Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1I.CC(CCC)C(=O)C(=O)C(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.[Cu]Cl.CN1CCCC1=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[Cl:9])=[CH:4][CH:3]=1
Reactant: Clc1ccccc1I
Reactant: Sc1ccc(Br)cc1
Agent: Cl[Cu]
Agent: CCCC(C)C(=O)C(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Clc1ccccc1Sc1ccc(Br)cc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
N-Methyl-2-pyrrolidone (10 mL) was added to 4-bromothiophenol (0.500 g, 2.64 mmol) in a sealed tube and the mixture was purged with argon for 5 minutes. To this mixture was added 2-chloro-iodobenzene (0.63 g, 2.64 mmol). Copper(I) chloride (0.131 g, 1.32 mmol), tetramethyl heptanedione (0.14 mL, 0.66 mmol) and cesium carbonate (1.70 g, 5.22 mmol) were added. The reaction mixture was stirred at 130° C. under argon for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through a celite bed. The filtrate was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield the crude product. Silica gel chromatography (neat hexanes) provided impure 1-bromo-4-(2-chlorophenylsulfanyl)-benzene (0.44 g). MS calcd. for C12H8BrS [(M−Cl)] 265, obsd. 265.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27]2>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[C:27]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: COc1ccc2c(c1)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Product: COc1ccc2c(c1)C(=Cc1[nH]c3c(c1C)C(=O)N(CCN1CCOCC1)CC3)C(=O)N2
Yield: 33.3 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-methoxy-1,3-dihydro-indol-2-one (prepared according to U.S. Pat. No. 6,114,371) as starting materials to give 2-(5-methoxy-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-morpholin-4-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (30 mg, 33.3%) as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[H][H]>>[C:5]1([CH:3]([OH:4])[CH2:2][OH:1])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(CO)c1ccccc1
Reactant: [H][H]
Product: OCC(O)c1ccccc1
Yield: 98 %

Procedure:
The reaction of α-hydroxyacetophenone was performed by the same method as in Example 3 except that the reaction was performed at a hydrogen pressure of 10 atm. As a result, optically active 1-phenyl-1,2-ethanediol with 97% ee was produced in a yield of 98%. The R and S isomers were not identified.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]1[CH2:36][NH:35][CH2:34][CH2:33][NH:32]1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:35]4[CH2:34][CH2:33][NH:32][CH:31]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[F:24])[CH2:36]4)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2]
Reactant: Fc1ccccc1C1CNCCN1
Reactant: CCOC(=O)c1cn(C)c2nc3cc(F)c(F)cc3cc2c1=O
Product: CCOC(=O)c1cn(C)c2nc3cc(N4CCNC(c5ccccc5F)C4)c(F)cc3cc2c1=O

