Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22]>C(Cl)Cl>[F:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][N:11]([C:21](=[O:23])[CH3:22])[CH2:10][CH2:9]2)=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)Cl
Reactant: Fc1nccnc1C1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(c2nccnc2F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2-fluoro-3-(piperidin-4-yl)pyrazine (0.311 g, 1.716 mmol) dissolved in DCM (5 mL) was added triethylamine (0.286 mL, 2.06 mmol), then acetyl chloride (0.134 mL, 1.89 mmol). The reaction mixture was stirred at RT for 1 h then partitioned between DCM and water. The aqueous layer was extracted with DCM (3×) and the combined organic layers were washed with brine, dried (Na2SO4) and concentrated to give 1-(4-(3-fluoropyrazin-2-yl)piperidin-1-yl)ethanone as a yellow oil. MS (ESI, pos. ion) m/z: 224.0 (M−56).
Reaction SMILES: [O:1]=[C:2]1[NH:21][C:5]2=[N:6][C:7]3[CH:8]=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:11][C:12]=3[CH:13]=[C:4]2[NH:3]1.[CH:22]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([NH:29][C:18](=[O:20])[CH2:17][CH2:16][CH2:15][O:14][C:10]2[CH:9]=[CH:8][C:7]3[N:6]=[C:5]4[NH:21][C:2](=[O:1])[NH:3][C:4]4=[CH:13][C:12]=3[CH:11]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NC1CCCCCC1
Reactant: O=C(O)CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1
Product: O=C(CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1)NC1CCCCCC1

Procedure:
This compound, m.p. 314°-316°, was prepared analogous to Example 15 from 4-[(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)oxy]butyric acid and N-cycloheptylamine.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.[C:14]1([CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>O1CCOCC1>[C:14]1([CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[N:21]2[CH2:22][CH2:23][N:24]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=3)[CH2:25][CH2:26]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)Cc1ccc(CBr)cc1
Reactant: c1ccc(C(c2ccccn2)N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)Cc1ccc(CN2CCN(C(c3ccccc3)c3ccccn3)CC2)cc1
Yield: 51.9 %

Procedure:
Using 2.8 g of methyl 4-bromomethylphenylacetate, 2.9 g of 1-[phenyl-(2-pyridyl)methyl]piperazine, 2 ml of triethylamine, and 100 ml of dioxane, the reaction procedure of Example 1 was otherwise repeated and recrystallized from benzene-hexane to provide 2.47 g of methyl 4-[[4-[phenyl-(2-pyridyl)methyl]-1-piperazinyl]methyl]phenylacetate melting at 122° C.-123° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9](OC)=[O:10])[N:4]=1.O.[NH2:16][NH2:17]>CCO>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([NH:16][NH2:17])=[O:10])[N:4]=1
Reactant: NN
Reactant: COC(=O)c1nccc(C(F)(F)F)n1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1nccc(C(F)(F)F)n1
Reaction time: 1 h
Yield: 86.1 %

Procedure:
To a solution of methyl 4-(trifluoromethyl)pyrimidine-2-carboxylate (500 mg, 2.4 mmol) in EtOH (12 mL) was added hydrazine monohydrate (0.24 mL, 4.9 mmol). After 1 h, the reaction was concentrated to afford the desired product as a white solid (426 mg, 85%). 1H NMR (400 MHz, CDCl3) δ 9.22 (d, J=5.0 Hz, 1H), 9.05 (s, 1H), 7.83 (d, J=5.0 Hz, 1H), 4.25 (br s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2.C([OH:19])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][C:11](=[O:19])[NH:12]2
Reactant: Clc1ccccc1-c1cccc2[nH]ccc12
Reactant: CCO
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: O=C1Cc2c(cccc2-c2ccccc2Cl)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To the suspension of 4-(2-chloro-phenyl)-1H-indole (2.4 g, 10.6 mmol) in t-BuOH:ethanol:acetic acid (67 mL: 40 mL: 21 mL) was added pyridinium tribromide (10.5 g, 32 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added acetic acid (52 mL). Zinc dust (3.5 g, 53 mmol) was added to the reaction mixture portionwise. After stirring for one hour, any unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water (3×), sat. NaHCO3, brine, dried over Na2SO4, concentrated and triturated with ether to give 1.96 g (76%) of 4-(2-chloro-phenyl)-1,3-dihydro-indol-2-one.
Reaction SMILES: [C:1]([C:5]1[CH:25]=[CH:24][C:8]([O:9][CH:10]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CS(O[CH2:31][CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[C:36]([O:35][C:34]([NH:33][CH2:32][CH2:31][O:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][CH:10]([O:9][C:8]2[CH:24]=[CH:25][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][CH:7]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:22][CH:21]=1)=[O:40])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)Oc1ccc(C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1)Oc1ccc(C(C)(C)C)cc1
Yield: 93.1 %

