Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[CH3:32][C:33]1[S:34][C:35]([S:39](Cl)(=[O:41])=[O:40])=[C:36]([CH3:38])[N:37]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:39]([C:35]1[S:34][C:33]([CH3:32])=[N:37][C:36]=1[CH3:38])(=[O:41])=[O:40]
Reactant: Cc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nc(C)c(S(=O)(=O)Nc2ccc(F)c(Nc3ncccc3-c3ncnc4c3ncn4C3CCCCO3)c2F)s1
Temperature: 50 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 2,4-dimethylthiazole-5-sulfonyl chloride (12 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 25 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-2,4-dimethylthiazole-5-sulfonamide (percentage yield: 87%), was obtained.
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:15]([OH:17])=O)[N:12]([CH3:14])[CH:13]=2)=[CH:5][CH:4]=1.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH3:34][NH:35][O:36][CH3:37]>C(Cl)Cl>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([C:15]([N:35]([CH3:34])[O:36][CH3:37])=[O:17])[N:12]([CH3:14])[CH:13]=2)=[CH:7][CH:8]=1
Reactant: CNOC
Reactant: Cn1cc(-c2ccc(Br)cc2)nc1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: [Na]
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)c1nc(-c2ccc(Br)cc2)cn1C
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 32 %

Procedure:
To a solution of ethyl 4-(4-bromophenyl)-1-methyl-1H-imidazole-2-carboxylate (1.66 g, 5.37 mmol) in MeOH (38 mL) was added 1N NaOH solution (19 mL). The reaction turned cloudy white and was stirred at room temperature for 30 minutes. The reaction mixture was concentrated in vacuo and pumped under high vacuum overnight to give the sodium salt of 4-(4-bromophenyl)-1-methyl-1H-imidazole-2-carboxylic acid as a white solid. The sodium salt of 4-(4-bromophenyl)-1-methyl-1H-imidazole-2-carboxylic acid was dissolved in anhydrous CH2Cl2 (40 mL) under nitrogen at −15° C. (ice/methanol bath) and N-methylmorpholine (1.1 equiv, 5.91 mmol) was added followed by isobutyl chloroformate (1.1 equiv, 5.91 mmol). The reaction mixture was stirred at −15° C. for 15 minutes and then N,O-dimethylhydroxylamine hydrochloride (1.0 equiv, 5.37 mmol) was added. The reaction was allowed to warm to room temperature and was stirred for 17 hours. The reaction was quenched with H2O (10 mL). The product was extracted using EtOAc (3×30 mL) and the combined organic layers were washed with brine (20 mL), dried over MgSO4, and concentrated in vacuo. Purification by silica gel chromatography (Analogix IF280, 20-100% EtOAc/hexanes) afforded the title compound as a tan solid (32%). ESMS [M+H]+: 324.2.
Reaction SMILES: C([Si](Cl)(CC)CC)C.Br[C:10]([Br:17])([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].[C:18]1(=[O:23])[CH2:22][CH2:21][CH:20]=[CH:19]1.Cl>C(#N)C.[Zn].CCOC(C)=O>[Br:17][C:10]([F:16])([CH:20]1[CH2:21][CH2:22][C:18](=[O:23])[CH2:19]1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(F)(Br)Br
Reactant: O=C1C=CCC1
Agent: CC[Si](Cl)(CC)CC
Agent: Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)C(F)(Br)C1CCC(=O)C1
Reaction time: 0.08 h
Yield: 87.6 %

Procedure:
Add 8.45 mL (50.4 mmol) of triethylsilyl chloride to a suspension of 2.99 g of activated Zn (45.8 mmol) in anhydrous acetonitrile (100 mL) at −20° C. and stir the mixture for 5 minutes. Add 8.0 mL (57.3 mmol) of ethyl 2,2-dibromo-2-fluoracetate and stir the mixture for 90 minutes at −20° C. Add 1.86 mL (22.9 mmol) of 2-cyclopenten-1-one, and stir the reaction mixture overnight, allowing the temperature to rise slowly to room temperature. Add HCl 1N (125 mL) and EtOAc (100 mL). Wash the organic layer with saturated NaHCO3 (2×150 mL), water (2×150 mL) and brine (2×150 mL), dry over anhydrous MgSO4, filter and concentrate under reduced pressure. Purify the residue by column chromatography using EtOAc/hexane (1:8) as eluent to give the title compound (5.36 g, 88% overall yield) as a colorless oil as a mixture of diastereoisomers.
Reaction SMILES: [CH2:1]([N:5]([CH2:33][CH2:34][CH2:35][CH3:36])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[NH:11][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:44][CH2:45][Cl:46]>CC#N.O>[Cl:46][CH2:45][CH2:44][N:11]1[CH:12]=[C:8]([C:6](=[O:7])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:33][CH2:34][CH2:35][CH3:36])[N:9]=[C:10]1[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24]
Reactant: CCCCN(CCCC)C(=O)c1c[nH]c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CCCCN(CCCC)C(=O)c1cn(CCCl)c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Temperature: 50 °C
Yield: 54.8 %

