Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([O-])=O.[K+].[Cl:6][C:7]1[C:12]([NH:13][C:14]([C:16]2[C:17]([NH:22][CH2:23][CH3:24])=[N:18][CH:19]=[CH:20][CH:21]=2)=[O:15])=[C:11]([CH3:25])[CH:10]=[C:9]([Cl:26])[N:8]=1.[Br:27]Br.O>CC(O)=O>[Br:27][C:20]1[CH:21]=[C:16]([C:14]([NH:13][C:12]2[C:7]([Cl:6])=[N:8][C:9]([Cl:26])=[CH:10][C:11]=2[CH3:25])=[O:15])[C:17]([NH:22][CH2:23][CH3:24])=[N:18][CH:19]=1
Reactant: BrBr
Reactant: CCNc1ncccc1C(=O)Nc1c(C)cc(Cl)nc1Cl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CCNc1ncc(Br)cc1C(=O)Nc1c(C)cc(Cl)nc1Cl
Reaction time: 0.5 h

Procedure:
Solid KOAc (22.2 g, 229 mmol) was added to a solution of crude N-(2,6-dichloro-4methyl-3-pyridinyl)-2-(ethylamino)-3-pyridinecarboxamide (61.98 g, <190 mmol) in AcOH (600 mL). A solution of Br2 (9.7 mL, 191 mmol) was then added over 30 min. After stirring 30 min, additional amounts of KOAc and Br2 were introduced until TLC indicated that no starting material remained (a total of 11.2 g of KOAc and 5.91 mL of Br2). The solution was then poured into water (2 L) and stirred for 20 min. The solid was removed by filtration and then dissolved in Et2O (1 L). The ethereal solution was washed with water (3×), aqueous saturated NaHCO3, brine then dried (MgSO4) to give a mixture containing, as the major component, the title compound (77.7 g, yellow foam). The material was used directly in the subsequent reaction.
Reaction SMILES: [C:1](=[NH:23])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)=[CH:8][CH:7]=1)[NH2:2].[CH:24]([CH:26]([CH2:31][C:32]1[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=1)[C:27](OC)=O)=[O:25].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[CH3:37][N:35]1[CH:36]=[C:32]([CH2:31][C:26]2[C:24](=[O:25])[N:23]=[C:1]([O:3][CH2:4][CH2:5][C:6]3[CH:7]=[CH:8][C:9]([O:12][C:13]4[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=4)=[CH:10][CH:11]=3)[NH:2][CH:27]=2)[CH:33]=[N:34]1
Reactant: COC(=O)C(C=O)Cc1cnn(C)c1
Reactant: N=C(N)OCCc1ccc(Oc2ccc(C(F)(F)F)nc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cn1cc(Cc2c[nH]c(OCCc3ccc(Oc4ccc(C(F)(F)F)nc4)cc3)nc2=O)cn1
Temperature: 130 °C
Yield: 24.6 %

Procedure:
To the solution of 2-(4-{[6-(trifluoromethyl)-3-pyridinyl]oxy}phenyl)ethyl imidocarbamate (200 mg, 0.456 mmol) and methyl 2-formyl-3-(1-methyl-1H-pyrazol-4-yl)propanoate (107 mg, 0.548 mmol) in NMP (3 mL) was added K2CO3 (252 mg, 1.825 mmol). The mixture was heated with a microwave reactor at 130° C. for 0.5 h. Purification via MDAP then afforded the title compound (53 mg, 0.112 mmol, 24.64% yield). LCMS: rt=2.92 min, [M+H+]=472
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH3:18].Br[C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=1>>[Br:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([C:20]2[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1Br
Reactant: Cc1cccnc1Br
Product: Cc1cccnc1-c1cc(C)c(Br)c(C)c1

Procedure:
The title compound is prepared from 2-bromo-1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene and 2-bromo-3-methyl-pyridine following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 7): tR=0.88 min; Mass spectrum (ESI+): m/z=276/278 (Br) [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]=1[OH:13])([O-:3])=[O:2].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C.[NH:47]1[CH2:51][CH2:50][C@@H:49]([OH:52])[CH2:48]1>ClCCl>[OH:13][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([N:47]1[CH2:51][CH2:50][C@@H:49]([OH:52])[CH2:48]1)=[O:9]
Reactant: O[C@@H]1CCNC1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1cccc([N+](=O)[O-])c1O)N1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 757.2 %

