Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([CH:14]=O)=[CH:9][CH:8]=2)[CH3:3].[NH2:16][C:17]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[C:18]=1[C:19]([NH2:21])=[O:20].S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH3:3][N:2]([CH2:4][C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([C:14]1[NH:21][C:19](=[O:20])[C:18]3[C:17](=[CH:25][C:24]([O:26][CH3:27])=[CH:23][C:22]=3[O:28][CH3:29])[N:16]=1)=[CH:9][CH:8]=2)[CH3:1]
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: CN(C)Cc1cc2cc(C=O)ccc2[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc4[nH]c(CN(C)C)cc4c3)nc2c1
Temperature: 120 °C
Reaction time: 5 h

Procedure:
To a solution of 2-dimethylaminomethyl-1H-indole-5-carbaldehyde (0.88 g crude, 4.35 mmol) and 2-amino-4,6-dimethoxy-benzamide (0.85 g, 4.35 mmol) in N,N-dimethylacetamide (15 mL) were added sodium hydrogen sulfite (58.5 wt %, 0.95 g, 5.22 mmol) and p-toluenesulfonic acid (0.99 g, 5.22 mmol). The reaction mixture was stirred at 120° C. for 5 hours under nitrogen, then cooled to room temperature, and concentrated under reduced pressure. 30% aqueous sodium carbonate (50 mL) was then added. The separated solid was filtered, washed with water (50 mL), and dried under vacuum. Crude compound was purified by the Simpliflash system (0-5% methanol in CH2Cl2 and 7 N ammonia in methanol 5% in CH2Cl2 as eluent) to give the title compound as an off-white solid. Yield: 0.83 g (50%). MP 187-188° C. 1H NMR (400 MHz, DMSO-d6): δ 11.82 (s, 1H), 11.34 (s, 1H), 8.38 (s, 1H), 7.93 (d, J=8.59 Hz, 1H), 7.40 (d, J=8.59 Hz, 1H), 6.73 (s, 1H), 6.49 (s, 1H), 6.40 (s, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.57 (s, 2H), 2.21 (s, 6H).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:29][C:30]1[N:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1>>[OH:28][CH2:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:33]3[CH:32]=[N:31][C:30]([CH3:29])=[N:35][CH:34]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Cc1ncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@H](CO)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 75 using (S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 78.1) and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine to afford an off-white solid. UPLC-MS (condition 1) tR=2.37 min, m/z=474.1 [M+H]+, m/z=472.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.51-1.65 (m, 1H) 1.79-1.90 (m, 1H) 2.17-2.30 (m, 1H) 2.68 (s, 3H) 2.99 (dd, J=10.76, 6.85 Hz, 1H) 3.11-3.23 (m, 2H) 3.22-3.30 (m, 3H) 4.61 (br. s, 1H) 7.35 (d, J=8.80 Hz, 2H) 7.85 (d, J=9.05 Hz, 2H) 8.04 (d, J=2.45 Hz, 1H) 8.76 (s, 2H) 8.77 (d, J=2.44 Hz, 1H) 10.15 (s, 1H).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:14]([Li])([CH2:16]C)[CH3:15].COS(OC)(=O)=O>C(OCC)C.O>[C:1]([N:8]1[CH2:9][C@H:10]([OH:13])[CH2:11][C@@H:12]1[CH2:16][CH:14]=[CH2:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: [Li]C(C)CC
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Solvent: COS(=O)(=O)OC
Solvent: O
Solvent: CCOCC
Product: C=CC[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: -78 °C
Yield: 69.2 %