Procedure:
(RS)-3-Ethoxycarbonyl-7-fluoro-8-[3-(2-fluorophenyl)-1-piperazinyl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 39, but starting with 3-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.59 g) and (RS)-2-(2-fluorophenyl)piperazine (1.08 g). After recrystallization in dimethylformamide (60 cc) containing ethanol (50%), the expected product (1.3 g) is obtained in the form of a yellow solid, m.p. 228° C.
Reaction SMILES: CC([N:4]=C=NC(C)C)C.[C:10]([C:13]1[CH:45]=[CH:44][C:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]([O:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][O:39]3)[C:26]3[CH:27]=[CH:28][C:29]([O:35][CH3:36])=[C:30]([CH:34]=3)[C:31](O)=[O:32])=[CH:21][CH:20]=2)=[C:15]([CH2:46][CH2:47][CH3:48])[C:14]=1[OH:49])(=[O:12])[CH3:11].O.ON1C2C=CC=CC=2N=N1>ClCCl>[C:10]([C:13]1[CH:45]=[CH:44][C:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]([O:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][O:39]3)[C:26]3[CH:27]=[CH:28][C:29]([O:35][CH3:36])=[C:30]([CH:34]=3)[C:31]([NH2:4])=[O:32])=[CH:21][CH:20]=2)=[C:15]([CH2:46][CH2:47][CH3:48])[C:14]=1[OH:49])(=[O:12])[CH3:11]
Reactant: CC(C)N=C=NC(C)C
Reactant: CCCc1c(OCc2ccc(C(OC3CCCCO3)c3ccc(OC)c(C(=O)O)c3)cc2)ccc(C(C)=O)c1O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCCc1c(OCc2ccc(C(OC3CCCCO3)c3ccc(OC)c(C(N)=O)c3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
Add N,N-diisopropylcarbodiimide (0.114 g, 0.902 mmol) to a solution of 5-[[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-2-methoxy-benzoic acid (0.450 g, 0.820 mmol) and 1-hydroxybenzotriazole hydrate (0.122 g, 0.902 mmol) in dichloromethane (0.2M). Stir the solution for 1 h at room temperature. Saturate the solution with ammonia gas and stir the solution for 24 h. Collect the precipitate as the title compound (0.440 g, 0.815 mmol, 98%): MS (m/z): 546 (M−1).
Reaction SMILES: COB1C2CC[CH2:11][CH:4]1[CH2:5]CC2.C([Mg]Br)(C)=C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:26]1[CH:31]=[CH:30][C:29]([C:32]2[C:45]([C:46]3[CH:51]=[CH:50][N:49]=[C:48]([NH:52][CH2:53][CH2:54][CH2:55][CH3:56])[N:47]=3)=[C:35]3[CH:36]=[CH:37][CH:38]=[C:39]([NH:40][CH2:41][CH2:42][CH2:43][CH3:44])[N:34]3[N:33]=2)=[CH:28][CH:27]=1.[OH-].[Na+].OO>O1CCCC1.O.CCOCC.CN(C)C=O>[CH2:41]([NH:40][C:39]1[N:34]2[N:33]=[C:32]([C:29]3[CH:30]=[CH:31][C:26]([C:4]([CH3:11])=[CH2:5])=[CH:27][CH:28]=3)[C:45]([C:46]3[CH:51]=[CH:50][N:49]=[C:48]([NH:52][CH2:53][CH2:54][CH2:55][CH3:56])[N:47]=3)=[C:35]2[CH:36]=[CH:37][CH:38]=1)[CH2:42][CH2:43][CH3:44]
Reactant: CCCCNc1nccc(-c2c(-c3ccc(Br)cc3)nn3c(NCCCC)cccc23)n1
Reactant: COB1C2CCCC1CCC2
Agent: C=C(C)[Mg]Br
Agent: O=P([O-])([O-])[O-]
Agent: OO
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)c1ccc(-c2nn3c(NCCCC)cccc3c2-c2ccnc(NCCCC)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.5 %

Procedure:
To a cold (−78° C.) solution of 9-methoxy-9-borabicyclo[3.3.1]nonane (1 mL, 1.0 M in hexane, 1.0 mmol) in tetrahydrofuran (5 mL) was added isopropenylmagnesium bromide (2.0 mL, 0.5 M in tetrahydrofuran, 1.0 mmol) dropwise. The resultant solution was stirred at −78° C. for 5 minutes, then allowed to warm to room temperature. After 1 hour, potassium phosphate (0.33 mL, 3 M aqueous, 1.0 mmol) was added followed by N,N-dimethylformamide (5 mL), 2-(4-Bromophenyl)-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (100 mg, 0.20 mmol), and bis(diphenylphosphinoferrocene)palladium(II) chloride dichloromethane complex (17 mg, 0.02 mmol). The resultant solution was stirred for 72 hours at room temperature. Ether was added followed by water. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (6:1 to 4:1 to 2:1 hexanes:ethyl acetate) provided impure product. This material was taken up in tetrahydrofuran, cooled to 0° C. and 1 mL each of 10% aqueous sodium hydroxide and 30% hydrogen peroxide were added. After 30 minutes, the mixture was quenched with saturated aqueous sodium thiosulfate. Aqueous workup as reported above followed by similar chromatography provided N-butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-(4-isopropenylphenyl)pyrazolo[1,5-a]pyridin-7-amine (25 mg, 27%) as an oil. 1H NMR (CDCl3): δ 8.00 (d, 1 H), 7.76 (d, 1 H), 7.62 (d, 2 H), 7.54 (d, 2 H), 7.30 (m, 1 H), 6.35 (d, 1 H), 6.07 (m, 1 H), 5.99 (d, 1 H), 5.46 (s, 2 H), 5.22 (broad, 1 H), 5.14 (s,1 H), 3.47 (m, 2 H), 3.36 (m, 2 H), 2.20 (s, 3 H), 1.77–1.42 (m, 8 H), 1.00–0.95 (m 6 H); MS m/z 455 (M+1). This material was treated with anhydrous hydrochloric acid in ether to provide the corresponding hydrochloride salt.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:14]N1C(=O)CCC1=O>C1(=O)OC(C)CO1>[Br:14][C:9]1[CH:8]=[CH:7][C:6]2[C:5]3[C:13](=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:12][C:11]=2[CH:10]=1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: O=C1CCC(=O)N1Br
Solvent: CC1COC(=O)O1
Product: Brc1ccc2c(c1)Cc1ccccc1-2
Yield: 95 %

