Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[NH:4]([C:8]1[S:9][CH:10]=[C:11]([CH2:13][S:14][CH2:15][CH2:16][NH:17][C:18](=[NH:22])[C:19](=[NH:21])[NH2:20])[N:12]=1)[C:5]([NH2:7])=[NH:6].C(Cl)Cl.[S:26](N1C(=O)C2=CC=CC=C2C1=O)N1C(=O)C2=CC=CC=C2C1=O.[OH-].[Na+]>C(N(CC)CC)C>[NH2:21][C:19]1[C:18]([NH:17][CH2:16][CH2:15][S:14][CH2:13][C:11]2[N:12]=[C:8]([NH:4][C:5]([NH2:7])=[NH:6])[S:9][CH:10]=2)=[N:22][S:26][N:20]=1
Reactant: N=C(N)Nc1nc(CSCCNC(=N)C(=N)N)cs1
Reactant: O=C1c2ccccc2C(=O)N1SN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N=C(N)Nc1nc(CSCCNc2nsnc2N)cs1
Reaction time: 1 h
Yield: 53.9 %

Procedure:
A mixture of crude N-{2-[(2-guanidinothiazol-4-yl)methylthio]ethyl}ethanediimidamide trihydrochloride (5.65 g, 13.7 mmoles) [prepared in Step A], 50 ml of CH2Cl2 and 5.7 ml of triethylamine was treated with N,N'-thiobisphthalimide (DMF solvate) (5.44 g; 13.7 mmoles) and stirred for one hour to give a thick suspension. The mixture was treated with 40 ml of 2N NaOH and the solvents were decanted from the gum-like material which had separated. The gum was washed with 40 ml of 2N NaOH, water, and then dissolved in methanol and concentrated to give 3.0 g of crude product. The product was purified by flash chromatography on 90 g of silica gel (230-400 mesh) using ethyl acetate-methanol (97:3) as the eluent to give 2.44 g (54%) of the title compound. Treatment of the product in 35 ml of acetone with one equivalent of cyclohexylsulfamic acid gave the salt which was then recrystallized from 95% aqueous ethanol to give the title compound as its cyclohexylsulfamate salt, mp. 171°-173.5° C.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1.[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].CO>C(OCC)(=O)C>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:33]3[CH2:32][CH2:31][N:30]([CH:22]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)[C:19]4[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=4)[CH2:35][CH2:34]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Clc1ccc(C(c2ccc(Cl)cc2)N2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-(bis(4-chlorophenyl)methylpiperazine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 82% overall yield. mp 123°-124°. FDMS m/e=510 (M+ of free base). α[D]589 =-8.46 (c=0.89, methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7]([C:13]([OH:15])=[O:14])=[C:6]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:5]2=O.O.[NH2:26][NH2:27]>C(O)C.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]([OH:8])=[C:4]([C:5]2[C:6]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[C:7]([C:13]([OH:15])=[O:14])[NH:26][N:27]=2)[CH:3]=1
Reactant: COc1ccc(-c2c(C(=O)O)oc3cc(O)c(Cl)cc3c2=O)cc1
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2c(-c3cc(Cl)c(O)cc3O)n[nH]c2C(=O)O)cc1
Temperature: 70 °C

Procedure:
6-Chloro-7-hydroxy-3-(4methoxy-phenyl)-4-oxo-4H-chromene-2-carboxylic acid (1 eq) was taken up in ethanol and hydrazine hydrate (3 eq) was added. To aid dissolution a few drops of NaHCO3 (aq) was added, and then all was heated at 70° C. under nitrogen for 2 hours. The solution was cooled to room temperature and concentrated in vacuo to a brown oil. This was partitioned between 1MHCl(aq) and diethyl ether. The organic phases were combined, washed with 1MHCl(aq), dried over MgSO4, filtered and concentrated in vacuo to give 5-(5-chloro-2,4dihydroxy-phenyl)-4-(4-methoxy-phenyl)-2H-pyrazole-3-carboxylic acid as a yellow foam.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:10][C:11](=O)[CH3:12]>CO>[OH:8][C:7]1[C:2]2[N:3]([CH:10]=[C:11]([CH3:12])[N:1]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1O
Reactant: CC(=O)CCl
Solvent: CO
Product: Cc1cn2cccc(O)c2n1
Temperature: 25 °C
Yield: 52 %