Procedure:
(3R)-1-BOC-3-hydroxypyrrolidine (1 g, 5.34 mmol) was dissolved in diethylether (50 ml), and filled with nitrogen. The reaction mixture was cooled to −78° C., N,N,N,N′-tetramethylethylenediamine (620 mg, 5.34 mmol) was added, and sec-butyllithium (1.4M cyclohexane solution 4.45 ml, 6.23 mmol) was slowly added. After being stirred for 30 min at the same temperature, dimethylsulfate (1.44 g, 10.68 mmol) was dissolved in diethylether (10 ml). The reaction solution was slowly heated to rt, diluted with water (12 ml), and extracted with diethylether. The organic extracts were dried over MgSO4, and the residue was purified by column chromatography (eluent, EtOAc/Hex=1/4) to give the title compound (840 mg, 70%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23](=[O:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[CH3:27][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:25])([CH3:27])[CH3:24])([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: CC(=O)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
To a solution of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazinan-2-one (20 g, 46.4 mmol) in anhydrous THF (200 mL) was added dropwise methylmagnesium bromide (31 mL, 144 mmol) at −78° C. under nitrogen. Then the mixture was stirred at rt for 1 h. The reaction mixture was quenched with aq NaHCO3 (50 mL) under ice water bath. The organic layers were separated. The aqueous layer was extracted with EtOAc (150 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude product, which was purified column chromatography (petroleum ether/EtOAc=5:1 to 2:1) to afford (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (13 g, 65%). After re-crystallization from EtOH, 4 g of the pure compound was obtained. 1H NMR (CDCl3): 1.06 (s, 3H), 1.12 (s, 3H), 1.44 (d, 3H), 2.14 (m, 3H), 2.21 (m, 1H), 2.33 (m, 1H), 2.76 (m, 1H), 5.54 (q, 1H), 6.74 (d, 2H), 7.16 (d, 2H), 7.28 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[CH:9]([Si:12](Cl)([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])([CH3:11])[CH3:10].N12CCCN=C1CCCCC2>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][Si:12]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)[Si](Sc1ccc(Br)cc1)(C(C)C)C(C)C

Procedure:
To a solution of 45 grams of 4-bromothiophenol in 250 mL of THF was added 53 mL of triisopropylsilyl chloride and 38 mL of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) under a nitrogen atmosphere. The reaction mixture heated spontaneously to reflux. The reaction mixture was allowed to cool and was diluted with 500 mL of hexanes. The resultant white suspension was filtered through a pad of Celite® (diatomaceous earth), and the filter cake was washed with additional hexanes and 100 mL of ether. The filtrate was washed with ice-cold 0.1 N aqueous HCl, water, aqueous NaHCO3, and saturated aqueous NaCl, dried over MgSO4, and concentrated under vacuum to obtain 82 grams of the title compound of Step A as a clear oil. 1H NMR (CDCl3, 300 MHz) δ 1.1 (m, 18H), 1.2 (m, 3H), 7.3-7.4 (m, 4H).
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[C:30](O)=[O:31]>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C@@H:3]([NH:2][C:30]([C:22]2[NH:21][C:29]3[C:24]([CH:23]=2)=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:31])[C:4]([N:6]2[CH2:7][CH2:8][CH:9]([OH:12])[CH2:10][CH2:11]2)=[O:5])=[CH:19][CH:18]=1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: N[C@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1
Agent: Cl
Product: O=C(N[C@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1)c1cc2ccccc2[nH]1

