Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.[F:34][CH:35]([F:46])[O:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40](O)=[O:41].Cl.CN(C)CCCN=C=NCC>CC#N>[F:34][CH:35]([F:46])[O:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40]([NH:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13])=[O:41]
Reactant: O=C(O)c1cccc(OC(F)F)c1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4cccc(OC(F)F)c4)c3C2=O)C(=O)N1
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.70 g, 2.2 mmol) in CH3CN (60 ml), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.82 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzenetriazole (0.35 g, 2.6 mmol) and 3-difluoromethoxy benzoic acid (0.45 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.62 g, 3.2 mmol). After stirring at room temperature overnight, the reaction mixture was concentrated in vacuo, and the residue was dissolved in CH2Cl2 (50 mL). The CH2Cl2 solution was then washed with water (2×30 mL) and brine (30 mL), and dried over MgSO4. Solvent was removed in vacuo, and the resulting oil was purified by ISCO silica gel flash chromatography (eluent: 0% MeOH in CH2Cl2 to 5% MeOH in 10 min then stay at this ratio for 15 min) to afford 3-difluoromethoxy-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-benzamide as a white solid (0.64 g, 65%): mp, 164-166° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.6 min (99%); 1H NMR (DMSO-d6): δ 2.04-2.09 (m, 1H), 2.53-2.64 (m, 2H), 2.85-2.93 (m, 1H), 4.92 (d, J=6.0 Hz, 2H), 5.14-5.20 (dd, J=5, 12 Hz, 1H), 6.97-7.86 (m, 8H), 8.97 (t, J=6.0 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.95, 30.91, 38.29, 48.86, 113.18, 116.60, 119.08, 120.02, 121.91, 125.34, 127.12, 128.74, 129.58, 131.48, 131.54, 113.18, 116.60, 119.08, 120.02, 121.91, 125.34, 127.12, 127.74, 128.58, 131.48, 131.54, 132.96, 134.64, 138.89, 147.66, 165.60, 166.94, 167.51, 169.81, 172.73. Anal Calcd for C22H17F2N3O6: C, 57.77; H, 3.75; N, 9.19; F, 8.31. Found: C, 57.62; H, 3.60; N, 8.99; F, 8.32.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[C:3]=1[NH:4][C:5](=[O:20])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:18][CH2:17][CH2:16][N:15]([CH3:19])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.[H][H]>[C].[Pd].CO>[NH2:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:2]([OH:1])[C:3]=1[NH:4][C:5](=[O:20])[C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:18][CH2:17][CH2:16][N:15]([CH3:19])[CH2:14][CH2:13]2)=[CH:10][CH:11]=1
Reactant: [H][H]
Reactant: CN1CCCN(c2ccc(C(=O)Nc3c(O)cccc3[N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCCN(c2ccc(C(=O)Nc3c(N)cccc3O)cc2)CC1
Yield: 81.9 %

Procedure:
A mixture of 2.14 g of 2′-hydroxy-4-(4-methyl-1,4-diazepan-1-yl)-6′-nitrobenzanilide, 43 ml of methanol and 467 mg of 10% palladium-carbon (wetting rate: 54.2%) was stirred in a hydrogen atmosphere of atmospheric pressure at 30° C. until the absorption of hydrogen had stopped. The catalyst was filtered out and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography using chloroform-methanol (20:1 to 10:1) to give 1.61 g of 2′-amino-6′-hydroxy-4-(4-methyl-1,4-diazepan-1-yl)benzanilide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[C:18]([OH:20])=[O:19].[CH2:21]1C[O:24][CH2:23][CH2:22]1.C(Cl)(=O)CC>N1C=CC=CC=1>[C:12]1([C:7]2[CH:6]=[C:5]([C:18]([OH:20])=[O:19])[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:23](=[O:24])[CH2:22][CH3:21])[CH:3]=3)[N:8]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccc2nc(-c3ccccc3)cc(C(=O)O)c2c1
Reactant: C1CCOC1
Agent: CCC(=O)Cl
Solvent: c1ccncc1
Product: CCC(=O)Nc1ccc2nc(-c3ccccc3)cc(C(=O)O)c2c1