Procedure:
In a similar manner to that described in Reference example 25, a reaction was carried out using ethyl 2-(4-t-butylphenoxy)-3-(4-hydroxyphenyl)propionate (2.37 g), which is the product of Reference example 36(b), t-butyl 2-methanesulfonyloxyethylcarbamate (3.60 g) and potassium carbonate (4.78 g) and the reaction mixture was treated to afford the title compound (3.13 g) as a colorless oil.
Reaction SMILES: C([O:4][C:5]([CH3:10])([CH3:9])[C:6](Cl)=[O:7])(=O)C.[Br:11][C:12]1[C:13]([F:22])=[C:14]2[C:20]([NH2:21])=[CH:19][NH:18][C:15]2=[N:16][CH:17]=1.C(N(CC)CC)C>ClCCl>[Br:11][C:12]1[C:13]([F:22])=[C:14]2[C:20]([NH:21][C:6](=[O:7])[C:5]([OH:4])([CH3:9])[CH3:10])=[CH:19][NH:18][C:15]2=[N:16][CH:17]=1
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(O)C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
1-Chloro-2-methyl-1-oxopropan-2-yl acetate (215 mg, 1.30 mmol) in dry dichloromethane (2 mL) was added dropwise to a solution of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (250 mg, 1.087 mmol; Example 1, Step H) and triethylamine (550 mg, 0.757 mL, 5.43 mmol) in dry dichloromethane (10 mL) cooled on an ice-bath. The resulting solution was stirred at room temperature for 1 hour. The solvent was evaporated. The residue was then stirred in THF (10 mL), treated with an aqueous 2N LiOH solution (3 mL), and stirred at room temperature for 18 hours. The mixture was evaporated under reduced pressure, and the residue dissolved in EtOAc and washed with water (3×20 mL). The organic layer was dried over MgSO4, filtered and concentrated to give N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxy-2-methylpropanamide (289 mg, 84% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.03 (br s, 1H), 9.27 (s, 1H), 8.36 (d, 1H), 7.69 (d, 1H), 5.84 (s, 1H), 1.37 (s, 6H); LCMS (APCI+) m/z 317.9 (M+H)+, Retention time=2.51 minutes.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]([C:10]([O:12][CH2:13][C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[O:11])=[CH:8][C:7]=2[CH:26]=O)[CH2:3][CH2:2]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]([C:10]([O:12][CH2:13][C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])=[O:11])=[CH:8][C:7]=2[CH2:26][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH2:2][CH2:3]1
Reactant: O=Cc1cc(C(=O)OCC(=O)OCc2ccccc2)ccc1OCC1CC1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(COC(=O)c1ccc(OCC2CC2)c(CN2CCOCC2)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
A solution of 2-(benzyloxy)-2-oxoethyl 4-(cyclopropylmethoxy)-3-formylbenzoate (3.73 g, 10.13 mmol) and morpholine (1.15 g, 13.17 mmol) in dry THF (50 ml), under argon atmosphere, was stirred for 15 minutes at RT. Na(OAc)3BH (2.79 g, 13.17 mmol) and CH3COOH (754 μl, 13.17 mmol) were added. CH3COOH was added to reach a pH between 5 and 6. The mixture stirred at RT for 24 hours. The solvent was removed, and the crude was dissolved in EtOAc and washed with NaHCO3 sat. sol. and brine. The organic phase was dried over Na2SO4, and the solvent was removed to give 2-(benzyloxy)-2-oxoethyl 4-(cyclopropylmethoxy)-3-(morpholinomethyl)benzoate (4.45 g, quantitative yield).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][O:8][N:9]=[C:10]([C:14]2[C:15](=[O:23])[CH2:16][C:17]([CH3:22])([CH3:21])[CH2:18][C:19]=2[OH:20])[CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:30](Cl)(=[O:32])[CH3:31]>C(Cl)Cl>[C:30]([O:23][C:15]1[CH2:16][C:17]([CH3:22])([CH3:21])[CH2:18][C:19](=[O:20])[C:14]=1[C:10](=[N:9][O:8][CH2:7][C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:11][CH2:12][CH3:13])(=[O:32])[CH3:31]
Reactant: CCCC(=NOCc1ccc(Cl)s1)C1=C(O)CC(C)(C)CC1=O
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=NOCc1ccc(Cl)s1)C1=C(OC(C)=O)CC(C)(C)CC1=O
Temperature: 0 °C

