Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:21])[C@H:7]([CH2:17][CH:18]([CH3:20])[CH3:19])[NH:8][C:9]([C@@H:11]1[CH2:15][CH2:14][C:13](=[O:16])[O:12]1)=[O:10])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[O:16]=[C:13]1[O:12][C@H:11]([C:9]([NH:8][C@H:7]([C:6]([OH:21])=[O:5])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:10])[CH2:15][CH2:14]1
Reactant: CC(C)C[C@H](NC(=O)[C@@H]1CCC(=O)O1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)[C@@H]1CCC(=O)O1)C(=O)O

Procedure:
To a solution of N-{[(S)-(5-Oxo-tetrahydrofuran-2-yl)carbonyl]}-L-leucine tertbutylester (800 mg, 2.67 mmols) in CH2Cl2 (3.0 ml) cooled at 0° C., was added freshly distilled anhydrous trifluoroacetic acid (0.5 ml). After a night at room temperature the solvent was evaporated at reduced pressure and the residue was dissolved in Et2O. By adding n-hexane the compound (2e) separated as a brown oil and was dried and decanted in high vacuum; 650 mg (100%); [a]D22=−7° (1, methanol); IR (CHCl3): 3413, 3036, 2957, 1787, 1725, 1678, 1526, 1172, 1191 cm−1; 1H-NMR (CDCl3): d 0.87 and 0.93 [two s, 6, CH2CH(CH3)2], 1.37-1.83 [m, 3, CH2CH(CH3)2], 2.06-2.73 (m, 4, ring CH2CH2), 4.30-4.63 (m, 1, ring CH), 4.67-4.92 (m, 1, aCH), 6.92 (d, 1, NH, J=8 Hz), 8.15 (s, 1, COOH). Calculated for C17H30N2O5.½ H2O (cyclohexylamine salt): C, 56.66; H, 8.89; N, 7.77. Found C, 57.00; H, 9.12; N 8.13%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[CH2:24]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[F:35])[CH2:25][CH3:26]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([N:27]([CH2:24][CH2:25][CH3:26])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[F:35])=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: CCCNc1ccc(F)cc1F
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Product: CCCN(c1cc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)nn1)c1ccc(F)cc1F
Temperature: 100 °C
Reaction time: 12 h

Procedure:
In a similar manner as in Example 2, 3,4-bis-(4-methoxyphenyl)-6-chloropyridazine (180 mg, 0.551 mmol) and N-(n-propyl)-2,4-difluoroaniline, as starting materials, were stirred 100° C. for 12 hours and then reacted at 170° C. for 10 hours, and post-treatment was then conducted, whereby the title compound was obtained as a pale yellow-brown amorphous solid (137.5 mg, 54.1%).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[Cl:9][C:10]1[CH:11]=[C:12]([C:19]([CH3:28])([CH3:27])[CH2:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[C:13]2[O:17][CH2:16][CH2:15][C:14]=2[CH:18]=1>CS(C)=O>[Cl:9][C:10]1[CH:11]=[C:12]([C:19]([CH3:28])([CH3:27])[CH2:20][C:21]2([C:22]([F:23])([F:24])[F:25])[CH2:2][O:26]2)[C:13]2[O:17][CH2:16][CH2:15][C:14]=2[CH:18]=1
Reactant: CC(C)(CC(=O)C(F)(F)F)c1cc(Cl)cc2c1OCC2
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(CC1(C(F)(F)F)CO1)c1cc(Cl)cc2c1OCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
To a solution of trimethylsulfoxonium iodide (343 mg, 1.56 mmol) in 3 mL of anhydrous DMSO was treated with NaH (60% in mineral oil, 66.0 mg, 1.65 mmol) in portions and the mixture was stirred at room temperature for 30 minutes. The mixture was transferred to a solution of 4-(5-chloro-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methylpentan-2-one (400 mg, 1.30 mmol) in 1 mL of anhydrous DMSO over 5 minutes and the resulting mixture was stirred overnight. The mixture was quenched with water and extracted with three 20 mL portions of ethyl acetate. The combined organic layers were washed with two 5 mL portions of water, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 380 mg (91% yield) of the title product as a yellow oil. The crude product was sufficiently pure and used without further purification.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][NH:13][CH2:12][C@H:11]([OH:15])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:16][CH2:17][O:18][C:19](C)=[O:20]>O1CCOCC1.O>[Si:1]([O:8][C@@H:9]1[CH2:10][C@@H:11]([OH:15])[CH2:12][N:13]([C:19]([O:18][CH2:17][C:16]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:14]=2)=[O:20])[CH2:14]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CNC[C@H](O)C1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](O)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
To a solution of (3R,5R)-5-(tert-butyldimethylsilyloxy)piperidin-3-ol (1 eq) in 20 mL of 1,4-dioxane and 8 mL of water was added benzyl chloro formate (1.5 eq). The mixture was stirred at room temperature for 4 hours. The crude mixture was diluted with 100 mL of EtOAc, washed with brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (EtOAc:hexanes=1:3) to yield (3R,5R)-benzyl 3-(tert-butyldimethylsilyloxy)-5-hydroxypiperidine-1-carboxylate (74%). LC/MS (m/z): 366.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1B1OCC(C)(C)CO1.Br[C:24]1[CH:37]=[CH:36][C:27]([O:28][C@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@@H:30]2[OH:35])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:24]1[CH:37]=[CH:36][C:27]([O:28][C@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@@H:30]2[OH:35])=[CH:26][CH:25]=1
Reactant: O[C@H]1CCCC[C@@H]1Oc1ccc(Br)cc1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(O[C@H]4CCCC[C@@H]4O)cc3)cc12
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 133.4 %