Procedure:
To a solution of fluorene (16.6 g, 0.1 mol), in propylene carbonate (125 mL), at 60° C., N-bromo succinimide (17.8 g, 0.1 mol) was added in one portion, and the mixture was allowed to cool over a period of 1 hour. The solids separated on dilution with water (2 L), were collected, dissolved in toluene (250 mL), and the toluene solution was washed with water. The solids left after concentration were recrystallized from ethanol-water, 23.3 g (95% yield), m.p. 95.6-101.3° C. Mass Spec: m/z 322, 324, 326 (M+ dibromo), 244,246 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N-:10]=[N+:11]=[N-:12].[Na+].[Cl-].[NH4+]>CN(C)C=O>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]1[NH:12][N:11]=[N:10][N:5]=1
Reactant: N#Cc1ccccc1N
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccccc1-c1nnn[nH]1
Temperature: 120 °C
Yield: 65.2 %

Procedure:
2-Aminobenzonitrile (9.44 g, 80 mmol), sodium azide, (6.24 g, 0.1 mol), ammonium chloride (5.12 g, 0.1 mol) and dimethylformamide (50 mL) were mixed and heated at 120° C. overnight. The solvent was evaporated and the residue taken up in water. The crude product was isolated by filtration and re-crystallised from water. A yield of 8.4 g of pure product was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@@:10]([NH:36][C:37](=[O:49])[C:38]2[CH:43]=[CH:42][C:41]([F:44])=[C:40]([C:45]([F:48])([F:47])[F:46])[CH:39]=2)([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=2)[C:11]2[CH:16]=[C:15]([O:17][C:18]([F:23])([F:22])[CH:19]([F:21])[F:20])[CH:14]=[C:13]([F:24])[CH:12]=2)=[CH:5][CH:4]=1)#[N:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C@@:10]([NH:36][C:37](=[O:49])[C:38]2[CH:43]=[CH:42][C:41]([F:44])=[C:40]([C:45]([F:48])([F:47])[F:46])[CH:39]=2)([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:33])([F:34])[F:35])[CH:26]=2)[C:11]2[CH:16]=[C:15]([O:17][C:18]([F:22])([F:23])[CH:19]([F:20])[F:21])[CH:14]=[C:13]([F:24])[CH:12]=2)=[CH:7][CH:8]=1
Reactant: N#Cc1ccc(C[C@](NC(=O)c2ccc(F)c(C(F)(F)F)c2)(c2cc(F)cc(OC(F)(F)C(F)F)c2)c2ccc(F)c(C(F)(F)F)c2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc(C[C@](NC(=O)c2ccc(F)c(C(F)(F)F)c2)(c2cc(F)cc(OC(F)(F)C(F)F)c2)c2ccc(F)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 36 %

