Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH:28][C:29]([CH:31]3[CH2:33][CH2:32]3)=[O:30])[CH2:19]2)[CH2:13][C:14](=[O:17])[NH:15][OH:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH3:34][C:35]([CH3:40])([CH3:39])[C:36](Cl)=[O:37]>C(#N)C>[CH3:34][C:35]([CH3:40])([CH3:39])[C:36]([O:16][NH:15][C:14]([CH2:13][C@@H:12]([N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[NH:28][C:29]([CH:31]2[CH2:33][CH2:32]2)=[O:30])[CH2:19]1)[C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)=[O:17])=[O:37]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOc1cc([C@@H](CC(=O)NO)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Solvent: CC#N
Product: CCOc1cc([C@@H](CC(=O)NOC(=O)C(C)(C)C)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reaction time: 24 h
Yield: 41.9 %

Procedure:
To a solution of (1R)-cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (180 mg, 0.4 mmol) in acetonitrile (2 mL) was added 2,2-dimethyl-propionyl chloride (0.064 mL, 0.5 mmol) at room temperature and kept for 24 hrs. The solution was extracted with ethyl acetate (15 mL) and sodium hydrogen carbonate (15 mL, sat). The organic layer was dried over MgSO4. Filtration and removal of solvent gave (1R)-cyclopropanecarboxylic acid {2-[2-(2,2-dimethyl-propionyloxycarbamoyl)-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (90 mg, 42% yield): mp, 146-148° C.; 1H NMR (DMSO-d6) δ 0.87-0.89 (m, 4H, 2CH2), 1.19 (s, 9H, 3CH3), 1.30 (t, J=7 Hz, 3H, CH3), 1.76-1.82 (m, 1H, CH), 3.04 (d, J=8 Hz, 2H, CH2), 3.73 (s, 3H, CH3), 3.97-4.05 (m, 2H, CH2), 4.19 (d, J=18 Hz, 1H, NCHH), 4.58 (d, J=18 Hz, 1H, NCHH), 5.66 (t, J=8 Hz, 1H, NCH), 6.87-6.94 (m, 3H, Ar), 7.19 (d, J=8 Hz, 1H, Ar), 7.50 (d, J=8 Hz, 1H, Ar), 8.23 (d, J=8 Hz, 1H, Ar), 10.55 (s, 1H, NH), 11.82 (s, 1H, NH); 13C NMR (DMSO-d6) δ 7.77, 14.69, 15.46, 26.71, 34.63, 37.63, 46.61, 51.03, 55.46, 63.78, 111.91, 112.07, 116.82, 117.32, 117.51, 119.24, 131.24, 132.76, 136.96, 142.24, 147.92, 148.55, 166.66, 168.00, 171.71, 175.41; Anal Calcd for C29H35N3O7: C, 64.79; H, 6.56; N, 7.82. Found: C, 64.91; H, 6.50; N, 7.84.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)([C:22]4[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=4)[OH:21])[CH:18]=3)[N:13]3[N:36]=[N:37][N:38]=[C:12]3[N:11]=2)[CH:7]=[CH:8][CH:9]=1.C(Cl)Cl>CO>[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)([C:22]4[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=4)[OH:21])[CH:18]=3)[N:13]3[N:36]=[N:37][N:38]=[C:12]3[NH:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc(C(O)(c2ccc3c(c2)c(-c2cccc(Cl)c2)nc2nnnn23)c2cncn2C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(C(O)(c2ccc3c(c2)C(c2cccc(Cl)c2)Nc2nnnn2-3)c2cncn2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
NaBH4 (0.003 mol) was added portionwise at room temperature to a mixture of intermediate 16 (0.003 mol) in methanol (15 ml). The mixture was stirred at room temperature for 2 hours and poured out into ice water. DCM was added. The mixture was extracted with DCM. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (1.3 g, 86%) was crystallized from 2-propanone/diethyl ether. The precipitate was filtered off and dried, yielding 1 g (67%) of 5-(3-chlorophenyl)-4,5-dihydro-α-(4-methoxyphenyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinazoline-7-methanol (intermediate 17), mp. 220° C.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[CH2:14]([N+:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])[CH3:15]>CO>[C:1]([O-:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=[O:7])=[CH:4][CH:3]=1.[CH2:14]([N+:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])[CH3:15].[CH2:14]([N+:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])[CH3:15]
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Agent: CC[N+](CC)(CC)CC
Agent: [OH-]
Solvent: CO
Product: O=C([O-])c1ccc(C(=O)[O-])cc1
Yield: 92 %

