Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:49][CH:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)[C:40](NC2C=CN(C)N=2)=[O:41])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:55][C:56]1[CH:60]=[CH:59][N:58]([C:61](=[O:67])[CH2:62][C:63]([OH:66])([CH3:65])[CH3:64])[N:57]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.C(OCC)(=O)C>[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:49][CH:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)[C:40]([NH:55][C:56]2[CH:60]=[CH:59][N:58]([C:61](=[O:67])[CH2:62][C:63]([OH:66])([CH3:65])[CH3:64])[N:57]=2)=[O:41])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: CC(C)(O)CC(=O)n1ccc(N)n1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(O)CC(=O)n1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 12 %

Procedure:
Triphenylphosphine (186 mg, 0.71 mmol) was dissolved in methylene chloride (3 mL) and cooled to 0° C. To this solution was added N-bromosuccinimide (143 mg, 0.81 mmol) and was stirred at 0° C. until it was completely dissolved and became light purple in color. The 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 157 mg, 0.47 mmol) was then added and it was stirred at 0° C. for 15 min and then warmed to 25° C. and stirred for 30 min. The reaction was chilled to 0° C. and the combined solution of 1-(3-amino-pyrazol-1-yl)-3-hydroxy-3-methyl-butan-1-one (87 mg, 0.47 mmol) and 2,6-lutidine (0.165 mL, 1.42 mmol) in methylene chloride (4 mL) was added. The mixture was continued to stir at 0° C. for 30 min and then at 25° C. for 3 h. The reaction was diluted with ethyl acetate (50 mL), washed with water (3×20 mL) and saturated aqueous brine solution (2×20 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 40% ethyl acetate/hexanes) eluted the desired product and an impurity simultaneously. Further purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 20% ethyl acetate/methylene chloride) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(3-hydroxy-3-methyl-butyryl)-1H-pyrazol-3-yl]-propionamide (28 mg, 12%) as a white powder: ESI-LRMS m/e calcd for C23H30ClN3O5S [M+] 495.2, found 496.2 [M+H+], 478.0 [M−H2O+H+], 396.0 [M−COCH2C(CH3)2OH]; 1H NMR (400 MHz, CDCl3) δ ppm 1.07-1.23 (m, 2H, CH2), 1.37 (s, 6H, 2×CH3), 1.44-1.98 (m, 8H, 4×CH2), 2.09-2.32 (m, 1H, CH), 3.23 (AB, Jgem=17.4 Hz, 2H, CH2), 3.27 (s, 3H, SO2CH3), 3.64 (t, J=7.5 Hz, 1H, CH), 7.02 (d, J=2.9 Hz, 1 H, Ar), 7.47 (dd, Jo=8.2, Jm=1.7 Hz, 1H, Ar), 7.60 (d, Jm=1.7 Hz, 1H, Ar), 8.08 (d, Jo=8.2 Hz, 1H, Ar), 8.14 (d, J=2.9 Hz, 1H, Ar), 8.46 (s, 1H, NH).
Reaction SMILES: [F:1][C:2]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:8]([F:19])[C:7]=1[F:20].C([Li])(CC)C.[F:31][C:32]1[C:37]([F:38])=[C:36]([O:39][CH2:40][CH3:41])[CH:35]=[CH:34][C:33]=1[CH:42]1[CH2:47][CH2:46][C:45](=O)[CH2:44][CH2:43]1.Cl>C(OCC)(=O)C.C1COCC1>[F:20][C:7]1[C:8]([F:19])=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][C:3]1[CH:21]=[CH:22][C:23]([C:45]2[CH2:46][CH2:47][CH:42]([C:33]3[CH:34]=[CH:35][C:36]([O:39][CH2:40][CH3:41])=[C:37]([F:38])[C:32]=3[F:31])[CH2:43][CH:44]=2)=[C:24]([F:25])[C:2]=1[F:1]
Reactant: CCOc1ccc(C2CCC(=O)CC2)c(F)c1F
Reactant: CCCCCCOc1ccc(CCc2cccc(F)c2F)c(F)c1F
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCOc1ccc(CCc2ccc(C3=CCC(c4ccc(OCC)c(F)c4F)CC3)c(F)c2F)c(F)c1F
Temperature: 30 °C
Reaction time: 2 h

