Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:11]([CH3:13])[CH3:12])[CH2:6]2.[CH3:14][C:15]1[CH:16]=[C:17]([Mg]Br)[CH:18]=[C:19]([CH3:21])[CH:20]=1>CCOCC>[CH3:14][C:15]1[CH:16]=[C:17]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[C:5]([CH:11]([CH3:13])[CH3:12])[CH2:6]3)[CH:18]=[C:19]([CH3:21])[CH:20]=1
Reactant: CC(C)C1=Cc2c(Cl)cccc2C1
Reactant: Cc1cc(C)cc([Mg]Br)c1
Solvent: CCOCC
Product: Cc1cc(C)cc(-c2cccc3c2C=C(C(C)C)C3)c1

Procedure:
4-chloro-2-isopropylindene (10 g, 54 mmol) and NiCl2(PPh3) (1.8 g, 2.8 mmol) were dissolved in 150 mL of Et2O. 3,5-Dimethylphenylmagnesium bromide (54 mmol) as a Et2O solution was added under vigorous stirring and the reaction was stirred overnight at room temperature. After overnight stirring, the reaction was slowly quenched with H2O to neutralize unreacted Grignard. The solution was subsequently treated with 100 mL of 10% HCl(aq), and neutralized with saturated sodium bicarbonate aqueous solution. The organic layer was dried with magnesium sulfate and the solvent was removed by rotary evaporation. The remaining residue was loaded onto a silica gel column and eluted with hexane. Yield was 5.5 g (39%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([OH:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([N:27]1[CH2:32][CH2:31][CH:30](O)[CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([O:19][CH:30]2[CH2:31][CH2:32][N:27]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:28][CH2:29]2)[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Product: COC(=O)c1ccc(OCc2ccccc2)cc1OC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Methyl 4-benzyloxy-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoate was prepared from methyl 4-benzyloxy-2-hydroxybenzoate and 1-Boc-4-hydroxypiperidine using a procedure similar to that described in Example 21-C. The crude material, in dichloromethane, was filtered and purified by chromatography over silica gel using a preparative high pressure chromatography apparatus, eluting with a gradient of 9:1 to 4:1 to 3:1 hexane:ethyl acetate to give 12.8 g of a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[C:4]([CH3:17])=[N:3]1.[H][H]>[Ni].CO>[NH2:14][C:11]1[CH:10]=[CH:9][C:8]([N:5]2[C:4]([CH3:17])=[N:3][N:2]([CH3:1])[C:6]2=[O:7])=[CH:13][CH:12]=1
Reactant: [H][H]
Reactant: Cc1nn(C)c(=O)n1-c1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CO
Product: Cc1nn(C)c(=O)n1-c1ccc(N)cc1
Yield: 95 %

Procedure:
A mixture of 9 parts of 2,4-dihydro-2,5-dimethyl-4-(4-nitrophenyl)-3H-1,2,4-triazol-3-one and 200 parts of methanol is hydrogenated at normal pressure and at room temperature with 3 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is triturated in 2,2'-oxybispropane. The product is filtered off and dried, yielding 7.5 parts (95%) of 4-(4-aminophenyl)-2,4-dihydro-2,5-dimethyl-3H-1,2,4-triazol-3-one; mp. 160° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]1[C:13]([C:34]#[N:35])=[C:14]([C:28]2[CH:33]=[CH:32][N:31]=[N:30][CH:29]=2)[S:15][C:16]=1[C:17]1[N:21]=[CH:20][N:19](C2CCCCO2)[N:18]=1.CO.Cl.O>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]1[C:13]([C:34]#[N:35])=[C:14]([C:28]2[CH:33]=[CH:32][N:31]=[N:30][CH:29]=2)[S:15][C:16]=1[C:17]1[NH:21][CH:20]=[N:19][N:18]=1
Reactant: N#Cc1c(-c2ccnnc2)sc(-c2ncn(C3CCCCO3)n2)c1Cc1ccc2ccccc2c1
Agent: Cl
Solvent: CO
Solvent: O
Product: N#Cc1c(-c2ccnnc2)sc(-c2nnc[nH]2)c1Cc1ccc2ccccc2c1
Temperature: 50 °C
Yield: 60.3 %