Procedure:
Terephthalic acid (2.5 g, 0.015 mol) was titrated with a 40% aqueous solution of tetraethylammonium hydroxide (11.3 mL). The solvent was evaporated to obtain a hard residue which was dissolved in methanol. The methanol was evaporated to obtain 5.8 g, 92% yield of salt. FIG. 43, FIG. 43A and FIG. 43B show a 1H NMR spectrum and FIG. 44 shows a 13C NMR spectrum of the salt in DMSO-d6.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1.[CH2:13]([O:15]CC)C>CN(C)C=O.CO>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([O:15][CH3:13])=[CH:3][C:4]=1[CH3:12]
Reactant: COC(=O)c1ccc(Br)cc1C
Reactant: CCOCC
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1ccc(OC)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 4-bromo-2-methylbenzoate (19.0 mmol) was dissolved in dimethylformamide (2.7 mL) and methanol (1.1 mL), and the solution was heated at 80° C. and then added with CuBr (1.09 mmol). After stirring was continued for 2 hours under heating, the mixture was cooled to room temperature. The mixture was added with diethyl ether (25 mL) and filtered. The filtrate was washed four times with water, an aqueous sodium bicarbonate solution, and then with saturated brine, and dried over sodium sulfated. The drying agent was removed by filtration and the filtrate was concentrated to give the title compound.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[CH:7]=[C:8]([C:14]#[N:15])[C:9]([C:12]#[N:13])=[CH:10][CH:11]=2)[CH2:3][CH2:2]1.Br[CH:17]([CH3:25])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>>[CH:1]1([CH2:4][N:5]([C:6]2[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[C:8]([C:14]#[N:15])[CH:7]=2)[C@H:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH3:25])[CH2:2][CH2:3]1
Reactant: N#Cc1ccc(NCC2CC2)cc1C#N
Reactant: CC(Br)C(=O)OC(C)(C)C
Product: C[C@@H](C(=O)OC(C)(C)C)N(CC1CC1)c1ccc(C#N)c(C#N)c1

Procedure:
Synthesized in a manner similar to example 1B using 4-[(cyclopropylmethyl)amino]-1,2-benzenedicarbonitrile and 1,1-dimethylethyl 2-bromopropanoate: MS (ES) m/z 326 (M+1).
Reaction SMILES: [I:1][C:2]1[C:3](O)=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:3]1[C:2]([I:1])=[CH:7][N:6]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:4]=1
Reactant: Oc1cc(C(F)(F)F)ncc1I
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1cc(Cl)c(I)cn1

Procedure:
A solution of 5-iodo-2-(trifluoromethyl)pyridin-4-ol (4.8 g, 16.6 mmol) in POCl3 (30 mL) was heated to 100° C. for 30 minutes. The resulting solution was concentrated under vacuum and the residue was neutralized by the addition of ice and aqueous potassium carbonate. The solution was extracted with ethyl acetate, dried (Na2SO4), filtered and concentrated under vacuum to give 4-chloro-5-iodo-2-(trifluoromethyl)pyridine. Retention time (min)=2.594, method [1], MS (ESI) 307.9 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([N+:14]([O-])=O)[CH:7]=1.C(O)(=O)C>ClCCl.[Zn]>[CH3:1][O:2][C:3](=[O:17])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([NH2:14])[CH:7]=1
Reactant: COC(=O)/C=C/c1ccc(OC)c([N+](=O)[O-])c1
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)/C=C/c1ccc(OC)c(N)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (E)-3-(4-methoxy-3-nitro-phenyl)-acrylic acid methyl ester (0.5 g) in dichloromethane (5 mL) was added zinc dust (2 g), followed by acetic acid (1 mL) and the resulting mixture was stirred at room temperature for 30 minutes. The solid was filtered off and washed with dichloromethane. The filtrate was evaporated under reduced pressure and the residue was purified by flash chromatography (DCM/acetone, 95/5) to give (E)-3-(3-amino-4-methoxy-phenyl)-acrylic acid methyl ester.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[Cl:25][C:26]1[CH:31]=[C:30]([NH2:32])[CH:29]=[CH:28][C:27]=1[CH3:33]>C(OCCO)C>[Cl:25][C:26]1[CH:31]=[C:30]([NH:32][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:29]=[CH:28][C:27]=1[CH3:33]
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Cc1ccc(N)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3ccc(C)c(Cl)c3)c2cc1OC
Yield: 99.2 %

