Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[H-].[Na+].I[CH:20]([CH3:22])[CH3:21]>C1(C)C=CC=CC=1.O.CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH:20]([CH3:22])[CH3:21])=[CH:4][CH:3]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)n1ccc2ccc(Br)cc21
Yield: 97.4 %

Procedure:
A mixture of 6-bromoindole (2.0 g, 10 mmol), K2CO3 (2.76 g, 20 mmol), NaH (0.48 g, 20 mmol), DMF (1 ml) and 2-iodopropane (8.5 g, 50 mmol) in 40 ml of toluene was heated at 90˜100° C. for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate (Na2SO4), concentrated in vacuo and the residue purified by column chromatography on silica gel, eluting with hexanes, to give (2.32 g, 97%) of the title product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[CH:10][C:9]=1[N+:13]([O-:15])=[O:14].[CH:16](=O)[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[N+:13]([C:9]1[CH:10]=[N:11][N:12]2[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH:16]2[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([O-:15])=[O:14]
Reactant: Nc1ccccc1-c1[nH]ncc1[N+](=O)[O-]
Reactant: O=CC=Cc1ccccc1
Product: O=[N+]([O-])c1cnn2c1-c1ccccc1NC2C=Cc1ccccc1
Yield: 85.5 %

Procedure:
5-(o-Aminophenyl)-4-nitropyrazole is reacted with cinnamaldehyde as described in Example 11 to give 1-nitro-5-styryl-5,6-dihydropyrazolo[1,5-c]quinazoline. M.p.: 171°-173° C. Yield: 85.5%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]([C:24]([C:26]2[CH:35]=[CH:34][C:29]3[NH:30][C:31](=[O:33])[O:32][C:28]=3[CH:27]=2)=[O:25])[CH:19]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(#N)C.O>[O:33]=[C:31]1[NH:30][C:29]2[CH:34]=[CH:35][C:26]([C:24]([C:20]3[N:21]=[CH:22][N:23]=[C:18]([N:1]4[CH2:2][CH2:3][CH:4]([N:7]5[C:15]6[C:10](=[N:11][CH:12]=[CH:13][CH:14]=6)[NH:9][C:8]5=[O:16])[CH2:5][CH2:6]4)[CH:19]=3)=[O:25])=[CH:27][C:28]=2[O:32]1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: O=C(c1ccc2[nH]c(=O)oc2c1)c1cc(Cl)ncn1
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc2[nH]c(=O)oc2c1)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
78 mg (0.40 mmol) 1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one, 0.10 g (0.40 mmol) 6-(6-chloro-pyrimidine-4-carbonyl)-3H-benzoxazol-2-one and 0.070 mL (0.40 mmol) DIPEA were combined in 2 mL DMF and shaken overnight at RT. The mixture was diluted with acetonitrile/water and purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([C:8]([F:11])([F:10])[F:9])[CH:4]([CH2:6][OH:7])[NH2:5].C(N(CC)CC)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][C:23]=1[N+:32]([O-:34])=[O:33]>C(Cl)Cl>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:5][CH:4]([CH2:6][OH:7])[CH:3]([C:8]([F:10])([F:9])[F:11])[C:2]([F:12])([F:13])[F:1])(=[O:30])=[O:29])=[CH:24][C:23]=1[N+:32]([O-:34])=[O:33]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: NC(CO)C(C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(S(=O)(=O)NC(CO)C(C(F)(F)F)C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 13.1 %

Procedure:
To a solution of 4,4,4,4′,4′,4′-hexafluoro-dl-valinol (0.50 g, 2.37 mmol), triethylamine (0.43 mL, 3.08 mmol) and CH2Cl2 (17.5 mL) at 0° C. was added a previously dissolved mixture of 4-chloro-3-nitro-benzenesulfonyl chloride (0.606 g, 2.37 mmol) in CH2Cl2 (5 mL). After 15 min, the ice bath was removed and the reaction allowed to warm up to 25° C. After 16 h, the reaction was then diluted with CH2Cl2 (20 mL) and poured into a separatory funnel containing a saturated NaHCO3 solution. The organic phase was separated, washed sequentially with 1N HCl solution, distilled water, brine, dried over MgSO4 and evaporated to afford the crude product which was purified using Biotage Flash™ chromatography, eluent: 3:1 hexanes-ethyl acetate, to afford the product as a solid (0.134 g, 13%). MS (−ESI) 428.9 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.C(O)(=O)C.C1C=CC=CC=1>[CH2:18]([O:17][C:15](=[O:16])[C:14]([C:12]#[N:13])=[C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH3:10])[CH3:19]
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCOC(=O)C(C#N)=C(C)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 60 %