Procedure:
(R)-2-Amino-3-(4-fluoro-phenyl)-1-(4-hydroxy-piperidin-1-yl)-propan-1-one hydrochloride (0.5 mmol) and 1H-indole-2-carboxylic acid (0.5 mmol) were coupled according to Procedure A (0-25° C. reaction temperature) and the product purified by chromatography on silica gel eluted with 25, 30, 50, 75 and 80% ethyl acetate in hexanes. Yield 150 mg, 60%; HPLC (60/40) 3.66 minutes (97%); mp 204-207° C.; PBMS 410 (MH+, 100%);
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C@H:8]2[CH2:9][C@@H:3]1[CH2:4][CH2:5][C:6]2=[O:7].S([O-])(OCCCCCCCCCCCC)(=O)=O.[Na+].[F:29][B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2.F[B-](F)(F)F>O>[F:29][C@@H:5]1[CH2:4][C@H:3]2[CH2:9][C@H:8]([C:2]2([CH3:10])[CH3:1])[C:6]1=[O:7]
Reactant: CC1(C)[C@H]2CCC(=O)[C@@H]1C2
Reactant: F[B-](F)(F)F
Agent: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: [Na+]
Solvent: O
Product: CC1(C)[C@H]2C[C@@H](F)C(=O)[C@@H]1C2
Temperature: 80 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
To a solution of (+)-nopinone (Aldrich, 1.0 g, 7.2 mmol) in water (35 mL), was added sodium dodecyl sulfate (Aldrich, 2.1 g, 7.2 mmol). The mixture was heated to 80° C. and then 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane tetrafluoroborate (Alfa-aesar, 2.8 g, 8.0 mmol) was added in two portions with one hour interval and stirred at 80° C. overnight. The reaction mixture was cooled and extracted with diethyl ether (3×30 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-20% of ethyl acetate in hexanes) to obtain 0.4 g of the title compound. MS (DCI/NH3) m/z 174 (M+NH4)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7]([C:13]([CH3:17])([CH3:16])[CH:14]=[O:15])=[CH:6][C:5]2=[O:18].I[CH2:20][CH2:21][CH2:22][CH3:23]>CC#N.[Ag]>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7]([C:13]([CH3:16])([CH3:17])[CH:14]=[O:15])=[CH:6][C:5]2=[O:18])[CH2:21][CH2:22][CH3:23]
Reactant: CC(C)(C=O)C1=CC(=O)c2cc(O)ccc2C1=O
Reactant: CCCCI
Agent: [Ag]
Solvent: CC#N
Product: CCCCOc1ccc2c(c1)C(=O)C=C(C(C)(C)C=O)C2=O
Temperature: 25 °C

Procedure:
A mixture of 2-(6-Hydroxy-1,4-dioxo-1,4-dihydro-2-naphthalenyl)-2-methylpropanal (compound 3 prepared in step II above) (125 mg, 0.52 mmol) and freshly prepared Ag2O (240 mg, 1.04 mmol) in CH3CN was ultrasonicated for 2 min to disperse the silver salt. Iodobutane (120 μL, 1.05 mmol) was added and the mixture was stirred over night at room temperature. The mixture was filtered on Celite and was washed with EtOAc. The crude product was purified on silica gel with hexane:EtOAc 4:1 but failed to yield pure material. The product was further purified on RP-HPLC. Yield: 53 mg (34%). 1H NMR (400 MHz, CDCl3) δ 0.99 (tr., 3H), 1.40 (s, 6 H), 1.52 (sext., 2 H), 1.82 (quint., 2 H), 4.11 (tr., 2H), 6.87 (s, 1 H), 7.18 (dd, 1 H), 7.48 (d, 1 H), 8.00 (dd, 1 H), 9.72 (s, 1 H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[N+:18]([C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]([CH2:31][CH2:32]Br)[CH2:26][CH2:25][CH2:24]2)([O-:20])=[O:19]>>[N+:18]([C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]([CH2:31][CH2:32][N:15]1[CH2:14][CH2:13][CH:12]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=3)[CH2:17][CH2:16]1)[CH2:26][CH2:25][CH2:24]2)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc2c(c1)CCCC2CCBr
Reactant: COc1ccc(C2CCNCC2)cc1OC
Agent: Cl
Product: COc1ccc(C2CCN(CCC3CCCc4cc([N+](=O)[O-])ccc43)CC2)cc1OC

