mixture was filtered and solvent evaporated in vacuo. Purification by flash chromatography (heptane:EtOAc 3:1) afforded the title compound as a white solid. (6.7 mg, 9.4%). MS (ESI): m/z [M−H]− 361.0
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1.CN([CH:26]=[O:27])C>C1COCC1>[Cl:16][C:17]1[C:22]([CH:26]=[O:27])=[N:21][CH:20]=[CH:19][N:18]=1
Reactant: Clc1cnccn1
Reactant: CN(C)C=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1nccnc1Cl
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A flame dried and cooled 100 mL round bottom flask was charged with 2,2,6,6-tetramethylpiperidine (2.5 mL, 14.96 mmol) and anhydrous THF (25 mL) under a nitrogen atmosphere. The contents were cooled to −78° C. and n-butyllithium (2.5 M in hexane, 5.7 mL, ˜14.28 mmol) was added dropwise over a 5 minute period. The reaction mixture was stirred at −78° C. for 5 minutes, bought to 0° C. and stirred at 0° C. for 25 minutes. The reaction mixture was recooled to −78° C. and 2-chloropyrazine (0.78 g, 1 mL, 6.8 mmol) was added over a 3 minute period. After 30 minutes at −78° C., anhydrous DMF (0.99 mL, 13.6 mmol) was added over 3 minutes and the contents stirred at −78° C. for a further 30 minutes. The reaction mixture was bought to 0° C., stirred at 0° C. for 15 minutes, recooled to −78° C. and quenched by the addition of acetic acid (4 mL) in THF (10 mL). The reaction mixture was stirred at room temperature for 10 minutes and partitioned between ethyl acetate (60 mL) and brine (30 mL). The ethyl acetate layer is separated, dried over sodium sulfate, concentrated under reduced pressure and purified by silica gel flash chromatography using dichloromethane and ethyl acetate (9.5:0.5, 400 mL) to yield the title compound a (950 mg). 1H-NMR of the compound was consistent with the desired structure.
Reaction SMILES: [CH3:1][N:2]([CH2:33][CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])[C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:6][CH:5]=1.C(=O)=O.CO.FC(F)(F)C1C=CC(C2N=CC(NC(C3C=CC(C(NCCC(O)=O)=O)=CC=3)CCC)=CN=2)=CC=1.C(O)(C(F)(F)F)=O.C(Cl)Cl.[OH-].[Na+]>O>[CH3:1][N:2]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:6][CH:5]=1
Reactant: CC(C)CC(Nc1ccc(C(=O)N(C)CCC(=O)OC(C)(C)C)cn1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: CCCC(Nc1cnc(-c2ccc(C(F)(F)F)cc2)nc1)c1ccc(C(=O)NCCC(=O)O)cc1
Agent: O=C=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CO
Product: CC(C)CC(Nc1ccc(C(=O)N(C)CCC(=O)O)cn1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 88.2 %

Procedure:
The title compound is obtained by a method analogous to the one described for example 1.23 except tert-butyl 3-(N-methyl-6-((3-methyl-1-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)butyl)amino)nicotinamido)propanoate used in the synthesis was resolved by chiral chromatography; Column: Chiralpak AD-H. Dimensions: 10 mm×250 cm. Mobile Phase: 65/35 CO2/methanol. Flow Rate: 10 mL/min. Modifier: none. Retention time: 4.23 min (peak 1), 6.81 min. (peak 2; >99% ee). Peak 2 (1.15 g, 2.02 mmol) was then deprotected under the TFA/DCM previously reported. Concentration of the reaction mixture under reduced pressure provide a crude orange gum. Water (150 mL) added to the gum and NaOH 1M aq. added slowly until reaching pH 11 to obtain a clear solution of the crude. Acidification to pH4 with 1N HCl followed by filtration of the solid formed (washed with plenty of water) provide 3-(N-methyl-6-((3-methyl-1-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)butyl)amino)nicotinamido)propanoic acid (915 mg, 88.2%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 0.91 (d, 3H) 0.95 (d, J=6.46 Hz, 3H) 1.49-1.59 (m, 1H) 1.61-1.71 (m, 1H) 1.71-1.82 (m, 1H) 2.52-2.55 (m, 2H) 2.92 (s, 3H) 3.53 (t, J=7.24 Hz, 2H) 5.09 (br. s., 1H) 6.56 (d, J=1.17 Hz, 1H) 7.44 (d, J=9.39 Hz, 1H) 7.50 (d, J=8.22 Hz, 2H) 7.54-7.65 (m, 1H) 7.67 (d, J=8.02 Hz, 2H) 7.75-7.82 (m, 2H) 7.83-7.89 (m, 2H) 8.00 (d, J=2.15 Hz, 1H) 12.27 (br. s., 1H); MS (M+1): 514.4.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[N:9]=[N:10][S:11][CH:12]=1)[C:5]([OH:7])=O.[NH2:13][CH:14]1[C:31](=[O:32])[N:16]2[C:17]([C:28]([OH:30])=[O:29])=[C:18]([CH2:21][S:22][C:23]3[S:24][CH:25]=[N:26][N:27]=3)[CH2:19][S:20][C@H:15]12>>[CH3:1][O:2][N:3]=[C:4]([C:8]1[N:9]=[N:10][S:11][CH:12]=1)[C:5]([NH:13][CH:14]1[C:31](=[O:32])[N:16]2[C:17]([C:28]([OH:30])=[O:29])=[C:18]([CH2:21][S:22][C:23]3[S:24][CH:25]=[N:26][N:27]=3)[CH2:19][S:20][C@H:15]12)=[O:7]
Reactant: CON=C(C(=O)O)c1csnn1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csnn1
Yield: 43.7 %