Procedure:
4-(2-Naphthylmethyl)-2-pyridazin-4-yl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]thiophene-3-carbonitrile (0.03178 g, 0.06641 mmol) was dissolved in methanol (3.00 mL, 74.0 mmol). HCl in water (12 M, 3.00 mL, 36.0 mmol) was added. The solution was heated at 50° C. for 60 min then cooled to rt. The mixture was evaporated in vacuo to remove the most of methanol. To the residue was added 30 mL saturated sodium bicarbonate solution, extracted with 40 mL ethyl acetate twice. The combined EtOAc layers were washed with 20 mL water then concentrated in vacuo. The resulting crystalline solid was collected by filtration to afford a pure product (0.0158 g, yield 60.3%). LCMS: (AA) ES+ 395. 1H NMR (300 MHz, d4-methanol) δ: 9.60 (s, 1H), 9.27-9.29 (m, 1H), 8.47 (s, 1H), 8.09-8.11 (m, 1H), 7.69-7.77 (m, 4H), 7.37-7.47 (m, 3H), 3.30 (s, 2H).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:30])([CH3:29])[O:6][CH2:7][C@@H:8]([O:10][C:11]1[CH:12]=[C:13]([CH:25]=[C:26]([OH:28])[CH:27]=1)[C:14]([NH:16][C:17]1[CH:21]=[CH:20][N:19]([CH:22]([CH3:24])[CH3:23])[N:18]=1)=[O:15])[CH3:9])([CH3:4])[CH3:3].[N:31]1([C:35]([C:37]2[CH:38]=[C:39]([Cl:44])[C:40](Cl)=[N:41][CH:42]=2)=[O:36])[CH2:34][CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:31]1([C:35]([C:37]2[CH:38]=[C:39]([Cl:44])[C:40]([O:28][C:26]3[CH:25]=[C:13]([CH:12]=[C:11]([O:10][C@@H:8]([CH3:9])[CH2:7][O:6][Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:30])[CH3:29])[CH:27]=3)[C:14]([NH:16][C:17]3[CH:21]=[CH:20][N:19]([CH:22]([CH3:24])[CH3:23])[N:18]=3)=[O:15])=[N:41][CH:42]=2)=[O:36])[CH2:34][CH2:33][CH2:32]1
Reactant: CC(C)n1ccc(NC(=O)c2cc(O)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)n1
Reactant: O=C(c1cnc(Cl)c(Cl)c1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)n1ccc(NC(=O)c2cc(Oc3ncc(C(=O)N4CCC4)cc3Cl)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)n1
Temperature: 160 °C
Yield: 94.2 %

