Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2](CC)CC(=O)CC.C1C(N)=CC=C(N)C=1.C(C([NH:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][CH:34](CC)[CH2:35][CH:36]([CH3:39])[CH2:37][CH3:38])=[CH:29][CH:28]=1)CC(C)CC)C>>[CH2:1]([C:27]1([NH2:26])[CH:28]=[CH:29][C:30]([NH:33][CH2:34][CH2:35][CH:36]([CH3:39])[CH2:37][CH3:38])=[CH:31][CH2:32]1)[CH3:2]
Reactant: CCC(C)CC(CC)Nc1ccc(NC(CC)CC(C)CC)cc1
Reactant: CCC(=O)CC(C)CC
Agent: Nc1ccc(N)cc1
Product: CCC(C)CCNC1=CCC(N)(CC)C=C1

Procedure:
A mixture of 768 g. (6 moles) 5-methyl-3-heptanone and 108 g. (1 mole) p-phenylenediamine was reacted and worked up in the same manner as that of Example 1 to give 330 g. (99%) residue of crude N,N'-bis(1-ethyl-3-methylpentyl)-p-phenylenediamine product [IVa, R2 =C2H5, R3 =CH2CH(CH3)C2H5 ] containing some mono-Schiff's base III-c and some di-Schiff's base III-d.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[F:25][C:26]([F:38])([F:37])[C:27]1[CH:32]=[CH:31][C:30](OB(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:30]4[CH:31]=[CH:32][C:27]([C:26]([F:38])([F:37])[F:25])=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCc3ccc(Br)cc3)CC2)CC1
Reactant: OB(O)Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCc3ccc(-c4ccc(C(F)(F)F)cc4)cc3)CC2)CC1

Procedure:
A solution of 0.05 m of 1-[trans-4-(trans-4-n-propylcyclohexyl)cyclohexyl]-2-(p-bromophenyl)ethane (DE 3317597) and 0.05 m of p-trifluoromethylphenylboric acid (prepared from p-bromotriflurotoluene by consecutive reaction with n-BuLi/B(OCH3)3 and H+ /H2O) in 100 ml of toluene and 50 ml of ethanol is refluxed for 4 hours after 0.0001 m of Pd(Ph3)4 and 50 ml of Na2CO3 solution (2M) have been added. Conventional extractive work-up and subsequent purification by chromatography and crystallization give 1-[trans-4-(trans-4-n-propylcyclohexyl)cyclohexyl]-2-(4-trifluoromethylbiphenyl-4'-yl)ethane.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:32]2[CH2:33][CH2:34][N:29]([C:23]3[CH:24]=[CH:25][CH:26]=[C:27]([CH3:28])[C:22]=3[CH3:21])[CH2:30][CH2:31]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccc(Cl)cc1
Reactant: Cc1cccc(N2CCNCC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N2CCN(CCCc3cc(-c4ccc(Cl)cc4)n(C(C)(C)C)n3)CC2)c1C