Procedure:
To a solution of (R)—N-(2-(4-cyanophenyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)-4-fluoro-3-(trifluoromethyl)benzamide, prepared as described in Procedure 56, (77% yield, 20 mg, 0.02 mmol) in THF (1.5 mL) at rt was added LAH (1.0 M in THF). The reaction mixture was stirred at rt for 5 h, then quenched by addition of 2 N LiOH. The solid was removed by filtration and the filtrate was concentrated. The resulting residue was purified by prep HPLC (YMC Sunfire 5μ C18 30×100 mm column, eluting with 20-90% MeOH/H2O containing 0.1% TFA, 10 min gradient, flow rate 40 mL/min, wavelength 220 nm) to provide (R)—N-(2-(4-(aminomethyl)phenyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)-4-fluoro-3-(trifluoromethyl)benzamide (Example 300) as a colorless film (5 mg, 36% yield). LCMS: RT=1.8 min [M+H] 713.26 (Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90% MeOH/H2O containing 0.1% TFA, 2 min gradient, flow rate 5 mL/min, wavelength 220 nm); HPLC: RT=4.31 min (Phenomenex Luna C18 4.6×50 mm column, eluting with 10-90% MeOH/H2O containing 0.2% PPA, flow rate 4 mL/min, wavelength 220 nm). 1H NMR (400 MHz, CD3OD) δ ppm 7.95 (1H, d, J=6.59 Hz), 7.46-7.48 (1H, m), 7.36 7.41 (2H, m), 7.22 (1H, t, J=9.45 Hz), 7.16 (2H, d, J=7.91 Hz), 6.99 (2H, dd, J=16.48, 9.45 Hz), 6.93 (1H, s), 6.73 (2H, d, J=7.91 Hz), 6.21H, t, J=49.7 Hz), 4.01-4.06 (1H, m), 3.93-3.99 (3H, m).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[CH:15]=O.[C:17]1([CH2:23][C:24](OC)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CC([O-])(C)C.[Na+].CN(C=O)C>C1(C)C=CC=CC=1>[C:11]([C:9]1[CH:10]=[C:6]2[N:5]=[CH:4][C:3]3[CH:15]=[C:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:24](=[O:25])[NH:1][C:2]=3[N:7]2[N:8]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1cc2ncc(C=O)c(N)n2n1
Reactant: COC(=O)Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc2ncc3cc(-c4ccccc4)c(=O)[nH]c3n2n1
Temperature: 105 °C
Reaction time: 48 h
Yield: 45.7 %

Procedure:
A solution of 7-amino-2-tert-butylpyrazolo[1,5-a]pyrimidine-6-carbaldehyde (1.5 g, 6.87 mmol, 1.00 eq.), methyl 2-phenylacetate (4.1 g, 27.30 mmol, 4.00 eq.) and NaOtBu (1.3 g, 13.53 mmol, 2.00 eq.) in toluene (30 mL) was stirred at 105° C. for about 30 min under nitrogen. Then the reaction mixture was added 30 mL of DMF and the mixture was stirred for about 2 days at 105° C. After concentrating under vacuum, the residue was diluted with water and extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:6) to give the resulted product (1 g, 46%) as a yellow solid. LCMS (m/e)=319 (M+H); 1H NMR (300 MHz, DMSO, δ, ppm) 8.82 (s, 1H), 8.42 (s, 1H), 7.72 (d, J=6.9 Hz, 2H), 7.50-7.38 (m, 3H), 6.72 (s, 1H), 1.42 (s, 9H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.CCN(CC)CC.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(O)C.C(Cl)Cl>[O:8]=[C:6]1[NH:7][C@@H:3]([CH2:2][O:1][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:4][CH2:5]1
Reactant: O=C1CC[C@H](CO)N1
Reactant: CS(=O)(=O)Cl
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.4 %

