Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[NH:12][C:11](=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.Cl[CH2:28][C:29]1[NH:33][N:32]=[N:31][N:30]=1>C1COCC1>[NH:30]1[C:29]([CH2:28][C@@H:10]2[CH2:9][C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[NH:12][C:11]2=[O:21])=[N:33][N:32]=[N:31]1
Reactant: O=C1CC[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N1
Reactant: ClCc1nnn[nH]1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1N[C@H](c2ccc(Cl)cc2)[C@@H](c2cccc(Cl)c2)C[C@H]1Cc1nnn[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 100 mL round-bottomed flask was placed under vacuum and heated with a heat gun to ensure dryness. The flask was allowed to cool to room temperature and a solution of 500 mg (1.56 mmol) of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 1, Step E) in THF (12 mL) under argon was added and cooled to 0° C. Butyllithium (1.6M in hexanes, 2440 μL, 3.90 mmol) was added followed by 5-chloromethyl-1H-tetrazole (185 mg, 1.561 mmol) and the reaction mixture was stirred for 15 minutes at 0° C. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The aqueous layer was acidified with 1M HCl. The aqueous layer was extracted with ethyl acetate (2×30 mL) and the combined organic layers were washed with sat. aq. NaCl solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by reversed phase preparatory HPLC (column: Gemini-NX C18 5 um column; Phenomonex, Torrance, Calif.; eluent: 0 to 100% MeCN +0.1% TFA in water +0.1% TFA, over 25 minutes) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:10][C:11]([O:13]CC)=[O:12])=[CH:5][CH:4]=1.[OH-].[Na+].[CH2:26](O)C>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[C:10]([CH3:26])[C:11]([OH:13])=[O:12])=[CH:7][CH:8]=1
Reactant: CCO
Reactant: CCOC(=O)C=C(c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C(=C(C)C(=O)O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 6.019 g of ethyl 3.3-bis(4-methoxyphenyl)acrylate (prepared as described in Preparation 107), 120 ml of ethanol and 80 ml of a 10% w/v aqueous solution of sodium hydroxide was stirred for 14 hours at room temperature. At the end of this time, the reaction mixture was heated on an oil bath at 100° C. for 4 hours, and then ethanol was distilled off. The residue was diluted with ice-water and washed with ethyl acetate. Concentrated hydrochloric acid was dropped onto the aqueous phase on an ice bath, to adjust the pH to a value of 2. The aqueous phase was extracted twice with methylene chloride. The combined methylene chloride extracts were washed with water dried over anhydrous sodium sulfate and condensed by evaporation under reduced pressure, to afford 5.117 g of the title compound as white crystals melting at 134°-135° C. (after recrystallisation from a mixture of methylene chloride and hexane).
Reaction SMILES: [NH2:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[S].[CH2:13](N)[CH2:14][NH2:15]>>[NH:5]1[CH2:13][CH2:14][N:15]=[C:4]1[C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH3:11])[C:2]=1[NH2:1]
Reactant: COc1cccc(C#N)c1N
Reactant: NCCN
Agent: [S]
Product: COc1cccc(C2=NCCN2)c1N
Temperature: 60 °C
Reaction time: 5 h
Yield: 50 %

