Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=O)=O.[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[C:28]2[CH2:34][C:35]([NH2:38])([CH3:37])[CH3:36].N1C2C(=CC=CC=2)C(CC(N)(C)C)=C1>>[ClH:24].[NH:30]1[C:31]2[C:27](=[CH:26][CH:25]=[CH:33][CH:32]=2)[C:28]([CH2:34][C:35]([NH:38][CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH3:36])[CH3:37])=[CH:29]1
Reactant: CC(C)(N)Cc1c[nH]c2ccc(Cl)cc12
Reactant: CS(=O)(=O)OCCCOc1ccccc1OCc1ccccc1
Agent: CC(C)(N)Cc1c[nH]c2ccccc12
Product: CC(C)(Cc1c[nH]c2ccccc12)NCCCOc1ccccc1OCc1ccccc1
Product: Cl

Procedure:
Proceeding as in Example 3, but replacing 2-[2-(cyclopropylmethyloxy)phenoxy]ethyl methanesulfonate with 3-(2-benzyloxyphenoxy)prop-1-yl methanesulfonate and [2-(5-chloro-1H-indol-3-yl)-1,1-dimethylethyl]amine with [2- (1H-indol-3-yl)-1,1-dimethylethyl]amine, gave [2-(1H-indol-3-yl)-1,1-dimethylethyl]{3-(2-benzyloxyphenoxy)prop-1-yl}amine hydrochloride.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C(N(CC)C(C)C)(C)C.C([O:23][C:24](=O)[CH:25]=[C:26]([O:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1)[CH2:27]Br)C>C(#N)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([N:6]1[CH2:27][C:26]([O:29][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32][CH:31]=2)=[CH:25][C:24]1=[O:23])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CCOC(=O)C=C(CBr)Oc1cccc2ccccc12
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC(C)C)N1CC(Oc2cccc3ccccc23)=CC1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 31.6 %