Procedure:
To a reaction mixture containing 3.6 gms (0.01 mol) of 2-{1-[(5-chlorothien-2-ylmethoxy)imino]butyl}-3-hydroxy-5,5-dimethylcyclohex-2-en-1-one and 0.87 gm (0.011 mol) of pyridine in 20 mls of methylene chloride stirred at 0° C. is added 0.89 gm (0.011 mol) of acetyl chloride. The mixture is then stirred at room temperature for 2 hours. The mixture is then worked up by washing with water, drying with anhydrous magnesium sulfate, and filtered. The filtrate is evaporated under vacuum affording 3-acetyloxy-2-{1-[(5-chlorothien-2-ylmethoxy)imino]butyl}-5,5-dimethylcyclohex-2-en-1-one.
Reaction SMILES: [O:1]([C:8]1[CH:28]=[CH:27][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([CH2:25][NH2:26])[CH:22]=[CH:23][CH:24]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.CN1C[CH2:39][CH2:38][C:37]1=[O:41]>ClCCl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=2)[CH2:25][NH:26][C:37](=[O:41])[CH2:38][CH3:39])=[CH:27][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCCC1=O
Reactant: NCc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)NCc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Yield: 58 %

Procedure:
N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)propionamide was prepared from (3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine and pyridine instead of N, N-diethylethanamine, 1-methylpyrrolidin-2-one, dichloromethane using Method G (58% yield). HPLC: 97%, RT=4.034 min. MS: m/z=425 [M+H]+, RT=3.34 min.
Reaction SMILES: CC(C)([O-])C.[Na+].Cl[C:8]1[N:13]=[C:12]([CH2:14][OH:15])[C:11]2[C:16]([O:38][CH3:39])=[N:17][N:18]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:10]=2[CH:9]=1.[C:40](=[O:50])([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[NH2:41]>C1COCC1>[CH2:43]([O:42][C:40](=[O:50])[NH:41][C:8]1[N:13]=[C:12]([CH2:14][OH:15])[C:11]2[C:16]([O:38][CH3:39])=[N:17][N:18]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:10]=2[CH:9]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: NC(=O)OCc1ccccc1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(CO)c12
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)OCc3ccccc3)nc(CO)c12
Temperature: 50 °C
Reaction time: 10 h
Yield: 57.8 %

Procedure:
A 20 mL scintillation vial was charged with sodium tert-butoxide (105 mg, 1.097 mmol), (6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)methanol (35B, 250 mg, 0.548 mmol), benzyl carbamate (124 mg, 0.822 mmol) and BrettPhos-Pd-G3 (24.85 mg, 0.027 mmol). THF (5 ml) was added, the vial flushed with argon, capped and the contents heated to 50° C. with stirring for 10 h. The mixture was cooled, diluted with ethyl acetate (10 mL), washed with aqueous sodium hydrogen carbonate (saturated, 2×20 mL), dried (MgSO4), filtered and the solvent evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel ISCO; 24 g prepacked, eluting with EtOAc/hexanes to afford benzyl(4-(hydroxymethyl)-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)carbamate (181 mg, 0.317 mmol, 57.8% yield) as a white solid. MS: [M+H]+ m/z 571.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:20]1([CH3:32])[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:21]=1[S:28](Cl)(=[O:30])=[O:29]>CN(C1C=CN=CC=1)C.C(#N)C>[C:20]1([CH3:32])[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:21]=1[S:28]([NH:12][S:9]([C:6]1[CH:5]=[CH:4][C:3]([CH:2]=[CH2:1])=[CH:8][CH:7]=1)(=[O:11])=[O:10])(=[O:29])=[O:30]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: C=Cc1ccc(S(N)(=O)=O)cc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=Cc1ccc(S(=O)(=O)NS(=O)(=O)c2c(C)cc(C)cc2C)cc1
Yield: 64.7 %