Procedure:
2-Amino-3-methoxybenzonitrile (Step 2, 26.6 g, 179 mmol) was suspended in ethylenediamine (250 mL) and degassed thoroughly. To this was added sulfur powder (8 g, 251 mmol) slowly, then the reaction was heated to 60° C. and stirred 5 h. The reaction was then cooled, concentrated under reduced pressure, then treated with water (300 mL). The resulting suspension was collected by vacuum filtration and washed with water. The solid was purified via silica gel chromatography (50-100% EtOAc/hexanes). Fractions containing product were combined, the solvent removed under reduced pressure to give the title compound (17.3 g, 50%): HPLC MS RT=1.05 min, MH+=192.1; 1H NMR (DMSO-d6) δ: 3.81 (3H, s), 3.90 (4H, s), 6.65 (1H, t), 6.86 (1H, dd), 7.03 (1H, dd).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:7]=2.C(=O)([O-])[O-].[K+].[K+].Cl.[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][CH:34]2[CH2:39][CH2:38][CH:37]([O:40][CH2:41][C:42]([N:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[O:43])[CH2:36][CH2:35]2)=[CH:29][C:28]=1[C:50]([F:53])([F:52])[F:51])([O-:26])=[O:25]>CN(C=O)C.CCOC(C)=O>[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][CH:34]2[CH2:35][CH2:36][CH:37]([O:40][CH2:41][C:42]([N:44]3[CH2:49][CH2:48][N:47]([CH2:2][C:3]4[CH:4]=[N:5][C:6]5[C:11]([CH:12]=4)=[CH:10][CH:9]=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:7]=5)[CH2:46][CH2:45]3)=[O:43])[CH2:38][CH2:39]2)=[CH:29][C:28]=1[C:50]([F:53])([F:52])[F:51])([O-:26])=[O:25]
Reactant: FC(F)(F)c1ccc2cc(CCl)cnc2c1
Reactant: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(Cc2cnc3cc(C(F)(F)F)ccc3c2)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
To a solution of 3-chloromethyl-7-trifluoromethyl-quinoline (140 mg, 0.57 mmol, 1.1 eq.) in DMF (10 ml) was added potassium carbonate (345 mg, 2.5 mmol, 5 eq.) then 2-[4-(4-Nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-piperazin-1-yl-ethanone hydrochloride (233 mg, 0.5 mmol, 1 eq.) was added. The solution was stirred overnight at 70° C. and diluted with EtOAc (25 ml) and washed with water (25 ml), saturated aqueous lithium chloride (25 ml) and brine (25 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue, which was applied onto a silica gel column and eluted with methanol in dichloromethane. The semi-purified material was further purified by HPLC to afford 2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-[4-(7-trifluoromethyl-quinolin-3-ylmethyl)-piperazin-1-yl]-ethanone as a yellow solid (111.2 mg, 30%). (CI, m/z): [M+H]+ 640; 1H NMR (400 MHz, CDCl3): δ 1.20-1.36 (m, 2H), 1.40-1.54 (m, 2H), 2.08-2.21 (m, 4H), 2.46-2.61 (m, 4H), 3.32-3.49 (m, 2H), 3.53-3.62 (m, 2H), 3.63-3.71 (m, 2H), 3.76 (s, 2H), 4.20 (s, 2H), 4.46 (d, J=7.6 Hz, 1H), 6.63 (dd, J=9.1, 2.6 Hz, 1H), 6.85 (d, J=2.5 Hz, 1H), 7.75 (dd, J=8.5, 1.6 Hz, 1H) 7.94 (d, J=8.5 Hz, 1H), 8.02 (d, J=9.0 Hz, 1H), 8.13 (d, J=1.2 Hz, 1H), 8.43 (s, 1H), 9.03 (d, J=2.1 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:5][C:6]([CH3:11])([CH3:10])[C:7]([OH:9])=O>CCCCCC>[CH3:10][C:6]1([CH3:11])[C:7](=[O:9])[C:3]2[C:2]([CH3:1])=[C:14]([CH3:15])[C:13]([CH3:16])=[CH:12][C:4]=2[O:5]1
Reactant: Cc1cc(OC(C)(C)C(=O)O)cc(C)c1C
Solvent: CCCCCC
Product: Cc1cc2c(c(C)c1C)C(=O)C(C)(C)O2
Yield: 90 %

Procedure:
Using 2-(3,4,5-trimethyl phenoxy)-2-methylpropionic acid obtained in Reference Example 40, the title compound was synthesized in the same manner as in Reference Example 41. Yield 90%. Melting point: 77-78° C. (hexane).
Reaction SMILES: [CH3:1][C:2](/[CH:4]=[CH:5]/[CH:6]1[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][CH2:9][C:7]1=[CH2:8])=[O:3].Cl.NO.C([O-])(=[O:20])C.[Na+]>C(O)C.O>[CH2:8]=[C:7]1[CH2:9][CH2:10][CH2:11][C:12]([CH3:14])([CH3:13])[CH:6]1[C:5](=[O:20])[CH2:4][C:2](=[O:3])[CH3:1]
Reactant: C=C1CCCC(C)(C)C1/C=C/C(C)=O
Reactant: CC(=O)[O-]
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=C1CCCC(C)(C)C1C(=O)CC(C)=O
Reaction time: 0.08 h
Yield: 96 %