Procedure:
Analogously to Example 5, reaction of 4-(3,4-dimethoxyphenyl)piperidine hydrochloride with 2-(6-nitrotetralin-1-yl)ethyl bromide gives 1-(2-(6-nitrotetralin-1-yl)ethyl)-4-(3,4-dimethoxyphenyl)piperidine.
Reaction SMILES: [CH2:1]([N:8]([CH2:15][Si](C)(C)C)[CH2:9]OCCCC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O:24][C:25]([NH:27][C:28]1([C:31]#[C:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:30][CH2:29]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([N:8]1[CH2:9][C:31]([C:28]2([NH:27][C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[CH2:30][CH2:29]2)=[C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:15]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C#CC1(NC(=O)OC(C)(C)C)CC1
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1=C(C2(NC(=O)OC(C)(C)C)CC2)CN(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
N-Benzyl-N-(n-butoxymethyl)trimethylsilylmethylamine (2.006 g, 7.176 mmol) and ethyl 3-(1-tert-butoxycarbonylaminocyclopropyl)propiolate (1.136 g, 4.485 mmol) were dissolved in dry dichloromethane (9 ml). While stirring at room temperature, a 1.0 M solution of trifluoroacetic acid in dichloromethane (0.72 ml, 0.72 mmol) was added thereto and the liquid reaction mixture was stirred for 3 hours. Then a saturated aqueous solution of sodium bicarbonate (20 ml) was added to the liquid reaction mixture followed by extraction with dichloromethane (20 ml×3). The combined organic layer was washed with a saturated aqueous solution of sodium chloride (30 ml) and dried over anhydrous magnesium sulfate. After filtering, the filtrate was concentrated under reduced pressure and the residue was subjected to flash silica gel column chromatography (eluent: chloroform) to obtain 1.449 g (83.6%) of the title compound as a colorless oily substance.
Reaction SMILES: [Al](OS(C(F)(F)F)(=O)=O)(OS(C(F)(F)F)(=O)=O)OS(C(F)(F)F)(=O)=O.[NH2:26][CH2:27][C:28]1[CH:29]=[C:30]([CH:36]=[CH:37][CH:38]=1)[N:31]([CH2:34][CH3:35])[CH2:32][CH3:33].[O:39]1[CH2:41][C@@H:40]1[C@@H:42]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CCOC(C)=O.O>[CH2:34]([N:31]([CH2:32][CH3:33])[C:30]1[CH:29]=[C:28]([CH:38]=[CH:37][CH:36]=1)[CH2:27][NH:26][CH2:41][C@@H:40]([OH:39])[C@@H:42]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:55])([CH3:54])[CH3:56])[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH3:35]
Reactant: CCN(CC)c1cccc(CN)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Agent: O=S(=O)(O[Al](OS(=O)(=O)C(F)(F)F)OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Product: CCN(CC)c1cccc(CNC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)c1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 21.7 %

Procedure:
Al(OTf)3 (0.0168 g, 0.036 mmol, 5 mol %) was added to a flask charged with 3-(aminomethyl)-N,N-diethylaniline (0.19 g, 1.07 mmol, 1.5 eq) under Ar. After stirring for 10 min tert-butyl (S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamate (0.187 g, 0.71 mmol, 1 eq) was added and the mixture was heated to 70° C. for 1 h. After cooling to room temperature the residue was dissolved in EtOAc with a few drops of water. After 20 min of vigorous stirring the mixture was filtered through cotton and dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo. Purification via flash chromatography yielded 0.0682 g (0.154 mmol, 22% yield) of the product.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[H-].[Na+].[Br:9][C:10]1[CH:11]=[N:12][C:13](Cl)=[N:14][CH:15]=1>O1CCCC1.[Cl-].[NH4+]>[Br:9][C:10]1[CH:11]=[N:12][C:13]([O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[N:14][CH:15]=1
Reactant: CN(C)CCO
Reactant: Clc1ncc(Br)cn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C)CCOc1ncc(Br)cn1
Reaction time: 0.08 h

Procedure:
2-Dimethylaminoethanol (0.113 mL, 1.113 mmol) was suspended in anhydrous tetrahydrofuran (10 mL). Sodium hydride (60% in mineral oil, 0.134 g, 3.334 mmol) was added and the mixture was stirred for 5 minutes. 5-Bromo-2-chloropyrimidine (0.2 g, 1.03 mmol) was added and the mixture was stirred for 2 hours. The reaction mixture was diluted with 10% aqueous ammonium chloride and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. LCMS method: 1, RT: 0.63 min, MI: 246-248 [M+1].
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C:5](=[O:25])[CH2:6][C:7]([CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)(O)[CH2:8][CH2:9][C:10]#[C:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1.COC(=O)CC(=O)CC(C1CCCC1)(O)CCC#CC1C=C(C)C(O)=CC=1C>>[CH:20]1([C:7]2([CH2:8][CH2:9][C:10]#[C:11][C:12]3[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=3)[O:26][C:3](=[O:2])[CH2:4][C:5](=[O:25])[CH2:6]2)[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: COC(=O)CC(=O)CC(O)(CCC#Cc1ccc(C)cc1)C1CCCC1
Agent: COC(=O)CC(=O)CC(O)(CCC#Cc1cc(C)c(O)cc1C)C1CCCC1
Product: Cc1ccc(C#CCCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1