Procedure:
Using 55.0 g (0.3 mol) of p-styrenesulfonamide, 3.7 g (0.03 mol) of 4-(N,N-dimethylamino)pyridine, 82.0 g (0.81 mol) of triethylamine, 91.8 g (0.42 mol) of 2-mesitylenesulfonyl chloride, and 500 ml of acetonitrile, reaction was conducted in the same manner as in Synthesis Example 1. As a result, 70.9 g of N-(2-mesitylenesulfonyl) -p-styrenesulfonamide was obtained (yield, 64.7%; light-yellow crystals; m.p., 146.5-147° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[C:21]1[CH:22]=[CH:23][C:24]([O:28][CH3:29])=[C:25]([NH2:27])[CH:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[C:21]1[CH:22]=[CH:23][C:24]([O:28][CH3:29])=[C:25]([NH:27][CH2:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:26]=1
Reactant: COc1ccc(-c2cc3ccccc3[nH]2)cc1N
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(-c2cc3ccccc3[nH]2)cc1NCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
4-Nitrobenzaldehyde (0.302 g, 2.0 mmol) was added to a stirred mixture of 5-(1H-indol-2-yl)-2-methoxy-phenylamine (0.476 g, 2.0 mmol) in methylene chloride (125 mL), followed by acetic acid (0.2 g). The resulting mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.46 g, 2.2 mmol) was added in one portion, and the resulting homogeneous solution was stirred at room temperature for 4 days. Saturated aqueous sodium bicarbonate solution (100 mL) was added and the mixture was stirred for 2 hours. The mixture was shaken, the organic layer was separated and dried over Na2SO4. The solvent was evaporated to give an orange solid. Recrystallization from ethyl acetate gave the product (290 mg), mp 198-199° C.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][N:13]([CH3:15])[NH2:14]>C(N(CC)CC)C.CO>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:14][N:13]([CH3:15])[CH3:12])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CN(C)N
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(C)Nc1cc(F)ccc1[N+](=O)[O-]
Yield: 48.8 %

Procedure:
10 g (0.0628 mol) of 2,4-difluoronitrobenzene was stirred for 4 days with 4.36 g (0.0728 mol) of N,N-dimethylhydrazine in 7.08 g of triethylamine and 100 ml methanol. The mixture was concentrated and the resulting solid dissolved in methylene chloride, washed with water and brine, dried with MgSO4 and concentrated to yield an orange solid. The solid was triturated in 95% ethanol/water, filtered and dried to give 6.1 g 4-fluoro-2-(2,2-dimethylhydrazino) nitrobenzene, m.p. 67°-71° C.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34](Cl)(=[O:38])[CH:35]([CH3:37])[CH3:36]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CC(C)C(=O)Cl
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)C(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 72.6 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.62 g, 4.08 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.60 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, isobutyryl chloride (0.24 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with 1N HCl (30 mL), H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the solid was purified from ether (10 mL) and hexane (10 mL) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}-2-methylpropanamide (0.48 g, 73%) as a white solid: mp 218-220° C.; 1H NMR (DMSO-d6) δ 11.13 (s, 1H), 8.39 (t, J=5.8 Hz, 1H), 7.87-7.78 (m, 2H), 7.66-7.63 (m, 1H), 5.19-5.12 (dd, J=6.9 and 12.5 Hz, 1H), 4.71 (d, J=5.8 Hz, 2H), 2.97-2.83 (m, 1H), 2.63-2.43 (m, 3H), 2.08-2.04 (m, 1H), 1.07 (d, J=6.9 Hz, 6H); 13C NMR (DMSO-d6) δ 176.52, 172.75, 169.82, 167.49, 166.95, 139.54, 134.77, 132.85, 131.50, 127.02, 121.77, 48.83, 37.48, 33.98, 30.92, 21.96, 19.53; Anal. Calcd. For C18H19N3O5: C, 60.50; H, 5.36; N, 11.76. Found: C, 60.48; H, 5.33; N, 11.64.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6]([NH2:10])(=[O:9])[CH:7]=[CH2:8].N12CCCCC1C=NCCC2>C(#N)C>[C:6]([CH2:7][CH2:8][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)(=[O:9])[NH2:10]
Reactant: c1c[nH]cn1
Reactant: C=CC(N)=O
Agent: C1=NCCCN2CCCCC12
Solvent: CC#N
Product: NC(=O)CCn1ccnc1
Temperature: 80 °C