Procedure:
A mixture of methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (80 mg, 0.15 mmol), (1S,2S)-2-(4-bromophenoxy)cyclohexanol (81 mg, 0.30 mmol), 2.0 M aqueous potassium carbonate (0.50 mL, 1.0 mmol), and Pd(dppf)Cl2 (10 mg, 0.01 mmol) in toluene/ethanol (1.44 mL/0.48 mL) was stirred at 110° C. for 2.5 hours. The mixture was poured into ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered, and concentrated to give a residue, which was purified by preparative TLC to give the title compound (80 mg, 90% yield) as a white solid.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19]2[N:28]=[C:27]([N:29]([CH3:31])[CH3:30])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[CH:13][CH:12]=1)C1C=CC=CC=1.[Br:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[C:36]([O:44][C:45]([F:48])([F:47])[F:46])[CH:35]=1>CO.C(Cl)Cl.[Pd]>[Br:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19]3[N:28]=[C:27]([N:29]([CH3:31])[CH3:30])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:13][CH:12]=2)(=[O:42])=[O:41])=[C:36]([O:44][C:45]([F:47])([F:46])[F:48])[CH:35]=1
Reactant: CN(C)c1nc(NCc2ccc(NC(=O)OCc3ccccc3)cc2)nc2ccccc12
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CN(C)c1nc(NCc2ccc(NS(=O)(=O)c3ccc(Br)cc3OC(F)(F)F)cc2)nc2ccccc12
Temperature: 50 °C
Reaction time: 41.5 h
Yield: 74.4 %

Procedure:
To a solution of {4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-phenyl}-carbamic acid benzyl ester (318 mg, 0.744 mmol) in MeOH (3 mL) was added 5% Pd/C (30 mg). The mixture was stirred at 50° C. under hydrogen atmosphere for 41.5 hr, filtered through a pad of celite, and concentrated. To a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (505 mg, 1.49 mmol) in CH2Cl2 (12 mL) was added PVP (6 mL). To the resulting suspension was added a solution of the above residue in CH2Cl2 (10 mL). The mixture was stirred at ambient temperature for 1.5 days, filtered, poured into saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by medium-pressure liquid chromatography (NH-silica gel, 33% EtOAc in hexane) to give 4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-phenyl}-2-trifluoromethoxy-benzenesulfonamide (330 mg, 74%) as a pale brown solid.
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:13][C:12]3[C:14]([O:18][C:19]4[CH:27]=[C:26]5[C:22]([C:23]([NH:29][C:30]([C:32]6[C:33](=[O:45])[N:34]([C:38]7[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=7)[CH:35]=[CH:36][CH:37]=6)=[O:31])=[N:24][N:25]5[CH3:28])=[CH:21][CH:20]=4)=[CH:15][CH:16]=[N:17][C:11]=3[NH:10][C:9]2=[O:46])=CC=1.FC(F)(F)C(O)=O>>[CH3:28][N:25]1[C:26]2[C:22](=[CH:21][CH:20]=[C:19]([O:18][C:14]3[C:12]4[CH2:13][NH:8][C:9](=[O:46])[NH:10][C:11]=4[N:17]=[CH:16][CH:15]=3)[CH:27]=2)[C:23]([NH:29][C:30]([C:32]2[C:33](=[O:45])[N:34]([C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)[CH:35]=[CH:36][CH:37]=2)=[O:31])=[N:24]1
Reactant: COc1ccc(CN2Cc3c(Oc4ccc5c(NC(=O)c6cccn(-c7ccc(F)cc7)c6=O)nn(C)c5c4)ccnc3NC2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(NC(=O)c2cccn(-c3ccc(F)cc3)c2=O)c2ccc(Oc3ccnc4c3CNC(=O)N4)cc21
Temperature: 80 °C
Reaction time: 22 h
Yield: 82.5 %