Procedure:
6-amino-2-phenylquinoline-4-carboxylic acid (378 mg, 1.4 mmol) was suspended in pyridine (0.2 mL) and anhydrous THF (25 mL), and propionyl chloride (370 mg, 4 mmol) was added dropwise to the suspension with vigorous stirring. After reflux for 1.5 hours, the reaction solution was concentrated to approximately 10 mL. To the residue, ethyl acetate was added, and the deposited precipitate was collected by filtration and washed with water and ethyl ether. The crystal was recrystallized from glacial acetic acid to obtain the title compound (362 mg, 1.13 mmol) as a yellow powder.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15]Cl)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[C:17]1([CH3:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[Ti](Cl)(Cl)(Cl)Cl.C(O)C>[CH3:23][C:17]1[CH:22]=[CH:21][C:20]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][C:12]([CH2:15][C:6]4[CH:7]=[CH:8][C:3]([CH3:2])=[CH:4][CH:5]=4)=[CH:11][CH:10]=3)=[CH:5][CH:4]=2)=[CH:19][CH:18]=1
Reactant: ClCc1ccc(-c2ccc(CCl)cc2)cc1
Reactant: Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCO
Product: Cc1ccc(Cc2ccc(-c3ccc(Cc4ccc(C)cc4)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A 500 mL flask was charged with 4,4′-bis(chloromethyl)-1,1′-biphenyl (25.1 g) and toluene (300 mL). To the clear solution stirring at room temperature was added titanium tetrachloride (1 mL) and the mixture instantly became dark brown. After 5 minutes, a second 1 mL aliquot of catalyst was added. After stirring overnight at room temperature, ethanol (10 mL) was added to kill the catalyst, and the mixture became a light, cream colored suspension. The organic layer was concentrated to dryness under vacuum on a rotary evaporator. The tan solid was suspended in 200 mL boiling toluene and treated with MgSO4. Vacuum filtration through glass fiber filter paper gave a clear solution to which 200 mL heptane was added while hot. The slightly turbid solution was cooled to room temperature, then in a freezer overnight to complete crystallization. White crystals, 17.4 g, mp=161.8 C, were recovered. GC/MS, HNMR, CNMR and IR were all consistent with the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[C:21]([Cl:23])[N:20]=[C:19]([C:24]([OH:26])=O)[CH:18]=3)[CH2:13][CH2:12]2)=[O:9])[NH:5][C:6]=1[CH3:7].Cl.[O:28]([NH2:30])[CH3:29]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[C:21]([Cl:23])[N:20]=[C:19]([C:24]([NH:30][O:28][CH3:29])=[O:26])[CH:18]=3)[CH2:13][CH2:12]2)=[O:9])[NH:5][C:6]=1[CH3:7]
Reactant: CON
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)nc(Cl)n3)CC2)cc1Br
Agent: Cl
Product: CONC(=O)c1cc(N2CCC(NC(=O)c3cc(Br)c(C)[nH]3)CC2)nc(Cl)n1

Procedure:
Title compound was synthesized by an analogous method to Example 8 by coupling 6-(4-{[(4-bromo-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-2-chloropyrimidine-4-carboxylic acid (Example 31) with methoxylamine hydrochloride (commercially available).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.Cl.[Cl:13][CH2:14][CH2:15][N:16]([CH2:24][CH2:25]Cl)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[ClH:13].[CH2:17]([N:16]1[CH2:24][CH2:25][C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)([C:10]#[N:11])[CH2:14][CH2:15]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1cccc(CC#N)c1
Reactant: ClCCN(CCCl)Cc1ccccc1
Agent: Cl
Product: COc1cccc(C2(C#N)CCN(Cc3ccccc3)CC2)c1