Procedure:
Using an analogous procedure to that described in Example 367, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 10 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 170.0 mg (1.2 mmol) of 2-chloro-4-amino-toluene to give 350.9 mg (99.4%) of the product as a yellow solid, m.p.>250° C., mass (electrospray, m/e): M+H 353.9,355.8.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:26])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[O:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].O>N1C=CC=CC=1>[C:27]([O:26][C:8]1([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][C:17]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)=[O:18])[CH2:12][CH2:13]1)(=[O:29])[CH3:28]
Reactant: O=C(CCCN1CCC(O)(c2ccc(Cl)cc2)CC1)c1ccc(F)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OC1(c2ccc(Cl)cc2)CCN(CCCC(=O)c2ccc(F)cc2)CC1

Procedure:
4-(4-(4-Chlorophenyl)-4-hydroxy-1-piperidinyl)-1-(4-fluorophenyl)-1-butanone (20 g) and acetic acid anhydride (16 g) in 200 ml of dried pyridine (KOH pellets) were refluxed for 2 h. The mixture was poured into cold H2O (0° C.) (2 liters) and extracted with isopropylether (2×200 ml). The combined organic phases were dried (MgSO4) and the solvent evaporated. The title compound was obtained after column chromatography on silica gel (eluent, ethyl acetate/dichloromethane/methanol, 1:1:1). Yield 10.6 g (48%). Mp 106°-110° C. (from isopropyl ether). The hydrochloride salt was precipitated from acetone. Mp 215° C. According to TLC analysis the content of Haloperidol was 0.5%.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4](NN)[N:3]=1.C(O)(=O)C>S([O-])([O-])(=O)=O.[Cu+2].O>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1
Reactant: NNc1nc(F)c(F)cc1F
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)O
Solvent: O
Product: Fc1cnc(F)c(F)c1
Yield: 86.7 %

Procedure:
8.2 g of the compound obtained in Step 2 was added to a mixture of 320 ml of acetic acid and 120 ml of water, and 400 ml of 10% aqueous copper sulfate was added thereto. The resulting mixture was refluxed for 24 hours while removing water using a Dean-Stark trap, and the residue was dried to obtain 5.8 g (yield: 87.1%) of the title compound.
Reaction SMILES: [C:1]([Si:5]([CH3:21])([CH3:20])[O:6][CH2:7][C:8]1[S:9][C:10]([C:13]([O:15][Si](C)(C)C)=[CH2:14])=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C([O:25][C@@H:26]1[C@@H:29]([C@H:30]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH3:31])[C:28](=O)[NH:27]1)(=O)C>>[Si:33]([O:32][C@@H:30]([C@@H:29]1[C@@H:28]([CH2:15][C:13]([C:10]2[S:9][C:8]([CH2:7][O:6][Si:5]([C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:20])[CH3:21])=[CH:12][CH:11]=2)=[O:14])[NH:27][C:26]1=[O:25])[CH3:31])([C:36]([CH3:39])([CH3:37])[CH3:38])([CH3:35])[CH3:34]
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: C=C(O[Si](C)(C)C)c1ccc(CO[Si](C)(C)C(C)(C)C)s1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1CC(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)s1

Procedure:
In the same manner as reference example 3, from tert-butyl(dimethyl)[(5-{1-[(trimethylsilyl)oxy]vinyl}thien-2-yl)methoxy]silane prepared in the above step and (2R,3R)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxo-2-azetidinyl acetate (20.99 g), there was obtained (3S,4R)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-{2-[5-({[tert-butyl(dimethyl)silyl]oxy}methyl) thien-2-yl]-2-oxoethyl}azetidin-2-one (10.32 g).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].C(OC([NH:28][C@H:29]1[C@@H:33]([CH3:34])[CH2:32][NH:31][CH2:30]1)=O)(C)(C)C.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:28][C@H:29]1[C@@H:33]([CH3:34])[CH2:32][N:31]([C:3]2[C:2]([Cl:1])=[C:11]3[C:6]([C:7](=[O:18])[C:8]([C:15]([OH:17])=[O:16])=[CH:9][N:10]3[CH:12]3[CH2:14][CH2:13]3)=[CH:5][C:4]=2[F:19])[CH2:30]1
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: C[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[C@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)C[C@H]1N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.2 %