Procedure:
1-(2,3-Difluorophenethyl)-2,3-difluoro-4-(hexyloxy)benzene (s-24) (3.6 g) and THF (100 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and cooled to −74° C. sec-Butyllithium (1.00M; n-hexane and cyclohexane solution; 12 ml) was added dropwise in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. 1-(2,3-Difluoro-4-ethoxyphenyl)-cyclohexan-4-one (s-25) (2.6 g) in a THF (50 ml) solution was added dropwise in the temperature range of −75° C. to −70° C., and the stirring was continued for 8 hours while the mixture was allowed to return to 25° C. The resulting reaction mixture was poured into a vessel containing a 1N-HCl aqueous solution (100 ml) and ethyl acetate (100 ml) and mixed with them. The mixture was then allowed to stand until it had separated into organic and aqueous layers, and the extraction was carried out. The resulting organic layers were separated, and washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. p-Toluenesulfonic acid (0.19 g) and toluene (100 ml) were added, and the mixture was heated to reflux for 2 hours, while distilled water was removed. After the reaction solution had been cooled to 30° C., water (200 ml) and toluene (100 ml) were added and mixed with it. The mixture was then allowed to stand until it had separated into two layers of organic and aqueous layers, and the extraction into an organic layer was carried out. The resulting organic layers were separated, and washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The resulting solution was purified by column chromatography using silica gel as a stationary phase powder and toluene as an eluent, and further purified by recrystallization from a mixed solvent of Solmix A-11 and heptane (Solmix A-11:heptane=1:2 by volume) and dried to give 1-(2,3-difluoro-4-(hexyloxy)phenethyl)-4-(4-(4-ethoxy-2,3-difluorophenyl)cyclohex-1-enyl)-2,3-difluorobenzene (No. 487) (3.1 g). The yield based on the compound (s-24) was 33.8%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1.[F:21][C:22]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>>[NH2:19][C:13]1[N:12]=[C:11]([NH2:20])[C:10]2[C:15](=[CH:16][CH:17]=[CH:18][C:9]=2[O:8][CH2:7][CH:4]2[CH2:5][CH2:6][N:1]([C:24]([C:23]3[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:22]=3[F:21])=[O:25])[CH2:2][CH2:3]2)[N:14]=1
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Reactant: O=C(Cl)c1ccc(F)cc1F
Product: Nc1nc(N)c2c(OCC3CCN(C(=O)c4ccc(F)cc4F)CC3)cccc2n1
Yield: 71 %

Procedure:
The amidation of 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (50 mg; 0.18 mmol) was carried out using 2,4-difluorobenzoyl chloride (65 mg; 0.37 mmol) via Method AA to yield 108 mg. (71% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.48 (m, 1H), 7.35 (m, 2H), 7.18 (m, 3H), 6.77 (d, J=8.0 Hz, 1H), 6.54 (d, J=8.0 Hz, 1H), 5.94 (br s, 2H), 4.53 (br d, J=13.2 Hz, 1H), 4.03 (d, J=6.0 Hz, 2H), 3.44 (m, 1H), 3.12 (t, J=12.8 Hz, 1H), 2.85 (m, 1H), 2.22 (m, 1H), 1.9 (d, J=12.4 Hz, 1H), 1.74 (d, J=12.4 Hz, 1H), 1.26 (m, 2H). MS m/z (ESI) 414 (M+H)+.
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[NH2:13][CH2:14][CH2:15][C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([OH:18])[CH3:17].C1CCN2C(=NCCC2)CC1>>[C:19]1([C:16]([OH:18])([CH2:15][CH2:14][NH:13][C:2]2[S:3][CH:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:6]=2)[CH3:17])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Clc1nc(-c2ccccc2)cs1
Reactant: CC(O)(CCN)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(O)(CCNc1nc(-c2ccccc2)cs1)c1ccccc1
Temperature: 100 °C
Yield: 20.5 %