Procedure:
A solution of compound 278 (22.00 mg; 0.03 mmol; 1.00 eq.) and trifluoroacetic acid (2.00 ml) was stirred at 80 degrees C. overnight. The reaction was stirred at 80 degrees C. for 22 hr. The reaction was concentrated, redissolved in DMSO, and treated with Et3N to pH 8. The solution was then purified directly via prep HPLC to afford 13 mg (60%) of 279 as a yellow solid. LC-MS (M+H=526, obsd.=526).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[CH:12]([CH3:17])[CH2:13][CH2:14][CH2:15]O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:27][CH2:15][CH2:14][CH2:13][CH:12]([CH3:17])[CH:11]([C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[F:25])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CC(CCCO)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(CCCBr)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
The 5-[(4-chlorophenyl)sulfonyl]-5-(2,5-difluorophenyl)-4-methyl-1-pentanol (290 mg, 0.746 mmol) obtained in Example 39 and carbon tetrabromide (290 mg, 0.874 mmol) were dissolved in methylene chloride (8 ml). While stirring under ice cooling, a solution obtained by dissolving triphenylphosphine (230 mg, 0.877 mmol) in methylene chloride (2 ml) was added dropwise to the resulting solution. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 3 days. To the reaction mixture were added carbon tetrabromide (290 mg, 0.874 mmol) and triphenylphosphine (230 mg, 0.877 mmol) under ice cooling, followed by stirring at room temperature for 6 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate=15:1), whereby the title compound (331 mg, 98%) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=O.C1([C:11]2[N:15](C)[C:14]([CH:17]=[O:18])=[CH:13]N=2)CC1>>[C:2]([C:3]1[N:15]([CH3:11])[C:14]([CH:17]=[O:18])=[CH:13][N:5]=1)([CH3:7])([CH3:6])[CH3:1]
Reactant: Cn1c(C=O)cnc1C1CC1
Reactant: CC(C)(C)C(N)=O
Product: Cn1c(C=O)cnc1C(C)(C)C

Procedure:
2-tert-Butyl-3-methyl-3H-imidazole-4-carbaldehyde was prepared from trimethyl acetamide in the same manner as 2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).
Reaction SMILES: COC1C=CC(B(O)O)=CC=1.Br[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.C(OC([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32](Br)[CH:33]=2)[CH:28]=[CH:27]1)=O)(C)(C)C>>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:32]2[CH:33]=[C:34]3[C:29]([CH:28]=[CH:27][NH:26]3)=[CH:30][CH:31]=2)[CH:14]=1
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(Br)cc21
Reactant: Brc1cccnc1
Agent: COc1ccc(B(O)O)cc1
Product: c1cncc(-c2ccc3cc[nH]c3c2)c1

Procedure:
The desired compound was prepared according to the method of Example 25, step 1, except substituting 6-indolylboronic acid, prepared as in step 1 for 4-methoxyphenylboronic acid, and 3-bromopyridine for 1-tert-butoxycarbonyl-6-bromoindole.
Reaction SMILES: CS(O)(=O)=O.[C:6]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])(=[O:16])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[OH:26]O>>[C:6]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][OH:26])=[O:24])(=[O:16])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCC(=O)NCCCCCC(=O)O
Reactant: OO
Agent: CS(=O)(=O)O
Product: CCCCCCCCCC(=O)NCCCCCC(=O)OO
Temperature: -15 °C
Yield: 97.8 %