Procedure:
A mixture of 4.86 g (26 mmol, 1 eq) of 3-nitrosalicylic acid and 12.16 g (26 mmol, 1 eq) of bromotripyrrolidinophosphonium hexafluorophosphate in 65 ml of dichloromethane and in the presence of 13.7 ml (78 mmol, 3 eq) of N,N-diisopropylethylamine was stirred at ambient temperature for 30 minutes. 4.52 g (4.10 mmol, 2 eq) of (R)-(+)-3-pyrrolidinol in solution in 10 ml of dichloromethane were added dropwise and the reaction medium was stirred at ambient temperature overnight. The reaction medium was extracted with a 1 N sodium hydroxide solution and separated by settling out. The aqueous phase was acidified with a 1N hydrochloric acid solution and extracted with ethyl acetate (5×150 ml). The organic phases were combined, dried over magnesium sulfate, filtered and evaporated. 7.83 g of (2-hydroxy-3-nitrophenyl)-((R)-3-hydroxypyrrolidin-1-yl)methanone were obtained in the form of a golden yellow amorphous solid. Crude yield>100%. HPLC: 93% [252].
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1.C1(C)C(S(O)(=O)=O)=CC=CC=1>C(Cl)Cl.CC1C=CC(S(O)(=O)=O)=CC=1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][O:9]2)=[CH:4][CH:3]=1
Reactant: C1=COCCC1
Reactant: Oc1ccc(I)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: ClCCl
Product: Ic1ccc(OC2CCCCO2)cc1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 92.1 %

Procedure:
To a stirred solution of 4-iodophenol (11.0 g, 50 mmol) in CH2Cl2 (50 ml) cooled with an ice bath, dihydropyran (5.0 g, 60 mmol) was added dropwise over 10 min at 0–5° C. After the solution became clear, toluenesulfonic acid, TsOH, (10 mg) was added. The solution was stirred at 20° C. for 15 min. Then it was quenched by addition of NaHCO3 (1 g) and 3 drops of water, and after stirring for 5 min at 20° C., the solvent was removed in vacuo and the residue was purified by column chromatography on silica gel with petroleum ether as eluent to give 14.0 g (92%) of 1 as colorless crystal; mp 66° C.; δH(CDCl3; 300 MHz): 7.55(d, J=8.3, 2H, Ar—H), 6.83(d, J=8.4, 2H, Ar—H), 5.37(t, J=3.1, 1H, OCHO), 3.86(m, 1H, THP), 3.59(m, 1H, THP), 1.87˜1.58(m, 6H, THP).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Li+].CC([N-]C(C)C)C.[C:21]([O:25]C(C)=O)(C)(C)[CH3:22].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2([C:41]3[CH:42]=[C:43]([C:49]([C:51]4[CH:56]=[CH:55][CH:54]=[C:53]([O:57][CH3:58])[CH:52]=4)=O)[C:44]([NH:47][CH3:48])=[N:45][CH:46]=3)[O:40][CH2:39][CH2:38][O:37]2)=[CH:32][CH:31]=1>C1COCC1>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2([C:41]3[CH:42]=[C:43]4[C:44](=[N:45][CH:46]=3)[N:47]([CH3:48])[C:21](=[O:25])[CH:22]=[C:49]4[C:51]3[CH:56]=[CH:55][CH:54]=[C:53]([O:57][CH3:58])[CH:52]=3)[O:40][CH2:39][CH2:38][O:37]2)=[CH:32][CH:31]=1
Reactant: CC(=O)OC(C)(C)C
Reactant: CNc1ncc(C2(c3ccc(Cl)cc3)OCCO2)cc1C(=O)c1cccc(OC)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1cccc(-c2cc(=O)n(C)c3ncc(C4(c5ccc(Cl)cc5)OCCO4)cc23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
To a solution of diisopropylamine (1.32 mL, 9.43 mmol) in THF, a solution of BuLi (7.86 mL, 7.08 mmol, 0.9 M solution in hexane) was added at −20° C. and the resulting mixture was stirred for 30 min. To this solution of LDA was added tBuOAc (0.95 mL, 7.08 mmol) at −78° C. The mixture was stirred for 30 min and a solution compound G (500 mg, 1.18 mmol) was added to it. The reaction mixture was allowed to warm to RT and stirred overnight. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with EtOAc (50 mL). The organic layer was dried (Na2SO4), filtered and evaporated. The crude product was purified by column chromatography to obtain 0.3 g (57%) of compound H off-white solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[C:6]=1[NH2:12])([CH3:3])[CH3:2].CO[C:15]1C(OC)=C[C:18]2[NH:19][C:20](CCCNC)=N[C:17]=2[CH:16]=1>>[CH:1]([O:4][C:5]1[C:6]2[N:12]=[C:15]([CH2:16][CH2:17][CH2:18][NH:19][CH3:20])[NH:11][C:7]=2[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cccc(N)c1N
Reactant: CNCCCc1nc2cc(OC)c(OC)cc2[nH]1
Product: CNCCCc1nc2c(OC(C)C)cccc2[nH]1