Procedure:
118 mg (85%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propanal (80 mg, 0.275 mmol), 1-(2,3-dimethylphenyl)piperazine (52 mg, 0.275 mmol), DIPEA (0.072 mL, 0.413 mmol) and NaBH(OAc)3 (175 mg, 0.825 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:5].CC[C:19](OCC)=[S:20].[C:24]([O:28]Cl)(C)(C)[CH3:25].C(N(CC)CC)C>C(Cl)Cl>[F:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]([C:3]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:2]=2[NH:1][C:24](=[O:28])[CH:25]3[S:20][CH3:19])=[O:5])=[CH:7][CH:8]=1
Reactant: CCOC(=S)CC
Reactant: CC(C)(C)OCl
Reactant: Nc1ccccc1C(=O)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSC1C(=O)Nc2c(C(=O)c3ccc(F)cc3)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 42.2 g (0.196 mole) of 2-amino-4'-fluorobenzophenone in 2 liters of methylene chloride was cooled to -65° C. and 26.5 g (0.198 mole) of ethyl methylthioacetate was added. A solution of 23.0 g (0.21 mole) of 95% tertiary butoxychloride in 50 ml of methylene chloride was added dropwise, keeping the temperature below -65° C. One hour after the addition was complete, 22.2 g (0.22 mol) of triethylamine was added dropwise and the mixture was allowed to warm to room temperature. The solution was concentrated to 700 ml and then washed with water. The organic solution was concentrated and the residue dissolved in 400 ml of methanol containing 30 ml of concentrated hydrochloric acid. The mixture was heated at reflux for one hour followed by cooling. The mixture was allowed to stand overnight, the crystals collected and washed with methanol to yield 31.4 g (53%) as bright yellow solid, m.p. 165°- 167.5° C.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C@@H:10]([OH:24])[CH2:11][C@@H:12]([C:20]([OH:23])([CH3:22])[CH3:21])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])=O)(C)(C)C.Cl.[C:33]([O:37][C:38]([NH:40][C@H:41]([C:48](O)=[O:49])[CH2:42][C:43]1[N:44]=[CH:45][S:46][CH:47]=1)=[O:39])([CH3:36])([CH3:35])[CH3:34].P(C#N)(OCC)(OCC)=O>O1CCOCC1.O1CCCC1.C(N(CC)CC)C>[C:33]([O:37][C:38]([NH:40][C@H:41]([C:48]([NH:8][C@@H:9]([CH2:25][CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1)[C@@H:10]([OH:24])[CH2:11][C@@H:12]([C:20]([OH:23])([CH3:21])[CH3:22])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])=[O:49])[CH2:42][C:43]1[N:44]=[CH:45][S:46][CH:47]=1)=[O:39])([CH3:35])([CH3:36])[CH3:34]
Reactant: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(C)(C)O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)(C)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 309 mg (0.698 mmole) of (2S, 4S, 5S)-5-(t-butoxycarbonylamino)-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-butylhexanamide (prepared as described in Preparation 29) in 6 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 30 minutes under an atmosphere of nitrogen. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and then benzene was added to the residue. The solvent was removed by distillation under reduced pressure from the resulting solution. The same operation was repeated, in total, three times, and the resulting residue was then dried by evaporation under reduced pressure for 8 hours. At the end of this time, 200.6 mg (0.737 mmole) of N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanine were added to a suspension of the dried material in 15 ml of anhydrous tetrahydrofuran, and then 0.13 ml (0.858 mmole) of 95% diethyl cyanophosphate and 0.3 ml of triethylamine were added to the resulting mixture, whilst ice-cooling and under an atmosphere of nitrogen. The mixture was then stirred for 5 hours, after which the solvent was removed by distillation under reduced pressure and the residue was purified by medium pressure silica gel column chromatography (using a 20:1 by volume mixture of methylene chloride and methanol as eluent), followed by recrystallization from a mixture of methylene chloride and diisopropyl ether, to give 457.8 mg or the title compound as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:25])=[C:7]([C:15]([C:17]2[CH:18]=[N:19][N:20]([CH2:23][CH3:24])[C:21]=2[OH:22])=[O:16])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])=[O:4].C(N(CC)CC)C.[CH3:33][CH2:34][S:35][C:36](Cl)=[O:37]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:25])=[C:7]([C:15]([C:17]2[CH:18]=[N:19][N:20]([CH2:23][CH3:24])[C:21]=2[O:22][C:36]([S:35][CH2:34][CH3:33])=[O:37])=[O:16])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])=[O:4]
Reactant: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(C(=O)OC)c2C)c1O
Reactant: CCSC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCSC(=O)Oc1c(C(=O)c2ccc(S(C)(=O)=O)c(C(=O)OC)c2C)cnn1CC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.2 %