Procedure:
Prepare by the method of example 74.1 using 3-methoxyphenyl-acetonitrile (3.68 g, 25 mmol) and N,N-bis(2-chloroethyl)-N-benzylamine hydrochloride (7.05 g, 26.25 mmol) to the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:11])[N:6]([CH2:8][CH2:9][OH:10])[CH:7]=1.[H-].[Na+].Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:25][CH3:26])=[CH:22][CH:23]=2)[N:18]=[CH:17][CH:16]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:11])[N:6]([CH2:8][CH2:9][O:10][C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH3:26])=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)[CH:7]=1
Reactant: COc1ccc2c(Cl)ccnc2c1
Reactant: O=c1ccc(Br)cn1CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(OCCn3cc(Br)ccc3=O)ccnc2c1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of 5-bromo-1-(2-hydroxyethyl)pyridin-2(1H)-one (3000 mg, 13.7 mmol) in DMF (25 mL) was added sodium hydride (60% dispersion in mineral oil, 632.6 mg, 27.5 μmol) portionwise. After stirred for 30 min at 23° C., additional DMF (20 mL) was added to the thick suspension. To this was added 4-chloro-7-methoxyquinoline (2664 mg, 13.7 mmol). Upon completion, the reaction was quenched with 5% NaHCO3 (100 mL), and the aqueous was extracted with CH2Cl2 (4×75 mL). The combined organics were dried over MgSO4, concentrated from toluene, and purified on 80 grams of silica eluting with 30-80% of 5% MeOH/CH2Cl2. The product was isolated as a white solid. MS (ESI pos. ion) m/z (MH+): 375/377. Calc'd exact mass for C17H15BrN2O3: 374. 13C NMR (101 MHz, CDCl3) δ ppm 48.66, 54.80, 64.75, 97.11, 98.75, 106.69, 114.92, 118.10, 121.48, 121.78, 137.81, 142.38, 150.57, 151.00, 159.87, 160.24, 160.40
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:11]([CH2:12][C@H:13]([C:25]([OH:27])=[O:26])[NH:14]C(OCC2C=CC=CC=2)=O)=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([CH2:8][N:9]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:11]([CH2:12][C@H:13]([C:25]([OH:27])=[O:26])[NH2:14])=[CH:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1cc(C[C@@H](NC(=O)OCc2ccccc2)C(=O)O)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Cn1cc(C[C@@H](N)C(=O)O)c2ccccc21
Yield: 90.9 %

Procedure:
The 136 g of product obtained in Step A are diluted with 1.5 liters of methanol and hydrogenated in the presence of 5 g of 10% Pd/C under an H2 pressure of 1.2 bars. After 12 hours of reaction at ambient temperature, the solution is filtered and then concentrated in vacuo. 87 g of the expected product are obtained in the form of a beige powder.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][N:10](CC3C=CC=CC=3)[C:9]=2[C:8](=[O:21])[N:7]([CH2:22][CH3:23])[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]>C(O)(=O)C.[OH-].[OH-].[Pd+2]>[CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][NH:10][C:9]=2[C:8](=[O:21])[N:7]([CH2:22][CH3:23])[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)n(CC)c(=O)c2c1ncn2Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCCCn1c(=O)n(CC)c(=O)c2[nH]cnc21
Reaction time: 8 h
Yield: 89 %

Procedure:
3-butyl-1-ethyl-7-(phenylmethyl)-3,7-dihydro-1H-purine-2,6-dione (0.353 g, 1.08 mmol) was dissolved in acetic acid (30 mL), 20% palladium hydroxide on carbon (0.238 g) was added, and the mixture was shaken under hydrogen (at 50 psi) overnight. The catalyst was removed by filtration through Celite® and washed with acetic acid. The filtrate was concentrated under reduced pressure to yield the title compound (0.227g, 89%); 1H NMR (400 MHz; CDCl3) δ: 0.97 (3H, t), 1.28 (3H, t), 1.38-1.47 (2H, m), 1.74-1.82 (2H, m), 4.12-4.17 (4H, m), 7.80 (1H, s); m/z 237[MH+].
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH:7](O)[CH3:8])[CH2:3][CH2:2]1.[OH:10][C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][CH:21]=1)[C:14]([O:16]CC)=[O:15]>>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][O:10][C:11]2[CH:12]=[C:13]([CH:19]=[CH:20][CH:21]=2)[C:14]([OH:16])=[O:15])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: CC(O)C1CCOCC1
Product: O=C(O)c1cccc(OCCC2CCOCC2)c1