Procedure:
A 400 mL beaker was charged with 100 mL of 98% methanesulfonic acid and 500 g (0.175 mol) of N-decanoyl-6-aminocaproic acid. The resulting solution was cooled in an ice bath and, with stirring, 33.1 g of 90% hydrogen peroxide (29.8 g, 0.877 mol of hydrogen peroxide) was added dropwise at a rate such that the temperature of the reaction mixture did not rise above 20° C. The addition required a total of 10 min. The resulting mixture was stirred at room temperature for 3 hrs., cooled to -15° C., and poured into 500 mL of ice water. The precipitated solid was extracted into 200 mL methylene chloride. The methylene chloride solution was separated, washed with 100 mL portions of water until the wash water was neutral (6 washings required), dried over sodium sulfate, and evaporated on a rotary evaporator to yield 51.6 g of white solid having a peroxyacid AvO of 4.93% (theoretical yield=52.7 g of AvO 5.32%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][C@@H:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=2[F:16])[CH2:5][N:4]([CH2:17][CH3:18])[C:3]1=[O:19].C(N(CC)C(C)C)(C)C.[CH:29]1[CH:34]=[CH:33][C:32]([O:35][C:36](OC2C=CC=CC=2)=[N:37][C:38]#[N:39])=[CH:31][CH:30]=1>ClCCl>[C:38]([N:37]=[C:36]([O:35][C:32]1[CH:33]=[CH:34][CH:29]=[CH:30][CH:31]=1)[NH:1][C@@H:2]1[CH2:8][CH2:7][C@@H:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=2[F:16])[CH2:5][N:4]([CH2:17][CH3:18])[C:3]1=[O:19])#[N:39]
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: CCN1C[C@H](c2cccc(F)c2F)CC[C@@H](N)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=NC#N)Oc2ccccc2)C1=O
Reaction time: 5 h
Yield: 80 %

Procedure:
A solution of (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-ethylazepan-2-one (135 mg, 0.503 mmol) in dichloromethane was treated N,N-diisopropylethylamine (65 mg, 0.503 mmol) and diphenyl N-cyanocarbonimidate (204 mg, 0.855 mmol). After 5 h, the reaction was quenched with 0.5N NaOH and the organic layer washed with water and brine. The combined aqueous layers were extracted with EtOAc. The combined organics were dried, filtered and concentrated. Purification by silica gel chromatography (EtOAc/hexanes) gave the title compound (166 mg). MS 413.3 (M+1).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Br:25])[CH:23]=3)[NH:18][CH:17]=2)=[CH:10][CH:9]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][C:27]1=O.C(N(CC)CC)C>ClCCCl>[Br:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH2:15][N:14]([C:27]1[CH2:28][CH2:29][CH2:30][N:26]=1)[C:11]1[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:13][CH:12]=1
Reactant: O=C1CCCN1
Reactant: COc1ccc(NCc2c[nH]c3ccc(Br)cc23)cc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(N(Cc2c[nH]c3ccc(Br)cc23)C2=NCCC2)cc1

