Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH3:19])[CH:16]=2)[C:11]1=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:19][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:20])[N:10]([CH:3]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:2][O:1][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:18]2
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc2c(c1)CN(C(CO)c1ccccc1)C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(c1)CN(C(COS(C)(=O)=O)c1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(2-Hydroxy-1-phenyl-ethyl)-5-methyl-2,3-dihydro-isoindol-1-one (4.72 g, 17.66 mmol) and triethylamine (5.36 g, 53.97 mmol, 7.38 mL) were taken up in anhydrous DCM (50 mL), under argon and cooled to 0EC. Methanesulfonyl chloride (2.22 g, 19.43 mmol, 1.5 mL) was added to the reaction over 10 min. The reaction was stirred for 1 h at 0EC then allowed to slowly warm to room temp and stirred for 4 h. The reaction was slowly poured into saturated sodium bicarbonate and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with 1N HCl, water, brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent removed under reduced pressure. The product was used in the next step without further purification. Yield 5.61 g. 1H NMR (CDCl3, 300 MHz): δ 2.44 (s, 3H), 3.01 (s, 3H), 4.15 (d, J=16 Hz, 1H), 4.43 (d, J=17 Hz, 1H), 4.77 (dd, J=5, 11 Hz, 1H), 5.03 (dd, J=9, 11 Hz, 1H), 5.76 (dd, J=5, 9 Hz, 1H), 7.20-7.38 (, 7H), 7.76 (d, J=8, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1.[H-].[Na+].CS(O[CH2:21][CH2:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][CH2:24]1)(=O)=O.C(OC(=O)NC1CCN(CCN2C3C(=CC=C(OC)C=3)C=CC2=O)CC1)(C)(C)C>ClCCl.CO>[C:33]([O:32][C:30](=[O:31])[NH:29][C@H:26]1[CH2:25][CH2:24][C@H:23]([CH2:22][CH2:21][N:8]2[C:7]3[CH:13]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[O:11][CH2:10][C:9]2=[O:12])[CH2:28][CH2:27]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: COc1ccc2c(c1)NC(=O)CO2
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCOS(C)(=O)=O)CC1
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2c(c1)N(CC[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)C(=O)CO2

Procedure:
6-Methoxy-2H-1,4-benzoxazin-3(4H)-one (Intermediate 48) (310 mg, 1.73 mmol) was deprotonated with sodium hydride and alkylated with 2-{trans-4-[(tert butoxycarbonyl)amino]cyclohexyl}ethyl methanesulfonate (Intermediate 76) (2 mmol) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/methanol (20:1) afforded the product as a solid (58%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Br[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:25])([C:21]([F:24])([F:23])[F:22])[C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[F:18][C:17]([F:19])([F:20])[C:16]([C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:6]2[CH2:5][CH2:4][NH:3][C@@H:2]([CH3:1])[CH2:7]2)=[CH:11][CH:12]=1)([OH:25])[C:21]([F:22])([F:24])[F:23]
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Reactant: C[C@H]1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@H]1CN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CCN1
Yield: 45.6 %

Procedure:
(S)-2-Methylpiperazine (28 mmol, 2.8 g), 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (28 mmol, 9.42 g) and potassium carbonate (55.9 mmol, 9.42 g) were stirred at room temperature in acetonitrile (50 mL) overnight The reaction mixture was diluted with ethyl acetate and filtered through dicalite. The filtrate was concentrated under vacuum and the resulting residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 85/15/1.5 dichloromethane/methanol/ammonia) to afford the title compound (4.55 g). MS (ESI) m/z 357.0 [M+H]+
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:4]([OH:6])=[O:5].[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]Cl)([O-:14])=[O:13].O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21][NH:2][CH:3]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:4]([OH:6])=[O:5])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccccc1SCl
Reactant: COC(=O)CC(N)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CC(NSc1ccccc1[N+](=O)[O-])C(=O)O