Procedure:
Prepared from tetrahydro-2H-pyran-4-yl-ethanol and ethyl 3-hydroxybenzoate.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[Cl:37][C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=1)[CH2:41][CH2:42][NH2:43]>>[Cl:37][C:38]1[CH:39]=[C:40]([CH2:41][CH2:42][NH:43][C:3]([C:5]2[N:14]3[C:8]([CH2:9][N:10]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[CH3:33])=[C:23]([CH3:34])[CH:22]=4)=[O:20])[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13]3)=[CH:7][CH:6]=2)=[O:4])[CH:44]=[CH:45][CH:46]=1
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Reactant: NCCc1cccc(Cl)c1
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCCc4cccc(Cl)c4)n3Cc3ccccc32)cc1C

Procedure:
The title compound was synthesized in the manner of Example 13 from 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 and 3-chlorophenethylamine, m.p. 174-176°C. MS [(+)ESI, m/z]: 574 [M+H]+ Anal. Calcd for C36H32CIN3O2: C, 75.31; H,5.62; N, 7.32. Found: C, 75.19; H, 5.55; N, 7.22.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].[OH-].[Na+].O.[Br:11][C:12]([CH3:17])([CH3:16])[C:13](Br)=[O:14]>C(Cl)(Cl)Cl>[Br:11][C:12]([CH3:17])([CH3:16])[C:13]([NH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4])=[O:14]
Reactant: CC(C)(Br)C(=O)Br
Reactant: CC(C)(N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(Br)C(=O)NC(C)(C)C(=O)O
Temperature: -10 °C
Reaction time: 15 h
Yield: 33.3 %

Procedure:
A stirring mixture of 2-aminoisobutyric acid (28.5 g, 0.28 mol), sodium hydroxide (11.1 g, 0.28 mol), 115 mL of water, and 30 mL of chloroform was cooled to −10° C. and stirred vigorously while a solution of 2-bromisobutyryl bromide (57.0 g, 0.25 mol) in 85 mL of chloroform was added dropwise. When addition was complete, the reaction flask was removed from the cold bath and allowed to warm to room temperature. The mixture stirred for 15 hours. Concentrated HCl (10 mL) was then added to the mixture and stirring was continued for another 30 minutes. A white solid (32.0 g) was filtered off, and the aqueous and organic phases of the filtrate were separated. The organic phase was dried over magnesium sulfate, filtered, and evaporated at reduce pressure to leave a white solid (21.0 g). The two solid portions were combined and recrystallized from toluene to afford 27.1 g (43%) of the title compound as a white solid with IR and NMR spectra consistent with the desired product.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][C:13]([C:16]([O:18]C(C)(C)C)=[O:17])([CH3:15])[CH3:14])/[C:8]([OH:10])=[O:9])[N:3]=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][C:13]([C:16]([OH:18])=[O:17])([CH3:15])[CH3:14])/[C:8]([OH:10])=[O:9])[N:3]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)O)c1nsc(N)n1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(C)(O/N=C(\C(=O)O)c1nsc(N)n1)C(=O)O
Reaction time: 0.17 h
Yield: 88 %

Procedure:
A solution of (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetic acid (17.8 g) and anisole (18 ml) in trifluoroacetic acid (36 ml) was stirred for 4.0 hours at room temperature. The reaction mixture was concentrated under reduced pressure and an aqueous solution of sodium bicarbonate was added thereto to adjust to pH 6.0. The aqueous solution was washed with ethyl acetate, adjusted to pH 3.8 with 6N hydrochloric acid and washed with ethyl acetate. The aqueous layer was separated and 6N hydrochloric acid was added thereto to adjust to pH 1.0. After the mixture was stirred for 10 minutes, the resultant precipitate was collected by filtration to give (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetic acid (13.0 g).
Reaction SMILES: CO[C:3](=O)[NH:4][CH2:5][CH2:6][CH:7]([C:14]1[CH:22]=[C:21]2[C:17]([CH:18]=[CH:19][NH:20]2)=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C2C(=CC(C(C3C=CC=CC=3)CCNC)=CC=2)C=C1>>[NH:20]1[C:21]2[C:17](=[CH:16][CH:15]=[C:14]([CH:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:6][CH2:5][NH:4][CH3:3])[CH:22]=2)[CH:18]=[CH:19]1
Reactant: COC(=O)NCCC(c1ccccc1)c1ccc2cc[nH]c2c1
Agent: CNCCC(c1ccccc1)c1ccc2[nH]ccc2c1
Product: CNCCC(c1ccccc1)c1ccc2cc[nH]c2c1
Yield: 24 %