Procedure:
A 1L two-necked round bottom flask containing molecular sieves (30 g, Type 4 Å) was vacuum flame-dried and cooled to room temperature. The flask was then charged with 2-amino-3-hydroxypyridine (11.2 g, 0.1 mol), chloroacetone (33.5 mL, 0.4 mol) and anhydrous methanol (400 mL) under argon. The resultant mixture was refluxed for 16 h, the molecular sieves were filtered off and the filtrate was concentrated in vacuo. The dark brown residue was dissolved in water (150 mL) and the resultant solution was extracted with diethyl ether (150 mL) and dichloromethane (2×50 mL). The dichloromethane extracts were combined and back-washed with water (20 mL). The aqueous layers were combined and adjusted to pH 10 with 40% aq NaOH, triggering precipitation of a solid. The precipitate was collected, washed successively with water (2×100 mL) and dichloromethane (100 mL), and dried over P2O5 in vacuo, giving 7.7 g (52% yield) of 8-hydroxy-2-methylimidazo[1,2-α]pyridine as a pale brown powder.
Reaction SMILES: F[B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+]([F:21])(CC1)CC2.[Cl:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][N:32]=1)[N:29]=[CH:28][CH:27]=[C:26]2[N:33]1[CH2:38][CH2:37][CH2:36][C@H:35]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:34]1>CC#N>[Cl:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][N:32]=1)[N:29]=[CH:28][C:27]([F:21])=[C:26]2[N:33]1[CH2:38][CH2:37][CH2:36][C@H:35]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:43])([CH3:45])[CH3:44])[CH2:34]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccnc3cnc(Cl)cc23)C1
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(F)cnc3cnc(Cl)cc23)C1
Reaction time: 18 h
Yield: 15 %

Procedure:
1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (1.0 equiv.) was added to a solution of (S)-tert-butyl 1-(6-chloro-1,7-naphthyridin-4-yl)piperidin-3-ylcarbamate (1.0 equiv.) in MeCN (0.14 M). After stirring for 18 hours, Na2CO3(sat.) was added to quench. The solution was partitioned between EtOAc and Na2CO3(sat.) washed further with NaCl(sat.), dried over MgSO4, concentrated and purified by silica gel chromatography (25-50-100% EtOAc/hexanes w/0.1% DIEA eluant) to yield (S)-tert-butyl 1-(6-chloro-3-fluoro-1,7-naphthyridin-4-yl)piperidin-3-ylcarbamate (15%), as well as recovered (S)-tert-butyl 1-(6-chloro-1,7-naphthyridin-4-yl)piperidin-3-ylcarbamate (55%). LCMS (m/z): 381.1/383.0 (MH+); LC Rt=4.20 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br>>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][Br:15]
Reactant: BrCCCCCBr
Reactant: COC(=O)CCCc1ccccc1O
Product: COC(=O)CCCc1ccccc1OCCCCCBr
Yield: 81 %

Procedure:
Using the procedure of example 108, 2-hydroxybenzenebutanoic acid methyl ester was converted into the title compound by alkylation with 1,5-dibromopentane, in 81% yield, as a colorless oil.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[S:8][CH:7]=1)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:11]1([C:9]2[S:8][CH:7]=[C:6]([CH:4]=[O:5])[CH:10]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CON(C)C(=O)c1csc(-c2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1csc(-c2ccccc2)c1