Procedure:
A mixture of (L)-leucine methyl ester hydrochloride (0.68 g, 3.74 mmol) in acetonitrile (9.35 mL) was treated with N,N-diisopropylethylamine (0.60 mL, 3.67 mmol). After addition was complete, the mixture was stirred at 60° C. for 1 h. At this time, the reaction was cooled to 25° C., treated with N,N-diisopropylethylamine (0.60 mL, 3.67 mmol) and acetonitrile (9.35 mL) and then heated to 80° C. Upon reaching 80° C., the reaction was treated with a solution of 4-bromo-3-(naphthalen-1-yloxy)-but-2-enoic acid ethyl ester (1.14 g, 3.4 mmol) in acetonitrile (8.5 mL). After the addition was complete, the reaction mixture was heated to 100° C. where it stirred overnight. At this time, the reaction mixture was cooled to 25° C. and was concentrated in vacuo. The residue was diluted with dichloromethane (75 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL), a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 30% ethyl acetate/hexanes) afforded (S)-4-methyl-2-[4-(naphthalen-1-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid methyl ester (0.38 g, 32%) as a light orange oil: HR-ES-MS m/z calculated for C21H23NO4 [M+H]+ 354.1700, observed 354.1700; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.88 (d, J=6.3 Hz, 3H), 0.95 (d, J=6.3 Hz, 3H), 1.42-1.72 (m, 2H), 1.74-1.90 (m, 1H), 3.67 (s, 3H), 4.38 (s, 2H), 4.69-4.77 (m, 1H), 4.75 (s, 1H), 7.51 (d, J=6.9 Hz, 1H), 7.54-7.67 (m, 3H), 7.91 (d, J=8.2 Hz, 1H), 7.98-8.08 (m, 2H).
Reaction SMILES: COC1C=C(C(Cl)=O)C=CC=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.[CH3:34][O:35][C:36]1[CH:37]=[C:38]([C:42]([N:44]=[C:45]=[S:46])=[O:43])[CH:39]=[CH:40][CH:41]=1>C1(C)C=CC=CC=1.C(O)C>[CH3:34][O:35][C:36]1[CH:37]=[C:38]([C:42]([N:44]=[C:45]=[S:46])=[O:43])[CH:39]=[CH:40][CH:41]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:45]([NH:44][C:42](=[O:43])[C:38]2[CH:39]=[CH:40][CH:41]=[C:36]([O:35][CH3:34])[CH:37]=2)=[S:46])=[CH:29][CH:28]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: COc1cccc(C(=O)Cl)c1
Agent: COc1cccc(C(=O)N=C=S)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cccc(C(=O)NC(=S)Nc2ccc(Oc3ncnc4cc(OC)c(OC)cc34)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
3-Methoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-methoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-methoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (67 mg, yield 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1([OH:34])[C:17]2[C:12](=[CH:13][C:14]([I:22])=[CH:15][C:16]=2[C:18]([F:21])([F:20])[F:19])[N:11]([CH2:23][C@H:24]2[CH2:27][C@H:26]([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH2:25]2)[C:10]1=[O:33].[CH3:35][O:36][C@@H:37]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:38]([OH:40])=[O:39].CCCCCC>C(OCC)(=O)C>[CH3:35][O:36][C@@H:37]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:38]([O-:40])=[O:39].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1([OH:34])[C:17]2[C:12](=[CH:13][C:14]([I:22])=[CH:15][C:16]=2[C:18]([F:20])([F:21])[F:19])[N:11]([CH2:23][C@H:24]2[CH2:25][C@H:26]([N:28]([CH2:29][CH3:30])[CH2:31][CH3:32])[CH2:27]2)[C:10]1=[O:33]
Reactant: CO[C@H](C(=O)O)c1ccccc1
Agent: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O)(c3c(F)cccc3Cl)c3c2cc(I)cc3C(F)(F)F)C1
Agent: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O)(c3c(F)cccc3Cl)c3c2cc(I)cc3C(F)(F)F)C1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CO[C@H](C(=O)[O-])c1ccccc1
Temperature: 6 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(2-chloro-6-fluorophenyl)-1-[trans-3-(diethylamino)-cyclobutylmethyl]-4-trifluoromethyl-3-hydroxy-6-iodo-1,3-dihydro-2H-indol-2-one (3.60 g, 5.89 mmol) in ethyl acetate (50 mL) was added (S)-α-methoxyphenylacetic acid (550 mg), and the mixture was heated to 6° C. and stirred for 1 hour. Then, the mixture was stirred at room temperature for 1 hour, and thereto was added hexane (10 mL), and the mixture was stirred for additional 30 minutes at room temperature. The precipitated solid was filtered (1.41 g). The solid was recrystallized from ethyl acetate (20 mL)/hexane (3.0 ml) to give (S)-methoxyphenylacetate of 3-(2-chloro-6-fluorophenyl)-1-[trans-3-(diethylamino)-cyclobutylmethyl]-4-trifluoromethyl-3-hydroxy-6-iodo-1,3-dihydro-2H-indol-2-one (970 mg). The resulting compound was converted to its nonsalt form. Thus, the titled compound (650 mg, 98% ee, 18% y.) was obtained.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][CH2:10][F:11])=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.CCCCCC.CON(C)[C:26]([CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1)=[O:27]>C1COCC1>[F:11][CH2:10][CH2:9][O:8][C:7]1[C:2]([C:26]([CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)=[O:27])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: FCCOc1cccnc1Br
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2ncccc2OCCF)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a solution of 28 (7.3 mmol) in THF was added 1.6 N butyllithium/hexane solution (7 ml) at −78° C. under N2 atmosphere. The solution was stirred at −78° C. for 1 hour and a solution of tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (1 g, 3.6 mmol) in THF was added. The solution was maintained at −78° C. for 4 hour, and then quenched with sat. aqueous NH4Cl and allowed to warm to rt with stirring. The organic layer was separated and then the aqueous layer was extracted with ethyl acetate. The combine extract was washed with water, dried over Na2SO4, filtered, concentrated, and the residue chromatographed on silica eluted with an ethyl acetate-hexane (1:4, v/v) and the aimed product was obtained. The yield was 40%. NMR (CDCl3): δ 1.47 (s, 9H), 1.62-1.70 (m, 4H), 2.83 (s, 2H), 3.64-3.73 (m, 1H), 4.17 (br, 2H), 4.25-4.36 (m, 2H), 4.68-4.87 (m, 2H), 7.23-7.26 (m, 1H), 7.38-7.40 (m, 1H), 8.25-8.30 (m, 1H).
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:11]=[C:12](C)[CH:13]=[CH:14][C:15]=2[OH:16])[N:3]=[C:4]2C=CC=C[C:5]=12.C(=O)([O-])[O-].[Na+].[Na+].CO>ClC(Cl)Cl>[C:15]1([O-:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: Cc1ccc(O)c(-n2nc3ccccc3n2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: [O-]c1ccccc1
Product: c1c[nH]nn1