Procedure:
[3-(1H-Indol-6-yl)-3-phenyl-propyl]-methyl-amine (110 mg, 24% yield) XVI was prepared as a hydrochloride salt from [3-(1H-indol-6-yl)-3-phenyl-propyl]-carbamic acid methylester (XV), using the procedure described for preparation of [3-(1H-indol-5-yl)-3-phenyl-propyl]-methyl-amine XI (see Example 2). MS (M+H)=265.
Reaction SMILES: [C:1]1([C:6]2[C:14]3[C:13]([C:15]#[N:16])=[CH:12][N:11]=[C:10]([O:17][CH3:18])[C:9]=3[N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1>CO.[Pd]>[CH:1]1([C:6]2[C:14]3[C:13]([C:15]#[N:16])=[CH:12][N:11]=[C:10]([O:17][CH3:18])[C:9]=3[N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:26])[CH3:25])[CH:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ncc(C#N)c2c(C3=CCCC3)cn(COCC[Si](C)(C)C)c12
Agent: [Pd]
Solvent: CO
Product: COc1ncc(C#N)c2c(C3CCCC3)cn(COCC[Si](C)(C)C)c12
Temperature: 50 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
To a solution of 3-(cyclopent-1-en-1-yl)-7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-4-carbonitrile (690 mg) in methanol (5 mL) was added 10% palladium/carbon (100 mg). The reaction mixture was stirred overnight under hydrogen atmosphere (1 atm) at 50° C., and the insoluble substance was removed by filtration through Celite. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (519 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([CH:18]([N:24]([CH3:26])[CH3:25])[CH2:19][CH2:20][CH2:21][CH2:22][OH:23])[CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1.C(N(CC)CC)C>CCOCC>[CH3:1][O:2][CH2:3][C:4]([O:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]([C:14]1([C:11]2[CH:10]=[CH:9][C:8]([Cl:7])=[CH:13][CH:12]=2)[CH2:15][CH2:16][CH2:17]1)[N:24]([CH3:26])[CH3:25])=[O:5]
Reactant: CN(C)C(CCCCO)C1(c2ccc(Cl)cc2)CCC1
Reactant: COCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COCC(=O)OCCCCC(N(C)C)C1(c2ccc(Cl)cc2)CCC1
Reaction time: 24 h

Procedure:
Methoxyacetyl chloride was added dropwise to a solution of the product of Example 144 and triethylamine in ether and the mixture stirred for 24 hours and then poured into ice-cold aqueous sodium hydroxide solution. The mixture was extracted with ether and the extract washed, dried and evaporated to given an oil. which was purified by flash chromatography on a silica column using ether as eluant to give 5-[1-(4-chlorophenyl)cyclobutyl]-5-dimethylaminopentyl 2-methoxyacetate as an oil the boiling point of which was not determined.
Reaction SMILES: N1C=CN=C1CN1C(=O)COC2N=C(C3C=CC(C4(N)CCC4)=CC=3)C(C3C=CC=CC=3)=CC1=2.C(OC(=O)[NH:41][C:42]1([C:46]2[CH:51]=[CH:50][C:49]([C:52]3[C:53]([C:63]4[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=4)=[CH:54][C:55]4[NH:56][C:57](=[O:62])[NH:58][CH2:59][C:60]=4[N:61]=3)=[CH:48][CH:47]=2)[CH2:45][CH2:44][CH2:43]1)(C)(C)C>>[NH2:41][C:42]1([C:46]2[CH:47]=[CH:48][C:49]([C:52]3[C:53]([C:63]4[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=4)=[CH:54][C:55]4[NH:56][C:57](=[O:62])[NH:58][CH2:59][C:60]=4[N:61]=3)=[CH:50][CH:51]=2)[CH2:45][CH2:44][CH2:43]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)NC4)cc2)CCC1
Agent: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(Cc3ncc[nH]3)C(=O)CO4)cc2)CCC1
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)NC4)cc2)CCC1
Yield: 108 %