Procedure:
A solution of 3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-hydroxy-N-[1-(1-methylethyl)-1H-pyrazol-3-yl]benzamide (103 mg, 0.24 mmol) and 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (66 mg, 0.29 mmol) in acetonitrile (2 mL), containing potassium carbonate (66 mg, 0.48 mmol), was heated in a microwave reactor at 160° C. for 6 hours. The reaction mixture was filtered and the filtrate evaporated to dryness under reduced pressure and purified by chromatography on silica, eluting with 50-100% ethyl acetate in hexane, to give the required product as a white foam (142 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[CH3:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=1B(O)O>COCCOC>[CH3:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11]
Reactant: Cc1ccc(C)c(B(O)O)c1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(C)c(-c2ccccc2CCC(=O)N(NC(=O)c2ccccc2)C(C)C)c1
Yield: 26 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (50 mg, 0.13 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 2,5-dimethyl-phenylboronic acid (29 mg, 0.19 mmol) and Pd[PPh3]4 (15 mg, 0.013 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product as a solid (14 mg, 26%). LC-MS m/e 415.36 (M+H+)
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[S:9][CH2:10][CH2:11][C:12]([OH:14])=O.C(N=C=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1.CN1CCOCC1>O>[O:14]=[C:12]1[CH2:11][CH2:10][S:9][C@@H:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C@H:3]2[NH:2]1
Reactant: N[C@@H]1CCCC[C@H]1SCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN1CCOCC1
Product: O=C1CCS[C@@H]2CCCC[C@H]2N1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To (±)-trans-2-amino-1-[2-(carboxy)ethylthio]-cyclohexane hydrochloride (0.240 g, 1 mmol) dissolved in 2 mL of dimethylformaamide at 0° C. was successively added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.356 g, 1.2 mmol), 1-hydroxy-7-azabenzotriazole (0.164 g, 1.2 mmol) and then finally N-methylmorpholine (0.252 g, 2.5 mmol). After stirring for an additional 5 mins., the reaction mixture was warmed to room temperature and stirred overnight at the same temperature. The following day the reaction mixture was diluted with water and extracted with methylene chloride.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:39][CH2:40][C@@H:41]([OH:53])[CH2:42][N:43]1[CH2:52][CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1>C(Cl)Cl>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[CH2:10][CH2:11][C:12]([NH:39][CH2:40][C@@H:41]([OH:53])[CH2:42][N:43]1[CH2:52][CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1)=[O:14]
Reactant: O=C(O)CCc1nc2ccccc2[nH]1
Reactant: NC[C@@H](O)CN1CCc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: O=C(CCc1nc2ccccc2[nH]1)NC[C@@H](O)CN1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.9 %

Procedure:
To a solution of 3-(1H-benzo[d]imidazol-2-yl)propanoic acid (300 mg, 1.579 mmol) in DCM (10 mL) was added HATU (722 mg, 1.895 mmol) and TEA (478 mg, 4.737 mmol). After stirring for 30 min at room temperature, (R)-1-amino-3-(3,4-dihydro isoquinolin-2(1H)-yl)propan-2-ol (488 mg, 2.368 mmol) was added and the resulting mixture then stirred at room temperature for 16 h. Once TLC analysis showed the reaction to be complete, the solvent was evaporated at reduced pressure and the residue purified by preparative HPLC to give the title compound (184.6 mg, 30.9%) as white solid. 1H NMR (400 MHz, METHANOL-d4) δ=7.56-7.46 (m, 2H), 7.22-7.17 (m, 2H), 7.13-7.07 (m, 3H), 7.02-6.97 (m, 1H), 3.94 (t, J=5.8 Hz, 1H), 3.61 (d, J=3.3 Hz, 2H), 3.40-3.35 (m, 1H), 3.25-3.18 (m, 3H), 2.89-2.84 (m, 2H), 2.79 (t, J=7.4 Hz, 2H), 2.74-2.69 (m, 2H), 2.47 (d, J=6.5 Hz, 2H). LCMS (m/z): 379.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([O:30][CH2:31][CH2:32][CH3:33])[C:9]([N:11]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[NH:12]C(OCC1C=CC=CC=1)=O)=[NH:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.O1CCCC1.[Pd]>[C:1]([O:5][C:6]([N:8]([O:30][CH2:31][CH2:32][CH3:33])[C:9]([N:11]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[NH2:12])=[NH:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCON(C(=N)N(NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCON(C(=N)N(N)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 28.3 %