Procedure:
To a solution of 3-benzyl 1-methyl 4-(4-(dibutylcarbamoyl)-1H-imidazol-2-yl)isophthalate (275 mg, 0.56 mmol) in dry MeCN (8.0 mL) was added cesium carbonate (182 mg, 0.56 mmol) and 1-bromo-2-chloroethane (80 mg, 0.56 mmol). The reaction mixture was heated at 50° C. for 10 h, diluted with water and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the crude product. The crude material was purified by flash chromatography (gradient from 0% to 2% MeOH/CH2Cl2) to provide the title compound (170 mg, 54%). 1H NMR (DMSO-d6) δ 8.46 (d, J=1.6 Hz, 1H), 8.26 (dd, J=8.0, 1.6 Hz, 1H), 7.85 (s, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.36-7.33 (m, 3H), 7.27-7.25 (m, 2H), 5.16 (s, 2H), 4.08-4.03 (m, 4H), 3.93 (s, 1.5H), 3.77-3.73 (m, 3.5H), 3.50-3.40 (m, 2H), 1.50-1.45 (m, 4H), 1.35-1.10 (m, 4H), 0.92-0.75 (m, 6H); MS(ESI+) m/z 555.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([OH:25])=O)=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([Br:22])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1[N:33]1[CH2:38][C@H:37]([CH3:39])[C@@H:36]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[C@H:35]([NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[CH2:34]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:22][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:13]([C:23]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][C:32]=3[N:33]3[CH2:38][C@H:37]([CH3:39])[C@@H:36]([O:40][Si:41]([C:44]([CH3:45])([CH3:46])[CH3:47])([CH3:43])[CH3:42])[C@H:35]([NH:48][C:49]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:55])[CH2:34]3)=[O:25])=[N:14]2)=[CH:19][CH:18]=1
Reactant: O=C(Nc1cc2ccc(Br)cc2nc1C(=O)O)OCc1ccccc1
Reactant: C[C@H]1CN(c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(Br)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.4 %

Procedure:
A mixture of 3-{[(benzyloxy)carbonyl]amino}-7-bromoquinoline-2-carboxylic acid (0.50 g, 1.2 mmol), tert-butyl ((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate (0.54 g, 1.2 mmol), and HATU (1.2 g, 3.1 mmol) in DMF (4.9 mL) and DIPEA (0.65 mL, 3.7 mmol) was stirred at room temperature for 2 h, then quenched with 50 mL of EtOAc and 30 mL of 1 M NaOH. The resulting layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were concentrated under reduced pressure. The residue was purified by flash chromatography on a 40 g silica gel column, eluting with 0-100% EtOAc in hexanes, to give the sub-title compound (0.565 g, 55%). LCMS calc. for C40H52BrN6O6Si [M+H]+: m/z=919.3. found: 819.4.
Reaction SMILES: I[C:2]1[C:3]([CH3:12])=[N:4][C:5]2[N:6]([N:9]=[CH:10][N:11]=2)[C:7]=1[NH2:8].[C:13]([Si:15]([CH3:18])([CH3:17])[CH3:16])#[CH:14].C(N(CC)CC)C>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:12][C:3]1[C:2]([C:14]#[C:13][Si:15]([CH3:18])([CH3:17])[CH3:16])=[C:7]([NH2:8])[N:6]2[N:9]=[CH:10][N:11]=[C:5]2[N:4]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1nc2ncnn2c(N)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nc2ncnn2c(N)c1C#C[Si](C)(C)C
Yield: 50.1 %