Procedure:
A mixture of 3′,4′-dichloroacetophenone (50 mmol), ethyl cyanoacetate (50 mmol), acetic acid (1.14 mL) ammonium acetate (400 mg), and benzene (50 mL) was heated to reflux in a Dean-Stark apparatus. After approximately 10 hours, additional ethyl cyanoacetate (50 mmol), acetic acid (1.14 mL), and ammonium acetate (400 mg) are added. After an additional 10 hours, the reaction was cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (240 mL), brine (40 mL), and dried (Na2SO4). After filtering, the extract was concentrated in vacuo and the desired product, as a 1:1 mixture of E and Z-isomers, was isolated by column chromatography on silica gel, eluting with 5% ethyl acetate in petroleum ether. The purified oil solidified on standing at room temperature. Yield: 60%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:47][C:48]([F:62])([F:61])[C:49]1[N:53]2[CH2:54][CH2:55][NH:56][CH2:57][C:52]2=[C:51]([C:58]([NH2:60])=[O:59])[N:50]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:56]1[CH2:55][CH2:54][N:53]2[C:49]([C:48]([F:62])([F:47])[F:61])=[N:50][C:51]([C:58]([NH2:60])=[O:59])=[C:52]2[CH2:57]1)=[O:5]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: NC(=O)c1nc(C(F)(F)F)n2c1CNCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)c1cc(Cc3n[nH]c(=O)c4ccccc34)ccc1F)CC2
Reaction time: 12 h
Yield: 19.4 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (150 mg, 0.50 mmol) was dissolved in 10 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (285 mg, 0.75 mmol), crude 3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide 10a (130 mg, 0.55 mmol) and N,N-diisopropylethylamine (0.2 mL, 1 mmol). After stirring for 12 hours, the reaction mixture was added with 50 mL of H2O and extracted with dichloromethane (60 mL×3). The organic phase was combined, concentrated under reduced pressure, added with 100 mL of ethyl acetate, washed successively with H2O (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxamide 10 (50 mg, yield 20.0%) as a white solid.
Reaction SMILES: [OH-].[CH2:2]([N+:9](C)(C)C)[C:3]1C=CC=C[CH:4]=1.[NH:13]1[CH:17]=[CH:16][N:15]=[C:14]1[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1.C(#N)C=C.O>CO.O1CCOCC1>[C:2]([CH:3]([C:20]1[NH:21][C:22]2[C:27]([C:19]=1[CH2:18][C:14]1[NH:15][CH:16]=[CH:17][N:13]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:4])#[N:9]
Reactant: c1ccc2c(Cc3ncc[nH]3)c[nH]c2c1
Reactant: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: C=CC#N
Product: CC(C#N)c1[nH]c2ccccc2c1Cc1ncc[nH]1
Reaction time: 8 h

Procedure:
A 40% solution of benzyltrimethylammonium hydroxide in methanol (0.5 ml) was added to a suspension of 3-(1-imidazolylmethyl) indole (1.97 g) in dioxan (25 ml) containing acrylonitrile (2.0 ml) to give a clear solution. The solution was heated to 50°-60° C. for 30 minutes and then allowed to cool and stand overnight at room temperature. It was then poured into water and the mixture was extracted with ethyl acetate (3×50 ml). The combined extracts were washed with water and dried (Na2SO4). Evaporation of the solvent gave 1-cyanoethyl-3-(1-imidazolylmethyl)indole (2.50 g) as an oil.
Reaction SMILES: FC(F)(F)S(O[CH2:7][C@@H:8]1[O:12][CH2:11][C@@H:10]([S:13][C:14](=[O:16])[CH3:15])[CH2:9]1)(=O)=O.CCN(C(C)C)C(C)C.[F:28][C:29]1[CH:34]=[CH:33][C:32]([SH:35])=[CH:31][CH:30]=1>C(Cl)Cl>[F:28][C:29]1[CH:34]=[CH:33][C:32]([S:35][CH2:7][C@@H:8]2[O:12][CH2:11][C@@H:10]([S:13][C:14](=[O:16])[CH3:15])[CH2:9]2)=[CH:31][CH:30]=1
Reactant: Fc1ccc(S)cc1
Reactant: CC(=O)S[C@@H]1CO[C@@H](COS(=O)(=O)C(F)(F)F)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)S[C@@H]1CO[C@@H](CSc2ccc(F)cc2)C1