Procedure:
Prepared from 3-isopropoxy-benzene-1,2-diamine in analogy to the methods described for [3-(5,6-dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amine.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>O>[CH3:18][N:17]([CH3:19])[CH:16]=[C:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:12])[F:13])=[CH:8][CH:7]=1)[C:10]#[N:11]
Reactant: COC(OC)N(C)C
Reactant: N#CCc1ccc(C(F)(F)F)cc1
Solvent: O
Product: CN(C)C=C(C#N)c1ccc(C(F)(F)F)cc1

Procedure:
4-(Trifluoromethyl)phenylacetonitrile (6.0 g.) in 5 ml. dimethylformamide-dimethylacetal was refluxed for 2 hours. Water was added and the final product was filtered, dried, and identified by NMR analysis.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH2:14]([C:16]1[O:20][C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)=[N:18][C:17]=1[CH2:32][CH2:33]O)[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C(Cl)Cl>[CH2:14]([C:16]1[O:20][C:19]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]([F:30])([F:31])[F:29])=[CH:25][CH:26]=2)=[N:18][C:17]=1[CH2:32][CH2:33][O:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8])[CH3:15]
Reactant: CCc1oc(-c2ccc(OC(F)(F)F)cc2)nc1CCO
Reactant: COC(=O)Cc1ccc(C)c(O)c1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCc1oc(-c2ccc(OC(F)(F)F)cc2)nc1CCOc1cc(CC(=O)OC)ccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
Under atmosphere of argon, a solution of methyl (3-hydroxy-4-methylphenyl)acetate (1.00 g) in methylene chloride (22 mL) was added by 2-{5-ethyl-2-[4-(trifluoromethoxy)phenyl]-1,3-oxazol-4-yl}ethanol (2.00 g), triphenylphosphine (2.18 g) and 1,1′-(azodicarbonyl)dipiperidine (2.10 g) and stirred overnight at room temperature. The reaction mixture was concentrated and the obtained residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1) to give the title compound (2.38 g) having the following physical data.
Reaction SMILES: [C:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][S:7](Cl)(=[O:9])=[O:8])([O:3][CH3:4])=[O:2].[CH2:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+]>ClCCl>[CH2:11]([CH:5]([CH2:6][S:7]([N:28]1[CH2:29][CH2:30][N:25]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:26][CH2:27]1)(=[O:9])=[O:8])[C:1]([O:3][CH3:4])=[O:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: COC(=O)C(Cc1ccccc1)CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)C(Cc1ccccc1)CS(=O)(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To a 3 L round bottom flask was added the resultant compound from Example 1E (370.5 g, 1.34 mol) and dichloromethane (2 L). The mixture was cooled to 0° C. in an ice water bath and a solution of N-benzyl piperazine (295.8 g, 1.68 mol) was added dropwise with vigorous stirring over 2 h. After the addition was completed, the mixture was stirred an additional 4 h while at 0° C. The solution was then poured into a separatory funnel containing 2 L of a 5% aqueous NaOH solution. The layers were partitioned and the organic layer was dried over potassium carbonate. Concentration in vacuo yielded an oil, which was filtered through 1 kg of silica gel using 3:2 hexane/ethyl acetate as an eluant. Concentration gave 467 g (84%) Of the desired product: 1H NMR (CDCl3) δ7.37-7.12 (m, 10H) , 3.66 (s, 3H) , 3.51 (s, 2H) , 3.42 (dd, 1H) , 3.29-3.13 (m, 5H) , 3.06 (dd, 1H) , 2.96-2.84 (m, 2H) , 2.50-2.42 (m, 4H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:30]([NH:29][C:26]3[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)=[O:31])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: COc1ccc(N=C=O)cc1
Product: COc1ccc(NC(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1