Procedure:
Reaction of equimolar amounts of phosphorus oxychloride, 3-(p-anisidinomethyl)-5-bromoindole, 2-pyrrolidinone and triethylamine in 1,2-dichloroethane according to the procedure of Example 35 provides 5-bromo-3-[(N-[1-pyrrolin-2-yl]-p-anisidino)methyl]indole. Acidification of the free base with ethanolic hydrogen chloride provides 5-bromo-3-[(N-[1-pyrrolin-2-yl]-p-anisidino)methyl]indole hydrochloride, m.p. 205.5°-207.5° C. (corr.).
Reaction SMILES: C([O:5][C:6]([C:8]1[O:9][C:10]2[C:18]([Cl:19])=[CH:17][C:16]3[C:20]4[CH:29]=[CH:28][C:27]([S:30]([OH:33])(=[O:32])=[O:31])=[CH:26][C:21]=4[C:22]([CH3:25])([CH3:24])[O:23][C:15]=3[C:11]=2[C:12](=[O:14])[CH:13]=1)=[O:7])CCC.O>C(O)(=O)C.Cl>[C:6]([C:8]1[O:9][C:10]2[C:18]([Cl:19])=[CH:17][C:16]3[C:20]4[CH:29]=[CH:28][C:27]([S:30]([OH:33])(=[O:32])=[O:31])=[CH:26][C:21]=4[C:22]([CH3:25])([CH3:24])[O:23][C:15]=3[C:11]=2[C:12](=[O:14])[CH:13]=1)([OH:7])=[O:5]
Reactant: CCCCOC(=O)c1cc(=O)c2c3c(cc(Cl)c2o1)-c1ccc(S(=O)(=O)O)cc1C(C)(C)O3
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)Oc2c(cc(Cl)c3oc(C(=O)O)cc(=O)c23)-c2ccc(S(=O)(=O)O)cc21

Procedure:
1.0 gm (2 millimols) of 2-(n-butoxycarbonyl)-4-oxo-6,6-dimethyl-8-sulfo-12-chloro-4H,6H-[2]-benzopyrano-[3,4-f]-[1]-benzopyran (see Example 11) was heated for 1 hour in a mixture of 12 ml of acetic acid and 5 ml of concentrated hydrochloric acid. Then, the reaction mixture was evaporated to dryness, and the residue was recrystallized from methanol. 0.5 gm (53% of theory) of the compound named in the heading, m.p. 257°-259° C, was obtained (with 2 mols of water of crystallization).
Reaction SMILES: [CH2:1]([C@H:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:5]([OH:7])=[O:6])[CH2:2][CH3:3].C(N(CC)CC)C.Br[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24].CC#N.O>C(Cl)Cl>[CH2:1]([C@H:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:5]([O:7][CH2:22][C:23](=[O:24])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:6])[CH2:2][CH3:3]
Reactant: CCCCCC[C@@H](CCC)C(=O)O
Reactant: O=C(CBr)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCC[C@@H](CCC)C(=O)OCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(R)-2-propyloctanoic acid (0.05 g, 0.268 mmol) was dissolved in 5 mL, CH2Cl2. Triethylamine (50 μL, 0.359 mmol) and 2-bromoacetophenone (0.06 g, 0.300) were added, and the reaction was stirred at room temperature for 5 hours. Once no SM was seen by TLC, the reaction mixture was concentrated under reduced pressure to remove all triethylamine. The residue was purified by silica-gel chromatography (0-10% EtOAc:hexanes) to give the product (Example 2). Ee of >98.5% was determined by HPLC [Chiralcel OJ-RH 4.6×150 mm; CH3CN/H2O=60/40; flow rate 1 mL min−1; detection, 244 nm; retention time, 10.7 min (S) and 11.9 min (R).] 1H-NMR (CDCl3, 500 MHz) δ 7.91 (d, 2H), 7.61-7.57 (m, 1H), 7.48 (t, 2H), 5.32 (s, 2H), 2.55-2.50 (m, 1H), 1.72-1.68 (m, 2H), 1.52-1.48 (m, 2H), 1.47-1.27 (m, 10H), 0.93 (t, 3H), 0.88 (t, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([CH3:20])=[C:12]([C:16]([F:19])([F:18])[F:17])[C:13]=2[CH2:14][OH:15])=[CH:5][CH:4]=1)[CH3:2].O[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[C:24]([CH3:35])[C:23]=1[CH3:36].C(C1C=CC(C2SC(C)=C(C(F)(F)F)C=2COC2C(F)=CC(CCC(OCC)=O)=CC=2F)=CC=1)C>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:10][C:11]([CH3:20])=[C:12]([C:16]([F:19])([F:17])[F:18])[C:13]=2[CH2:14][O:15][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[C:24]([CH3:35])[C:23]=2[CH3:36])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(-c2sc(C)c(C(F)(F)F)c2CO)cc1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Agent: CCOC(=O)CCc1cc(F)c(OCc2c(-c3ccc(CC)cc3)sc(C)c2C(F)(F)F)c(F)c1
Product: CCc1ccc(-c2sc(C)c(C(F)(F)F)c2COc2ccc(CCC(=O)O)c(C)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 220 by coupling of [2-(4-ethylphenyl)-5-methyl-4-(trifluoromethyl)thiophen-3-yl]methanol and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate followed by hydrolysis of ethyl 3-(4-((2-(4-ethyl phenyl)-5-methyl-4-(trifluoromethyl)thiophen-3-yl)methoxy)-3,5-difluorophenyl)propanoate to afford the desired product as an off-white solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH:13]=[CH:12]2)=[C:4]([NH2:17])[N:3]=1.[CH:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C>[CH:11]1([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([NH:24][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:3][C:4]=3[NH2:17])[CH2:16][CH2:15][CH2:14][CH:13]=[CH:12]1
Reactant: NC1CCCCC1
Reactant: Nc1nc(Cl)nc2c1ncn2C1C=CCCC1
Solvent: CCO
Product: Nc1nc(NC2CCCCC2)nc2c1ncn2C1C=CCCC1
Yield: 77 %

