Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.C(Cl)(=O)C(Cl)=O.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:34]3[C:29](=[N:30][CH:31]=[N:32][C:33]=3[NH2:35])[N:28]([C@H:36]3[CH2:41][CH2:40][C@H:39]([N:42]4[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]4)[CH2:38][CH2:37]3)[N:27]=2)=[CH:22][C:21]=1[O:49][CH3:50]>ClCCl.CN(C=O)C.N1C=CC=CC=1>[NH2:35][C:33]1[N:32]=[CH:31][N:30]=[C:29]2[N:28]([C@H:36]3[CH2:41][CH2:40][C@H:39]([N:42]4[CH2:43][CH2:44][N:45]([CH3:48])[CH2:46][CH2:47]4)[CH2:38][CH2:37]3)[N:27]=[C:26]([C:23]3[CH:24]=[CH:25][C:20]([NH:19][C:10]([C:2]4[NH:1][C:9]5[C:4]([CH:3]=4)=[CH:5][CH:6]=[CH:7][CH:8]=5)=[O:12])=[C:21]([O:49][CH3:50])[CH:22]=3)[C:34]=12
Reactant: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2[nH]1
Reaction time: 8 h

Procedure:
To 1H-2-indolecarboxylic acid (0.738 g, 4.58 mmol) in dichloromethane (14 mL) was added oxalyl chloride (4 mL, 45.8 mmol) and DMF (1 drop). The reaction mixture was stirred overnight. Solvent was evaporated and the residue was dissolved in dichloromethane (5 mL). Half of the dichloromethane solution (2.5 mL) was added to a solution of trans-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.50 g, 1.145 mmol) in pyridine (6 mL) at 0° C. After 30 minutes, the solid as collected by filtration. Water was then added to the solid and the pH of the solution was adjusted to 10 with sodium hydroxide (1.0N). The aqueous was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (80:20) as mobile phase to give trans-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1H-2-indolecarboxamide (0.312 g, 47%). 1H NMR (DMSO-d6) δ 1.49 (m, 2H), 2.05 (m, 6H), 2.15 (s, 3H), 2.32 (m, 5H), 2.51 (m, 4H), 3.97 (s, 3H), 4.66 (m, 1H), 7.10 (m, 1H), 7.22 (m 1H), 7.30 (d, J=7.98 Hz, 1H), 8.11 (d, J=8.14 Hz, 1H), 8.24 (s, 1H), 9.44 (s, 1H).
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([CH2:12][CH3:13])[CH:9]2[C:14]([OH:16])=[O:15])C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH2:12]([CH:10]1[CH2:11][NH:8][CH:9]1[C:14]([OH:16])=[O:15])[CH3:13]
Reactant: CCC1CN(C(c2ccccc2)c2ccccc2)C1C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCC1CNC1C(=O)O

Procedure:
8 g of 2B, 100 ml of ethanol and 70 g of 5% palladium charcoal catalyst was hydrogenated at ambient temperature at a hydrogen pressure of between 3 and 4 atomospheres absolute for 10 hours in a Parr apparatus. The resulting mixture was filtered, evaporated to dryness and partitioned between methylene chloride and water. The aqueous phase was separated, evaporated to a low bulk and poured onto a Dowex 8-50 x(H) resin column. Isolation of the imino acid was achieved by eluting the washed column with a 2M ammonia solution. Evaporation of the washings left a white solid which on recrystallization from ethanol deposited an isomer mixture [1α:3β] of 2. Evaporation of the recrystallizing medium left additional 2, having a different isomer composition [2α:3β].
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([S:25](=[O:28])(=[O:27])[NH2:26])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([S:25](=[O:28])(=[O:27])[NH2:26])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: NS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: NS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
A solution of 818 mg of Sodium Nitrite in 13 mL of water was added dropwise to a solution of 2 g of methyl 4-amino-2-chlorobenzoate in 5 mL of HCl and 15 mL of AcOH at 0° C. The reaction was removed from the ice bath and stirred at room temperature for 15 minutes. Simultaneously a solution of 460 mg of Copper II Chloride Dihydrate in 1 mL of water was added to a saturated solution of sulfur dioxide gas in 10 mL of AcOH at 0° C. The cooled solution containing Copper II Chloride and sulfur dioxide gas was slowly added to the re-cooled initial solution containing Sodium Nitrite. The reaction was warmed to room temperature and stirred until gas no longer evolved. The reaction was filtered through celite and poured into a beaker of stirred icewater until a yellow-orange solid crashed out. The icewater solution was filtered thru a Buchner funnel to collect the methyl 2-chloro-4-(chlorosulfonyl)benzoate precipitate and was dried for 24 hours under vacuum. 1 g of methyl 2-chloro-4-(chlorosulfonyl)benzoate was added to a solution of 2 mL of 2M solution of Ammonia in MeOH and 970 μL DIPEA in 5 mL MeOH. Upon completion the reaction was concentrated, extracted twice with saturated bicarbonate, dried with Magnesium Sulfate, filtered and concentrated to give methyl 2-chloro-4-sulfamoylbenzoate. 777 mg of methyl 2-chloro-4-sulfamoylbenzoate was hydrolyzed via Procedure M to yield crude 2-chloro-4-sulfamoylbenzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 91 mg of crude 2-chloro-4-sulfamoylbenzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-sulfamoylbenzamide. MS (Q1) 422 (M)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13].Cl.[C:15](=N)(OCC)[CH3:16]>C(O)C>[CH3:15][C:16]1[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][OH:1])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:13]=1
Reactant: CCOC(C)=N
Reactant: Nc1ccccc1NCCCCO
Agent: Cl
Solvent: CCO
Product: Cc1nc2ccccc2n1CCCCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.6 %