Procedure:
1-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-3-(4-methoxy-phenyl)-urea was prepared starting from intermediate D and 4-(methoxy)-phenylisocyanate. MS calcd. for C24H21ClN3O3 [(M+H)+] 434.1, obsd. 434.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[Cl:13].[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23]>C1COCC1>[Cl:13][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:22]([NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH3:14])=[O:23]
Reactant: Cc1ccccc1N=C=O
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(Cl)c1
Reaction time: 24 h
Yield: 73.8 %

Procedure:
To a mixture of methyl 4-amino-3-chlorophenylacetate (1.00 g, 5.01 mmol) and 2-methylphenyl isocyanate (0.60 ml, 5.01 mmol) in THF (20 ml) was added Et3 N (0.14 ml, 1.00 mmol) at room temperature. After 1 day stirring, 2-methylphenyl isocyanate (0.60 ml, 5.01 mmol) was added to the reaction mixture and stirred 17 h. The reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give methyl 3-chloro-4-[N′-(2-methylphenyl) ureido]phenylacetate (1.23 g, 74%) as a colorless powder. 1H-NMR (CDCl3) δ 2.34 (s, 3H), 3.54 (s, 2H), 3.68 (s, 3H), 6.24 (br, 1H1), 6.99 (br, 1H), 7.15 (dd, J=8.3, 2.0 Hz, 1H), 7.21–7.31 (m, 5H), 7.44 (d, J=7.6 Hz, 1H), 8.20 (d, J=8.5 Hz, 1H); MS (ESI) m/z 333 (M++1), 335 (M++3).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[CH:39]=[C:38]([CH3:40])[C:37]([S:41](Cl)(=[O:43])=[O:42])=[C:36]([CH3:45])[C:35]=1[CH3:46]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:41]([C:37]4[C:38]([CH3:40])=[CH:39][C:34]([O:33][CH3:32])=[C:35]([CH3:46])[C:36]=4[CH3:45])(=[O:43])=[O:42])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1C
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4c(C)cc(OC)c(C)c4C)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 4-methoxy-2,3,6-trimethyl-benzenesulfonyl chloride. Purity (ELSD, based on MW=633.7)=80%.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8])(=[O:3])[CH3:2].Br[CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:36]=[CH:35][C:28]2[C:29](=[O:34])[CH:30]=[C:31]([CH3:33])[O:32][C:27]=2[CH:26]=1.C(N(CC)CC)C>O1CCCC1>[C:1]([O:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:36]=[CH:35][C:28]3[C:29](=[O:34])[CH:30]=[C:31]([CH3:33])[O:32][C:27]=3[CH:26]=2)[CH2:12][CH2:11]1)=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C(=O)NC1CCNCC1
Reactant: Cc1cc(=O)c2ccc(OCCCBr)cc2o1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccccc1C(=O)NC1CCN(CCCOc2ccc3c(=O)cc(C)oc3c2)CC1

Procedure:
A mixture of 4.9 g. (0.02 mol) 4-(2-acetoxybenzamido)-piperidine, 5.6 g. (0.02 mol) 7-(3-bromopropoxy)-2-methyl-4H-1-benzopyran-4-one, 13.9 ml. (0.10 mol) triethylamine and 100 ml. tetrahydrofuran is heated under reflux for 10 hours and then evaporated. The 7-{3-[4-(2-acetoxybenzamido)-piperidino]-propoxy}-2-methyl-4H-1-benzopyran-4-one obtained as a crude product is mixed with 100 ml. 1 N aqueous sodium hydroxide solution, stirred for 1 hour, filtered, washed with ethyl acetate and the aqueous phase then neutralised. The precipitate obtained is taken up in acetone, mixed with excess ethereal hydrochloric acid and the dihydrochloride of the desired end product isolated; m.p. 169°-170° C. The yield is 4.6 g. (45% of theory).
Reaction SMILES: [Na].[CH2:2]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[CH2:22][CH2:21][CH:20]([C:23]([O:25][CH3:26])=[O:24])[CH2:19]2)=[CH:13][CH:12]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:34])C=CC=CC=1>C1COCC1>[CH3:26][O:25][C:23]([C:20]1([OH:34])[CH2:21][CH2:22][N:18]([CH2:17][C:14]2[CH:13]=[CH:12][C:11]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:16][CH:15]=2)[CH2:19]1)=[O:24]
Reactant: CCCCCCCCCc1ccc(CN2CCC(C(=O)OC)C2)cc1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: [Na]
Solvent: C1CCOC1
Product: CCCCCCCCCc1ccc(CN2CCC(O)(C(=O)OC)C2)cc1
Temperature: -72 °C
Reaction time: 0.33 h
Yield: 6.9 %