Procedure:
A solution of 30 g of γ-ionone in 75 ml of ethanol was added to a solution of hydroxylamine hydrochloride (12 g) and sodium acetate (21.6 g) in 30 ml of water. The addition was completed within 5 minutes. The reaction was slightly exothermic, the reaction mixture was stirred for 30 minutes, then it was concentrated under reduced pressure. Thereafter 30 ml of water and 30 ml of ether were added to the said mixture, and it was extracted with petroleum-ether. After drying and concentration, the combined organic extracts yielded a thick oil (31.2 g). An aliquot was distilled in a small distillation tube at a temperature of 180° and a pressure of 0.001 Torr. There was thus obtained a pure product which, as shown by vapour phase chromatography, constituted a mixture of the γ-ionone oxime in the form of the two syn- and anti-isomers in a ratio of 20:80.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([C:12]([OH:14])=O)[C:4](=[O:11])[N:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2.C(N1C=CN=C1)([N:17]1C=CN=C1)=O.N>CN(C)C=O>[CH:1]1[CH:2]=[C:3]([C:12]([NH2:17])=[O:14])[C:4](=[O:11])[N:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2
Reactant: O=C(O)c1ccc2ccccn2c1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2ccccn2c1=O
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
To a suspension of 4H-quinolizin-4-one-3-carboxylic acid (2.27 g) in dry N,N-dimethylformamide (22.7 ml) was added 1,1'-carbonyldiimidazole (2.92 g). The resulting suspension was heated to 100° C. and kept for 30 minutes. After cooling to room temperature the resulting solution was treated with dry ammonia and stirred for 20 minutes. The crystals separated was collected by filtration and washed with water to give 4H-quinolizin-4-one-3-carboxamide (1.94 g).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[N:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[C:32]([OH:36])[CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:36][C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([C:27]3[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=3)[CH:31]=2)=[N:3][CH:4]=1
Reactant: Oc1cccc(-c2ccncc2)c1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2cccc(-c3ccncc3)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 3-pyridin-4-ylphenol (J. Heterocycl. Chem. 1991, 28, 933): 1H-NMR (CDCl3) δ 8.69 (2H, dd, J=4.4, 1.6 Hz), 8.57 (1H, d, J=2.8 Hz), 8.15 (1H, d, J=2.6 Hz), 8.12 (1H, br.s), 8.00 (2H, dd, J=6.8, 1.9 Hz), 7.61–7.42 (7H, m), 7.27–7.22 (1H, m), 5.45–5.34 (1H, m), 3.89 (3H, s), 1.61 (3H, d, J=6.9 Hz); MS (ESI) m/z 488 (M+H)+, 486 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[NH:4][N:3]=1.C(O)(=O)C.[Br:12][CH:13]([C:19](=O)[CH3:20])[C:14](OCC)=[O:15]>C(OCC)C>[Br:12][C:13]1[C:19]([CH3:20])=[N:7][C:5]2[N:4]([N:3]=[C:2]([CH3:1])[CH:6]=2)[C:14]=1[OH:15]
Reactant: Cc1cc(N)[nH]n1
Reactant: CCOC(=O)C(Br)C(C)=O
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1cc2nc(C)c(Br)c(O)n2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.1 %