Procedure:
2-(4-Hydroxybutylamino)phenylamine (3.6 g) and ethyl acetimidate hydrochloride (3.7 g) was dissolved in ethanol (20 ml) and stirred at room temperature for 11/2 hours. The mixture was evaporated under vacuum and the residue partitioned between ethyl acetate (30 ml) and water (20 ml). The organic phase was separated, dried over Na2SO4, filtered and evaporated to give the title compound as a brown oil (2.8 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]#[N:8])=[CH:2]1.[CH3:9][CH:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1>>[CH3:9][CH:10]1[CH2:15][CH2:14][C:13](=[C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[C:7]#[N:8])[CH2:12][CH2:11]1
Reactant: CC1CCC(=O)CC1
Reactant: N#CCc1ccsc1
Product: CC1CCC(=C(C#N)c2ccsc2)CC1

Procedure:
The expected intermediate is obtained in the manner described in General Protocol A starting from 3-thienylacetonitrile and 4-methylcyclohexanone.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH:10]([CH2:12][CH:13]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15](OC)=[N:14]3)[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-:28].[NH4+:29]>>[ClH:28].[C:1]1([N:7]2[CH2:11][CH:10]([CH2:12][CH:13]3[NH:14][C:15](=[NH:29])[CH2:16][CH2:17][CH2:18][CH2:19]3)[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: [Cl-]
Reactant: COC1=NC(CC2CN(c3ccccc3)N=C2c2ccccc2)CCCC1
Product: Cl
Product: N=C1CCCCC(CC2CN(c3ccccc3)N=C2c2ccccc2)N1