Procedure:
To a solution of 0.52 mL (0.52 mmol) of 1.0M sodium hexamethylsilazide in THF at −78° C. was added 153 mg (0.44 mmol) of (R/S)-1-(4-nonylphenyl)methyl-pyrrolidin-3-yl carboxylic acid, methyl ester (from EXAMPLE 34, Step C) in 1 mL of THF while maintaining the internal temperature at less −72° C. After 20 min, 172 mg (0.65 mmol) of 2-(phenylsulfonyl)-3-phenyloxaziridine (Davis Reagent) in 1 mL of THF was added while maintaining the internal temperature at less −69° C. After stirring for 1.25 h at −78° C., the reaction was quenched with 1N NaHCO3 and warmed to rt. After removing volatiles under reduced pressure, the reaction mixture was diluted with 50 mL of 1N NaHCO3 and 50 mL of sat'd NaCl. The aqueous phase was extracted with 3×50 mL of CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by flash chromatography using 4:1 v/v hexane/EtOAc and 4:1 v/v hexane/acetone as the gradient to afford 11 mg (7%) of the title compound as a colorless film: RF: 0.39 (4:1 v/v hexane/acetone); 1H-NMR (500 MHz) δ 0.90 (t, J=6.8, 3H), 1.28-1.33 (m, 12H), 1.59-1.64 (m, 2H), 2.02 (m, 1H), 2.42 (m, 1H), 2.60 (t, J=7.8, 2H), 2.67 (m, 1H), 2.86 (ABq, J=10.1, 2H), 2.97 (m, 1H), 3.69 (s, 2H), 3.82 (s, 3H), 7.14 (d, J=7.9, 2H), 7.26 (d, J=7.9, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][C@@H:11]([OH:14])[CH2:12][OH:13])=[CH:7][CH:6]=1.[C:17]1(C)[CH:22]=CC(S([O-])(=O)=O)=C[CH:18]=1.[NH+]1C=CC=CC=1.COC(OC)(C)C>CN(C=O)C>[CH3:18][C:17]1([CH3:22])[O:14][C@H:11]([CH2:10][O:9][C:8]2[CH:15]=[CH:16][C:5]([CH2:4][CH2:3][CH2:2][OH:1])=[CH:6][CH:7]=2)[CH2:12][O:13]1
Reactant: OCCCc1ccc(OC[C@@H](O)CO)cc1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: COC(C)(C)OC
Product: CC1(C)OC[C@@H](COc2ccc(CCCO)cc2)O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To (S)-3-[4-(3-hydroxy-propyl)-phenoxy]-propane-1,2-diol (11.5 g, 50.9 mmol) in dry DMF (150 ml) is added pyridinium p-toluenesulfonate (1.28 g, 5 mmol) and 2,2-dimethoxypropane (31 ml, 250 mmol). The mixture is stirred at room temperature for 18 hours and then the solvent is removed in vacuo. The residue is dissolved in EtOAc (150 ml) and washed with water, saturated aqueous sodium hydrogen carbonate solution, brine, dried (MgSO4) and concentrated in vacuo. The residue is purified by chromatography on silica eluting with 1:4 EtOAc/iso-hexane to 1:1 EtOAc/iso-hexane to afford (3-[4-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-propan-1-ol as a colourless oil; 1H NMR (CDCl3): 1.25 (1H, br), 1.39 (3H, s), 1.43 (3H, s), 1.85 (2H, pent, J=6.9 Hz), 2.63 (2H, tr, J=6.9 Hz), 3.63 (2H, tr, J=6.9 Hz), 3.90 (2H, m), 4.02 (1H, m), 4.12 (1H, m), 4.50 (1H, pent, J=6.8 Hz), 6.82 (2H, d, J=7.4 Hz), 7.10 (2H, d, J=7.4 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Li]CCCC>>[C:16]1([CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][CH:5]=3)[CH2:9][CH2:10]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=Cc1ccccc1
Reactant: Cc1cccc(N2CCNCC2)c1
Agent: [Li]CCCC
Product: Cc1cccc(N2CCN(CCc3ccccc3)CC2)c1