Procedure:
A mixture of 3-methyl-1H-pyrazol-5-amine (0.186 g, 1.92 mmol) and acetic acid (3.71 mL, 65.2 mmol) was slightly heated until complete dissolution and the resultant solution was cooled to RT and mixed with ethyl 2-bromo-3-oxobutanoate (1.20 g, 5.74 mmol). The resultant reaction mixture was stirred at RT for 16 h, after which time the reaction mixture was diluted with diethyl ether, cooled to 0° C. and stirred at that temperature for 30 min. The white solid precipitate was separated by filtration and washed with cold diethyl ether and dried to give the desired product (363 mg, 78%) as a white solid. LCMS calculated for C8H9BrN3O (M+H)+: m/z=242.0, 244.0. found: 241.9, 244.0.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]1([C:14]2[C:15]3[CH:16]=[CH:17][C:18]([C:50]([O:52]C(C)(C)C)=[O:51])=[CH:19][C:20]=3[N:21]3[CH2:27][C:26]([C:28]4[N:32]([CH:33]5[CH2:35][CH2:34]5)[N:31]=[C:30]([CH:36]([CH3:38])[CH3:37])[C:29]=4[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:25][C:24]4[CH:44]=[C:45]([O:48][CH3:49])[CH:46]=[CH:47][C:23]=4[C:22]=23)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>ClC(Cl)C>[CH:8]1([C:14]2[C:15]3[CH:16]=[CH:17][C:18]([C:50]([OH:52])=[O:51])=[CH:19][C:20]=3[N:21]3[CH2:27][C:26]([C:28]4[N:32]([CH:33]5[CH2:34][CH2:35]5)[N:31]=[C:30]([CH:36]([CH3:37])[CH3:38])[C:29]=4[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:25][C:24]4[CH:44]=[C:45]([O:48][CH3:49])[CH:46]=[CH:47][C:23]=4[C:22]=23)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CCOC(=O)c1c(C(C)C)nn(C2CC2)c1C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC(C)(C)C)cc3n2C1
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(C(C)C)nn(C2CC2)c1C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Reaction time: 2.5 h
Yield: 99.8 %

Procedure:
TFA (2.8 mL, 37 mmol) was added to a stirring solution of tert-butyl 13-cyclohexyl-6-(1-cyclopropyl-4-(ethoxycarbonyl)-3-isopropyl-1H-pyrazol-5-yl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-10-carboxylate (350 mg, 0.527 mmol) in dichloroethane (5 mL) at room temperature. The reaction was allowed to stir for 2.5 hrs and then was concentrated to dryness to give expected product (320 mg, 0.526 mmol, quant) consistent by LCMS.
Reaction SMILES: [CH:1]1([CH:4]([N:8]2[CH:12]=[C:11]([C:13]3[N:18]4[CH:19]=[CH:20][N:21]=[C:17]4[CH:16]=[C:15]([C:22]4[CH:23]=[N:24][N:25](COCC[Si](C)(C)C)[CH:26]=4)[N:14]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:25]1[CH:26]=[C:22]([C:15]2[N:14]=[C:13]([C:11]3[CH:10]=[N:9][N:8]([CH:4]([CH:1]4[CH2:3][CH2:2]4)[CH2:5][C:6]#[N:7])[CH:12]=3)[N:18]3[CH:19]=[CH:20][N:21]=[C:17]3[CH:16]=2)[CH:23]=[N:24]1
Reactant: C[Si](C)(C)CCOCn1cc(-c2cc3nccn3c(-c3cnn(C(CC#N)C4CC4)c3)n2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCC(C1CC1)n1cc(-c2nc(-c3cn[nH]c3)cc3nccn23)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.5 %

Procedure:
To a solution of 3-cyclopropyl-3-(4-(7-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (Example 32, 65.0 mg, 0.137 mmol) in DCM (2 mL) was added trifluoroacetic acid (2 mL) and the mixture was stirred at ambient temperature for 1.5 hours. The mixture was concentrated and the residue was partitioned into EtOAc (3 mL) and saturated NaHCO3 (3 mL). The biphasic mixture was stirred for 15 minutes and NaCl was added until saturated. The EtOAc layer was removed and the remaining aqueous portion was extracted with EtOAc. The combined EtOAc extracts were dried over MgSO4, filtered through a Celite plug and concentrated. The residual solid was dissolved in 10% MeOH/EtOAc and eluted through a SiO2 column using 10% MeOH/EtOAc for elution. The solution was concentrated to give the title compound (46 mg, 98% yield) as a white solid. MS (apci) m/z=345.2 (M+H).
Reaction SMILES: [NH2:1][C@H:2]([C:20]([OH:22])=[O:21])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:19]=[CH:18][C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:9]=1[N+:10]([O-:12])=[O:11].C1C(=O)N([O:30][C:31]([O:33][CH2:34][CH:35]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41]3[C:36]2=[CH:37][CH:38]=[CH:39][CH:40]=3)=O)C(=O)C1>C(COC)OC.C([O-])([O-])=O.[Na+].[Na+]>[NH:1]([C:31]([O:33][CH2:34][CH:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:42]2[C:47]1=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:30])[C@H:2]([C:20]([OH:22])=[O:21])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:19]=[CH:18][C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: N[C@@H](CCCCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(N[C@@H](CCCCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(=O)O)OCC1c2ccccc2-c2ccccc21
Reaction time: 8 h