Procedure:
A mixture of 2-chloro-4-phenylthiazole (300 mg, 1.5 mmol), 4-amino-2-phenyl-butan-2-ol (294 mg, 1.5 mmol) and DBU (1.5 mL) was heated to 100° C. under N2 in a microwave for 2 h. After the material was consumed, the mixture was neutralized with 1 N HCl solution (5 mL), extracted with CH2Cl2 (3×5 mL). The combined organic extracts were dried over Na2SO4 and concentrated to leave a residue, which was purified by column chromatography (1:2 petroleum ether/EtOAc) to afford 2-phenyl-4-(4-phenylthiazol-2-ylamino)butan-2-ol (100 mg, 20%).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][CH2:7][CH:8]([O:26]C(=O)C)[CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[NH:18][C:17]3=[O:25])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[OH-].[K+].C(O)C>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH:8]([OH:26])[CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[NH:18][C:17]3=[O:25])[CH2:14][CH2:15]2)=[CH:30][CH:31]=1
Reactant: CC(=O)OC(COc1ccc(F)cc1)CN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=c1[nH]c2ccccc2n1C1CCN(CC(O)COc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2.2 g of 1-{1-[3-(p-fluorophenoxy)-2-acetyloxypropyl]-4-piperidyl}-2-oxobenzimidazoline, 1.1 g of potassium hydroxide, 5 ml of water and 20 ml of ethanol is stirred at room temperature for one hour. The reaction mixture is poured into 200 ml of water. After cooling, the precipitate formed is collected by filtration and dried to give 1-{1-[3-(p-fluorophenoxy)-2-hydroxypropyl]-4-piperidyl}-2-oxobenzimidazoline, m.p. 175° - 176° C. Recrystallization from benzene gives white crystals, m.p. 177° - 178° C.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[ClH:19].[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: C1CNCCN1
Product: CCc1cc(-c2ccc(S(=O)(=O)N3CCNCC3)s2)c(C)[nH]c1=O
Product: Cl
Yield: 73.3 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with piperazine as described in Steps 5 and 6, Example 24 to give the title compound as a solid (73.3% yield). LC/MS: RT 2.07 min; m/e 368 (M+H); 1H NMR (δ, ppm): 11.8 (1H, br s), 9.5 (1H, s), 7.65 (1H, d); 7.35 (1H, s); 7.3 (1H, d), 3.2 (8H, m), 2.4 (2H, q), 2.36 (3H, s), 1.1 (3H, t).
Reaction SMILES: [C:1]([OH:11])(=O)[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[CH3:12][NH:13][C@H:14]1[CH2:33][N:18]2[C:19]3[C:24]([C:25]([CH2:26][C:27]([O:29]CCC)=[O:28])=[C:17]2[CH2:16][CH2:15]1)=[CH:23][CH:22]=[CH:21][CH:20]=3>>[CH3:12][N:13]([C:1](=[O:11])[CH:2]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:3])[C@H:14]1[CH2:33][N:18]2[C:19]3[C:24]([C:25]([CH2:26][C:27]([OH:29])=[O:28])=[C:17]2[CH2:16][CH2:15]1)=[CH:23][CH:22]=[CH:21][CH:20]=3
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: CC(C(=O)O)c1ccccc1
Product: CC(C(=O)N(C)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1)c1ccccc1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from hydratropic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 391.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:29])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH3:28])([CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=1)[CH2:9][CH2:8]2)(=[O:3])[CH3:2].[H][H]>CO.C1C=CC=CC=1.C(OCC)(=O)C.[Pd]>[C:1]([O:4][C:5]1[C:6]([CH3:29])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=1)([CH3:28])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(COc1ccc([N+](=O)[O-])cc1)O2
Agent: [Pd]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(COc1ccc(N)cc1)O2