Procedure:
2-Methoxyimino-2-(1,2,3-thiadiazol-4-yl)-acetic acid (syn isomer) (0.6 g.) and 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (1.1 g.) were reacted according to similar manners to those of Examples 12 and 15 to give 7-[2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.7 g.), mp 90° to 98° C. (dec.).
Reaction SMILES: C(O[C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:23])[CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.CON(C)C(=O)C1C=CC([CH2:34][O:35][Si:36]([CH:43]([CH3:45])[CH3:44])([CH:40]([CH3:42])[CH3:41])[CH:37]([CH3:39])[CH3:38])=CC=1>>[N:20]1[CH:19]=[CH:18][C:17]([CH2:16][C:15]([C:12]2[CH:11]=[CH:10][C:9]([CH2:34][O:35][Si:36]([CH:37]([CH3:39])[CH3:38])([CH:43]([CH3:45])[CH3:44])[CH:40]([CH3:42])[CH3:41])=[CH:14][CH:13]=2)=[O:23])=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cc1
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccccc2)cc1
Product: CC(C)[Si](OCc1ccc(C(=O)Cc2ccncc2)cc1)(C(C)C)C(C)C

Procedure:
Following the procedure for the preparation of 1-(4-Benzyloxy-phenyl)-2-pyridin-4-yl-ethanone but substituting N-Methoxy-N-methyl-4-triisopropylsilanyloxymethyl-benzamide provided the title compound. MS: (M+H m/z=384.1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:22][C:23](=[O:28])[CH2:24][C:25]([OH:27])=[O:26])[CH:5]=[C:6]([CH3:21])[C:7]=1[O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]([CH3:20])[CH3:19].C[O-].[Mg+2:31].C[O-]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:22][C:23](=[O:28])[CH2:24][C:25]([O-:27])=[O:26])[CH:5]=[C:6]([CH3:21])[C:7]=1[O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]([CH3:19])[CH3:20].[Cl:1][C:2]1[CH:3]=[C:4]([NH:22][C:23](=[O:28])[CH2:24][C:25]([O-:27])=[O:26])[CH:5]=[C:6]([CH3:21])[C:7]=1[O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]([CH3:19])[CH3:20].[Mg+2:31]
Reactant: Cc1cc(NC(=O)CC(=O)O)cc(Cl)c1Oc1ccc2[nH]cc(C(C)C)c2c1
Agent: C[O-]
Agent: [Mg+2]
Product: Cc1cc(NC(=O)CC(=O)[O-])cc(Cl)c1Oc1ccc2[nH]cc(C(C)C)c2c1