Procedure:
A stirred mixture of 3.4 g (49.9 mmoles) of imidazole, 3.55 g (49.9 mmoles) of acrylamide, and 7.6 g (49.9 mmoles) of 1,5-diazabicyclo[5.4.0]undec-5-ene (DBu) in 100 mL of sieve dried acetonitrile was heated at 80° C. under nitrogen for 2.0 hours. The mixture was let cool, where upon the product crystallized out of the solution.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].CC1(C)C(C)(C)OB([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[C:49]([F:52])([F:51])[F:50])O1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=5[C:49]([F:52])([F:51])[F:50])[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC1(C)OB(c2ccccc2C(F)(F)F)OC1(C)C
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5ccccc5C(F)(F)F)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 4,4,5,5-tetramethyl-2-(2-trifluoromethyl-phenyl)-[1,3,2]dioxaborolane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][O:15][CH2:16][C:17]([OH:19])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:42][N:43]([CH:60]([C:68](=[O:71])[NH:69][CH3:70])[CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)[C:44](=[O:59])[CH:45]([NH:57][CH3:58])[CH2:46][C:47]1[CH:56]=[CH:55][C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=1.C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][O:15][CH2:16][C:17](=[O:19])[N:57]([CH3:58])[C@@H:45]([C:44](=[O:59])[N:43]([CH3:42])[C@@H:60]([C:68](=[O:71])[NH:69][CH3:70])[CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)[CH2:46][C:47]1[CH:56]=[CH:55][C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC(=O)C(Cc1ccccc1)N(C)C(=O)C(Cc1ccc2ccccc2c1)NC
Reactant: CC(C)(C)OC(=O)N1CCCCC1COCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)COCC1CCCCN1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a solution of 2-(carboxymethoxymethyl)piperidine-1-carboxylic acid tert-butylester (225 mg, 0.82 mmol) in 5 ml of dichloromethane was added 1-hydroxy-7-azabenzotriazole (112 mg, 0.82 mmol) and 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (173 mg, 0.90 mmol) and the mixture was to stirred for 30 min. N-Methyl-2-methylamino-N-(1-methylcarbamoyl-2-phenylethyl)-3-(2-naphthyl)propionamide (332 mg, 0.82 mmol) in dichloromethane (5mL) was added followed by diisopropylethylamine (0.14 ml, 0.82 mmol) and the mixture was stirred overnight at room temperature. The mixture was washed with water (5 ml) aqueous sodium bicarbonate (5 ml), water (2×5 ml), brine (5 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed on silica (20 g) with ethyl acetate to give 416 mg of 2-([N-methyl-N-{(1R)-1-(N-methyl-N-[(1R)-1-(methylcarbamoyl)-2-phenylethyl]carbamoyl)-2-(2-naphthyl)ethyl}carbamoyl]methoxymethyl)piperidin-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26]([OH:28])=O)[CH:21]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:29]=1.[F:30][C:31]1[CH:32]=[C:33]([C@@H:38]2[CH2:43][CH2:42][C:41]([CH3:45])([CH3:44])[CH2:40][NH:39]2)[CH:34]=[C:35]([F:37])[CH:36]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:37][C:35]1[CH:34]=[C:33]([CH:38]2[CH2:43][CH2:42][C:41]([CH3:45])([CH3:44])[CH2:40][N:39]2[C:26]([C:22]2[N:23]=[CH:24][N:25]=[C:20]([N:17]3[CH2:16][CH2:15][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:29]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:19][CH2:18]3)[CH:21]=2)=[O:28])[CH:32]=[C:31]([F:30])[CH:36]=1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Reactant: CC1(C)CC[C@@H](c2cc(F)cc(F)c2)NC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CC(C)(C)CCC4c4cc(F)cc(F)c4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
65 mg (0.16 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid and 70 mg (0.16 mmol) (S)-2-(3,5-difluorophenyl)-5,5-dimethylpiperidine in 0.04 mL (0.72 mmol) DIPEA and 0.80 mL DMF were combined with 65 mg (0.17 mmol) HATU and stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.