Procedure:
0.4 mmol of [Ir(1-phenylisoquinoline)2Cl]2 of Formula 44 and 0.88 mmol of 3-(2H-benzotriazole-2-yl)-4-hydroxyphenyl methane of Formula 45 and 2.0 mmol of sodium carbonate were added to a 250 ml branched flask and dissolved in 40 ml of trichloromethane and 15 mL of methanol to react in a nitrogen atmosphere at room temperature for 2 to 10 hours. After the reaction was completed, the reaction solution was Celite filtered and precipitated in hexane to obtain triazole phenolate represented by Formula 3. The obtained red solid was refined using silica gel column (methylene chloride:acetone=10:1). The structure of the final product was analyzed using a 1H NMR spectrum:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][C:13]=3[CH:26]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[CH2:27]([N:29]=[C:30]=S)[CH3:28].O.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C>[CH2:27]([NH:29][C:30]1[NH:1][C:2]2[CH:3]=[C:4]([C:9]3[CH:10]=[CH:11][C:12]4[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:14][C:13]=4[CH:26]=3)[CH:5]=[CH:6][C:7]=2[N:8]=1)[CH3:28]
Reactant: CCN=C=S
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(N)c(N)c3)cc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CCNc1nc2ccc(-c3ccc4c(c3)CN(C(=O)OC(C)(C)C)CCO4)cc2[nH]1
Temperature: 60 °C
Yield: 39.5 %

Procedure:
A solution of 1,1-dimethylethyl 7-(3,4-diaminophenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (750 mg, 2.10 mmol) in ethyl acetate (20 mL) was treated with ethyl isothiocyanate (184 uL, 2.10 mmol). The mixture was heated to 60° C. for 4.25 h. After cooling to rt, water was added and the layers were partitioned. The organic phase was washed once with saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated. The residue was then dissolved in ethyl acetate (20 mL), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (403 mg, 2.10 mmol) was added. The mixture was heated to 60° C. for 50 minutes before cooling to rt. Water was added, and the biphasic mixture was partitioned. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (gradient: 98:2 dichloromethane:methanol to 90:10 dichloromethane:methanol) to provide 1,1-dimethylethyl 7-[2-(ethylamino)-1H-benzimidazol-6-yl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (337 mg, 0.83 mmol, 39% yield) as an orange film. 1H NMR (400 MHz, DMSO-d6) δ 10.83 (br s, 1H), 7.47-7.38 (m, 2H), 7.32 (s, 1H), 7.20-7.08 (m, 2H), 7.05-6.96 (m, 1H), 6.68-6.58 (m, 1H), 4.55-4.40 (m, 2H), 4.09-3.98 (m, 2H), 3.77-3.65 (m, 2H), 3.33-3.26 (m, 2H), 1.41-1.28 (m, 9H), 1.18 (t, 3H); MS (EI) for C23H28N4O3: 409 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:19]([NH2:21])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=2)[C@H:12]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:19]([NH2:21])=[O:20])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: NC(=O)[C@@H]1CCCCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Product: NC(=O)[C@@H]1CCCCC[C@@H]1N(Cc1ccc(C(F)(F)F)cc1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 58 %

Procedure:
The titled compound (127 mg) was prepared in 58% yield from cis-2-(4-chlorobenzenesulfonylamino)-cycloheptanecarboxylic acid amide (150 mg, 0.45 mmol) and 1-bromomethyl-4-trifluoromethyl-benzene according to the N-alkylation procedure described in Example 11: 1H NMR (DMSO-d6) δ 7.80 (m, 2 H, J=8.0 Hz), 7.62 (m, 4 H), 7.52 (d, 2 H, J=8.0 Hz), 7.35 (s br, 1 H), 6.70 (s br, 1 H), 4.61 (AB2,2 H,Δv=20,Jab=104 Hz), 3.98 (m, 1 H), 2.80 (m, 1 H), 2.29 (m, 1 H), 1.74 (m, 2 H), 1.43 (m, 5 H), 1.22 (m, 2 H); MS m/e 511.05 (M+Na)+.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O=[C:7]1[NH:23][C:11]2[CH2:12][C@H:13]3[C@H:18]([CH2:19][C:10]=2[CH:9]=[CH:8]1)[N:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15][CH2:14]3.[NH4+].[OH-]>CN(C)C=O>[ClH:3].[Cl:3][C:7]1[CH:8]=[CH:9][C:10]2[CH2:19][C@H:18]3[C@@H:13]([CH2:14][CH2:15][CH2:16][N:17]3[CH2:20][CH2:21][CH3:22])[CH2:12][C:11]=2[N:23]=1
Reactant: CCCN1CCC[C@H]2Cc3[nH]c(=O)ccc3C[C@@H]21
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCN1CCC[C@H]2Cc3nc(Cl)ccc3C[C@@H]21
Product: Cl
Temperature: 135 °C
Reaction time: 17 h
Yield: 79.4 %