Procedure:
9.2 g (50 millimoles) of DL-2-amino-3-methoxycarbonyl-propionic acid hydrochloride (i.e., DL-aspartic acid O62 -methyl ester HCl), 10.5 g of o-nitrophenylsulfenyl chloride, 50 ml of water, 70 ml of tetrahydrofuran and 24.3 g of potassium carbonate are treated in the same manner as described in Example 1-(1). 9.8 g of DL-2-(o-nitrophenylsulfenylamino)-3-methoxycarbonyl-propionic acid are obtained. M.p. 108°- 109° C.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2([OH:16])[CH2:15][CH2:14][CH2:13][CH2:12]2)[N:8]=[N:7]1)C.[OH-].[Na+].C.OS([O-])(=O)=O.[Na+]>O.CCOC(C)=O>[OH:16][C:11]1([C:9]2[N:8]=[N:7][N:6]([CH2:5][C:4]([OH:17])=[O:3])[CH:10]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCOC(=O)Cn1cc(C2(O)CCCC2)nn1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)Cn1cc(C2(O)CCCC2)nn1
Yield: 87 %

Procedure:
To a solution of ethyl[4-(1-hydroxycyclopentyl)-1H-1,2,3-triazol-1-yl]acetate (Preparation 293, 36.4 g, 151 mmol) in water (50 mL), was added a solution of NaOH (7.60 g, 190 mmol) in water (25 mL). The solution was refluxed with activated charcoal, filtered through Celite, and NaHSO4 (25.8 g, 190 mmol) added. EtOAc (50 mL) was added to the filtrate. The formed precipitate was separated by filtration, dissolved in EtOAc (100 mL), and the solution was filtered. The water layer was extracted with EtOAc (10×50 mL), and the combined extracts were evaporated to a volume of 100 mL. The precipitate was filtered, washed with ethyl acetate (2×50 mL), and concentrated under reduced pressure to afford the title compound as a colorless crystalline substance in 87% yield, 27.8 g. mp 124.0-126.0° C.; MS m/z 212 [M+H]+
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1.[CH2:12]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1.O>[CH2:12]([N:19]1[CH2:24][CH2:23][C:22]([C:5]2[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=2)([OH:25])[CH2:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Brc1ccc(Br)cc1
Agent: II
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: OC1(c2ccc(Br)cc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of magnesium (1.77 g) and iodine (0.81 g) in THF (60 mL) was added a solution of 1,4-dibromobenzene (8.94 mL) in THF (5 mL), and the mixture was stirred at room temperature for 30 min. The reaction mixture was cooled to 0° C., a solution of 1-benzylpiperidin-4-one (13.2 mL) in THF (5 mL) was slowly added dropwise thereto, and the reaction mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (9.19 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14])[CH2:6][C:5]2([CH3:20])[CH3:19].N1C=CC=CC=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:28]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][S:33]([C:29]1[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=1)(=[O:35])=[O:34])[CH2:6][C:5]2([CH3:20])[CH3:19]
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(Cl)cc21
Reactant: O=S(=O)(Cl)c1cccnc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2cccnc2)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)aniline (100 mg, 0.35 mmol) in dichloromethane (5 mL) was added pyridine (0.6 mL) and pyridine-3-sulfonyl chloride (112 mg, 0.35 mmol) at ice-bath. The reaction mixture was stirred at room temperature for 6 h. The reaction mixture was washed with water. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed by brine, dried over anhydrous sodium sulfate, concentrated in vacuum. The residue was purified by HPLC to give pyridine-3-sulfonic acid [2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide. LC/MS m/e obsd. (ESI+) [(M+H)+] 427.90.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10])[CH:5]=[O:6].[H-].[Na+].Cl[CH2:15][O:16][CH3:17].O>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[O:10][CH2:15][O:16][CH3:17])[CH:5]=[O:6]
Reactant: COCCl
Reactant: Cc1cc(C=O)cc(C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1c(C)cc(C=O)cc1C
Reaction time: 0.33 h
Yield: 94.5 %

