Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:21][CH:20]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34].C(N(CC)CC)C.[ClH:47]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[ClH:47].[C:33]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH:6]=[C:5]2[NH:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)=[CH:23][CH:24]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2nc(-c3ccccc3)cc(Nc3ccc(OCC4CCCCC4)cc3)c2c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc2nc(-c3ccccc3)cc(Nc3ccc(OCC4CCCCC4)cc3)c2c1

Procedure:
This compound was prepared from the corresponding 6-amino-4-(p-cyclohexylmethoxyanilino)-2-phenylquinoline with acetic anhydride, DMAP, and triethylamine in methylene chloride, followed by treatment with HCl to form the hydrochloric salt.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25]>>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1
Reactant: Oc1ccccc1F
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: Fc1ccccc1Oc1nc(Nc2cc[nH]n2)cc2ccccc12

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 2-fluoro-phenol to give [1-(2-fluoro-phenoxy)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 321 (MH+).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:20]=[CH:19][C:9]([CH2:10]P(=O)(OCC)OCC)=[CH:8][CH:7]=1)([O-:5])=[O:4].[Br:21][C:22]1[CH:23]=[C:24]([C:32]2([CH3:35])[CH2:34][CH2:33]2)[C:25]([O:30][CH3:31])=[C:26]([CH:29]=1)[CH:27]=O.O>C1COCC1.C1OCCOCCOCCOCCOC1>[Br:21][C:22]1[CH:29]=[C:26](/[CH:27]=[CH:10]/[C:9]2[CH:8]=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:20][CH:19]=2)[C:25]([O:30][CH3:31])=[C:24]([C:32]2([CH3:35])[CH2:33][CH2:34]2)[CH:23]=1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Reactant: COc1c(C=O)cc(Br)cc1C1(C)CC1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1c(/C=C/c2ccc([N+](=O)[O-])cc2)cc(Br)cc1C1(C)CC1
Reaction time: 0.08 h
Yield: 101.5 %

Procedure:
Sodium hydride (60% dispersion, 0.10 g, 2.6 mmol) and 15-crown-5 (0.038 g, 0.17 mmol) were added to THF (5 mL) at 0° C. and stirred for 5 min. To the reaction mixture was then added dropwise over 5 min a solution of diethyl (4-nitrobenzyl)phosphonate (0.52 g, 1.9 mmol) in THF (5 mL), and stirring was continued at 0° C. for 5 min. To this reaction mixture was then added dropwise over 10 min a solution of 74b (0.47 g, 1.7 mmol) in THF (10 mL). The reaction mixture was stirred for 30 min at 0° C. then for 90 min at RT. Water was carefully added, and the mixture was partitioned between water and EtOAc. The EtOAc layer was washed sequentially with water and brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with EtOAc/hexane to afford 0.67 g (94%) of 5-bromo-2-methoxy-1-(1-methylcyclopropyl)-3-[(E)-2-(4-nitrophenyl)vinyl]benzene (75) as a yellow solid (0.67 g, 94%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:17]([C:18](=[O:24])[CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:16][NH:15][C:12]2=[CH:13][N:14]=1.Cl[C:26]1[N:27]=[N:28][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:30][CH:31]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:17]([C:18](=[O:24])[CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:16][N:15]([C:26]3[N:27]=[N:28][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:30][CH:31]=3)[C:12]2=[CH:13][N:14]=1
Reactant: CCC(CC)C(=O)c1c[nH]c2cnc(-c3c(C)cccc3C)cc12
Reactant: CC(C)Oc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(CC)C(=O)c1cn(-c2ccc(OC(C)C)nn2)c2cnc(-c3c(C)cccc3C)cc12
Temperature: 149 °C