Procedure:
Phosphorus oxychloride (272 g, 165 mL, 175 mol) was added over 6 hours to a solution of (±)-trans2-oxo-6-propyl-1,2,5,5a,6,7,8,9,9a,10-decahydropyrido -[2,3-g]quinoline (5.75 g, 23.4 mMol) in dimethylformamide (250 mL) at 135° C. The reaction was stirred at 135° C. for 17 hours, poured over ice, and made basic with NH4OH and extracted with methylene chloride. The extract was dried (Na2SO4) and concentrated to give the crude product as a brown oil. Purification by flash chromatography (5% methanol in methylene chloride, 0.5% NH4OH) gave the desired product as a brown oil (5.6 g, 90% yield).
Reaction SMILES: C(O[C:6]([C:8]1[N:13]=[C:12]([CH2:14][CH3:15])[C:11]2[C:16]([CH3:19])=[N:17][S:18][C:10]=2[C:9]=1[OH:20])=[O:7])CCC.[NH2:21][CH2:22][C:23]([OH:25])=[O:24]>>[CH2:14]([C:12]1[C:11]2[C:16]([CH3:19])=[N:17][S:18][C:10]=2[C:9]([OH:20])=[C:8]([C:6]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:7])[N:13]=1)[CH3:15]
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1nc(CC)c2c(C)nsc2c1O
Product: CCc1nc(C(=O)NCC(=O)O)c(O)c2snc(C)c12

Procedure:
The title compound was synthesized in analogy to Example 1 from 4-ethyl-7-hydroxy-3-methyl-isothiazolo[4,5-c]pyridine-6-carboxylic acid butyl ester and glycine: MS (m/z) 296.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:27])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[N:9]=2)[CH:7]=1.C(OC(=O)[N:34]([S:40]([C:43]1[CH:48]=[C:47]([Cl:49])[C:46](F)=[CH:45][C:44]=1[F:51])(=[O:42])=[O:41])[C:35]1[N:36]=[CH:37][S:38][CH:39]=1)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[F:59][C:60]([F:65])([F:64])[C:61]([OH:63])=[O:62]>CS(C)=O.O>[F:59][C:60]([F:65])([F:64])[C:61]([OH:63])=[O:62].[Cl:49][C:47]1[C:46]([O:27][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=2[C:8]2[CH:13]=[CH:12][N:11]=[C:10]([N:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[N:9]=2)=[CH:45][C:44]([F:51])=[C:43]([S:40]([NH:34][C:35]2[N:36]=[CH:37][S:38][CH:39]=2)(=[O:41])=[O:42])[CH:48]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc(-c3cc(Cl)ccc3O)n2)CC1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: O
Product: O=S(=O)(Nc1cscn1)c1cc(Cl)c(Oc2ccc(Cl)cc2-c2ccnc(N3CCNCC3)n2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.9 %