Procedure:
A mixture of [N,N′-di(tert-butoxycarbonyl)] 3-(benzyloxycarbonylamino)-1-propoxyguanidine (760 mg, 1.7 mmol), as prepared in the preceding step, and 10% Pd/C (80 mg) in ethanol (20 mL) and tetrahydrofuran (20 mL) was hydrogenated under hydrogen (balloon) for 30 min. The catalyst was removed by filtration through Celite, the filtrate was concentrated in vacuo, and the residue was purified by Waters Sep-Pak (10 g, 95:5 methylene chloride:methanol saturated with ammonia) to give the title compound as a colorless oil (160 mg, 28%). 1H-NMR (300 MHz, CDCl3) δ4.12 (t, J=6.1 Hz, 2H), 2.85 (t, J=6.7 Hz, 2H), 1.84 (pentet, J=6.2 Hz, 2H), 1.50 (s, 9H), 1.48 (s, 9H).
Reaction SMILES: OS(O)(=O)=O.[OH:6][C:7]1[CH:22]=[CH:21][C:10]2[NH:11][C:12]([CH2:17][C:18]([OH:20])=[O:19])=[N:13][S:14](=[O:16])(=[O:15])[C:9]=2[CH:8]=1.[CH3:23][CH2:24]O>>[CH2:23]([O:19][C:18](=[O:20])[CH2:17][C:12]1[NH:11][C:10]2[CH:21]=[CH:22][C:7]([OH:6])=[CH:8][C:9]=2[S:14](=[O:16])(=[O:15])[N:13]=1)[CH3:24]
Reactant: CCO
Reactant: O=C(O)CC1=NS(=O)(=O)c2cc(O)ccc2N1
Agent: O=S(=O)(O)O
Product: CCOC(=O)CC1=NS(=O)(=O)c2cc(O)ccc2N1
Temperature: 80 °C

Procedure:
EtOH (15 mL) and 150 μL of H2SO4 (conc.) were added into the compound 10c (5.03 mmol) and the mixture was heated to 80° C. for 45 minutes with stirring. The solvent was partially evaporated to half of the original volume under reduced pressure. EtOAc (30 mL) was added and the resulted mixture was washed with H2O (15 mL×3) via extraction. The aqueous layer was back extracted with EtOAc once (60 mL) and the combined organic layer was dried over anhydrous MgSO4, filtered, concentrated to give the desired product (4b) (1.11 g) as a gray solid. This crude material was directly used in next step without further purification. LC-MS: (ESI+) m/e=285.10 [M+1]+ (exact ms: 284.05).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([OH:19])=O)[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[F:25][C:26]([F:38])([F:37])[C:27]1[C:35]2[C:30](=[CH:31][C:32]([NH2:36])=[CH:33][CH:34]=2)[NH:29][N:28]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([NH:36][C:32]3[CH:31]=[C:30]4[C:35]([C:27]([C:26]([F:38])([F:37])[F:25])=[N:28][NH:29]4)=[CH:34][CH:33]=3)=[O:19])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: Nc1ccc2c(C(F)(F)F)n[nH]c2c1
Product: CCC(C(=O)Nc1ccc2c(C(F)(F)F)n[nH]c2c1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
82 mg (0.23 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 51 mg (0.25 mmol, 1.1 eq.) of 3-(trifluoromethyl)-1H-indazole-6-amine were reacted according to General Method 6. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 30 mg (25% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][NH:6][C:7]([C:9]1O[CH:11]=[C:12]([C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8].C(O)C.[NH2:36][CH2:37][CH2:38][OH:39]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][NH:6][C:7]([C:9]1[N:36]([CH2:37][CH2:38][OH:39])[CH:11]=[C:12]([C:24](=[O:29])[C:25]([CH3:27])([CH3:26])[CH3:28])[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:8]
Reactant: NCCO
Reactant: CC(C)(C)C(=O)c1coc(C(=O)NCc2cccc(Cl)c2)c(OCc2ccccc2)c1=O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)c1cn(CCO)c(C(=O)NCc2cccc(Cl)c2)c(OCc2ccccc2)c1=O
Temperature: 60 °C
Reaction time: 11 h

Procedure:
To a solution of 3-benzyloxy-5-(2,2-dimethylpropionyl)-4-oxo-4H-pyran-2-carboxylic acid 3-chlorobenzylamide (113 mg) in tetrahydrofuran (0.7 ml)-ethanol (0.7 ml) was added 2-aminoethanol (0.015 ml) and the mixture was stirred at 60° C. for 11 hr. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:1) to give 3-benzyloxy-5-(2,2-dimethylpropionyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (91 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[N:20]3[C:14]([CH2:15][NH:16][C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[CH:13][CH:12]=2)=[O:10])[CH:2]=1.C(N(CC)C(C)C)(C)C.[C:34]([C:38]1[CH:48]=[CH:47][C:41]([O:42][CH2:43][C:44](Cl)=[O:45])=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35]>O1CCCC1>[C:34]([C:38]1[CH:48]=[CH:47][C:41]([O:42][CH2:43][C:44]([N:16]2[C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[CH2:19][N:20]3[C:11]([C:9]([NH:8][CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:10])=[CH:12][CH:13]=[C:14]3[CH2:15]2)=[O:45])=[CH:40][CH:39]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)c1ccc(OCC(=O)Cl)cc1
Reactant: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1NC2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(OCC(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 58.4 %