Procedure:
To a solution of 1-[5-(2,6-dimethyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-2-ethyl-butan-1-one (100 mg, 0.31 mmol) (Step 4, Example 1) in 2 mL of DMF, 3-chloro-6-isopropoxy-pyridazine (161 mg, 0.93 mmol) is added, followed by Cs2CO3 (306 mg, 0.93 mmol). The mixture is heated to 149° C. for 18 h under nitrogen. The mixture is diluted with EtOAc (7 mL) and washed with water (3×5 mL) and brine (5 mL), dried (Na2SO4), and concentrated under reduced pressure. Chromatography of the residue on silica gel (hexane-EtOAc, 1:1) gives 1-[5-(2,6-dimethyl-phenyl)-1-(6-isopropoxy-pyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-2-ethyl-butan-1-one as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:25])[C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[C:26]([C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>CN(C)C=O.C(OCC)(=O)C>[C:26]([C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([NH:1][C:2]2[CH:3]=[C:4]([N:9]([CH3:25])[C:10]3[N:15]=[C:14]4[S:16][C:17]([NH:19][C:20]([CH:22]5[CH2:23][CH2:24]5)=[O:21])=[N:18][C:13]4=[CH:12][CH:11]=3)[CH:5]=[CH:6][C:7]=2[F:8])=[O:38])=[CH:32][CH:31]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CN(c1ccc(F)c(N)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(c1ccc(F)c(NC(=O)Nc2ccc(C(C)(C)C)cc2)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 17.1 %

Procedure:
N-{5-[(3-Amino-4-fluorophenyl)(methyl)amino][1,3]thiazolo[5,4-b]pyridin-2-yl}cyclopropanecarboxamide (120 mg, 0.34 mmol) produced in Example 1(x) was dissolved in N,N-dimethylformamide (1.5 mL), 1-tert-butyl-4-isocyanatobenzene (72 μL, 0.40 mmol) was added, and the mixture was stirred at room temperature for 6 hr. The reaction mixture was diluted with ethyl acetate (10 mL), and washed successively with saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=50/50→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (31 mg, 17%) as a colorless powder.
Reaction SMILES: [C:1]([C:3]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].Br[C:12]1[CH:13]=[C:14]([CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH:15]=[CH:16][CH:17]=1>>[F:24][C:23]([F:25])([F:26])[C:22]([NH:21][CH2:20][CH2:19][CH2:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:2]#[C:1][C:3]2([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH:13]=1)=[O:27]
Reactant: O=C(NCCCc1cccc(Br)c1)C(F)(F)F
Reactant: C#CC1(O)CCCCCC1
Product: O=C(NCCCc1cccc(C#CC2(O)CCCCCC2)c1)C(F)(F)F

Procedure:
Coupling of 1-ethynylcycloheptanol with bromide 3, following the method used to prepare Example 17 gave 2,2,2-trifluoro-N-(3-(3-((1-hydroxycycloheptyl)ethynyl)phenyl)propyl)acetamide as a pale yellow oil. Yield (1.78 g, 60%): 1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 7.26 (t, J=7.6, 1H), 7.17-7.22 (m, 3H), 5.26 (s, 1H), 3.16 (q, J=6.0 Hz, 2H), 2.56 (t, J=7.2 Hz, 2H), 1.91-1.97 (m, 2H), 1.73-1.79 (m, 4H), 1.45-1.63 (m, 8H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:11])([CH3:10])[CH2:8][OH:9].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:11])([CH3:10])[CH2:8][O:9][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][O:12]1
Reactant: C1=COCCC1
Reactant: CC(C)(CO)CCCCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)(CCCCCBr)COC1CCCCO1
Temperature: 25 °C
Yield: 56.3 %