Procedure:
The title compound is prepared by the procedure of Example 23 using 0.308 g of product from Example 22 in 1 ml of methylene chloride, 107 microliter of 4-fluorothiophenol, and 174 microliter of Hunig's base to give 0.236 g of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:11]2[S:15][C:14]([C:16](O)=[O:17])=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[C:4]([CH3:19])[C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1.Cl.[CH3:31][O:32][C:33](=[O:37])[CH2:34][CH2:35][NH2:36].O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH3:31][O:32][C:33](=[O:37])[CH2:34][CH2:35][NH:36][C:16]([C:14]1[S:15][C:11]([CH:9]([O:8][C:6]2[CH:7]=[C:2]([CH3:1])[C:3]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=3)=[C:4]([CH3:19])[CH:5]=2)[CH3:10])=[CH:12][CH:13]=1)=[O:17]
Reactant: COC(=O)CCN
Reactant: Cc1cc(OC(C)c2ccc(C(=O)O)s2)cc(C)c1-c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)CCNC(=O)c1ccc(C(C)Oc2cc(C)c(-c3ccc(C(F)(F)F)cc3)c(C)c2)s1
Yield: 74.6 %

Procedure:
To a mixture of (-±)-5-[1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxy)-ethyl]-thiophene-2-carboxylic acid (0.545 g, 1.30 mmol), 3-amino-propionic acid methyl ester hydrochloride (0.199 g, 1.43 mmol), and 1-hydroxybenzotriazole hydrate (HOBt, 0.217 g, 1.60 mmol) in DMF (13.0 mL) is added N,N-diisopropylethylamine (0.67 mL, 3.84 mmol), then N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI, 0.330 g, 1.72 mmol) and stirred overnight. The reaction mixture is poured into H2O (25 mL) and extracted with EtOAc (3×25 mL). Combined organic extracts are washed with H2O, brine, dried over MgSO4, filtered, and concentrated. The residue is loaded onto silica gel and eluted using hexanes with an ethyl acetate gradient from 0% to 75% to provide (±)-3-({5-[1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxy)-ethyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (0.490 g, 75%) as a white foam. MS (ES): 504.3 [M−H]−.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:10](=[C:12]([C:16]([OH:18])=O)[CH:13]=[CH:14][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC2N(O)N=[N:25]C=2C=1.[NH4+].[Cl-].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C.O>[C:1]1([C:7]2[O:8][C:9]3[C:10](=[C:12]([C:16]([NH2:25])=[O:18])[CH:13]=[CH:14][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc2oc(-c3ccccc3)nc12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cccc2oc(-c3ccccc3)nc12
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of 2-phenylbenzo[d]oxazole-4-carboxylic acid in DMF (15 mL) was added HOBt (148 mg, 1.1 mmol), NH4Cl (54 mg, 1.0 mmol), DIPEA (387 mg, 3.0 mmol) and EDCI (211 mg, 1.1 mmol). The mixture was stirred at 25° C. for 10 hr. Then water (10 mL) was added and aqueous hydrochloric acid (1 N) to pH=3 and extracted with ethyl acetate (100 mL×4). The organic phase was washed with saturated sodium bicarbonate solution and brine, concentrated and dried in vacuum. The crude product was purified by pre-HPLC to obtain 2-phenylbenzo[d]oxazole-4-carboxamide as a white solid (40 mg). 1H-NMR (400 MHz, DMSO-d6) δ 7.47-7.56 (m, 1H), 7.63-7.68 (m, 3H), 7.93-8.01 (m, 3H), 8.28-8.30 (d, J=8 Hz, 2H), 8.47 (s, 1H); LC-MS (ESI) m/z 239 [M+1]+.
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[C:24]([O:28][C:29]([N:31]([CH2:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1)[CH3:32])=[O:30])([CH3:27])([CH3:26])[CH3:25]>CN(C=O)C>[C:24]([O:28][C:29]([N:31]([CH2:33][C:34]1[CH:40]=[CH:39][C:37]([NH:38]/[C:4](=[C:11]2\[C:12](=[O:23])[NH:13][C:14]3[C:19]\2=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)/[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:36][CH:35]=1)[CH3:32])=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CN(Cc1ccc(N)cc1)C(=O)OC(C)(C)C
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Solvent: CN(C)C=O
Product: CN(Cc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1)C(=O)OC(C)(C)C