Procedure:
The title material of Example 144 is reacted with ammonium chloride by the method of Example 5 to generate the title compound.
Reaction SMILES: CO[C:3]([C:5]1[C:10]([N+:11]([O-])=O)=[C:9]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[N:8]=[C:7]([N:23]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[N:25]=[CH:24]2)[N:6]=1)=[O:4].[NH:32]1C2C=CC=CC=2N=C1.[H-].[Na+].ClC1N=C([C:50](OC)=[O:51])C([N+]([O-])=O)=C(NC2C=CC=CC=2OC)N=1>O1CCCC1>[N:23]1([C:7]2[N:8]=[C:9]3[C:10]([NH:11][C:50](=[O:51])[N:14]3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[C:5]([C:3]([NH2:32])=[O:4])[N:6]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[CH:24]1
Reactant: COC(=O)c1nc(-n2cnc3ccccc32)nc(Nc2ccccc2OC)c1[N+](=O)[O-]
Reactant: COC(=O)c1nc(Cl)nc(Nc2ccccc2OC)c1[N+](=O)[O-]
Reactant: c1ccc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(-n3cnc4ccccc43)nc21
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
Methyl-2-(1H-benzo[d]imidazol-1-yl)-6-(2-methoxyphenylamino)-5-nitropyrimidine-4-carboxylate. To a solution of 1H-benzo[d]imidazole (0.354 g, 3.0 mmol) in tetrahydrofuran (20 mL) was added sodium hydride (0.120 g, 60% in mineral oil, 30 mmol). The reaction mixture was stirred at 60° C. for 15 min. Methyl 2-chloro-6-(2-methoxyphenylamino)-5-nitropyrimidine-4-carboxylate (See Example 30.A) (1.014 g, 3 mmol) was added and the resulting solution was stirred for 4 h. The reaction mixture was extracted with EtOAc (3×25 mL) and washed with brine (3×25 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The crude material was subjected to silica gel chromatography (25%-40% EtOAc in hexanes). Concentration of the desired fractions afforded the titled compound as yellow solid (1.0 g). MS (ESI) m/z 421.4 [M+1]+.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1)([O-:3])=[O:2].[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.N1CCCCC1>C1(C)C=CC=CC=1>[F:11][C:12]1[CH:19]=[CH:18][C:15](/[CH:16]=[C:4](\[N+:1]([O-:3])=[O:2])/[CH2:5][CH:6]2[O:10][CH2:9][CH2:8][O:7]2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=[N+]([O-])CCC1OCCO1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: O=[N+]([O-])/C(=C\c1ccc(F)cc1)CC1OCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flask equipped with a Dean-Stark trap and a reflux condenser, a solution of 2-(2-nitro-ethyl)-[1,3]dioxolane (162.5 g, 1.1 mol) in toluene (1.2 L) was treated with 4-fluorobenzaldehyde (124 g, 1.0 mol) followed by piperidine (15 mL, 0.15 mol). The solution was heated at reflux under N2 for 16 h, then was cooled to rt and washed with water (2×300 mL) and satd. aq. NaCl (2×300 mL). Charcoal and MgSO4 were added, and the suspension was stirred for 1 h. Filtration and concentration of the filtrate provided the title compound, which was used in the next reaction without further purification. 1H NMR (400 MHz, CDCl3): 8.15 (s, 1H), 7.70-7.65 (m, 2H), 7.18-7.10 (m, 2H), 5.23 (t, J=4.5, 1H), 4.10-3.80 (m, 4H), 3.26 (d, J=4.5, 2H). The (Z)-olefin geometry was confirmed by nuclear Overhauser effect (NOE) studies (Stott et al. J. Magn. Reson. 1997, 125, 302-324) with a mixing time of 0.8 sec. When proton at 8.15 ppm was selectively inverted, NOE was observed at 3.25 ppm and 7.65 ppm.
Reaction SMILES: [CH:1]1([Cr:6]C2C=CC=C2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cr]>CCCCCC>[CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cr+2:6]
Reactant: C1=CC([Cr]C2C=CC=C2)C=C1
Agent: [Cr]
Solvent: CCCCCC
Product: [Cr+2]
Product: c1cc[cH-]c1
Reaction time: 0.5 h

Procedure:
Four olefin polymerization catalyst samples were then prepared by slurrying 0.4 gram portions of each of the activated silica supports made as in the preceeding paragraph with 20 mg. portions of bis(cyclopentadienyl)chromium [II] (chromocene) in about 100 ml. of n-hexane. The slurries were stirred for about 30 minutes to allow the chromium compound to deposit on the activated supports. Control A was prepared as in the preceeding paragraph from silica treated as in A but without adding any (NH4)2SiF6.
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].O[NH:10][C:11]([O:13]CC)=[O:12].[C:16]1(=[O:23])[NH:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[CH2:16]([C:17]([CH2:11][OH:12])([CH2:6][OH:7])[CH2:18][CH3:19])[OH:23].[CH3:17][C:18]1[C:1]([N:10]=[C:11]=[O:13])=[CH:2][C:21]([N:22]=[C:16]=[O:23])=[CH:20][CH:19]=1
Reactant: CCOC(=O)NO
Reactant: O=C1CCCCCN1
Agent: OCCCCCCO
Product: CCC(CO)(CO)CO
Product: Cc1ccc(N=C=O)cc1N=C=O