Procedure:
To a suspension of N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 76, Step C (0.300 g, 0.942 mmol), and N,N-diisopropylethylamine (0.26 mL, 1.508 mmol) in dry tetrahydrofuran (10 mL) was added dropwise 4-tert-butylphenoxyacetyl chloride (0.32 g, 1.41 mmol) and the reaction mixture was stirred at room temperature under nitrogen for 21 hours. The reaction was then quenched by the addition of 2 M sodium hydroxide (5 mL) and the mixture partitioned between ethyl acetate (50 mL) and 2 M sodium hydroxide (50 mL). The organic phase was separated, washed with 2 M sodium hydroxide (50 mL), water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford a yellow foam. Purification by flash chromatography using a solvent gradient of 0 to 4% methanol in dichloromethane gave a colorless syrup that was triturated with diethyl ether to afford the title compound (0.280 g, 58%) as a white solid, m.p. 85° C.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1C(O)=O.N[C@H](C(O)=O)C[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([N:1]2[C:2]3=[N:1][CH:2]=[CH:3][CH:4]=[C:3]3[CH2:4][C:5]2=[O:6])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C1CC[C@@H](C(=O)O)N1
Product: O=C1Cc2cccnc2N1c1ccccc1
Yield: 55 %

Procedure:
The compound was prepared as described by Ting, Kaminski, et al., in "Substituted 1,3-Dihydro-2H-pyrrolo[2,3-b]pyridin-2-ones as Potential Antiinflammatory Agents", J. Med. Chem., 1990, 33, 2697-2706 in 55% yield; mp 116.0°-117.0° C.; IR(KBr): 1727 cm-1 (CO); 1H NMR(CDCl3TMS): d 3.73 (s, 2H, CH2 --CO), [7.00 (dd, 1H), 7.39 (dd, 1H), 8.18 (d, 1H), 2,3-subs. Pyr], 7.51 (m, 5H, Phe); mass spec m/e 211 (M+1); Anal calcd for C13H10N2O, MW 210.24: C, 74.27; H, 4.79; N, 13.33. Found: C, 74.11; 4.73; N, 12.92.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.[Li]C(C)(C)C.CCCCCC.[I:26]I>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])[C:5]([I:26])=[CH:4][CH:3]=1
Reactant: II
Reactant: CC(C)(C)C(=O)Nc1cccc(Cl)n1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)C(=O)Nc1nc(Cl)ccc1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
To a solution of N-(6-chloropyridin-2-yl)-2,2-dimethylpropionamide (20 g, 94 mmol) in dry THF (500 mL) at −78° C., 1.3 M t-BuLi in hexane (220 mL, 282 mmol) is added dropwise. The reaction mixture is stirred for 30 min and a solution of iodine (29 g, 114 mmol) in dry THF is added. The reaction mixture is stirred for 3 h at −78° C. then is warmed to ambient temperature and stirred for another 1 h. The reaction mixture is quenched with 1N HCl and is extracted with ethyl acetate (2×250 mL). The organic layers are separated and washed with Na2S2O3 solution and saturated NaHCO3 solution, respectively. The combined organic layers are dried (Na2SO4) and evaporated under reduced pressure. The crude residue is purified by flash column chromatography using 20% EtOAc/petroleum ether to afford the title compound as a pale yellow solid (15 g, 49%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Si](C)(C)C)=[C:10]([F:18])[CH:9]=2)[N:5]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[C:3]=1[Cl:23].[I:24]Cl.[O-]S([O-])=O.[Na+].[Na+]>ClCCl>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([I:24])=[C:10]([F:18])[CH:9]=2)[N:5]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[C:3]=1[Cl:23]
Reactant: ClI
Reactant: COC(=O)c1nc(-c2ccc([Si](C)(C)C)c(F)c2)cc(N)c1Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1nc(-c2ccc(I)c(F)c2)cc(N)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.2 %