Procedure:
To a solution of 7-bromo-2,2-dimethylheptan-1-ol (36.0 g, 133.0 mmol) in dichloromethane (60 mL) was added p-toluenesulfonic acid (0.28 g, 1.3 mmol) and 3,4-dihydro-2H-pyran (18.54 g, 213 mmol) at 5-10° C. under cooling with an ice-water bath. The mixture was stirred and allowed to warm to room temperature overnight. The reaction solution was filtered through neutral alumina (200 g), which was rinsed with dichloromethane (500 mL). Concentration of the solvent gave the crude product as a brown oil, which was subjected to column chromatography on silica gel (240 g) using hexanes:ethyl acetate (50:1) as eluent to yield 2-(7-bromo-2,2-dimethylheptyloxy)-tetrahydropyran as a colorless oil (23.0 g, 48%). 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 4.54 (t, 1 H, J=3.0 Hz), 3.84 (m, 1 H), 3.51-3.39 (m, 4 H), 2.98 (d, 1 H, J=9.3 Hz), 1.89-1.80 (m, 3 H), 1.70-1.40 (m, 7 H), 1.29-1.22 (m, 4 H), 0.89 (s, 6 H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 99.3, 76.6, 62.1, 39.3, 34.3, 34.2, 33.0, 30.8, 29.2, 25.7, 24.7, 23.2, 19.6. HRMS (LSIMS, nba): Calcd. for C14H27BrO2: 307.1272, found: 307.1245.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].C(=O)([O-])[O-].[K+].[K+]>O.C1COCC1.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>[N+:18]([C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:1]=1[C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:1]=2)=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19])([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Reactant: OB(O)c1ccccc1
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: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cc(-c2ccccc2)ccc1-c1ccc(-c2ccccc2)cc1[N+](=O)[O-]

Procedure:
2.4 g (2.1 mmol) of Pd(PPh3)4 are added to a well-stirred, degassed suspension of 18.8 g (154.5 mmol) of phenylboronic acid, 30 g (74.6 mmol) of 2,5-dibromonitrobenzene and 53 g (212.7 mmol) of potassium carbonate in a mixture of 300 ml of water and 300 ml of THF, and the mixture is heated under reflux for 20 hours. After cooling, the organic phase is separated off, washed three times with 200 ml of water and once with 200 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo in a rotary evaporator. The grey residue is recrystallised from hexane. The deposited crystals are filtered off with suction, washed with a little MeOH and dried in vacuo; yield: 23 g, 80% of theory; purity: 99.2% according to HPLC.
Reaction SMILES: [F:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[C:10]1(=[O:16])[O:15][C:13](=[O:14])[CH2:12][CH2:11]1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC(Cl)C(Cl)Cl>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[C:3]([OH:9])[C:2]=1[F:1]
Reactant: Oc1cccc(Cl)c1F
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)C(Cl)Cl
Product: O=C(O)CCC(=O)c1ccc(Cl)c(F)c1O
Temperature: 130 °C
Yield: 18.9 %

Procedure:
To a stirred and cooled solution of 2-fluoro-3-chloro-phenol (21.9 g, 0.15 mol) and succinic anhydride (15.3 g, 0.15 mol) in 1,1,2,2-tetrachloroethane (135 mL) was added anhydrous aluminum chloride (38.7 g, 0.29 mol) portion-wise. The reaction mixture was stirred at room temperature for 3 hours and then heated at 130° C. for 2 hours. After being cooled to room temperature, to the reaction mixture were added concentrated hydrochloric acid and ice alternatively in small portions. The resulting mixture was extracted with ethyl acetate (75 mL×3). The combined organic layers were evaporated. The solid residue was basified by slow addition of an aqueous solution of 2N sodium hydroxide solution under cooling conditions, and then extracted with ethyl acetate (30 mL×3). The aqueous layer was acidified by dropwise addition of concentrated hydrochloric acid to a pH of about 2, and then extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Column chromatography (silica gel, 100-120 mesh, 15% ethyl acetate in hexane) gave 4-(4-chloro-3-fluoro-2-hydroxy-phenyl)-4-oxo-butyric acid (7.0 g, 19%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.59 (t, J=6.26 Hz, 2H), 3.31 (t, J=6.28 Hz, 2H), 7.15 (d, J=6.56 Hz, 1H), 7.74 (d, J=6.56 Hz, 1H), 11.90-12.31 (m, 2H).
Reaction SMILES: [H-].[Na+].CS(O[CH2:8][CH2:9][CH2:10][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH3:12])(=O)=O.[CH3:20][CH:21]([CH3:24])[CH2:22][SH:23]>O1CCCC1>[CH2:22]([S:23][CH2:8][CH2:9][CH2:10][N:11]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH3:12])[CH:21]([CH3:24])[CH3:20]
Reactant: CC(C)CS
Reactant: CN(CCCOS(C)(=O)=O)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)CSCCCN(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.4 %