Procedure:
A solution of 9.0 g of 3,5-dimethyl-4-hydroxybenzaldehyde in 20 ml of dimethylformamide was added dropwise and whilst ice-cooling to a suspension of 3.14 g of a 55% w/w dispersion of sodium hydride in 50 ml of dimethylformamide. The mixture was then stirred for 20 minutes, after which 5.8 g of methyl chloromethyl ether were added, whilst ice-cooling. The resulting mixture was then stirred at room temperature for one hour. At the end of this time, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was then washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure to give 11.0 g of the title compound.
Reaction SMILES: [I:1]I.N1C=CC=CC=1.[Si:9]([O:16][C@@H:17]1[CH2:21][C:20](=[O:22])[CH:19]=[CH:18]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].Cl>C(Cl)Cl>[Si:9]([O:16][C@@H:17]1[CH2:21][C:20](=[O:22])[C:19]([I:1])=[CH:18]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C=CC(=O)C1
Reactant: II
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1C=C(I)C(=O)C1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
The procedure described in Johnson, C. R., Braun, M. P. J. Am. Chem Soc. 1993, 115, 11014 was followed with modification. A solution of I2 (6.55 g, 25.8 mmol) and pyridine (12 mL) in CH2Cl2 (12 mL) was cannula transferred to a 0° C. solution of (R)-4-((tert-butyldimethylsilyl)oxy)cyclopent-2-enone (3.17 g, 14.9 mmol) and pyridine (5.4 mL) in CH2Cl2 (5.4 mL). The reaction was allowed to warm to room temperature and after 2 h, 100 mL 1 M HCl was added. The resulting mixture was extracted with CH2Cl2 (3×60 mL) and the combined organic solution was washed with 100 mL saturated NaHSO3 solution and 50 mL brine and then was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography (ethyl acetate/hexanes) gave the title compound (4.997 g, 99%).
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.[Cl:21][C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1>>[Cl:21][C:22]1[CH:23]=[C:24]([S:28]([C:4]2([CH2:7][O:8][C:9]3[CH:18]=[CH:17][CH:16]=[C:15]4[C:10]=3[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]4)[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]2)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Product: Nc1nc(N)c2c(OCC3(S(=O)(=O)c4cccc(Cl)c4)CCNCC3)cccc2n1
Yield: 99 %

Procedure:
The sulfonamide was obtained by reacting 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (50 mg; 0.18 mmol) and 3-chlorobenzenesulfonyl chloride (78 mg; 0.37 mmol) via Method AA to yield 80 mg. (99% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.82 (m, 1H), 7.72 (m, 3H), 7.32 (t, J=8.4 Hz, 1H), 7.11 (br s, 2H), 6.75 (d, J=8.0 Hz, 1H), 6.50 (d, J=7.6 Hz, 1H), 5.93 (br s, 2H), 3.96 (d, J=6.4 Hz, 2H), 3.72 (br d, J=11.6 Hz, 2H), 2.32 (t, J=12 Hz, 2H), 1.84 (m, 3H), 1.36 (m, 2H). MS m/z (ESI) 448 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([I:16])[CH:10]=2)=[O:7])=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[CH2:28]([O:30][C:31](=[O:44])[C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:34][CH:33]=1)[CH3:29]>CN(C1C=CN=CC=1)C.O1CCOCC1>[CH2:28]([O:30][C:31](=[O:44])[C:32]1[CH:33]=[CH:34][C:35]([N:38]2[CH2:39][CH2:40][N:41]([C:2]3[CH:18]=[CH:17][C:5]([C:6](=[O:7])[NH:8][C:9]4[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([I:16])[CH:10]=4)=[CH:4][N:3]=3)[CH2:42][CH2:43]2)=[CH:36][CH:37]=1)[CH3:29]
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc(NC(=O)c2ccc(Cl)nc2)cc1I
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccc(C)c(I)c4)cn3)CC2)cc1
Temperature: 120 °C
Yield: 65 %

Procedure:
A solution of 6-chloro-N-(3-iodo-4-methyl-phenyl)-nicotinamide (50 mg, 0.13 mmol), a catalytic amount of DMAP, diisopropylethyl amine (0.07 mL, 0.41 mmol), 4-(piperazin-1-yl)-benzoic acid ethyl ester (94 mg, 0.41 mmol) in 5 mL in dioxane was heated at 120° C. in a sealed tube for about 23 h. The reaction mixture was cooled, followed addition of another portion of 4-(piperazin-1-yl)-benzoic acid ethyl ester (94 mg, 0.41 mmol) and diisopropyl ethyl amine (0.07 mL, 0.41 mmol) and the mixture was re-heated at 120° C. for 3 more days. The reaction mixture was then cooled and partitioned between EtOAc and aq. saturated Na2CO3. The organic layer was then collected, dried over Na2SO4 filtered and concentrated. The residue was chromatographed with a silica gel column and 20-40% EtOAc in hexanes to afford the product (23 mg. Yield: 65%). HRMS m/z calcd for C26H27N4O3I [M+H]: 571.1201. Found: 571.1197.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[C:24](=[O:26])[CH3:25])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27]I.[H-].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[C:24](=[O:26])[CH3:25])[CH3:27])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Nc2ccc(OCc3ccccc3)cc2)c(C(C)=O)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C)c2ccc(OCc3ccccc3)cc2)c(C(C)=O)c1
Temperature: 25 °C