Procedure:
5-Hydroxy-1-ethylpyrazol-4-yl 3-(methoxycarbonyl)-2-methyl-4-(methylsulfonyl)phenyl ketone (510 mg, 1.39 mmol) was dissolved in dry tetrahydrofuran-(20 mL), and triethylamine (281 mg, 2.78 mmol) was added thereto. A solution (4 mL) of 96% S-ethyl chlorothiolformate (217 mg) dissolved in dry tetrahydrofuran was added thereto little by little under cooling with ice water. The reaction mixture was stirred for 90 minutes while the reaction temperature was allowed to warm to room temperature. The reaction mixture was poured into ice water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:4) to obtain the desired product as an oil (417 mg, 0.92 mmol) (yield: 66%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[C:5]2[S:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15].C(N(CC)CC)C.[NH2:29][CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[N:34]1[CH:35]=[CH:36][C:31]([CH2:30][NH:29][C:11]([C:6]2[NH:7][C:8]3[C:4]([C:5]=2[S:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)=[O:13])=[CH:32][CH:33]=1
Reactant: NCc1ccncc1
Reactant: O=C(O)c1[nH]c2ccc(Cl)cc2c1S(=O)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCc1ccncc1)c1[nH]c2ccc(Cl)cc2c1S(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of 5-chloro-3-phenylsulfinylindole-2-carboxylic acid (0.096 g, 0.3 mmol), triethylamine (0.061 g, 0.6 mmol), 4-aminomethylpyridine (0.043 g, 0.4 mmol) in dry dimethylformamide was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent) (0.155 g, 0.35 mmol). The mixture was stirred at room temperature under nitrogen for three days. Following evaporation, the residue was partitioned between ethyl acetate and water. The ethyl acetate phase was separated and washed with dilute hydrochloric acid. The acidic extract was neutralized with aqueous sodium bicarbonate and the product extracted into ethyl acetate. The ethyl acetate extract was washed well with aqueous sodium bicarbonate, then brine, and dried over magnesium sulfate. Evaporation afforded a solid residue which was recrystallized from ethyl acetate to give the title compound, mp 233°-235° C. Anal. Calcd for C21H16ClN3O2S: C, 61.54; H, 3.93; N, 10.25. Found: C, 61.39; H, 3.95; N, 10.36. NMR (DMSO-d6) δ9.62 (1H, t, J=6 Hz), 8.53 (2H, d, J=6 Hz), 7.80 (1H, d, J=2 Hz), 7.67 (2H, m), 7.64 (2H, d, J=9 Hz), 7.44-7.54 (3H, m), 7.33 (3H, m), 4.60 (2H, dq, J=9, 6 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[C:12]([C:20](OC)=[O:21])[CH:11]=1)#[N:2].[BH4-].[Na+].O>CO>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:11]=[C:12]([CH2:20][OH:21])[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:15]=1)#[N:2]
Reactant: COC(=O)c1cc(C(=O)OC)cc(-c2ccc(C)cc2C#N)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(CO)cc(-c2ccc(C)cc2C#N)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of dimethyl 2′-cyano-4′-methylbiphenyl-3,5-dicarboxylate (343 mg, 1.05 mmol) in methanol (20 mL) was cooled at 0° C. and sodium tetrahydroborate (0.60 g, 16 mmol) was added slowly. The mixture was stirred at rt for 6 h, and then treated with water (20 mL). The volatiles were removed in vacuo and the acqueous phase was extracted with CH2Cl2 (30 mL×3). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography to afford the title compound.
Reaction SMILES: [C:1]([CH:8]([C@H:12]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[CH:23]=2)[CH:16]=1)[CH2:13][NH2:14])[C:9]([OH:11])=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].FC(F)(F)C(O)=[O:33].S(=O)(=O)(O)O>>[C:1]([CH:8]([C@H:12]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[CH:23]=2)[CH:16]=1)[CH2:13][NH2:14])[C:9]([OH:11])=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[ClH:21].[NH2:14][CH2:13][C@@H:12]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28](=[O:33])[NH2:29])[CH:23]=2)[CH:16]=1)[CH2:8][C:1]([OH:3])=[O:2]
Reactant: O=C(O)C(F)(F)F
Agent: CC(C)(C)OC(=O)C(C(=O)O)[C@@H](CN)c1ccc(Cl)c(-c2cccc(C#N)c2)c1
Agent: O=S(=O)(O)O
Product: Cl
Product: NC[C@H](CC(=O)O)c1ccc(Cl)c(-c2cccc(C(N)=O)c2)c1

Procedure:
Boc-(3R)-4-amino-3-[4-chloro-3-(3-cyanophenyl)phenyl]butanoic acid (52a) was synthesized using the general Suzuki cross coupling procedure. Crude Boc-(3R)-4-amino-3-[4-chloro-3-(3-cyanophenyl)phenyl]butanoic acid (52a) (130 mg, 0.32 mmol) was treated with 1 mL of trifluoroacetic acid/conc. sulfuric acid (4:1) and stirred for 1 h at room temperature. Trifluoroacetic acid was removed in vacuo. The crude residue was purified by preparative HPLC to provide the title compound (52) as a white solid. 1H-NMR (400 MHz, CD3OD): δ 2.78-2.83 (m, 1H), 2.65-2.71 (m, 1H), 3.19-3.25 (dd, J=22.0, 9.2 Hz, 1H), 3.32-3.47 (m, 2H), 7.92-7.93 (m, 1H), 7.87-7.89 (d, J=7.6, 1 Hz), 7.62-7.64 (d, J=7.6 Hz, 1H), 7.51-7.54 (m, 2H), 7.32-7.38 (m, 2H); MS (ESI) m/z 333.00 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:17])([S:13][CH2:14][CH2:15][OH:16])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].[Cl:18][CH:19]([CH2:23][Cl:24])[C:20](O)=[O:21]>C1CCCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:18][CH:19]([CH2:23][Cl:24])[C:20]([O:16][CH2:15][CH2:14][S:13][C:2]([F:1])([F:17])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6])=[O:21]
Reactant: O=C(O)C(Cl)CCl
Reactant: OCCSC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCCCC1
Product: O=C(OCCSC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(Cl)CCl
Yield: 96.5 %