Procedure:
To a stirred suspension of sodium hydride (336 mg: 60% dispersion in oil) in anhydrous tetrahydrofuran (12 ml) was added a solution of 3-(N-t-butoxycarbonyl-N-methylamino)propyl methanesulfonate (2.139 g) in tetrahydrofuran (10 ml) dropwise over 5 minutes. After being stirred for 30 minutes, the mixture was cooled to 0° C., and 2-methyl-1-propanethiol (758 mg) was added dropwise at 0°-5° C. The mixture was then allowed to warm to ambient temperature and stirred for 24 hours. Additional 168 mg of sodium hydride and 379 mg of 2-methyl-1-propanethiol was added above the same condition. After being stirred for another 16 hours, the solvent was evaporated and the resulting residue was dissolved in ethyl acetate (100 ml). The solution was washed with 0.5N hydrochloric acid (100 ml), water (100 ml), aqueous sodium bicarbonate (100 ml), water (100 ml), and brine (100 ml) successively, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (6:4 V/V) to give 3-(N-t-butoxycarbonyl-N-methylamino)propyl isobutyl sulfide (595 mg) as an oil.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][C:11]1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:10]([O:8][C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:9])[CH3:11]
Reactant: O=C(O)C1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)C1CCCCC1
Temperature: 78.5 °C
Reaction time: 8 h
Yield: 2904.2 %

Procedure:
To a solution of cyclohexanecarboxylic acid (23.1 g, 180 mmol) in ethanol (100 mL) was added p-TsOH (1.027 g, 5.4 mmol). The mixture was heated to 78-79° C., and for several hours solvent was slowly distilled off whereas the volume was kept relatively constant by addition of fresh ethanol. Stirring at reflux temperature was continued overnight. An additional portion of p-TsOH (685 mg, 3.6 mmol) was added and the reaction mixture was stirred at 79° C. for an additional 5 h. The cooled reaction mixture was concentrated to nearly ¼ volume, diluted with TBME and extracted with cold aq. NaHCO3. The aqueous phase was extracted with TBME. The organic phases were washed with water until neutral, combined, dried over sodium sulfate and concentrated to give 26.5 g crude product which was distilled at 40° C. (0.25 mbar) to afford 24.5 g (87%) cyclohexanecarboxylic acid ethyl ester, GC purity >99% (area). 1H-NMR (CDCl3, 300 MHz): ppm 1.22 (t, 3H), 1.08-1.80 (m, 8H), 1.85-1.92 (m, 2H), 2.23-2.32 (m, 1H), 4.11 (q, 2H).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C([Li])(CC)C.C1CCCCC1.I[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>O1CCCC1>[CH2:6]([O:5][P:4]([CH:9]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:10][CH2:11][CH:12]=[CH2:13])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCCCCCCCCCI
Reactant: C=CCCCP(=O)(OCC)OCC
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: C=CCCC(CCCCCCCCCC)P(=O)(OCC)OCC
Temperature: 0 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
A solution of 4-pentenyl phosphonic acid diethyl ester (2.832 g, 13.7 mmol) in anhydrous tetrahydrofuran (20 mL) and cooled to about −78° C. A 1.3 M solution of sec-butyl lithium in cyclohexane (15 mL, 19.5 mmol) was added slowly to the mixture keeping the temperature below −60° C. 1-Iododecane (6.32 g, 23.6 mmol, 1.8 eq.) was then added slowly to the reaction mixture. The mixture was warmed to 0° C. and was stirred for three hours. The reaction was then quenched with NH4Cl (saturated, 20 mL). The mixture was warmed to room temperature and the THF was removed by rotary evaporation. The resulting solution was extracted with ethyl acetate (50 mL). The organic layer was separated and dried over Na2CO3. The solvent was removed and the resulting residue was purified by column chromatography (silica, ethyl acetate/hexane=2/8 then 4/6) to provide the pure product (3.46 g, 73% yield). 1H NMR (CDCl3) δ=5.8 (m, 1H), 5.0 (m, 2H), 4.1 (m, 4H), 2.2 (m, 2H), 1.8-1.2 (m, 27H), 0.9 (t, 3 H). 31P NMR (CDCl3) δ=35.8.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([CH:8]=[CH:9][CH:10]=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][C:15]([CH3:17])=[O:16]>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][CH:10]([OH:11])[CH2:14][C:15](=[O:16])[CH3:17])=[CH:12][CH:13]=1)([O-:3])=[O:2]
Reactant: O=CC=Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)CC(O)C=Cc1ccc([N+](=O)[O-])cc1
Reaction time: 168 h
Yield: 67 %