Procedure:
Prepared analogously to Example 89 from 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(N-tert.butoxycarbonyl-N-methyl-amino)methyl-aniline in DMF.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].O=P(Cl)(Cl)Cl.[NH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25].C(N(CC)CC)C>CN(C=O)C.CCO>[OH:25][CH2:24][CH2:23][CH2:22][CH2:21][NH:20][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1O
Reactant: NCCCCO
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc2ccccc2c1NCCCCO
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
A suspension of 4-hydroxy-3-nitroquinoline (Gerster et al. J Med Chem 2005, 48, 3481) in DMF (0.7 M) was treated dropwise with POCl3 (1.2 eq) and stirred at 50° C. for 30 min. The reaction mixture was poured into ice-water and extracted twice with CH2Cl2. The combined organic layers were washed with water, dried (Na2SO4) and concentrated. The crude product obtained was added to a solution of 4-amino-butanol (1.3 eq) and triethylamine (1.9 eq) in EtOH and heated to reflux for 15 min. After concentration, flash chromatography on silica gel (gradient elution, 2→4% MeOH—CHCl3) afforded 4-(4-hydroxybutyl)amino-3-nitroquinoline as a yellow solid in 97% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH:11]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[N:20]=[CH:19]2)[C:12]([F:15])([F:14])[F:13])([O-])=O.Cl.C(=O)(O)[O-].[Na+]>CO.[Zn]>[F:15][C:12]([F:13])([F:14])[CH:11]([NH:10][C:5]1[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[N:20]=[CH:19]2
Reactant: O=[N+]([O-])c1ccccc1NC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Nc1ccccc1NC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(F)(F)F
Reaction time: 1 h
Yield: 10.9 %

Procedure:
To a solution of 100 mg (0.23 mmol) of (2-nitrophenyl)-{2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethyl}amine in 10 mL of methanol was added 304 mg (4.65 mmol) of zinc powder followed by the addition of 4.65 mL (4.65 mmol) of 1 N aqueous HCl. After 1 hour, the mixture was made basic with saturated aqueous sodium bicarbonate and extracted with three 15 mL portions of ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by prep-TLC using 10-20% EtOAc/hexanes to provide 10 mg (14%) of the title compound as a white solid. MS m/z 401 (MH+).
Reaction SMILES: C(N(CC)CC)C.[C:8](Br)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:28][C:29]([CH3:39])([CH2:37][CH3:38])[CH2:30][C:31]1[N:32]=[C:33]([CH3:36])[NH:34][CH:35]=1>C(Cl)Cl>[CH3:28][C:29]([CH3:39])([CH2:37][CH3:38])[CH2:30][C:31]1[N:32]=[C:33]([CH3:36])[N:34]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:35]=1
Reactant: CCC(C)(C)Cc1c[nH]c(C)n1
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (34 mL, 0.24 mol) followed by trityl bromide (62 g, 0.19 mol) (portionwise) were added to a 0° C. solution of 4-(2,2-dimethylbutyl)-2-methyl-1H-imidazole (26.4 g, 0.16 mol) in methylene chloride (300 mL). After stirring at ambient temperature overnight, the reaction mixture was filtered and washed with water and brine, dried (magnesium sulfate), filtered and concentrated in vacuo. Chromatography over silica eluting with 10-40% ethyl acetate/hexane afforded the title compound.
Reaction SMILES: [C:1]([N:8]([CH2:16][CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CO.[OH-].[Na+]>C1COCC1>[C:1]([N:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:26][CH:27]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COC(=O)c1ccc(CCN(Cc2ccccn2)C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCc1ccc(C(=O)O)cc1)Cc1ccccn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.7 %