Procedure:
Fmoc-Lys(Dnp) was prepared from Lys(Dnp) as follows. Fmoc N-hydroxysuccinimide ester (1.89 g; 5.60 mmol) was dissolved in 30 mL of dimethoxyethane and stored at 4° C. Lys(Dnp) (1.63 g; 4.67 mmol) was dissolved in 10 mL of 10% aqueous Na2CO3 and added slowly to the dimethoxyethane solution. The reaction proceeded for 2 hours at 4° C. and overnight at room temperature. The solution was filtered, and the filtrate acidified to a pH of about 3 with concentrated HCl. Dimethoxyethane was removed by heating the solution under reduced pressure. The solution was extracted with ethyl acetate, and the ethyl acetate layer reduced by heating under reduced pressure to an oil. The oil [Fmoc-Lys(Dnp)] was used without further purification.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([CH:14]=O)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]C)=O>>[NH:1]([C:8]1[N:13]=[C:12]([CH2:14][N:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C:22]2=[O:24])[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccnc(Nc2ccccc2)n1
Reactant: COC(=O)CCCCN
Agent: Cl
Product: O=C1CCCCN1Cc1ccnc(Nc2ccccc2)n1
Yield: 48.8 %

Procedure:
By an analogous process to Method 4, 2-anilinopyrimidin-4-carbaldehyde (Method 3; 3.24, 16.2 mmol) was treated with methyl 5-aminopentanoate hydrochloride (3.0 g, 17.9 mmol) to give the title compound (2.23 g, 51%) as a pale yellow solid. NMR: 1.85 (m, 4H), 2.5 (s, 2H), 3.4 (s, 2H), 4.58 (s, 2H), 6.63 (d, 1H), 7.05 (t, 1H), 7.3 (m, 3H), 7.62 (d, 2H), 8.34 (d, 1H); m/z 305.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[NH:40]N>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:40][C:35]3[C:36]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:37][CH:38]=[CH:39][C:34]=3[CH3:33])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(Br)c3)CC2)c1
Reactant: Cc1ccccc1NN
Agent: Cl
Product: Cc1cccc2c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(-c3cccc(Br)c3)[nH]c12