Procedure:
To a 250-mL round bottom flask, equipped with a stir bar, was added methyl 4-amino-3-chloro-6-(3-fluoro-4-(trimethylsilyl)phenyl)picolinate (0.328 g, 0.930 mmol), and dichloromethane (5.0 mL). To this solution iodine monochloride (0.141 mL, 2.79 mmol) was added. The reaction mixture was allowed to stir at room temperature for 18 hrs. Another portion of iodine monochloride (0.141 mL, 2.79 mmol) was added, and the reaction was allowed to stir at room temperature for an additional 4.5 hrs. The reaction mixture was poured into 1 M Na2SO3, and the layers were partitioned. The aqueous phase was extracted with additional ethyl acetate (2×100 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated to afford the title compound as a white solid (0.375 g, 99%):
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([S:20](Cl)(=[O:22])=[O:21])[CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.Cl.[NH2:33][C:34]([NH2:36])=[NH:35]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([S:20](=[O:22])(=[O:21])[N:33]=[C:34]([NH2:36])[NH2:35])[CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N=C(N)N
Reactant: COC(=O)CC(c1ccccc1)c1ccc(OC)c(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CC(c1ccccc1)c1ccc(OC)c(S(=O)(=O)N=C(N)N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(3-chlorosulfonyl-4-methoxy-phenyl)-3-phenyl-propionic acid methyl ester (500 mg, 1.36 mmol) in DCM (50 mL) is added triethylamine (0.57 ml, 4.08 mmol) and guanidine hydrochloride (0.14 g, 1.50 mmol). The reaction mixture is stirred at RT overnight, then diluted with DCM (100 mL). The reaction mixture is washed with an aqueous saturated solution of NaHCO3 (30 mL), water (30 mL) then brine (30 mL). The organic phase is then dried over MgSO4, filtered and concentrated in vacuo. Purification of the residue by reverse phase chromatography (Isolute™ C18, 0-100% acetonitrile in water with 0.1% TFA) affords the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:9][NH:10][CH:11]1[CH2:16][C:15]([CH3:18])([CH3:17])[NH:14][C:13]([CH3:20])([CH3:19])[CH2:12]1>C(O)CCC>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:10]([CH3:9])[CH:11]2[CH2:12][C:13]([CH3:19])([CH3:20])[NH:14][C:15]([CH3:18])([CH3:17])[CH2:16]2)=[CH:6][CH:7]=1
Reactant: CNC1CC(C)(C)NC(C)(C)C1
Reactant: Clc1ccc(Cl)nn1
Solvent: CCCCO
Product: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To 3,6-dichloropyridazine (4 g, 26.8 mmol) and N,2,2,6,6-pentamethylpiperidin-4-amine (7.32 g, 43.0 mmol) in a 300 mL round bottom flask was added butan-1-ol (67 mL) to give a colorless solution. The mixture was heated to 120° C. for 72 h. Butan-1-ol was removed using a rotary evaporator. The residue was partitioned between water and DCM, and the water layer was further extracted with DCM. The combined organic layers were washed with water and brine, dried over MgSO4, and concentrated in vacuo. The black crude material was stirred in small amount of EtOAc overnight, and the resulting off-white solid was collected to provide 6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine, Intermediate 1-1 (4.18 g, 14.78 mmol, 55.0% yield). LCMS Rt=0.8 min (condition B), MS (M+1)=283.5. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.40 (d, J=9.60 Hz, 1H), 7.14 (d, J=9.60 Hz, 1H), 4.96-5.13 (m, 1H), 2.93 (s, 3H), 1.59-1.68 (m, 2H), 1.51 (t, J=12.38 Hz, 2H), 1.20 (s, 6H), 1.33 (s, 6H).