Procedure:
At −78° C., to a solution of 38f (2.5 mmol) in 5 mL THF under argon protection was added a solution of LiAlH4 in THF (1N, 1.42 mL) and stirring continued at 1h at −20° C. The reaction mixture was placed on an ice bath and quenched by 20% H2SO4 solution, extracted with ethyl acetate and dried over MgSO4. The solvent was removed under reduced pressure and purified by column chromatography to yield 5-phenylthiophene-3-carbaldehyde (not shown) (84.8%). 1H NMR (CDCl3) δ 9.98 (s, 1H), 8.04 (d, 1H, J=1.5 Hz), 7.86 (br, 1H), 7.61-7.58 (br, 2H), 7.47-7.33 (m, 3H), 7.35-7.32 (m, 1H), 6.78 (d, 1H, J=4.0 Hz); MS (ESI) m/z 210.9 (M+Na)+. To a solution of 5-phenylthiophene-3-carbaldehyde (0.195 g, 1.04 mmoL) in 5 mL THF was added a THF solution of 3,4,5-trimethoxyphenylmagnesiumbromide (0.5 N, 2.3 mL, 1.14 mmol) at 0° C. The mixture was allowed to stir for 30 min and quenched with satd. NH4Cl, extracted with ethyl ether, dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 40f. (70.5%). 1H NMR (CDCl3) δ 7.55-7.52 (m, 2H), 7.40-7.35 (m, 3H), 7.30 (br, 1H), 7.20 (br, 1H), 6.72 (s, 2H), 6.01 (d, 1H, J=3.9 Hz), 3.86 (s, 6H), 3.85 (s, 3H), 2.42 (d, 1H, J=3.9 Hz); MS (ESI) m/z 339.1 (M−OH)−.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7](Cl)=[O:8].[CH3:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[CH3:10][CH:11]1[CH2:16][CH2:15][N:14]([C:7]([C:3]2[CH:4]=[N:5][O:6][C:2]=2[CH3:1])=[O:8])[CH2:13][CH2:12]1
Reactant: CC1CCNCC1
Reactant: Cc1oncc1C(=O)Cl
Product: Cc1oncc1C(=O)N1CCC(C)CC1

Procedure:
of melting point 44° to 45° C., prepared from 5-methyl-4-isoxazolecarboxylic acid chloride and 4-methyl-piperidine.
Reaction SMILES: C([O:5][C:6](=[O:32])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:26](=O)[CH2:27][C:28]([CH3:30])=O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.Cl.[F:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41][NH2:42])=[CH:37][CH:36]=1.C([O-])(=O)C.[Na+]>>[F:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]2[C:26]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:32])[S:12][CH:13]=3)=[CH:27][C:28]([CH3:30])=[N:42]2)=[CH:37][CH:36]=1
Reactant: NNc1ccc(F)cc1
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)C(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1cc(C)nn1-c1ccc(F)cc1

Procedure:
A compound obtained using 2-[(4-{2-[acetoacetyl(heptyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 446-1, and (4-fluorophenyl)hydrazine hydrochloride and sodium acetate for neutralization, and by an operation similar to that of Example 446 was purified by silica gel chromatography (elution solvent; chloroform:methanol=10:1) to give the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:22])[CH2:10][CH2:11][CH2:12][N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(=O)([O-])O.[Na+]>ClCCl>[CH3:30][S:31]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:22])[CH2:10][CH2:11][CH2:12][N:13]([C:14]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:20])[CH3:21])=[CH:5][CH:4]=1)(=[O:33])=[O:32]
Reactant: CN(CCCC(=O)c1ccc(CO)cc1)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCCC(=O)c1ccc(COS(C)(=O)=O)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.1 %

Procedure:
The compound (651 mg, 2.12 mmol) obtained in Example 78a was dissolved in dichloromethane (20 mL), triethylamine (0.590 mL, 4.24 mmol) and methanesulfonyl chloride (0.245 mL, 3.18 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The resulting organic layer was dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a crude 4-{4-[(tert-butoxycarbonyl)(methyl)amino]butanoyl}benzyl methanesulfonate (851 mg) as a yellow oily substance.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14](O)=[O:15])=[CH:10][C:9]=2[OH:17])[N:3]=1.Cl.[CH3:19][N:20](C)[CH2:21]CCN=C=NCC.ON1C2C=CC=CC=2N=N1.CNC>CN(C=O)C.O>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:20]([CH3:21])[CH3:19])=[O:15])=[CH:10][C:9]=2[OH:17])[N:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1cc(C)n(-c2ccc(C(=O)O)cc2O)n1
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)n(-c2ccc(C(=O)N(C)C)cc2O)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 28.4 %