Procedure:
To a solution of 4-nitrocinnamaldehyde 8 (110 mg, 0.61 mmol; alternatively other aldehyde acceptors are shown in the Figures and can be obtained commercially or as described herein) in 15 mL of DMF and 31 mL of acetone (alternatively other ketone donors are shown in the Figures and can be obtained commercially or as described herein), PBS buffer (571 mL, degassed and kept under argon) was added slowly to avoid precipitation. Antibody 38C2 (8.0 mL of a 120 mM solution) was added. The final concentrations of 4-nitrocinnamaldehyde and Ab38C2 were 1.0 mM and 1.9 mM, respectively in a total volume of 625 mL containing 5% (v/v) of acetone. The reaction mixture was kept in a dark place at room temperature for seven days under Argon. The reaction mixture was saturated with sodium chloride and extracted with 3×150 mL of ethyl acetate. The extracts were dried over MgSO4 and evaporated to yield 140 mg of crude product. Purification by FC (1:2, ethyl acetate/hexane) gave 96 mg (67%) of pure aldol product (30) with an ee of 91%.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]3[N:10]=[C:11]([C@H:13]4[CH2:18][CH2:17][C@H:16]([O:19][CH2:20][CH:21]([OH:23])[CH3:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C1COCC1>[CH3:33][S:34]([O:23][CH:21]([CH3:22])[CH2:20][O:19][C@H:16]1[CH2:17][CH2:18][C@H:13]([C:11]2[O:12][C:8]3[CH:7]=[C:6]([O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[CH:25]=[CH:24][C:9]=3[N:10]=2)[CH2:14][CH2:15]1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)CO[C@H]1CC[C@H](c2nc3ccc(OCC4CC4)cc3o2)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(CO[C@H]1CC[C@H](c2nc3ccc(OCC4CC4)cc3o2)CC1)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-({trans-4-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]cyclohexyl}oxy)propan-2-ol (271 mg) and triethylamine (0.22 mL) in THF (5 mL) was added methanesulfonyl chloride (0.1 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr, and extracted with ethyl acetate and water. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (283 mg).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9]2=[N:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:17][N:8]2[C:7]1=[O:24])[CH2:2][CH2:3][CH2:4][CH3:5].[Br:25]N1C(=O)CCC1=O.C1(O)C=CC=CC=1>C1COCC1>[Br:25][C:12]1[NH:11][C:10]2[C:9]3=[N:15][C:16]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[N:17][N:8]3[C:7](=[O:24])[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]=2[N:13]=1
Reactant: CCCCCn1c(=O)n2nc(-c3ccccc3)nc2c2[nH]cnc21
Reactant: O=C1CCC(=O)N1Br
Solvent: Oc1ccccc1
Solvent: C1CCOC1
Product: CCCCCn1c(=O)n2nc(-c3ccccc3)nc2c2[nH]c(Br)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the mixture of 4-pentyl-8-phenyl-1,4-dihydro-5H-[1,2,4]triazolo[5,1-i]purin-5-one (25 mg, 0.078 mmol) in THF (5 mL) was added N-Bromosuccinimide (19 mg, 0.11 mmol). After stirring at room temperature for 1 hour, phenol was added to quench the reaction. The reaction mixture was concentrated, and the residue was purified by preparative LCMS (method B) to provide the desired product as white powder. 1HNMR (400 MHz, CD3OD): δ 8.25 (m, 2H), 7.50 (m, 3H), 4.31 (t, J=7.3 Hz, 2H), 1.88 (m, 2H), 1.43 (m, 4H), 0.95 (m, 3H). LCMS calculated for C17H18BrN6O (M+H): 401.1; found: 401.0, 403.0.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][NH:11][CH2:12]2)=[CH:7][CH:6]=1)([O-:4])=[O:3].C(N(CC)CC)C.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[CH:23]=[CH2:24]>C(O)C>[CH2:27]([O:26][C:22]([CH2:23][CH2:24][N:11]1[CH2:10][CH2:9][C:8]2[C:13](=[CH:14][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][CH:7]=2)[CH2:12]1)=[O:25])[CH3:28]
Reactant: C=CC(=O)OCC
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CCN1CCc2ccc([N+](=O)[O-])cc2C1
Reaction time: 8 h