Procedure:
To a solution of commercially available (R)-(−)-5-(hydroxymethyl)pyrrolidin-2-one (5 g, 43.4 mmol) in ethanol-free CHCl3 (150 ml), Et3N (6.9 g, 68.3 mmol) and methanesulfonyl chloride (5.96 g, 52.0 mmol) were added dropwise at 0° C. The mixture was left stirring at room temperature for 3 hours, then it was diluted with DCM and washed with a saturated aqueous solution of NaHCO3. After drying (Na2SO4) the solvent was removed under reduced pressure and the residue was purified by flash chromatography (DCM/MeOH 95/5 respectively) to give the title compound as a pale yellow solid (5.9 g, 70% yield).
Reaction SMILES: COC1C=CC(N2CCN(CCC3C=CC=CC=3)CC2)=CC=1C.[F:24][C:25]1[CH:30]=[C:29]([O:31]C)[C:28]([F:33])=[CH:27][C:26]=1[N:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:36][CH2:35]1>>[F:33][C:28]1[CH:27]=[C:26]([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:36][CH2:35]2)[C:25]([F:24])=[CH:30][C:29]=1[OH:31]
Reactant: COc1cc(F)c(N2CCN(CCc3ccccc3)CC2)cc1F
Agent: COc1ccc(N2CCN(CCc3ccccc3)CC2)cc1C
Product: Oc1cc(F)c(N2CCN(CCc3ccccc3)CC2)cc1F
Yield: 85.9 %

Procedure:
Production Example 10 was repeated except that 1-(4-methoxy-3-methylphenyl)-4-phenethylpiperazine was replaced with 1-(2,5-difluoro-4-methoxyphenyl)-4-phenethylpiperazine (571 mg). The resulting crude product was purified on TLC (developer, chloroform: methanol=15:1) to provide 2,5-difluoro-4-(4-phenethylpiperazin-1-yl)phenol (470 mg).
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19]1[C:28]3[C:23](=[CH:24][C:25]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:26][CH:27]=3)[CH:22]=[C:21](Br)[C:20]=1[O:38][CH3:39])=[C:14]([O:40][CH3:41])[C:13](Br)=[CH:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:43]1([Mg]Br)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CCOCC>[CH2:1]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19]1[C:28]3[C:23](=[CH:24][C:25]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:27][CH2:26][CH2:25][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:26][CH:27]=3)[CH:22]=[C:21]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:20]=1[O:38][CH3:39])=[C:14]([O:40][CH3:41])[C:13]([C:10]1[CH:9]=[CH:18][CH:17]=[CH:16][CH:11]=1)=[CH:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCCCCCCCc1ccc2c(-c3c(OC)c(Br)cc4cc(CCCCCCCC)ccc34)c(OC)c(Br)cc2c1
Reactant: Br[Mg]c1ccccc1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCCc1ccc2c(-c3c(OC)c(-c4ccccc4)cc4cc(CCCCCCCCCCCCCCCCCC)ccc34)c(OC)c(-c3ccccc3)cc2c1
Reaction time: 0.25 h
Yield: 50.6 %

Procedure:
A suspension of 80 mg of Ni[PPh3 ]2Cl2 and 20 ml of ether were added to 1.9 g of Compound 3, and stirred for 15 minutes in a nitrogen atmosphere. 10 mmol of phenylmagnesium bromide were added and refluxed for 4 hours. After cooling down, the solution was quenched with 20 ml of 1N hydrochloric acid and extracted with chloroform. The organic layer was evaporated under reduced pressure, and purified with column chromatography (silica gel, hexane/benzene) to get 670 mg of pure 6,6'-dioctadecyl-3,3'-diphenyl-2,2'-dimethoxy-1,1'-binaphthyl. (yield 36%) (Compound 4).
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[CH:6]([O:15][CH:16]1[CH2:19][NH:18][CH2:17]1)[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[CH:30]1([N:36]=[C:37]=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>C(Cl)Cl>[F:25][C:3]([F:2])([F:24])[C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[CH:6]([O:15][CH:16]1[CH2:19][N:18]([C:37]([NH:36][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:38])[CH2:17]1)[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1
Reactant: CSc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Reactant: O=C=NC1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CSc1ccc(C(OC2CN(C(=O)NC3CCCCC3)C2)c2ccccc2C(F)(F)F)cc1