Procedure:
41.9 parts by weight of hexane-1,6-diol are melted together in powder form at about 85° C and then treated at 130° C with 583 parts by weight of a hydroxyurethane with a hydroxyl content of 6% by weight obtained from 1 mol of hexane-1,6-diol, 0.7 mol of 1,1,1-trimethylolpropane, 1.8% by weight of caprolactam and 1.3 mol of tolylene diisocyanate (mixture of isomers 2,4 : 2,6 = 80 : 20) to form a highly fluid melt which can easily be stirred. Its viscosity is about 320 cP at 105° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:17]O>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: CO
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)c(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
To a solution of 2,6-dichloro-5-fluoronicotinic acid (16) (5 g, 23.8 mmol) in methanol (50 ml) was added thionyl chloride in dropwise (5.66 g, 47.62 mmol) at 0° C. and 2 drops of DMF [vigourous bubbling was observed]. The mixture was stirred at room temperature for 3 h. To this methanol was added and stirred the reaction mixture for 2 h at RT. The reaction mixture is concentrated under reduced pressure to and the mixture was poured in to ice cold water (20 mL) and extracted with dichloromethane (2×50 mL). The combined organic layer was washed with water, brine and solvent was evaporated under reduced pressure to yield methyl 2,6-dichloro-5-fluoronicotinate (17) (5 g, 93.8%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:31]1[CH2:30][CH2:29][N:28]([C:25]3[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=3)[CH2:33][CH2:32]1)=[O:19])=[N:5]2
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Product: COc1ccc(N2CCN(C(=O)Nc3nc4cc(F)ccc4nc3OC)CC2)cc1
Yield: 80 %

Procedure:
Ethyl N-(6-fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(4-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound (yield, 80%). 1H NMR (200 MHz, CDCl3): δ 3.18 (s, 4H), 3.79 (s, 6H), 4.08-4.15 (m, 4H), 6.85-6.98 (m, 4H), 7.22-7.76 (m, 4H).
Reaction SMILES: [ClH:1].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C@H:12]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:18]=2)[NH2:13])=[CH:3]1.[C:25]([N:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)(C)C>[ClH:1].[C:19]1([C:17]2[N:18]=[C:14]([C@H:12]3[CH2:11][C:4]4[C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[NH:2][C:3]=4[C:36]4([CH2:37][CH2:38][N:33]([C:25](=[O:32])[C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH2:34][CH2:35]4)[NH:13]3)[NH:15][CH:16]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N[C@H](Cc1c[nH]c2ccccc12)c1nc(-c2ccccc2)c[nH]1
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Agent: Cl
Solvent: CC(C)O
Product: O=C(c1ccccc1)N1CCC2(CC1)N[C@@H](c1nc(-c3ccccc3)c[nH]1)Cc1c2[nH]c2ccccc12
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
To a solution of (1R)-2-(1H-indol-3-yl)-1-(4-phenyl-1H-imidazol-2-yl)-1-ethanamine hydrochloride (1 g, 2.65 mmol) in isopropanol (15 ml) was added N-benzoyl-4-piperidone (2.64 g, 13 mmol). The solution was refluxed for about one hour and cooled to about 20° C. The solvent was removed under reduced pressure. The residue was treated with dichloromethane (30 ml) and stirred for about 30 min at about 20° C. The resulting precipitate was collected by filtration, washed with dichloromethane and diethyl ether, and dried to afford 1.2 g of the title product as the hydrochloride salt. Melting point: 240-244° C.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>O1CCCC1>[Cl:2][CH2:3][C:4]1[CH:5]=[C:6]([NH:7][S:19]([CH3:18])(=[O:21])=[O:20])[CH:8]=[CH:9][CH:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(CCl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
873 mg (4.903 mmol) of 3-(chloromethyl)aniline hydrochloride (Example 89A) were initially charged in 4 ml of tetrahydrofuran, and 2.48 g (24.514 mmol) of triethylamine were added. A solution of 421 mg (3.677 mmol) of methanesulfonyl chloride in 3 ml of tetrahydrofuran was slowly added dropwise, and the reaction solution was stirred at RT for 2 h. The reaction solution was concentrated using a rotary evaporator and the residue was purified by preparative HPLC (Chromasil, water/acetonitrile).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:16]([CH2:22][OH:23])[CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]([NH:28][C@@H:29]([CH:33]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:30](O)=[O:31])=[O:27]>>[CH3:24][O:25][C:26](=[O:27])[NH:28][C@H:29]([C:30](=[O:31])[NH:21][CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]([N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:22][OH:23])[CH:33]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Reactant: CC(C)CN([C@H](CO)CCCCN)S(=O)(=O)c1ccc(N)cc1
Product: COC(=O)N[C@H](C(=O)NCCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1)C(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared from (1S)-4-amino-N-(5-amino-1-hydroxymethyl-pentyl)-N-isobutyl-benzenesulfonamide (XII) (example 28, step D) as described in general procedure B using (2S)-2-methoxycarbonylamino-3,3-diphenyl-propionic acid (step A). The final product was obtained in 67% yield (121 mg).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH2:16][CH2:17][N:18]([C:21](=[O:31])[CH2:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH:20]=2)=[C:11]([C:32]2[CH2:36][C:35]([CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])([CH2:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[O:34][N:33]=2)[CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].C1COCC1>[C:49]([O:48][C:46](=[O:47])[CH2:45][C:35]1([CH2:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[O:34][N:33]=[C:32]([C:11]2[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][C:12]=2[CH:15]2[CH2:16][CH2:17][N:18]([C:21](=[O:31])[CH2:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:20]2)[CH2:36]1)([CH3:50])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)CCC(=O)N1CC=C(c2ccc(OCc3ccccc3)cc2C2=NOC(CC(=O)OC(C)(C)C)(CC(=O)OC(C)(C)C)C2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCC(=O)N1CCC(c2ccc(O)cc2C2=NOC(CC(=O)OC(C)(C)C)(CC(=O)OC(C)(C)C)C2)CC1
Yield: 76.6 %