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-(2-methylphenyl)hydrazine hydrochloride: ESMS m/e: 572 (M+H)+.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11]1[CH:27]=[CH:26][C:14]([CH2:15][NH:16][C:17]2([C:21]3[S:22][CH:23]=[CH:24][N:25]=3)[CH2:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1.[CH2:28]([Sn:32](Cl)([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH3:31]>O1CCCC1>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][NH:16][C:17]2([C:21]3[S:22][C:23]([Sn:32]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:24][N:25]=3)[CH2:20][CH2:19][CH2:18]2)=[CH:26][CH:27]=1
Reactant: COc1ccc(CNC2(c3nccs3)CCC2)cc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(C2(NCc3ccc(OC)cc3)CCC2)s1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A freshly prepared solution of lithium diisopropylamide (12.83 mmol) in anhydrous tetrahydrofuran (15 mL) at −10° C. was added dropwise via cannula over 20 minutes to a −78° C. solution of N-(4-methoxybenzyl)-1-(thiazol-2-yl)cyclobutanamine (1.6 g, 5.83 mmol) (Example 112B) in anhydrous tetrahydrofuran (45 mL). The temperature was maintained below −70° C. during the addition, and after the addition, the reaction was stirred 45 minutes at −78° C. Tributyltin chloride (1.89 mL, 7.00 mmol) was then added dropwise. The cold bath was removed, and the reaction was allowed to warm to ambient temperature over 20 minutes. The reaction was quenched with saturated ammonium chloride, and the product was extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 10% to 20% ethyl acetate in hexanes, to provide the title compound. MS ESI(+) m/z 565.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[N+:9]([O-:11])=[O:10].[H-].[Na+].I[CH3:15]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]([CH3:15])[C:4](=[O:8])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CI
Reactant: O=c1[nH]ccc(Cl)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc(Cl)c([N+](=O)[O-])c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
To a stirred solution of 4-chloro-3-nitropyridin-2(1H)-one (3.0 g, 17 mmol) in N,N-dimethylformamide (50 mL) was added sodium hydride (60% w/w, 1.0 g, 25.5 mmol) in batches at 0° C. The mixture was stirred at room temperature for 30 minutes. Then iodomethane (2.9 g, 20.4 mmol) was added dropwise to the above solution at room temperature. The resultant solution was stirred at room temperature for 12 hours. Once starting material was consumed, the reaction mixture was quenched with ice water (100 mL) at 0-10° C., and extracted with ethyl acetate (100 mL×3). The organic phase was washed with brine (100 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give 4-chloro-1-methyl-3-nitropyridin-2(1H)-one (3 g, 94%) as a yellow solid. LRMS (M+H+) m/z: calcd 188.0. found 188.
Reaction SMILES: Br[CH2:2][C:3]([N:5]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([CH3:25])[CH:19]=1)[CH2:6][CH2:7][C:8]1[CH:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=1)=[O:4].[CH3:26][C:27]1[NH:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CC(OC)(C)C>[CH3:25][C:20]1[CH:19]=[C:18]([N:5]([CH2:6][CH2:7][C:8]2[CH:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)[C:3](=[O:4])[CH2:2][N:28]2[C:29]3[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=3[N:31]=[C:27]2[CH3:26])[CH:23]=[CH:22][C:21]=1[CH3:24]
Reactant: Cc1nc2ccccc2[nH]1
Reactant: Cc1ccc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)CBr)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CC#N
Product: Cc1ccc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)Cn2c(C)nc3ccccc32)cc1C
Yield: 57.6 %

Procedure:
A suspension of 2-bromo-N-(3,4-dimethyl-phenyl)-N-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-acetamide (134 mg, 0.32 mmol), 2-methylbenzimidazole (85 mg, 0.65 mmol) and potassium carbonate (67 mg, 0.48 mmol) in acetonitrile (1 mL) was irradiated in the microwave for 20 min. at 140° C. The reaction mixture was diluted with TBME (15 mL) and washed with water (15 mL) and brine (15 mL). The aqueous layers were extracted with tert-butylmethylether (15 mL) and the combined organic layers dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate:methanol=50:50:0 to 0:95:5) afforded the title compound (86 mg, 57%) as a light brown oil. MS m/e: 467.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-])=O.[NH4+].[Cl-]>C(O)C.O.[Fe]>[NH2:11][C:3]1[CH:4]=[C:5]([C:8](=[O:10])[CH3:9])[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: CC(=O)c1ccc(C)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(=O)c1ccc(C)c(N)c1
Temperature: 80 °C
Yield: 89.4 %

Procedure:
A mixture of 1-(4-methyl-3-nitrophenyl)ethanone (5.37 g, 30 mmol), iron powder (8.4 g, 150 mmol) and NH4Cl (1.62 g, 30 mmol) in ethanol (100 mL) and water (10 mL) was heated at 80° C. overnight. The mixture was then heated at 110° C. for 5 hours and allowed to cool to room temperature. The resulting suspension was filtered and the filter cake was washed with ethanol. The filtrate was concentrated and the residue was dissolved in ethanol and filtered. The filtrate was concentrated to give 4 g of the title compound as a yellow solid. MS(ESI(+)) m/e 149.8 (M+H)+.