Procedure:
This compound is obtained in a manner analogous to Example 6a starting from 3-({3-chloro-4-[(3-isopropyl-1H-indol-5-yl)oxy]-5-methylphenyl}amino)-3-oxo-propionic acid (Example 6) and magnesium methoxide.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][N:18]([C:22](Cl)=[O:23])[CH2:17][C:16]=3[CH:25]=2)=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.Cl.[C:36]([CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)#[N:37]>ClCCl>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][N:18]([C:22]([N:41]4[CH2:42][CH2:43][CH:38]([C:36]#[N:37])[CH2:39][CH2:40]4)=[O:23])[CH2:17][C:16]=3[CH:25]=2)=[CH:8][CH:7]=1
Reactant: N#CC1CCNCC1
Reactant: O=C(Cl)N1CCOc2ccc(-c3ccc(-c4ncc[nH]4)nc3)cc2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1CCN(C(=O)N2CCOc3ccc(-c4ccc(-c5ncc[nH]5)nc4)cc3C2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
Dichloromethane (2 mL) was added to 7-[6-(1H-imidazol-2-yl)pyridin-3-yl]-2,3-dihydro-1,4-benzoxazepin-4(5H)-carbonyl chloride was obtained in step 4 followed by diisopropylethylamine (0.12 mL, 0.65 mmol) and 4-cyanopiperidine hydrochloride (25 mg, 0.16 mmol). The mixture was stirred at room temperature for 30 min and then concentrated. Purification of the residue by preparative reverse phase HPLC (0.1% aqueous ammonium acetate-acetonitrile) provided the title compound (18 mg, 32% yield) as a colorless solid. 1H NMR (400 MHz, DMSO-d6): 12.84 (br. S, 1H), 8.86 (d, 1H), 8.11 (m, 2H), 7.71 (d, 1H), 7.61 (dd, 1H), 7.25 (br. s, 1H), 7.10 (br. s, 1H), 7.06 (d, 1H), 4.49 (s, 2H), 4.23 (m, 2H), 3.61 (m, 2H), 3.30 (m, 2H), 3.00 (m, 3H), 1.87 (m, 2H), 1.73 (m, 2H); MS (EI) for C24H24N6O2: 429 (MH+).
Reaction SMILES: [C:1]([NH:9][C@@H:10]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:26]([O:33][C:34](=[O:40])[C@@H:35]1[CH2:39][CH2:38][CH2:37][NH:36]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:26]([O:33][C:34](=[O:40])[C@@H:35]1[CH2:39][CH2:38][CH2:37][N:36]1[C:14](=[O:16])[CH2:13][CH2:12][C:11](=[O:17])[C@@H:10]([NH:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)CCC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of the free acid compound 4 (100 mg, 0.3055 mmol, 1.0 eq.) and L-proline benzyl ester hydrochloride (74 mg, 0.3055 mmol, 1.0 eq.) in dry CH2Cl2 (10 mL) was cooled at 0° C. 1-Hydroxybenzotriazole hydrate (HOBt) (42 mg, 0.3055 mmol, 1.0 eq.), N-ethyl-N′-(dimethylaminopropyl)-carbodiimide hydrochloride (EDC.HCl) (59 mg, 0.3055 mmol, 1.0 eq.) and iPr2NEt (0.10 mL, 0.6110 mmol, 2.0 eq.) were added and the resulting mixture stirred at 0° C. for 2 h. The cooling bath was removed and the reaction mixture then stirred for a further 48 h at room temperature. The reaction mixture was diluted with H2O (30 mL) and the extracted with EtOAc (3×30 mL). The combined organic extract were washed sequentially with saturated aqueous NaHCO3 (30 mL), brine (30 mL), and dried over anhydrous MgSO4. Evaporation of the solvent gave a crude residue, which was subjected to column chromatography on silica gel elution with 50% EtOAc-hexane afforded the desired compound (5S)-5-[(N-benzoyl)amino]-4-oxo-6-phenyl-hexanoyl-L-proline benzyl ester as a pale yellow viscous oil which foams (0.138 g, 88%); Rf 0.23 (50% EtOAc-hexane); IR (liquid film) ν 1726 (CO), 3200 (NH) cm−1; 1H NMR (300 MHz, CDCl3) δH 1.98 (2H, m, —CH2), 2.21 (2H, m, —CH2), 2.65 (2H, m, —CH2CO), 3.00 (1H, m, —CHαPh), 3.12 (1H, m, —CHβPh), 3.35 (2H, m, —CH2CO), 3.60 (2H, m, —CH2N), 4.52 (1H, m, —CHN), 5.03 (1H, m, —CH—), 5.14 (2H, dd, J=1.8 and 8.4 Hz, —OCH2Ph), 6.93 (1H, d, J=6.9 Hz, —NH—) and 7.15-7.77 (15H, m, Ar—H); 13C NMR (75 MHz, CDCl3) δC 22.8, 24.7, 28.3, 28.9, 29.2, 34.1, 34.6, 36.8, 46.5, 46.9, 58.9, 59.6, 66.7, 66.8, 126.8, 126.9, 127.0, 127.9, 128.3, 128.5, 128.7 (2C), 129.4, 131.6, 133.9, 135.7, 136.7, 166.9, 170.3, 171.9 and 207.4; HRMS m/z calcd for C31H32N2O5 (M+) 512.23436, found 512.23112.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[NH2:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:28])[C:18]=2[N:17]=[C:16]1[CH3:29]>>[O:6]=[S:5]1(=[O:7])[CH2:4][CH2:3][CH2:2][N:9]1[CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:28])[C:18]=2[N:17]=[C:16]1[CH3:29]
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCOCCN
Reactant: O=S(=O)(Cl)CCCCl
Product: Cc1nc2c(N)nc3ccccc3c2n1CCOCCN1CCCS1(=O)=O
Yield: 48.9 %