Procedure:
According to GP, 2.22 mmol (=0.39 g) of 1-(3-methylphenyl)piperazine and 2.22 mmol (=0.23 g=0.25 ml) of styrene are reacted with 5 mol % (=0.111 mmol=70 μl) of n-BuLi solution. Column-chromatographic separation with ethyl acetate gives the product 4-(2-phenyl-1-ethyl)-1-(3-tolyl)piperazine as a light-brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH2:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[Br:17][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH2:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2C(N)=O)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: NC(=O)c1ccccc1-c1ccc(CBr)cc1
Reaction time: 20 h

Procedure:
A mixture of 4'-methylbiphenyl-2-carboxamide (2.1 g), N-bromo-succinimide (2.5 g) and azobisisobutyronitrate (AIBN; 82 mg) in benzene (20 ml) was stirred for 20 hours at 60° to 70° C. Resulting crystalline precipitates were collected by filtration, washed with isopropylether and suspended in water. The suspension was stirred for 30 minutes, and insoluble materials were collected by filtration and dried to give crude crystals. Recrystallization from ethyl acetate--methanol afforded colorless needles (1.6 g, 55%), m.p. 220°-221° C.(decomp.).
Reaction SMILES: [OH:1][CH:2]([CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][C@H:5]([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[OH-].[K+].Cl[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:30][CH2:29]1>C(O)CC>[CH3:14][C@@H:5]([NH:4][CH2:3][C@H:2]([OH:1])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][N:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:30][CH2:29]2)=[CH:9][CH:8]=1
Reactant: ClCCN1CCN(c2ccccc2)CC1
Reactant: C[C@H](Cc1ccc(O)cc1)NCC(O)COc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCCO
Product: C[C@H](Cc1ccc(OCCN2CCN(c3ccccc3)CC2)cc1)NC[C@H](O)COc1ccccc1
Temperature: 0 °C

Procedure:
A mixture of 0.5 g of p-[(R)-2-[[(RS)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenol, 185 mg of potassium hydroxide, 410 mg of 1-(2-chloroethyl)-4-phenyl-piperazine and 15 ml of n-propanol was heated to 60° for 2.5 hours. The reaction mixture was poured on to ice-water and extracted with ethyl acetate. After evaporation of the solvent and chromatography of the crude product on silica gel with chloroform/n-propanol/saturated ammonia (1000:10:1) there were obtained 340 mg of pure, amorphous (S)-1-[[(R)-α-methyl-p-[2-(4-phenyl-1-piperazinyl)ethoxy]phenethyl]amino]-3-phenoxy-2-propanol, [α]D20 =-19° (c=0.8 in methanol), ε222 =21890.
Reaction SMILES: Cl[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[Na+].[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([S:16]([O-:18])=[O:17])[CH:11]=1.CS(C)=O>O>[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([S:16]([C:2]2[CH:6]=[CH:5][S:4][C:3]=2[CH:7]=[O:8])(=[O:18])=[O:17])[CH:11]=1
Reactant: O=S([O-])c1cccnc1
Reactant: O=Cc1sccc1Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1sccc1S(=O)(=O)c1cccnc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 28.6 %

Procedure:
A mixture of 3-chlorothiophene-2-carbaldehyde (0.16 g), pyridine-3-sulfinic acid sodium salt (0.30 g) and dimethyl sulfoxide (2.0 mL) was heated at 80° C. for 3 hours and then at 90° C. for 3 hours. The mixture was diluted with water, extracted with ethyl acetate and the combined organic extract was dried over magnesium sulfate. The solvent was removed under reduced pressure to afford the title compound as a grey solid (0.079 g).