Procedure:
tert-Butyl 4-[4-(5-chloro-2-hydroxyphenyl)pyrimidin-2-yl]piperazine-1-carboxylate (Preparation 2, 48.6 mg, 0.11 mmol), tert-butyl[(5-chloro-2,4-difluorophenyl)sulfonyl]1,3-thiazol-4-ylcarbamate (Preparation 4, 43.6 mg, 0.11 mmol) and potassium carbonate (21.9 mg, 0.16 mmol) were mixed in dimethylsulfoxide (1 mL) and shaken at ambient temperature for 18 hours. The reaction mixture was diluted with water and the precipitate collected by filtration. The solid was dissolved in dichloromethane (2.0 mL) and dried over anhydrous magnesium sulfate. The mixture was filtered and trifluoroacetic acid (0.060 mL, 0.78 mmol) was added to the filtrate. After 2 hours the reaction mixture was concentrated in vacuo to a residue and purified by reverse phase HPLC to afford the title compound as a tan glass (55 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH:14]=[O:15])=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]([CH:19]([CH3:21])[CH3:20])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([Mg]Br)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+].O>O1CCCC1>[CH2:1]([O:8][C:9]1[C:13]([CH:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[OH:15])=[C:12]([CH:16]([CH3:17])[CH3:18])[N:11]([CH:19]([CH3:21])[CH3:20])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C=O)c(OCc2ccccc2)nn1C(C)C
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1c(C(O)c2ccccc2)c(OCc2ccccc2)nn1C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-benzyloxy-4-formyl-1,5-diisopropyl-1H-pyrazole (0.21 g) in tetrahydrofuran (10 mL) was added a solution of phenylmagnesium bromide in tetrahydrofuran (1 mol/L, 1.5 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. A saturated ammonium chloride aqueous solution and water were added to the reaction mixture, and the mixture was purified by column chromatography on aminopropylated silica gel (eluent: tetrahydrofuran). Further purification by column chromatography on silica gel (eluent: hexane/ethyl acetate=10/1-2/1) to give the adduct material, [3-benzyloxy-1,5-diisopropyl-1H-pyrazole-4-yl]phenyl methanol. The obtained adduct material was dissolved in ethanol, and a catalytic amount of 10% palladium-carbon powder was added to the solution. The mixture was stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (0.16 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[Br:43][C:44]1[CH:45]=[C:46]([C@H:50]([NH2:52])[CH3:51])[CH:47]=[CH:48][CH:49]=1>C(Cl)(Cl)Cl>[Br:43][C:44]1[CH:45]=[C:46]([C@H:50]([NH:52][C:35]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][C:18]=2[F:23])=[O:41])[CH3:51])[CH:47]=[CH:48][CH:49]=1
Reactant: C[C@@H](N)c1cccc(Br)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@H](C)c4cccc(Br)c4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (79 mg) was dissolved in chloroform (2 ml) and triethylamine (0.2 ml) to prepare a solution. A solution of triphosgene (70 mg) in chloroform (0.4 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1R)-1-(3-bromophenyl)ethylamine (70 mg) in chloroform (0.4 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (58 mg, yield 43%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].F[C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[C:37]([CH3:43])[CH:36]=1>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:17]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:19]=[C:20]([O:22][C:35]3[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[C:37]([CH3:43])[CH:36]=3)[CH:21]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(F)ccc1C#N
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Product: Cc1cc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)NC3CCC(NC(=O)OC(C)(C)C)CC3)c2)ccc1C#N
Yield: 71.3 %

Procedure:
Following the procedure of Example 69(b) {4-[3-(4-cyanophenoxy)-5-hydroxy-benzoylamino]cyclohexyl}carbamic acid tert-butyl ester 0.85 g (1.88 mmol) and 4-fluoro-2-methyl-benzonitrile (0.508 g, 3.76 mmol) were used to afford 0.76 g of the required product. 1H NMR (DMSO-d6): δ 1.20 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 2.45 (3H, s), 3.15 (1H, m), 3.7 (1H, m), 6.72 (1H, d), 7.02 (1H, d), 7.2 (4H, m), 7.5 (2H, s), 7.8 (1H, d), 7.88 (2H, d), 8.34 (1H, d).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH:33]1([N:39]=[C:40]=[O:41])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>C(#N)C>[CH:33]1([NH:39][C:40]([NH:13][CH2:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][N:18]([CH:25]2[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]2=[O:32])[C:19]3=[O:24])=[O:41])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=NC1CCCCC1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(N2Cc3c(CNC(=O)NC4CCCCC4)cccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.9 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.4 g, 2.9 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.6 g, 1.9 mmol) in acetonitrile (100 mL). The mixture was heated for 30 minutes, then cooled to room temperature. Cyclohexyl isocyanate (0.4 g, 2.9 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was filtered and the solid was stirred with water (25 mL) to give 0.9 g of crude product. The crude product was recrystallized from methanol to give 1-cyclohexyl-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-urea (0.12 g, 16%) as a white solid: mp 309-311° C.; 1H NMR (DMSO-d6) δ 0.97-1.75 (m, 10H), 1.99-2.04 (m, 1H), 2.32-2.64 (m, 3H), 2.86-2.98 (m, 1H), 4.27-4.51 (m, 4H), 5.11-5.18 (dd, J=4.9 and 13.1 Hz, 1H, CH), 5.86 (d, J=7.9 Hz, 1H), 6.26 (t, J=5.5 Hz, 1H, NH), 7.47-7.62 (m, 3H, Ar), 11.01 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.64, 24.44, 25.29, 31.16, 33.32, 46.09, 47.50, 47.85, 51.47, 121.36, 128.18, 130.26, 131.61, 136.28, 139.77, 157.20, 168.09, 170.97, 172.82; Anal. calcd. for C21H26N4O4: C, 63.30; H, 6.58; N, 14.06. Found: C, 63.18; N, 6.58; N, 13.99.