Procedure:
Following the procedure for 1-((1H-imidazol-2-yl)methyl)-6-(4-(1-aminocyclobutyl)phenyl)-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one, tert-butyl(1-(4-(2-oxo-7-phenyl-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-6-yl)phenyl)cyclobutyl)carbamate (12 mg, 0.03 mmol) was reacted to afford the title compound (12 mg, 97%). LCMS (Method D): RT=0.684 min, M+1=371. 1H NMR (500 MHz, MeOD): 7.42-7.38 (4H, m), 7.31-7.28 (3H, m), 7.23 (1H, s), 7.21-7.18 (2H, m), 4.66 (2H, s), 2.81-2.75 (2H, m), 2.63-2.57 (2H, m), 2.26-2.24 (1H, m), 1.99-1.97 (1H, m).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.FC(F)(F)S(O)(=O)=O.[C:21](Cl)(=[O:23])[CH3:22].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][C:2]([F:11])([F:12])[F:1])=[CH:5][C:6]=1[C:21](=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: Oc1ccc(CC(F)(F)F)cc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(CC(F)(F)F)ccc1O
Temperature: 150 °C

Procedure:
To a solution of 4-(2,2,2-trifluoroethyl)phenol (1.00 g, 5.68 mmol) in CH2Cl2 (5.0 ml) was added trifluoromethanesulfonic acid (0.0151 ml, 0.170 mmol) with stirring. A solution of acetic chloride (0.444 ml, 6.25 mmol) in CH2Cl2 (5.0 ml) was added drop wise to the reaction. After stirred 45 min at RT, all the phenol was consumed. The product mixture was diluted with CH2Cl2, washed with saturated sodium bicarbonate. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was dried in vacuum until no weight loss was observed. To the above residue was added anhydrous aluminum(III) chloride (0.757 g, 5.68 mmol). The mixture was heated at 150° C. for 1 h until all the starting material was consumed (monitored by TLC). The resulted brown gum was cooled to 0° C., diluted with diethyl ether and 1N HCl. Layers were separated. The aqueous layer was extracted with ether. The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel column (2-15% EtOAc/hexane) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([C@@H:14]([NH:18]C(=O)OC(C)(C)C)[CH:15]([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]([C@@H:14]([NH2:18])[CH:15]([CH3:16])[CH3:17])=[O:13])[CH2:10][CH2:11]1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](N)C(=O)N1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Yield: 92 %

Procedure:
The product from Example 7, Step (a) (1.57 g) was dissolved in dichloromethane (14 ml) and trifluoroacetic acid (4 ml) was added. After 2 hours at room temperature the solution was evaporated and aqueous NaOH (2M) was added. The product was extracted with ethyl acetate, the combined organic extracts dried, filtered and concentrated to give the sub-title product as an oil (1.12 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:24][N:25]2C(=O)C3C(=CC=CC=3)C2=O)=[N:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:7]=1.O.NN>CCO>[Cl:1][C:2]1[C:3]([CH2:24][NH2:25])=[N:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:12])[F:13])[CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ncc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1ncc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Yield: 64.9 %

Procedure:
To a stirred solution of (E)-2-((3-chloro-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)pyridin-2-yl)methyl)isoindoline-1,3-dione (200 mg, 0.358 mmol) in EtOH (5 mL) was added hydrazine hydrate (89.6 mg, 1.79 mmol), and the reaction mixture was heated at reflux for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in CH2Cl2. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the title compound as a solid (100 mg). The product obtained in this reaction was carried on to the next step without further purification.