Procedure:
Using the general method of Example 5, chloropropylsulfonyl chloride (0.13 ml, 1.05 mmol) was reacted with 1-[2-(2-aminoethoxy)ethyl]-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (0.3 g, 1.05 mmol). Recrystallization from 2-propanol yielded 0.2 g of 1-{2-[2-(1,1-dioxidoisothiazolidin-2-yl)ethoxy]ethyl}-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine as an off-white powder, m.p. 186.0-187.0° C.
Reaction SMILES: O[C:2]1[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:2]1[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1nn(C)c(=O)c(C)c1O
Product: CCOC(=O)c1nn(C)c(=O)c(C)c1Cl
Temperature: 85 °C
Yield: 86 %

Procedure:
A mixture of ethyl 4-hydroxy-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxylate (1.85 g, 8.72 mmol) and POCl3 (9 mL) was heated for 16 hours at 85° C. POCl3 was removed under reduced pressure. Then the crude material was quenched with ice-water. The mixture was neutralized with saturated aqueous NaHCO3 (pH˜6 to 7) and extracted with EtOAc (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography (100% hexanes to 5 to 10 to 20% EtOAc in hexanes) to afford 1.72 g (86%) of the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].I[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[CH3:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:22][C:21]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N:10]1[CH2:9][CH2:8][C:7]2[C:12](=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:11]1=[O:14]
Reactant: Cc1ccncc1I
Reactant: O=C1NCCc2ccc([N+](=O)[O-])cc21
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2ccc([N+](=O)[O-])cc2C1=O
Yield: 16.9 %

Procedure:
Using analogous reaction conditions as described in Example 1, 7-nitro-3,4-dihydro-2H-isoquinolin-1-one (I-24a: 600 mg, 3.125 mmol) was reacted with 3-iodo-4-methyl-pyridine (684.3 mg, 3.125 mmol), 1,4-dioxane (10 mL), copper iodide (59.5 mg, 0.3125 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (147.5 mL, 0.9375 mmol) and potassium phosphate (1.65 g, 7.8125 mmol) to afford the crude product. Purification by column chromatography on silica gel (50% ethylacetate in hexane) afforded 150 mg of the product (17% yield).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][NH:9][C:10]1[CH:15]=[C:14]([CH:16]([OH:39])[C:17]2[C:22]([NH:23][S:24]([C:27]3[CH:32]=[CH:31][C:30](C)=[C:29]([C:34]([F:37])([F:36])[F:35])[CH:28]=3)(=[O:26])=[O:25])=[CH:21][C:20]([Cl:38])=[CH:19][N:18]=2)[CH:13]=[CH:12][N:11]=1)(C)(C)C.O1CCOC[CH2:43]1>O=[Mn]=O>[Cl:38][C:20]1[CH:21]=[C:22]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:34]([F:37])([F:36])[F:35])[C:28]=2[CH3:43])(=[O:26])=[O:25])[C:17]([C:16]([C:14]2[CH:13]=[CH:12][N:11]=[C:10]([NH:9][CH2:8][CH2:7][OH:6])[CH:15]=2)=[O:39])=[N:18][CH:19]=1
Reactant: C1COCCO1
Reactant: Cc1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(O)c2ccnc(NCCO[Si](C)(C)C(C)(C)C)c2)cc1C(F)(F)F
Agent: O=[Mn]=O
Product: Cc1c(C(F)(F)F)cccc1S(=O)(=O)Nc1cc(Cl)cnc1C(=O)c1ccnc(NCCO)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To the dioxane (1 mL) solution of N-[2-({2-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-pyridin-4-yl}-hydroxy-methyl)-5-chloro-pyridin-3-yl]-4-methyl-3-trifluoromethyl-benzenesulfonamide from step 1, was added MnO2 (440 mg, 5 mmol). The mixture was stirred at 80° C. for 1 hour, filtered, concentrated. The deprotection was performed in 4 M HCl in dioxane (4 mL) and water (1 mL) for 1 hour at RT. The solvent was evaporated and the residue was purified with HPLC to give N-{5-chloro-2-[2-(2-hydroxy-ethylamino)-pyridine-4-carbonyl]-pyridin-3-yl-}-methyl-3-trifluoromethyl-benzenesulfonamide: 1H NMR (400 MHz, CDCl3) δ 8.3 (s, 1 H), 8.15 (d, 2H), 8.05 (s, 1 H), 7.9 (d, 1 H), 7.4 (d, 1 H), 6.7 (m, 2H), 3.8 (m, 2H), 3.5 (m, 2 H), 2.5 (s, 3H); MS m/z: 515 (M+H)+.