Procedure:
1,1,1,2,2,3,3,4,4-nonafluoro-4-iodobutane (138.4 g (400 mmol)) was dissolved in a mixture liquid of DMF (400 ml) and water (80 ml), and mercaptoethanol (32.2 g (400 mmol)) was added. Further, sodium formate (27.2 g (400 mol)), sodium sulfite heptahydrate (100.9 g (400 mmol)) were added, and stirred at room temperature (23° C.) for one night. Water (1 L) and isopropyl ether (1 L) were added to the reaction liquid, which was separated. A water layer was further extracted with isopropyl ether (500 ml×2). The organic layer was washed with 10% hydrochloric acid (500 ml), water (500 ml) and a saturated saline solution (500 ml), dried over anhydrous magnesium sulfate and filtered. The solvent was distilled off to give 2-(perfluorobutylthio)ethanol. Then, p-toluene sulfonic acid monohydrate (2.5 g (13.1 mmol)) was added to a solution of 2-(perfluorobutylthio)ethanol (50 g (equivalent to 158 mmol)) and 2,3-dichloropropionic acid (22.5 g (157 mmol)) in cyclohexane (500 ml), and was subjected to dehydration condensation reaction (bath temperature: 90° C.) for one night by using a Dean-Stark method. The reaction liquid was filtered with celite. An organic layer was washed with water three times and with saturated saline solution, and dried over anhydrous magnesium sulfate. The filtration and concentration under reduced pressure gave crude 2-(perfluorobutylthio)ethyl 2,3-dichloropropionate (63.8 g). Yield: 96.5%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:5]=1[NH2:19])([O-:3])=[O:2].Cl.Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1>>[N+:1]([C:4]1[CH:9]=[C:8]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:7]=[CH:6][C:5]=1[NH2:19])([O-:3])=[O:2]
Reactant: FC(F)(F)c1cc(Cl)ccn1
Reactant: CC1(C)OB(c2ccc(N)c([N+](=O)[O-])c2)OC1(C)C
Agent: Cl
Product: Nc1ccc(-c2ccnc(C(F)(F)F)c2)cc1[N+](=O)[O-]

Procedure:
Following the procedure as described in Example 2, STEP A, the title compound was prepared from 2-nitro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (0.300 g, 1.14 mmol, as prepared in the previous step) and 4-chloro-2-trifluoromethyl-pyridine hydrochloride (322 mg, 1.48 mmol) and was obtained as an orange solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH2:36][CH2:37][OH:38])[CH:33]=2)[NH:28][C:27]=1[C:39]([OH:41])=O.[NH2:42][CH2:43][C:44]1[C:45]([F:61])=[C:46]([O:51][C:52]2[CH:53]=[C:54]([CH:57]=[C:58]([Cl:60])[CH:59]=2)[C:55]#[N:56])[C:47]([Cl:50])=[CH:48][CH:49]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH2:36][CH2:37][OH:38])[CH:33]=2)[NH:28][C:27]=1[C:39]([NH:42][CH2:43][C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[C:46]([O:51][C:52]2[CH:53]=[C:54]([C:55]#[N:56])[CH:57]=[C:58]([Cl:60])[CH:59]=2)[C:45]=1[F:61])=[O:41]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: O=C(O)c1[nH]c2ccc(OCCO)cc2c1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c4ccc(OCCO)cc4c3Br)c2F)c1
Reaction time: 8 h
Yield: 51.3 %