Procedure:
A mixture of tert-butyl 4-(4-(4-(benzyloxy)-2-(5,5-bis(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-4-oxobutanoate (52.1 mg), 10% Pd/C (containing about 55% water, 20 mg), and THF (1 mL) was stirred at room temperature for 6 hours in a hydrogen atmosphere. The catalyst was filtered off, and then, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (35.0 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH:13]=O)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:15][O:16][CH:17]([O:21][CH3:22])[CH2:18][NH:19][CH3:20].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][N:19]([CH3:20])[CH2:18][CH:17]([O:21][CH3:22])[O:16][CH3:15])=[CH:11][NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CNCC(OC)OC
Reactant: O=Cc1c[nH]nc1-c1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(CN(C)Cc1c[nH]nc1-c1ccc(F)cc1)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
A solution of 3-(4-fluorophenyl)-1H-pyrazole-4-carbaldehyde (3 g, 15.78 mmol, 1.00 equiv) and (2,2-dimethoxyethyl)(methyl)amine (2.3 g, 19.30 mmol, 1.22 equiv) in acetic acid (1.89 g, 31.47 mmol, 2.00 equiv) and 1,2-dichloroethane (30 mL) was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (10 g) was then added and the resulting solution was stirred at room temperature for 3 h. The resulting mixture was washed with 2×20 mL of 5% potassium carbonate solution and 2×20 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give 3.29 g (71%) of N-((3-(4-fluorophenyl)-1H-pyrazol-4-yl)methyl)-2,2-dimethoxy-N-methylethanamine as a yellow oil. LCMS (method C, ESI): RT=0.63 min, m/z=294.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=1[Cl:29].[H-].[Na+].CN(C)C=O>O>[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:24][C:23]=1[Cl:29]
Reactant: COCCOc1cc2nccc(Cl)c2cc1C(=O)OC
Reactant: Nc1ccc(O)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1C(=O)OC

Procedure:
Methyl 4-chloro-7-(2-methoxyethoxy)-6-quinolinecarboxylate (4.9 g), 4-amino-3-chlorophenol (2.0 g), sodium hydride (550 mg) and dimethylformamide (20 ml) were stirred together at 100° C. for 2 hours. The mixture was returned to room temperature, water was added, and extraction was performed with ethyl acetate. Silica gel was added to the extract solution and the solvent was distilled off under reduced pressure. The silica gel was charged into a dry column packed with silica gel, and purification was performed by column chromatography (hexane:ethyl acetate=1:1, followed by ethyl acetate) to obtain 3.2 g of the target substance as a violet solid.
Reaction SMILES: C([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH2:18])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.Cl[C:21]1[C:26]([Cl:27])=[CH:25][C:24]([C:28]([F:31])([F:30])[F:29])=[CH:23][N:22]=1.F[C:33](F)(F)[C:34](O)=O>ClCCl>[Cl:27][C:26]1[C:21]([N:18]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:21][CH2:33][CH3:34])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:19])[S:12][CH:13]=2)=[N:22][CH:23]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:25]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN)cs1
Solvent: ClCCl
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The compound obtained using 2-{[4-(2-aminoethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester synthesized in Example 7 and 2,3-dichloro-5-(trifluoromethyl)pyridine as starting materials and by operations similar to those of Example 265-1 and Example 265-2 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=50:1) to give the title compound.