Procedure:
[II; R=5-CH3O, R'=CH3, R"=H, OR°=4-OCH2C6H5, Alk=CH3 ] is obtainable by N-alkylation of 1-[2-(4-benzyloxyphenylamino)-5-methoxyphenyl]ethanone (Example 1b) with methyl iodide in the presence of sodium hydride. A preferred procedure is to add slowly methyl iodide in excess to a cooled (0° C.) suspension of starting material and sodium hydride in an inert solvent, e.g. dimethylformamide, and stirring the reaction mixture at ambient temperature until the reaction is complete.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[CH2:7][CH2:6]1.C(N(CC)CC)C.O1C[CH2:29][CH2:28][CH2:27]1.C(Cl)(=O)C=C>O>[CH:27]([O:1][CH2:2][CH2:3][CH2:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[CH2:9][CH2:10]1)=[CH:28][CH3:29]
Reactant: OCCC[C@H]1CC[C@H](c2cccc(F)c2F)CC1
Reactant: C1CCOC1
Agent: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC=COCCC[C@H]1CC[C@H](c2cccc(F)c2F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
First, 9.3 g of 1-[trans-4-(3-hydroxypropyl)cyclohexyl]-2,3-difluorobenzene, 4.1 g of triethylamine, and 100 ml of dry tetrahydrofuran were placed in a 200 ml flask. Then, 3.6 g of acryloyl chloride was added dropwise to the reaction mixture under ice water cooling. The reaction mixture was allowed to warm to room temperature and stirred overnight. Water was added to the reaction mixture, and an organic layer was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: benzene/hexane=2/3) and recrystallized from hexane to obtain 6 g of 1-[trans-4-(3-propenyloxypropyl)cyclohexyl]-2,3-difluorobenzene (Y: 53%). The compound thus obtained had a purity of 99.8% by GC, 100% by HPLC, and of 1 spot by TLC. Furthermore, the compound had an m.p. of 35.5° C. to 36.9° C.
Reaction SMILES: Br[C:2]1[C:3]([F:12])=[C:4]([CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO>[Cl:13][C:14]1[CH:19]=[C:18]([C:2]2[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([CH2:10][OH:11])[C:3]=2[F:12])[CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COc1ccc(CO)c(F)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(CO)c(F)c1-c1cccc(Cl)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 74.1 %

Procedure:
Into a 100 mL round bottom flask was added (3-bromo-2-fluoro-4-methoxy-phenyl)-methanol (I-31, 1.04 g, 4.0 mmol), 3-chlorophenylboronic acid (0.76 g, 4.8 mmol), Pd(PPh3)4 (0.45 g, 0.41 mmol), Na2CO3 (6 mL, 2M aq), toluene, (32 mL), and EtOH (11 mL). The reaction was degassed with N2, then stirred at 80° C. for 24 hours. Water was added and the product was extracted with ethyl acetate. The combined organics were concentrated and filtered through a SiO2 plug eluting with 50% ethyl acetate/hexanes. The solid was triturated with ether and filtered. The filtrate was concentrated and triturated with ether and filtered. The filter cakes were combined and purified by flash column chromatography eluting with 20% acetone/hexanes to give (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-methanol (I-32, 0.79 g, 67%) as a white solid.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]=1[CH3:21])(=[O:3])[CH3:2].[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=O.C(O)C.[OH-].[K+]>C(OCC)(=O)C>[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=[CH:2][C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]=1[CH3:21])=[O:3]
Reactant: O=Cc1ccccc1F
Reactant: CC(=O)c1c(C)n(CCN2CCOCC2)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)C=Cc2ccccc2F)c2ccccc2n1CCN1CCOCC1