Procedure:
36 mg of 4-(3,5-dimethyl-1H-pyrazol-1-yl)-3-hydroxybenzene carboxylic acid was dissolved in 0.4 ml of DMF, and 36 mg of 1-(3-dimethylamino propyl)-3-ethylcarbodiimide hydrochloride, 25 mg of 1-hydroxybenzotriazole, and 93 μl of dimethylamine (2.0M THF solution) were added and stirred at room temperature for 4 hours. To the reaction mixture was added 10 ml of water, and extracted with 15 ml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and purified using a preparative thin-layer silica gel column chromatography (ethyl acetate) to yield 11.4 mg of the title compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([C:15](=[O:28])[CH2:16][O:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1)[NH2:14]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:14][NH:13][C:15](=[O:28])[CH2:16][O:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(OCC(=O)NN)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(OCC(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 100 °C
Yield: 77 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added methyl 4-(2-hydrazino-2-oxoethoxy)benzoate. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 185 mg of the title compound (77%) as a yellow solid in 99.1% purity by HPLC (Rt: 5.34, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][C@@H:5]([OH:20])[C:6]1[C:16](=[O:17])[C:15]2[C:14]([OH:18])=[CH:13][CH:12]=[C:11]([OH:19])[C:10]=2[C:8](=[O:9])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37](O)(=[O:45])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>CN(C)C1C=CN=CC=1.ClCCl>[C:37]([O:20][CH:5]([C:6]1[C:16](=[O:17])[C:15]2[C:10]([C:8](=[O:9])[CH:7]=1)=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=2[OH:18])[CH2:4][CH:3]=[C:2]([CH3:21])[CH3:1])(=[O:45])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reactant: CCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCC(=O)OC(CC=C(C)C)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 42 %

Procedure:
288 mg (1 mmole) of shikonin, 226 mg (1.1 mmole) of dicyclohexylcarbodiimide and 30 mg (0.25 mmole) of 4-dimethylaminopyridine were dissolved in 3 ml of dry dichloromethane. To the resulting solution was added 144 mg (1 mmole) of n-octanoic acid at 0° C. under nitrogen gas, and the mixture was stirred for 30 minutes and then at room temperature for further 3 hours. The resulting product was separated and purified according to the procedures as described in Example 1 to obtain 174 mg (Yield: 42%) of the title compound having the following structure as a red oil.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:25]=[C:26]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:28][CH:29]=3)[CH2:20][CH2:19]2)[CH:10]=[CH:9]1>>[CH3:34][CH:32]([CH3:33])[C:31]([NH:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH:21]2[CH2:20][CH2:19][N:18]([CH2:17][C:15]3[CH:14]=[CH:13][CH:12]=[C:11]4[C:16]=3[N:8]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=[CH:10]4)[CH2:23][CH2:22]2)[CH:25]=1)=[O:35]
Reactant: Ic1cccnc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4cc[nH]c34)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4ccn(-c5cccnc5)c34)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 3-iodopyridine and N-{3-[1-(1H-indol-7-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 453.1 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([O:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C@@H:9]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)C1C=CC=CC=1.O.[H][H]>C(O)C.[Pd]>[F:29][C:26]([F:27])([F:28])[C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=1)[CH2:15][O:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][C@H:9]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: [H][H]
Reactant: FC(F)(F)c1cc(CO[C@H]2OCCN(Cc3ccccc3)[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: FC(F)(F)c1cc(CO[C@H]2OCCN[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Yield: 79.8 %