Procedure:
A mixture of Example 4A (275 mg, 1.0 mmol), ethynyltrimethylsilane (283 μL, 2.6 mmol), bis(triphenylphosphine)palladium(II) dichloride (35 mg, 0.05 mmol), CuI (10 mg, 0.05 mmol), and triethylamine (279 μL, 2 mmol) in acetonitrile (4 mL) was heated at 90° C. under an atmosphere of nitrogen for 1 h. The resulting-mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4), filtered, and concentrated in vacuuo. The residue was purified by flash chromatograph on silica gel (eluting with ethyl acetate) to provide the title compound as a pale yellow solid (123 mg, 50% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[CH:5]([OH:9])[C:6]([OH:8])=O.[NH2:14][CH2:15][CH:16]1[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=2)[CH2:17]1>>[CH3:27][O:26][C:20]1[CH:19]=[C:18]2[C:23]([CH2:24][CH2:25][CH:16]([CH2:15][NH:14][C:6](=[O:8])[CH:5]([C:4]3[CH:10]=[CH:11][C:12]([Cl:13])=[C:2]([Cl:1])[CH:3]=3)[OH:9])[CH2:17]2)=[CH:22][CH:21]=1
Reactant: O=C(O)C(O)c1ccc(Cl)c(Cl)c1
Reactant: COc1ccc2c(c1)CC(CN)CC2
Product: COc1ccc2c(c1)CC(CNC(=O)C(O)c1ccc(Cl)c(Cl)c1)CC2
Yield: 81.5 %

Procedure:
By following the procedure of Example 1(i) but starting from 3,4-dichloromandelic acid (3.1 g, 0.014 mol) and 2-aminomethyl-7-methoxy-1,2,3,4-tetrahydronaphthalene (2.67 g, 0.014 mol), N-[(7-methoxy-1,2,3,4-tetrahydronaphth-2-yl) methyl]-3,4-dichloromandelamide (4.5 g) is obtained as an oily product characterised by the following IR absorption maxima 3380 (b): O--H, CON--H; and 1641: NHC=0 cm-1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:18]([OH:20])=O)[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:33][C:34]1[NH:38][N:37]=[N:36][N:35]=1>>[NH:35]1[C:34]([NH:33][C:18]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([C:8]3[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:12][CH:13]=3)[N:5]=2)=[O:20])=[N:38][N:37]=[N:36]1
Reactant: CC(=O)Nc1ccc(-c2cc(C)cc(C(=O)O)n2)cc1
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(=O)Nc1ccc(-c2cc(C)cc(C(=O)Nc3nnn[nH]3)n2)cc1
Yield: 72.1 %

Procedure:
In the same manner as described in Example 1-(1), 4-methyl-6-(4-acetylaminophenyl)-2-pyridinecarboxylic acid (1.0 g), carbonyldiimidazole (0.72 g) and 5-aminotetrazole (0.38 g) are reacted to give N-(5-tetrazolyl)-4-methyl-6-(4-acetylaminophenyl)-2-pyridinecarboxamide (0.9 g). M.P. 309°-310° C. (decomp.) (wetted at about 290° C.) (recrystallized from dimethylformamide-ethanol)
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[N:4]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.CCN(C(C)C)C(C)C.[C:51](Cl)(=[O:53])[CH3:52]>C1COCC1>[C:17]1([C@H:15]([NH:14][C:12](=[O:13])[NH:11][C:9]2[N:8]=[CH:7][C:6]3[C:2]([NH:1][C:51](=[O:53])[CH3:52])=[N:3][N:4]([C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:5]=3[CH:10]=2)[CH3:16])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)Cl
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(N)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of (R)-1-(3-amino-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (900 mg, 1.671 mmol) and DIEA (0.584 mL, 3.34 mmol) in THF (16 mL) at 0° C. was treated drop-wise with a solution of acetyl chloride (0.131 mL, 1.838 mmol) in THF (0.5 mL). The reaction was stirred at 0° C. for 10 min, then allowed to warm to room temperature and stirred for 1 h. The solvent was evaporated in vacuo and purified by flash chromatography (0-30% EtOAc/DCM) to afford (R)—N-(6-(3-(1-phenylethyl)ureido)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)acetamide. MS ESI calc'd. For C36H32N6O2 [M+1]+ 581. found 581.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[SH:7].Cl.Cl.Cl[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20]2[N:24]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:23]3[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=3[N:21]=2)[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)C>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:24]2[C:23]3[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=3[N:21]=[C:20]2[NH:19][CH:16]2[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][S:7][C:2]3[N:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:18][CH2:17]2)=[CH:27][CH:28]=1
Reactant: Sc1ncccn1
Reactant: Fc1ccc(Cn2c(NC3CCN(CCCl)CC3)nc3ccccc32)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccc(Cn2c(NC3CCN(CCSc4ncccn4)CC3)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 35.8 %