Procedure:
The desired product was prepared analogously to example F(1), substituting 5-cyclopentyl-5-hydroxy-3-oxo-9-p-tolyl-non-8-ynoic acid methyl ester (400 mg, 1.1 mmol) from Step 2 below in place of 5-cyclopentyl-5-hydroxy-9-(4-hydroxy-2,5-dimethyl-phenyl)-3-oxo-non-8-ynoic acid methyl ester. Yield: 180 mg, 50%.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][C:12]([CH2:16][N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)([OH:15])[CH2:11][CH2:10]2)[CH:6]=[CH:5][N:4]=1.[F:23][C:24]1[CH:35]=[CH:34][C:27]([C:28](S(Cl)(=O)=O)=[O:29])=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:35]=[CH:34][C:27]([C:28]([N:20]2[CH2:21][CH2:22][N:17]([CH2:16][C:12]3([OH:15])[CH2:11][CH2:10][N:9]([C:7]4[CH:6]=[CH:5][N:4]=[C:3]([CH3:2])[N:8]=4)[CH2:14][CH2:13]3)[CH2:18][CH2:19]2)=[O:29])=[CH:26][CH:25]=1
Reactant: O=C(c1ccc(F)cc1)S(=O)(=O)Cl
Reactant: Cc1nccc(N2CCC(O)(CN3CCNCC3)CC2)n1
Agent: Cl
Product: Cc1nccc(N2CCC(O)(CN3CCN(C(=O)c4ccc(F)cc4)CC3)CC2)n1

Procedure:
Using an analogous procedure to that described in Example 14, 1-(2-methylpyrimidin-4-yl)-4-(1-piperazinomethyl)piperidin-4-ol hydrochloride was reacted with 4-fluorobenzoylsulphonyl chloride to give 1-(4-fluorobenzoyl)-4-[1-(2-methylpyrimidin-4-yl]-4-hydroxy-4-piperidylmethyl]piperazine m.p. 114-117° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:18][CH:19]([OH:21])[CH3:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:21][CH:19]([CH3:20])[CH3:18])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: CC(C)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)Oc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
A mixture of 1.0 g of 4-chloro-2-fluoronitrobenzene and 9.3 g of caesium carbonate in 10 ml of 2-propanol is heated at 60° C. for 24 h. The mixture is then concentrated and the residue is taken up with 100 ml of a mixture of water and ethyl acetate. The aqueous phase is extracted three times with 50 ml of ethyl acetate. The combined organic phases are washed with 50 ml of a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. The residue is purified on 90 g of silica, elution being carried out with 95/5 heptane/ethyl acetate, so as to obtain 885 mg of 4-chloro-1-nitro-2-(propan-2-yloxy)benzene in the form of a yellow solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH3:7])=[O:3].[NH2:8][C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=1)[NH:12][C:13](=[O:19])/[CH:14]=[C:15](\[O:17][CH3:18])/[CH3:16].O1CCCC1>C(N(CC)CC)C>[CH2:5]([O:4][C:2]([NH:8][C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=1)[NH:12][C:13](=[O:19])/[CH:14]=[C:15](\[O:17][CH3:18])/[CH3:16])=[O:3])[CH2:6][CH3:7]
Reactant: CO/C(C)=C\C(=O)Nc1cccc(N)c1
Reactant: CCCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCOC(=O)Nc1cccc(NC(=O)/C=C(/C)OC)c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 68.5 %

Procedure:
27 g of propyl chloroformate were slowly added to a mixture of 41.2 g of m-amino-3-methoxy-crotonanilide, 300 ml of tetrahydrofuran and 22.2 g of triethylamine and the mixture was stirred for 16 hours at 20° C. The mixture was filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8- 2 methylene chloride-acetone mixture to obtain 40 g of m-(n-propyloxycarbonylamino)-3-methoxy-crotonanilide melting at 115° C. Crystallization from chloroform did not change the melting point.
Reaction SMILES: CCOCC.C(C(C)=O)C.[CH3:11][C:12](O)([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[CH2:13][CH3:14]>O>[CH3:11][CH:12]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[CH:13]=[CH2:14]
Reactant: CCC(C)(O)Cc1ccc(C)cc1
Solvent: CCOCC
Solvent: O
Solvent: CCC(C)=O
Product: C=CC(C)Cc1ccc(C)cc1