Procedure:
To 125 ml of suspension in ethanol of 136 g of 7-nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride was added 98 ml of triethylamine and 83 ml of ethyl acrylate, and the solution was heated and stirred overnight under reflux. The solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate, washed with water, and dried with anhydrous sodium sulfate. After separating the desiccant by filtration, the filtrate was concentrated under reduced pressure to obtain 2-(2-(ethoxycarbonyl)ethyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline. The thus obtained 2-(2-(ethoxycarbonyl)ethyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline was dissolved in 1,000 ml of ethanol, and a catalytic amount of 10% palladium-carbon was added to the solution. The solution was stirred overnight under hydrogen atmosphere. The catalyst was separated by filtration, and the filtrate was concentrated under reduced pressure to obtain 7-amino-2-(2-(ethoxycarbonyl)ethyl)-1,2,3,4-tetrahydroisoquinoline, which was a solid.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20](=O)[C:21](F)(F)F)[CH2:16][CH2:15]2)[CH:10]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH2:9]1)=[O:7].[CH2:42](OC1(O[Si](C)(C)C)CC1)C>C(Cl)(Cl)Cl>[F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:15][CH2:16][N:17]([CH:20]4[CH2:42][CH2:21]4)[CH2:18][CH2:19]3)[CH:10]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH2:9]2)=[O:7])[CH:33]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:35]=1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC(N2CCN(C(=O)C(F)(F)F)CC2)C(c2ccc(Cl)cc2)C1
Solvent: ClC(Cl)Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC(N2CCN(C3CC3)CC2)C(c2ccc(Cl)cc2)C1

Procedure:
The title compound, MS: m/e=560.2 (M+H+), [α]58920=−24.38, [α]54620=−30.39, [α]43620=−64.51 (c=0.6154, chloroform), was prepared in accordance with the general methods of example 102 (step1) and example 110 (step2) from (−)-(1-{4-[1-(3,5-bis-trifluoromethyl-benzoyl)-3-(4-chloro-phenyl)-piperidin-4-yl]-piperazin-1-yl}-2,2,2-trifluoro-ethanone and [(1-ethoxycyclopropyl)-oxy]trimethylsilane.