Procedure:
A mixture of 1.12 parts of 2-pyrimidinethiol, 4.6 parts of N-[1-(2-chloroethyl)-4-piperidinyl]-1-(4-fluorophenylmethyl)-1H-benzimidazol-2-amine dihydrochloride, 4 parts of potassium carbonate and 80 parts of 2-propanone was stirred for 3 days at room temperature. The reaction mixture was filtered and the filtrate was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanone and 2,2'oxybispropane, yielding 1.7 parts (35.8%) of 1-[(4-fluorophenyl)methyl]-N-[1-[2-(2-pyrimidinylthio)ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 146.1°-147.7° C. (compound 91).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:16](C(O)=O)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[Br:25]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:25][C:16]1[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)=[N:9][N:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=12
Reactant: Cc1cccc(-c2nn3ccccc3c2C(=O)O)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(-c2nn3ccccc3c2Br)n1
Yield: 87.7 %

Procedure:
A solution of 2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine-3-carboxylic acid (0.92 g, 3.6 mmol), sodium bicarbonate (1.04 g, 12.4 mmol), and N-bromosuccinimide (0.71 g, 4.0 mmol) in DMF (25 mL) is stirred for 2 hours at room temperature. The reaction is then diluted with water (50 mL) and extracted with EtOAc (3×15 mL). The organic layer is washed with brine and dried over sodium sulfate. The solvent is removed in vacuo to afford 0.91 g (87%) of desired product as a dark green solid. UV (95% EtOH) λmax 282 nm (ε 12089), 233 nm (ε 21813). TOF MS ES+ exact mass calculated for C13H10BrN3 (p+1): m/z=288.0136. Found: 287.0058. Anal. Calcd for C13H10BrN3: C, 54.19; H, 3.50; N, 14.58. Found: C, 54.10; H, 3.60; N, 14.48.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[N:15][CH:14]=[CH:13][C:5]=1[C:6](Cl)=[N:7]2.[CH:17]([Mg]Br)([CH3:19])[CH3:18]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Cl-].[Ni+2]>[Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[N:15][CH:14]=[CH:13][C:5]=1[C:6]([CH:17]([CH3:19])[CH3:18])=[N:7]2
Reactant: Clc1nc2ccnc(Cl)c2c2cnccc12
Reactant: CC(C)[Mg]Br
Agent: [Ni+2]
Agent: [Cl-]
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1nc2ccnc(Cl)c2c2cnccc12
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,6-dichloropyrido[4,3-c]-1,6-naphthyridine (50 mg, 0.200 mmol) and 1,2-bis(diphenylphosphino)ethanenickel(II) chloride (1.056 mg, 1.999 μmol) in THF (0.4 mL). The mixture was cooled to −10° C. in a methanol-ice bath, and isopropylmagnesium bromide (220 μl 0.220 mmol, 1 M in THF) was added dropwise. The reaction mixture was stirred at −10° C. for 30 min. The mixture was then allowed to warm to room temperature and then stirred for 30 min. The reaction mixture was quenched with aqueous ammonium chloride (saturated), and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to afford 1-chloro-6-isopropylpyrido[4,3-c]-1,6-naphthyridine as a red solid. LRMS (APCI) calc'd for (C14H13ClN3) [M+H]+, 258.1; found 258.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]#[N:16])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:19][OH:20].C(N(CC)CC)C>C(O)(C)C>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15](=[NH:16])[NH:19][OH:20])[CH2:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CCN(C#N)CC1
Reactant: NO
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC1CCN(C(=N)NO)CC1

Procedure:
(1-Cyano-piperidin-4-ylmethyl)-carbamic acid tert-butyl ester (2 g, 8.36 mmol), hydroxylamine hydrochloride (3.48 g, 50.14 mmol) and triethylamine (5.92 g, 58.5 mmol) were stirred in 30 ml of isopropanol at room temperature for 4 hours. The mixture was evaporated. After addition of water (pH4) and ethyl acetate, the organic layer was separated and evaporated.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12]CC)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].O.[OH-].[Li+:17]>O1CCCC1>[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([O-:12])=[O:11])[CH2:8][CH2:9]1)([CH3:3])[CH3:2].[Li+:17]
Reactant: CCOC(=O)C1CCN(C(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N1CCC(C(=O)[O-])CC1
Reaction time: 8 h
Yield: 100 %