Procedure:
A mixture of 0.68 g (1.37 mmole) of 4-benzyl-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenylmorpholine and 280 mg of 10% Pd/C in 36 mL of 97:3 ethanol:water was stirred under one atmosphere of hydrogen for 15 hr. The mixture was filtered through Celite, the filter cake was washed generously with ethanol, and the filtrated was concentrated in vacuo. The residue was purified by flash chromatography on 68 g of silica eluting with 1 L of 33:67 hexanes: diethyl ether, then 1 L of 25:75 hexanes: diethyl ether to give 0.443 g (80%) of an oil, which by 1H NMR was pure cis morpholine.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([OH:13])[C@@H:10]([O:14][CH2:15][CH:16]=[CH2:17])[CH2:9]1)=O)(C)(C)C.[ClH:18].O1CCOCC1>C(Cl)Cl>[ClH:18].[CH2:15]([O:14][C@H:10]1[CH2:9][NH:8][CH2:12][C@@H:11]1[OH:13])[CH:16]=[CH2:17]
Reactant: C=CCO[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C=CCO[C@H]1CNC[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(3S,4S)-3-Allyloxy-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester synthesized by the method described in the patent literature (DE4234330) (139 mg, 0.57 mmol) was dissolved in methylene chloride (2.4 ml). A 4 N solution of hydrochloric acid in dioxane (0.628 ml, 2.45 mmol) was added and the mixture was stirred at room temperature for two hours. The reaction solution was concentrated under reduced pressure to give (3S,4S)-4-allyloxy-pyrrolidin-3-ol hydrochloride (105 mg). This was used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: OCc1ccc(F)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(OCc2ccc(F)cc2)cc1

Procedure:
The title compound is prepared in analogy to Example 3a) from 4-fluorobenzyl alcohol and 4-fluoro-nitrobenzene. Yield: 86% of a yellowish solid. Mp=124–126° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1
Reactant: Clc1cc(Cl)n2nccc2n1
Reactant: C1COCCN1
Solvent: C1COCCO1
Product: Clc1cc(N2CCOCC2)n2nccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
5,7-Dichloro-pyrazolo[1,5-a]pyrimidine (400 mg, 2.13 mM) was dissolved in 1,4-dioxane (8 mL), then morpholine (372 μL, 4.26 mM) was added to the solution and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off from the reaction mixture, the resulting residue was diluted with water and extracted with methylene chloride. The extracts thus obtained were combined, dried over anhydrous sodium sulfate and the solvent was then distilled off to give the title compound (461 mg, yield: 91%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].O1CCCC1.[BH4-].[Na+]>CO>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([OH:3])[CH3:2])=[CH:9][CH:8]=2)=[CH:11][CH:12]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(=O)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(O)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 96.4 %

Procedure:
120.9 g (0.4 mol) of 4'-acetyl-4-benzyloxybiphenyl, 400 ml of tetrahydrofuran and 100 ml of methanol were supplied into a four-necked flask equipped with a stirrer and a thermometer. Then 15.14 g (0.4 mol) of sodium borohydride was added at 15°-25° C. over a period of 2 hours. The mixture was kept at the same temperature for 5 hours, then poured into ice-water and extracted twice with 500 ml of chloroform. The organic layer was concentrated under reduced pressure to obtain 117.4 g of 4-benzyloxy-4'-(1-hydroxyethyl)biphenyl in a 96.5% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[CH3:16]O>S(=O)(=O)(O)O>[CH3:16][O:14][C:13](=[O:15])[CH2:12][C:4]1[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[C:2]([F:1])[CH:3]=1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)c(F)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Yield: 97 %

Procedure:
A solution of 3-fluoro-4-(trifluoromethyl)phenylacetic acid (2.50 g, 11.25 mmol) in methanol (25 mL) was treated slowly with 4 drops of concentrated sulfuric acid. The resulting reaction mixture was heated under reflux for 15 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove methanol. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded (3-fluoro-4-trifluoromethyl-phenyl)-acetic acid methyl ester (2.58 g, 97%) as a colorless oil: EI-HRMS m/e calcd for C10H8F4O2 (M+) 236.0460, found 236.0457.