Procedure:
24.3 g of 6-acetoxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman were dissolved in a mixture of 200 ml of methanol and 20 ml of benzene and reacted for 3 hours under a hydrogen pressure of 45-55 lb/sq. inch (3.1-3.8 bars), using Pearl's hydrogen adding apparatus, in the presence of 7 g of 10% w/w palladium-on-carbon. The palladium-on-carbon was removed by filtration from the reaction mixture and washed with a mixture of 600 ml of acetone and 60 ml of concentrated hydrochloric acid. The filtrate and the washings were combined and the mixture was neutralized with sodium bicarbonate. The solvent was then distilled off, and the crude crystals obtained were dissolved in ethyl acetate. The ethyl acetate solution was washed with water and dried over anhydrous sodium sulfate. The ethyl acetate was then distilled from the extract, and the crude substance obtained was washed with a 1:1 by volume mixture of benzene and cyclohexane, giving the desired 6-acetoxy-2-(4-aminophenoxymethyl)-2,5,7,8-tetramethylchroman, melting at 138°-140° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28].[H-].[Na+].Br[CH2:32][CH2:33][CH2:34][CH2:35][Cl:36].O>CN(C)C=O>[Cl:36][CH2:35][CH2:34][CH2:33][CH2:32][NH:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reactant: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCCCl)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
1.01 g (2.59 mmol) of 5-amino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one obtained in Example 66 was dissolved in 20 ml of dimethylformamide under argon atmosphere, 228 mg of sodium hydride (60% oil dispersion) and 1.5 ml of 1-bromo-4-chlorobutane were added under ice-cooling and the mixture was stirred at room temperature for 3 hours. 228 mg of sodium hydride (60% oil dispersion) and 1.5 ml of 1-bromo-4-chlorobutane were further added and the mixture was stirred for additional 1 hour. Water was added to the reaction solution and the mixture was extracted three times with ethyl acetate. The organic layer was washed twice with an aqueous saturated solution of sodium chloride and 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=6:1) to give 396 mg (32%) of 5-(4-chlorobutylamino)-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[C:10]([CH3:13])[CH:11]=2)[CH:6]([CH2:15][CH2:16][C:17]#N)[CH2:5]1)(=[O:3])[CH3:2].[OH-:19].[K+].[OH2:21]>CCO>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[C:10]([CH3:13])[CH:11]=2)[CH:6]([CH2:15][CH2:16][C:17]([OH:21])=[O:19])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: [OH-]
Reactant: O
Reactant: CC(=O)N1CC(CCC#N)c2c(C)cc(C)cc21
Agent: [K+]
Solvent: CCO
Product: CC(=O)N1CC(CCC(=O)O)c2c(C)cc(C)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Acetyl-3-(2-cyanoethyl)-4,6-dimethylindoline (4.5 g) was dissolved in EtOH (150 ml), and a solution of KOH (10.4 g) in water (50 ml) was added, which was followed by refluxing for 15 hr. EtOH was evaporated under reduced pressure, and the aqueous layer was adjusted to weak acidic with 6N hydrochloric acid and extracted with CHCl3 (100 ml). The CHCl3 layer was washed with water and dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure. The residue was dissolved in CHCl3 (20 ml) and Ac2O (1.9 g) was added, which was followed by stirring at room temperature for 1 hr. CHCl3 (100 ml) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3 /MeOH=50/1-10/1) to give 3.4 g of 1-acetyl-3-(2-carboxyethyl)-4,6-dimethylindoline.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[CH:10]3)=[C:4]([F:18])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[C:22]([NH2:27])[N:21]=1.Cl.C(=O)(O)[O-].[Na+]>O>[NH2:27][C:22]1[N:23]=[C:24]([NH:1][C:2]2[CH:17]=[CH:16][C:5]([O:6][C:7]3[CH:8]=[C:9]4[C:13](=[CH:14][CH:15]=3)[NH:12][N:11]=[CH:10]4)=[C:4]([F:18])[CH:3]=2)[CH:25]=[C:20]([Cl:19])[N:21]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Nc1ccc(Oc2ccc3[nH]ncc3c2)c(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1nc(Cl)cc(Nc2ccc(Oc3ccc4[nH]ncc4c3)c(F)c2)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
1.65 g (6.78 mmol) of 5-(4-amino-2-fluorophenoxy)-1H-indazole (from example XII) are suspended in 90 ml of water. 1.11 g (6.78 mmol) of 4,6-dichloro-2-pyrimidineamine and 0.68 ml of concentrated aqueous hydrogen chloride solution are added, and the mixture is stirred at 100° C. overnight. For work-up, the reaction solution is made alkaline with saturated sodium bicarbonate solution and extracted 3× with ethyl acetate. The organic phase is dried with sodium sulfate and concentrated using a rotary evaporator.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][NH:48][CH2:49][CH2:50][CH3:51]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:48]([CH3:47])[CH2:49][CH2:50][CH3:51])=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCCNC
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCCN(C)C(=O)CC1CCN(C(=O)N2C(c3cnc(C(C)(C)C)cc3OCC)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with n-methyl-1-propylamine (Aldrich) to give the title product. LC-MS (ES+) 720 [(M+H)+].
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([N:9]([CH2:13][C:14](Cl)=[CH2:15])[C:10]([NH2:12])=[S:11])[CH:6]=[CH:7][CH:8]=1.C(C(C)=O)C(C)C.Cl.C(=O)([O-])O.[Na+]>O>[NH:12]=[C:10]1[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:4]=2)[CH:13]=[C:14]([CH3:15])[S:11]1
Reactant: C=C(Cl)CN(C(N)=S)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=N)s1
Temperature: 90 °C
Reaction time: 7 h
Yield: 83.8 %