Procedure:
Following a procedure similar to that described in Example 20A above, 14.75 g. (0.0516 mole) of 3-acetyl-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indole (Example 20A) was reacted with 2-fluorobenzaldehyde in 260 ml. of ethanol in the presence of 3.44 g. (0.061 mole) of potassium hydroxide pellets and the product, in the form of the free base, recrystallized from ethyl acetate to give 10.0 (54%) of 3-(2-fluorocinnamoyl)-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indole. m.p. 113°-116° C.
Reaction SMILES: [C:1]([C@@H:4]([NH:9][C:10](=[O:41])[C@@H:11]([C@H:33]1[C:37](=[O:38])[O:36][C:35]([CH3:40])([CH3:39])[O:34]1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)=[CH:20][CH:19]=1)[C:5]([CH3:8])([CH3:7])[CH3:6])(O)=[O:2].[CH3:42][O:43][CH2:44][C@@H:45]([NH2:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C(OCC)(=O)C>[CH3:39][C:35]1([CH3:40])[O:34][C@@H:33]([C@@H:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[C:22]([CH3:24])[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=3)=[CH:20][CH:19]=2)[C:10]([NH:9][C@H:4]([C:1]([NH:52][C@@H:45]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:44][O:43][CH3:42])=[O:2])[C:5]([CH3:6])([CH3:7])[CH3:8])=[O:41])[C:37](=[O:38])[O:36]1
Reactant: COc1cccc(-c2ccc(CCCCCC[C@@H](C(=O)N[C@H](C(=O)O)C(C)(C)C)[C@@H]3OC(C)(C)OC3=O)cc2C)c1
Reactant: COC[C@@H](N)c1ccccc1
Solvent: CCOC(C)=O
Product: COC[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CCCCCCc1ccc(-c2cccc(OC)c2)c(C)c1)[C@@H]1OC(C)(C)OC1=O)C(C)(C)C)c1ccccc1
Yield: 64.9 %

Procedure:
According to the method of Example 25(a), (2R)-N-[(1S)1-(carboxy)-2,2-dimethylpropyl]-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-5-[(3′-methoxy-2-methylbiphen-4-yl)propyl]pentanamide (Preparation 34)(220 mg, 0.42 mmol) was reacted with (1S)-2-methoxy-1-phenylethylamine (63 mg, 0.42 mmol) at room temperature for 2.5 h. The mixture was poured into ethyl acetate (75 mL) and washed with 0.5M aqueous sodium dihydrogenphosphate (2×50 mL) and 5% aqueous sodium bicarbonate (50 mL)(solid sodium chloride was added to give phase separation). The organic solution was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with hexane:ethyl acetate=30:70 to 60:40) to give a white solid which was purified again by flash chromatography (sorbsil C60, (20-40μ) silica gel, eluting with hexane:ethyl acetate 35:65) to give (2R)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-N-[(1S)-2,2-dimethyl-1-({[(1S)-2-methoxy-1-phenylethyl]amino}carbonyl)propyl]-5-[(3′-methoxy-2-methylbiphen-4-yl)propyl]pentanamide as a white solid (191 mg, 69%).
Reaction SMILES: [NH2:1][C:2]([N:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)[CH2:5][CH2:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][C:12]([CH3:19])([CH3:18])[C:13]([O:15]CC)=[O:14])=[CH:9][CH:8]=1)=[S:3].Br[CH2:34][C:35](=O)[C:36]([F:39])([F:38])[F:37]>>[CH3:18][C:12]([O:11][C:10]1[CH:20]=[CH:21][C:7]([CH2:6][CH2:5][N:4]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:27][CH:28]=2)[C:2]2[S:3][CH:34]=[C:35]([C:36]([F:39])([F:38])[F:37])[N:1]=2)=[CH:8][CH:9]=1)([CH3:19])[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)C(N)=S)cc1
Reactant: O=C(CBr)C(F)(F)F
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2nc(C(F)(F)F)cs2)cc1)C(=O)O

Procedure:
Similarly prepared from ethyl 2-[4-(2-{(aminocarbonothioyl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate and 3-bromo-1,1,1-trifluoroacetone.