Procedure:
To a solution of 3-[2-(trifluoromethyl)-4′-(methylthio)benzhydryloxy]azetidine hydrochloride (118) (100 mg, 0.26 mmol) in anhydrous DCM (5 mL) was added MP-carbonate (3.10 mmol/g; 250 mg, 0.84 mmol) and cyclohexyl isocyanate (33 μL, 0.26 mmol). The resultant mixture was shaken at ambient temperature for 16 h, after which time it was poured onto a DCM-wetted SCX-2 (1 g) cartridge. The sample was eluted with DCM (18 mL), then evaporated to afford the desired product as a white, crystalline solid (65 mg, 52%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[C:8]2([NH:16]S(C(C)(C)C)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CI>CC#N>[NH2:16][C:8]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=2)[CH2:6][C:7]21[CH2:23][CH2:24][CH:25]([O:28][CH3:29])[CH2:26][CH2:27]2
Reactant: CCOC(=O)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CCOC(=O)C1(N)c2cc(Br)ccc2CC12CCC(OC)CC2
Reaction time: 0.08 h
Yield: 57.1 %

Procedure:
To a solution of compound 6 (230 mg, 0.55 mmol) in CH3CN (15 mL) was added K2CO3 (304 mg, 2.2 mmol). After being stirred for 5 min, MeI (155 mg, 1.1 mmol) was added. The reaction mixture was stirred at 60° C. for 15 min in a CEM microwave reactor. The mixture was concentrated in vacuo, the residue was purified by prep-TLC to give compound 7 (120 mg, 50%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1.[Br:14][C:15]1[CH:20]=[CH:19][C:18](O)=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([O:1][CH2:2][CH:3]2[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Reactant: Oc1ccc(Br)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(COc2ccc(Br)cc2)C1
Temperature: 110 °C
Yield: 84.7 %

Procedure:
A mixture of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (200 mg, 1.07 mmol), 4-bromophenol (222 mg, 1.28 mmol), triphenylphosphine (368 mg, 1.40 mmol) and DIAD (259 mg, 1.28 mmol) in anhydrous THF (5 mL) was heated to 110° C. under nitrogen for 5 hours. The reaction mixture was concentrate in vacuo to give a brown residue, which was purified by flash chromatography (petroleum ether/ethyl acetate 20:1 to 5:1) to give tert-butyl 3-[(4-bromophenoxy)methyl]azetidine-1-carboxylate (310 mg, 84%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.38 (d, 2H), 6.78 (d, 2H), 4.06 (m, 4H), 3.79 (m, 2H), 2.96 (m, 1H), 1.45 (s, 9H).
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[C:7]([CH3:10])[S:8][CH:9]=1)[CH2:3][NH2:4].Cl[CH2:12][C:13](OCC)=[O:14]>C(OCC)(=O)C.CO>[CH3:10][C:7]1[S:8][CH:9]=[C:5]([CH:2]2[O:1][CH2:12][C:13](=[O:14])[NH:4][CH2:3]2)[N:6]=1
Reactant: Cc1nc(C(O)CN)cs1
Reactant: CCOC(=O)CCl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1nc(C2CNC(=O)CO2)cs1

Procedure:
Prepared analogously to Example S by reaction of 2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine with ethyl chloroacetate and purification on a silica gel column using ethyl acetate/methanol=19:1 as eluant.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH:11]1([N:14]([C@H:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C@@H:20]([CH3:28])[CH2:19]2)[C:15](=[O:17])[CH3:16])[CH2:13][CH2:12]1.C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1>[CH:11]1([N:14]([C@H:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([C:2]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=3)=[O:9])[C@@H:20]([CH3:28])[CH2:19]2)[C:15](=[O:17])[CH3:16])[CH2:12][CH2:13]1
Reactant: CC(=O)N(C1CC1)[C@@H]1C[C@H](C)Nc2ccccc21
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)N(C1CC1)[C@@H]1C[C@H](C)N(C(=O)c2cccnc2)c2ccccc21
Temperature: 50 °C
Yield: 52.4 %

Procedure:
Nicotinoyl chloride hydrochloride (1.46 g) was added to a solution of Cis-N-cyclopropyl-N-(2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-acetamide (0.4 g) in pyridine (20 ml). The mixture was heated at 50° C. for 3 hours. After cooling, an aqueous solution of sodium carbonate was added and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and then the solvent was removed under reduce pressure. The crude compound was crystallized in diethyl ether to give Cis-N-cyclopropyl-N-[2-methyl-1-(pyridine-3-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl]-acetamide (0.3 g, 52.6% yield).