Procedure:
N-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)thiourea (1.47 g) and stannic chloride n-hydrate (n=4 to 5) (0.09 g) were added to methyl isobutyl ketone (7.50 g) at room temperature, and the mixture was heated to 90° C. and stirred at the same temperature for 7 hours. After cooling, 35% hydrochloric acid (0.52 g) was added to the reaction mixture with stirring, and the mixture was heated to 90° C. and stirred at the same temperature for 2.5 hours. After cooling, water was added to the reaction mixture, which was then neutralized by addition of sodium hydrogen carbonate and extracted with methyl isobutyl ketone. The organic layer was washed with water. The solvent was removed by distillation under reduced pressure, which afforded 1.08 g of 2-imino-3-(3-(trifluoromethyl)phenyl)-5-methyl-4-thiazoline (75% yield as a corrected value from the below-mentioned purity). From the results of analysis by liquid chromatography, the purity was determined to be 89%.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[F:15][CH:16]([F:29])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([NH2:27])[CH3:26])=[CH:21][C:20]=1[CH3:28]>>[Cl:13][C:12]1[C:3]2[CH2:2][N:27]([CH:25]([C:22]3[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH:16]([F:15])[F:29])=[C:20]([CH3:28])[CH:21]=3)[CH3:26])[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: Cc1cc(C(C)N)ccc1OCC(F)F
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)ccc1OCC(F)F
Yield: 65 %

Procedure:
The title compound is prepared in 65% yield (136 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethanamine hydrochloride (143 mg, 0.57 mmol, Amine-27, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[N:18]=3)[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.C(N(CC)CC)C>C(OCC)(=O)C.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[N:18]=3)[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: Cc1cc(C)nc(N2CCN(c3ccc([N+](=O)[O-])c(Cl)c3)CC2)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(C)nc(N2CCN(c3ccc(N)c(Cl)c3)CC2)c1
Yield: 64.2 %

Procedure:
Stannous chloride dihydrate (2.6 g, 11.5 mmol) was added to a solution of 1-(3-chloro-4-nitro-phenyl)-4-(4,6-dimethyl-pyridin-2-yl)-piperazine (800 mg, 2.31 mmol) in a mixture of ethyl acetate (20 mL) and ethanol (5 mL). The reaction mixture was heated at reflux for 2 h, allowed to cool to ambient temperature and basified with triethylamine. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography over neutral alumina with 10% ethyl acetate in petroleum ether as eluent to afford 2-chloro-4-[4-(4,6-dimethyl-2-pyridyl)piperazin-1-yl]aniline (470 mg, 64%) as a viscous light brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[O:16]=[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:14][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(OCC(=O)OCc2ccccc2)cc1
Yield: 99 %

Procedure:
A mixture of ethyl p-hydroxybenzoate (4.98 g), benzyl bromoacetate (4.75 ml) and K2CO3 (4.14 g) was stirred for 15 hr in 30 ml of DMF. The reaction mixture was diluted with water (200 ml) and extracted with a 1:1 ether:hexane mixture. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered, and evaporated leaving 9.3 g, (99%) of the title compound as a heavy oil; TLC, Rf =0.71, Et2O: hexane (1:1).