Procedure:
Ethyl 1-isopropylpiperidine-4-carboxylate (Farmaco., 1993, Vol. 48, p. 1439) (3.43 g) was dissolved in tetrahydrofuran (60 ml), and water (15 ml) and lithium hydroxide (421 mg) were added at room temperature to stir the mixture overnight. The reaction mixture was concentrated under reduced pressure to obtain the title compound (3.05 g) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:41])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([CH3:40])[CH:35]=2)[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:16]([N:14]([CH3:15])[C:12]1[C:11]([C:19]([F:21])([F:20])[F:22])=[CH:10][C:9]2[NH:23][C:24](=[O:41])[CH2:25][C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]4[CH:39]=[CH:38][N:37]=[C:36]([CH3:40])[CH:35]=4)[CH:29]=3)=[N:7][C:8]=2[CH:13]=1)([CH3:17])[CH3:18]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C(C)C)cc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)C(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (5-(isopropyl-methyl-amino)-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M276) (0.44 g, 0.75 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (252 mg, 72%).
Reaction SMILES: C1(C)C=CC=CC=1.C([N:10](CC)CC)C.[F:15][CH:16]1[CH2:23][C@@:22]2(C(O)=O)[C@H:18]([C:19](=[O:35])[N:20]([C@@H:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH3:28])[CH2:21]2)[CH2:17]1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C(OCC)(=O)C>[NH2:10][C@:22]12[CH2:23][CH:16]([F:15])[CH2:17][C@@H:18]1[C:19](=[O:35])[N:20]([C@@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:28])[CH2:21]2
Reactant: CCN(CC)CC
Reactant: C[C@H](c1ccccc1)N1C[C@@]2(C(=O)O)CC(F)C[C@H]2C1=O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@H](c1ccccc1)N1C[C@@]2(N)CC(F)C[C@@H]2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
Toluene (10 mL) and triethylamine (565 μL, 4.05 mmol) were added to (1R,5R)-7-fluoro-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octan-1-ylcarboxylic acid (590 mg, 2.03 mmol). Then, diphenylphosphoryl azide (567 μL) was added, and the mixture was stirred at room temperature for 30 minutes. Thereafter, the reaction solution was heated to reflux for one hour and blended with a mixture of ethyl acetate-saturated sodium bicarbonate water. The organic layer was dried over magnesium sulfate and filtered. Then, the solvent was evaporated under reduced pressure. The residue was dissolved in dioxane (10 mL). 6N hydrochloric acid (10 mL) was added, and the mixture was heated with stirring at 70° C. for two hours. After washing with ether, the aqueous layer was made basic with a 10 M sodium hydroxide solution, followed by extraction with toluene five times. The extract was dried over magnesium sulfate and filtered, and then the solvent was evaporated under reduced pressure to give 476 mg (90%) of the title compound as a colorless oil. The product was used for the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10]3[CH2:13][S:14][CH2:15][C:9]=3[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1.ClC1C=CC2N(C)C(=O)C3CSCC=3NC=2C=1.N1C=CC=CC=1.ClN1C(=O)CCC1=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10]3=[CH:13][S:14][CH:15]=[C:9]3[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1
Reactant: CN1C2=C(CSC2)C(=O)Nc2cc(Cl)ccc21
Agent: CN1C(=O)C2=C(CSC2)Nc2cc(Cl)ccc21
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: c1ccncc1
Product: CN1c2ccc(Cl)cc2NC(=O)c2cscc21

Procedure:
To a suspension of 0.53g. of the mixture of 7 -chloro-4-methyl-1,3,4,9-tetrahydro-10H-thieno[3,4-b] [1,5] benzodiazepin-10-one and 6-chloro-9-methyl-1,3,4,9-tetrahydro-10H-thieno[3,4-b] [1,5] benzodiazepin-10-one (prepared as described in Example 17) in 5 ml. of dry pyridine is added, in portions, 0.27 g. of N-chlorosuccinimide. The resulting solution is heated on a steam bath for 15-20 minutes, cooled, diluted with water and filtered. The solid is recrystallized from methanol to give a yellow solid which consists of the single isomer of the title, m.p. 244°-246°C. (dec.).