Procedure:
The compound obtained in Example 9-3 (446.1 mg) was dissolved in THF (4.5 ml) and methanol (4.5 ml) After the addition of 1 mol/l aqueous solution of sodium hydroxide (4.5 ml), the mixture was stirred for 5 hours at room temperature. After the reaction, the solvent was removed by distillation and the residue was dissolved in distilled water. Aqueous solution of hydrochloric acid (1 mol/l) was added to the solution to adjust the pH to 3-4. The settled-down oily product was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation and the residue was dried under vacuum to obtain the title compound (432.2 mg) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([N+:20]([O-:22])=[O:21])=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][CH2:25][CH2:26][C:27]#[N:28].C(N(CC)CC)C.O>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([N+:20]([O-:22])=[O:21])=[C:18]([NH:28][CH2:27][CH2:26][C:25]#[N:24])[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CCCN
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc(Cl)c2[N+](=O)[O-])CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc(NCCC#N)c2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
4-(6-Chloro-5-nitro-pyrimidin-4-yl)piperazine-1-carboxylic acid t-butyl ester (3.0 g) was dissolved in acetonitrile (30 mL), and then 3-aminopropionitrile (0.71 mL) and triethylamine (1.58 mL) were added to this solution. After stirring the reaction solution at room temperature for 14 hours, water (60 mL) was added. The reaction solution was stirred at room temperature for 30 minutes, and then the precipitate was collected by filtration. The obtained yellow solid was washed with water and hexane to give the title compound (1.97 g).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:12][C@H:11]([CH3:13])[NH:10][CH2:9][C@H:8]2[CH3:14])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>ClCCl>[Cl:24][CH2:25][C:26]([N:10]1[CH2:9][C@H:8]([CH3:14])[N:7]([CH2:6][C:5]2[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:12][C@H:11]1[CH3:13])=[O:27]
Reactant: O=C(Cl)CCl
Reactant: C[C@@H]1CN[C@@H](C)CN1Cc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CCl
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
To a solution of (2R,5S)-1-(4-fluoro-benzyl)-2,5-dimethyl-piperazine (2.5 g, 11.2 mmol) in dry dichloromethane (11 mL) at 0° C. was added triethylamine (1.57 mL, 11.2 mmol) followed by chloroacetyl chloride (0.86 mL, 11.2 mmol). The resulting reaction mixture was stirred for 30 minutes. The reaction was then filtered through a pad of celite, washed with dichloromethane and the resulting filtrate was concentrated. Chromatography on silica gel gave the title compound (2.84 g).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:14]([N:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([NH2:27])[CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:27][C@@H:23]2[CH2:24][CH2:25][CH2:26][N:21]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:22]2)=[O:11])=[CH:12][CH:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)c2ccc(C(C)(C)C)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-t-butylbenzoic acid (1.15 g, 6.45 mmol), (R)—N-BOC-3-aminopiperadine (1.00 g, 4.99 mmol), BOP (3.42 g, 7.73 mmol), and N-methylmorpholine (2.5 mL, 22.7 mmol) in DMF (10 mL) was stirred at rt for 2 hr and then heated at 55° C. for 3 hr. It was then diluted with ethyl acetate (150 mL), washed sequentially with water (3×50 mL) and brine (50 mL), and dried over anhydrous MgSO4. Removal of solvent under vacuum provided a crude product of the titled compound, which was used in the next step without further purification.
Reaction SMILES: O=[C:2]([CH2:22][CH3:23])[CH2:3][C:4]1([C:17](OCC)=[O:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:30].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>C(O)C>[CH2:22]([CH:2]1[CH2:3][C:4]2([CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)[C:17](=[O:18])[NH:30]1)[CH3:23]
Reactant: [BH3-]C#N
Reactant: CCOC(=O)C1(CC(=O)CC)CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCO
Product: CCC1CC2(CCN(C(=O)OC(C)(C)C)CC2)C(=O)N1
Temperature: 80 °C

Procedure:
To a stirred solution of 1-tert-butyl 4-ethyl 4-(2-oxobutyl)piperidine-1,4-dicarboxylate (0.78 g, 2.38 mmol) in ethanol (24 mL) in a sealed tube was added ammonium acetate (2.39 g, 31.0 mmol), sodium cyanoborohydride (0.422 g, 6.72 mmol) and magnesium sulfate (1.577 g, 13.10 mmol) and the resulting mixture was heated for 16 hours at 80° C. The reaction mixture was filtered over CELITE® to remove MgSO4 and the filtrate was concentrated. The residue was re-dissolved in DCM (20 mL) and washed with saturated NaHCO3 (10 ml), water (10 mL) and brine (10 mL). The organic layer was dried over anhydrous MgSO4, filtered, concentrated, then purified by silica gel column chromatography (40 g RediSep Gold column) using (0-10) % MeOH/EtOAc to give the title compound.