Procedure:
was obtained from 0.77 mol of metallic magnesium and 0.59 mol of p-methyl benzyl chloride. To this was added 0.6 mol of an ether solution of methyl ethyl ketone. After thorough reaction, a large excess of water was added to hydrolyze the reaction product. The resulting 3-methyl-4-(p-tolyl)-3-butanol was passed through a reaction tube packed with active alumina at 200° to 300°C. to afford the desired 3-methyl-4-(p-tolyl) butene almost quantitatively.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>>[C:21]([O:20][C:18]([CH2:17][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)COc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
Prepared analogously to Example 13 from 4-cyano-4'-hydroxy-biphenyl and tert.butyl bromoacetate.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([NH:10][C:11]([CH:13]2[CH:17]([CH3:18])[CH2:16][N:15]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:14]2)=O)[CH:7]=[N:8][CH:9]=1)=O.[OH-].[NH4+:27]>CO>[CH2:19]([N:15]1[CH2:16][CH:17]([CH3:18])[CH:13]([C:11]2[NH:27][C:3](=[O:2])[C:5]3=[CH:9][N:8]=[CH:7][N:6]3[N:10]=2)[CH2:14]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cncn1NC(=O)C1CN(Cc2ccccc2)CC1C
Agent: [OH-]
Solvent: CO
Product: CC1CN(Cc2ccccc2)CC1c1nn2cncc2c(=O)[nH]1
Temperature: 130 °C
Reaction time: 48 h
Yield: 40.6 %

Procedure:
To a 300 mL sealed tube was added a mixture of compound 4 (4.7 g, 13.7 mmol), NH4OAc (11 g, 14.3 mmol) and ammonium hydroxide (50 mL) in MeOH (120 mL). The reaction mixture was stirred at 130° C. for 2 days. After cooling down, the reaction mixture was concentrated in vacuo. The residue was diluted with CH2Cl2 (100 mL) and washed with water (50 mL×2). The organic phase was separated and dried over Na2SO4. After filtering, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluted with DCM/MeOH=50:1 to 30:1) to afford compound 5 (1.8 g, 40.6% yield) as a white solid. LC-MS: m/z 310.17 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 8.02 (s, 1H), 7.85 (s, 1H), 7.39˜7.28 (m, 5H), 3.82 (d, J=12.4 Hz, 1H), 3.58 (d, J=12.4 Hz, 1H), 3.41˜3.37 (m, 1H), 2.99 (d, J=6.4 Hz, 1H), 2.72˜2.70 (m, 1H), 2.54˜2.50 (m, 1H), 2.44˜2.40 (m, 1H), 1.95˜1.91 (m, 1H), 1.20 (d, J=6.4 Hz, 3H).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].C1(C([O-])=O)C2C(=CC=CC=2)C=CC=1.[K+].[Br:28][CH2:29][CH2:30]Br>C(O)C>[Br:28][CH2:29][CH2:30][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: BrCCBr
Reactant: Oc1cccc2ccccc12
Agent: O=C([O-])c1cccc2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: BrCCOc1cccc2ccccc12
Yield: 50.2 %

Procedure:
A solution of 144.0 g (1 mole) α-naphthol and 56.1 g (1 mole) potassium hydroxide in 600 ml of 95% ethanol was stirred 1.5 hr at room temperature. To this solution of potassium naphthalate was added 930.0 g (5.0 mole) of 1,2-dibromoethane, and the solution was heated at reflux overnight. The reaction mixture was filtered, and the filtrate stripped to dryness under reduced pressure in a rotary evaporator. The resulting oil was dissolved in chloroform and the solution extracted with 10% aqueous sodium hydroxide. The chloroform layer was dried and stripped of chloroform to yield 126 g (50.3%) of dark brown oil.