Procedure:
HATU (0.061 g, 0.161 mmol) was added to a DMF (2 mL) solution of 3-bromo-5-[(2-hydroxyethyl)oxy]-1H-indole-2-carboxylic acid (0.048 g, 0.161 mmol), 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.161 mmol) and DIPEA (0.028 mL, 0.161 mmol). The solution was stirred overnight and partitioned between water and EtOAc. The organic was washed with a 15% aqueous solution of Na2CO3, dried over MgSO4 and filtered. Evaporation of the EtOAc and trituration in acetone afforded the title compound (0.049 g, 47%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.91 (s, 1H), 8.49 (t, 1H), 7.77-7.89 (m, 1H), 7.51-7.57 (m, 2H), 7.43-7.51 (m, 2H), 7.37 (d, 1H), 6.96 (ddd, 1H), 6.89 (s, 1H), 4.86 (t, 1H), 4.62 (d, 2H), 4.02 (t, 1H), 3.69-3.82 (m, 1H). LCMS: m/z=592.2 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:34][CH2:35][CH3:36])[N:10]3[N:37]=[CH:38][N:39]=[C:9]23)[CH2:4][CH2:3]1.[O:40]1[CH2:44][CH:43](O)[CH:42]([OH:46])[CH2:41]1.CC1C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[O:33]=[C:31]1[O:30][N:29]=[C:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:19]2[CH:18]=[CH:17][C:16]([CH2:15][C:12]3[C:13](=[O:14])[N:8]([CH:5]4[CH2:6][CH2:7][C:2]5([O:46][CH:42]6[CH2:41][O:40][CH2:44][CH:43]6[O:1]5)[CH2:3][CH2:4]4)[C:9]4[N:10]([N:37]=[CH:38][N:39]=4)[C:11]=3[CH2:34][CH2:35][CH3:36])=[CH:21][CH:20]=2)[NH:32]1
Reactant: OC1COCC1O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC3(CC2)OC2COCC2O3)c2ncnn12
Yield: 65.9 %

Procedure:
A mixture of 4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.30 g), tetrahydrofuran-3,4-diol (0.11 g), 4-methylbenzenesulfonic acid (0.011 g) and toluene (20 mL) was heated under reflux for 6 hr using a Dean-Stark trap. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography and recrystallized (ethyl acetate-hexane) to give the title compound as a colorless solid (0.23 g, 68%).
Reaction SMILES: Cl[C:2]([N:4]1[C:13]2[C:8](=[CH:9][C:10]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14][C:11]=3[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)=[O:3].[CH2:26]([OH:34])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>N1C=CC=CC=1>[N:4]1([C:2]([O:34][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:3])[C:13]2[C:8](=[CH:9][C:10]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14][C:11]=3[CH:12]=2)[CH2:7][CH2:6][CH2:5]1
Reactant: OCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2cc3c(cc2CC1)N(C(=O)Cl)CCC3
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCc2cc3c(cc2CC1)N(C(=O)OCCc1ccccc1)CCC3
Temperature: 100 °C
Reaction time: 5.5 h

Procedure:
To a solution of 200 mg of t-butyl 1-(chlorocarbonyl)-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate in 2 ml of pyridine was added 140 μl of phenethyl alcohol, followed by stirring at 100° C. for 5.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 68 mg of 8-t-butyl 1-(2-phenylethyl) 3,4,6,7,9,10-hexahydro-1H-azepino[4,5-g]quinoline-1,8(2H)-dicarboxylate as a yellow viscous substance.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:21][CH2:22][C:23]4([O:37][CH3:38])[CH2:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)[CH:14]=[C:15]([F:20])[CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.FC(F)(F)C(O)=O>C(Cl)Cl>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:21][CH2:22][C:23]4([O:37][CH3:38])[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH:14]=[C:15]([F:20])[CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: COC1(COc2cc(F)cc3ccc(-c4nnc5ccccn45)nc23)CCCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC1(COc2cc(F)cc3ccc(-c4nnc5ccccn45)nc23)CCCNCC1
Yield: 124.5 %

Procedure:
tert-butyl 4-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-yloxy)methyl)-4-methoxyazepane-1-carboxylate (0.032 g, 0.061 mmol) was added to a mixture of trifluoroacetic acid and DCM (1:1) for 1 hour. The reaction was concentrated and co-evaporated several times with diethyl ether to yield 32 mgs of the desired product as a white solid. MS ESI (+) m/z 422 (M+1) detected.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[N:18]=[CH:17]2>C(#N)C>[ClH:1].[CH2:23]([N:19]1[C:20]2[C:16](=[CH:15][C:14]([NH:13][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:22][CH:21]=2)[CH:17]=[N:18]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1ccc2c(cnn2Cc2ccccc2)c1
Reactant: Clc1ncnc2ccc(I)cc12
Solvent: CC#N
Product: Cl
Product: Ic1ccc2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c2c1
Yield: 92 %

Procedure:
4-Chloro-6-iodoquinazoline (5.8 g) was treated with 5-amino-1-benzy-1H-indazole (3.90 g) in acetonitrile (500 ml) at reflux under N2 for 18 hours (Procedure A). Subsequent cooling and filtration gave the title compound (8.26 g); m/z (M+1)+478.