Procedure:
A mixture of 2-chloro-9-(2-cyclohexenyl)-9H-adenine (300 mg., 1.2 mmole) and 1 ml. of cyclohexylamine in 3 ml. of ethanol is heated at 120°-125° C. for a period of 89 hrs. in a sealed tube and then evaporated in vacuo to give an oil. Purification of residual oil by column chromatography on silica gel affords 288 mg (77%) of 9-(2-cyclohexenyl)-2-cyclohexylamino-9H-adenine, m.p. 108°-111° C. IR (KBr): 3315, 3170, 2925, 2845, 1630, 1600, 1530, 1470, 1405 cm-1. UV: λmaxEtoH 224 nm(ε26,500), 259 nm(ε11,100), 291 nm(ε9,900). NMR(CDCl3): δ 0.9-2.3(16H,m), 3.75(1H,br.s), 4.95(1H,br.s), 5.4-6.2(2H,m), 7.42(1H,s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH2:38]([O:40][C:41]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)=[O:42])[CH3:39]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:46]3[CH2:45][CH2:44][N:43]([C:41]([O:40][CH2:38][CH3:39])=[O:42])[CH2:48][CH2:47]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: CCOC(=O)N1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCCCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and piperazine-1-carboxylic acid ethyl ester according to conditions described in general procedure C. Mp: 105-106° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.14-1.18 (m, 3 H), 1.60-1.62 (m, 6 H), 3.11-3.33 (m, 8 H), 3.52 (s, 4 H), 4.00-4.05 (m, 2 H), 6.22-6.24 (m, 1 H), 6.97 (d, J=11.3 Hz, 2 H), 7.17 (d, J=9.1 Hz, 1 H), 7.42-7.45 (m, 1 H), 7.48 (s, 1 H), 7.57-7.62 (m, 3 H), 7.85 (d, J=8.0 Hz, 1 H), 7.99 (d, J=8.0 Hz, 1 H), 8.29-8.30 (m, 1 H), 10.46 (s, 1 H).
Reaction SMILES: C(O)C.[Cl:4][C:5]1[CH:6]=[C:7]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH:8]=[N:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[S:20][C:19](=[O:21])[NH:18][C:17]2=[O:22])=[CH:12][CH:11]=1.[BH4-].[Na+]>O>[Cl:4][C:5]1[CH:6]=[C:7]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:8][NH:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[S:20][C:19](=[O:21])[NH:18][C:17]2=[O:22])=[CH:14][CH:15]=1
Reactant: O=C1NC(=O)C(c2ccc(N=Cc3ccc(Cl)c(Cl)c3)cc2)S1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1NC(=O)C(c2ccc(NCc3ccc(Cl)c(Cl)c3)cc2)S1
Temperature: 50 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
Into 40 ml of ethanol were suspended 0.40 g of 5-(4-(3,4-dichlorobenzylideneamino) phenyl)thiazolidine-2,4-dione, and, after added 0.24 g of sodium borohydride, the suspension was stirred for 2 hours at 50° C. The reaction mixture was poured into 200 ml of water, which was extracted with ethyl acetate. The organic layer was washed with water and dried. Then, solvent was distilled off. The residue was recrystallized from iso-propanol to obtain 0.20 g of title compound.