Procedure:
A mixture of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (1.8 g), anhydrous acetonitrile (18 ml), cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (reference example 3; 1.81 g) and DBU (0.90 g) was refluxed for an hour. The resulting mixture was concentrated under reduced pressure, the resulting residue was dissolved in chloroform and washed with 10% aqueous citric acid solution. The chloroform layer was further washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in hot methanol (25 ml) and, after cooling, the resulting precipitate was collected by filtration. Then this precipitate was suspended in methanol (18 ml), to this solution was added concentrated hydrochloric acid (18 ml) dropwise and stirred at room temperature for 15 minutes. The reacting mixture was neutralized with concentrated aqueous ammonia, after cooling, the resulting precipitate was collected by filtration and washed with water, methanol and ether successively to give the title compound (1.67 g) as white powder, mp 240°-243° C. (decompd.).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[S:29](Cl)([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30]>N1C=CC=CC=1>[CH3:36][C:35]1[CH:37]=[CH:38][C:32]([S:29]([O:19][C@@H:18]2[CH2:17][C:16]3[C@@:22]([CH3:23])([C@@H:24]4[C@@H:13]([CH2:14][CH:15]=3)[C@@H:12]3[CH2:11][CH2:10][C@H:9]([C@@H:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH3:8])[C@@:27]3([CH3:28])[CH2:26][CH2:25]4)[CH2:21][CH2:20]2)(=[O:31])=[O:30])=[CH:33][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@H]2CC[C@@]3(C)C(=CC[C@H]4[C@@H]5CC[C@H]([C@H](C)CCCC(C)C)[C@@]5(C)CC[C@@H]43)C2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
50 g (0.129 mmol) of cholesterol are dissolved in 250 ml of pyridine and cooled to about 5° C. with ice/water. Under argon, 49 g (0.258 mol) of tosyl chloride are added in portions thereto. When the addition is complete, the mixture is stirred for a further 15 minutes with cooling. The ice-bath is then removed and the mixture is stirred for 2 days at room temperature to complete the reaction. The resulting fine suspension is poured onto 1.2 liters of ice-water and stirred for 30 minutes. The precipitate is filtered off with suction, washed thoroughly with H2O and dried under a high vacuum at 40°. The substance, which still contains a large amount of pyridine hydrochloride, is dissolved in CH2Cl2 and the organic phase is washed twice with water, once with 1N hydrochloric acid and again with water. After drying over Na2SO4 and concentration in a rotary evaporator, the residue is recrystallised from CH2Cl2 /hexane, yielding cholesteryl tosylate; m.p. 130°-131°.
Reaction SMILES: [CH2:1]1[CH2:3][CH:2]1[CH2:4][OH:5].[H-].[Na+].[Br:8][C:9]1[CH:10]=[CH:11][C:12](F)=[N:13][CH:14]=1>CN(C=O)C.CC(=O)OCC>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:5][CH2:4][CH:2]2[CH2:3][CH2:1]2)=[N:13][CH:14]=1
Reactant: OCC1CC1
Reactant: Fc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1ccc(OCC2CC2)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 2-cyclopropyl-methanol (6.15 g) and DMF (12 mL) was added NaH (60% in mineral oil, 1.5 g) at 0° C. After stirring for 4 hours at r.t. the mixture was diluted with DMF (5 mL) and 5-bromo-2-fluoro-pyridine (6.00 g) was slowly added keeping the reaction temperature below 30° C. After 30 minutes at r.t. the mixture was heated to 130° C. for 1 hour by microwave irradiation. After cooling to r.t. the mixture was diluted with EA and washed with water (3 times). The organic phase was dried (Na2SO4) and concentrated. The residue was purified by SGC to provide the subtitle compound. MS ESI+: m/z=228 [M+H]+.
Reaction SMILES: [H-].[Na+].[H][H].[Cl:5][C:6](Cl)=[CH:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].Cl>CO.CN(C)C=O>[Cl:5][C:6]#[C:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14]
Reactant: OCCCCOCC=C(Cl)Cl
Reactant: [H][H]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: OCCCCOCC#CCl
Temperature: 50 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
In a reaction vessel containing 10 ml of N,N-dimethylformamide and 0.088 g of 60% sodium hydride (in oil) was put 0.070 g of methanol under ice cooling, and the mixture was stirred until the evolution of hydrogen gas ceased, to which 0.40 g of 4-(3,3-dichloro-2-propenyloxy)butanol was added. After stirring at 50° C. for 3 hours, the reaction mixture was poured into diluted hydrochloric acid and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over magnesium sulfate and then concentrated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.20 g of 4-(3-chloro-2-propynyloxy)butanol (yield, 62%), nD24.6 1.4720.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24](I)=[CH:23][C:22]=4[F:28])=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[CH3:29][C@@H:30]1[CH2:34][CH2:33][S:32](=[O:36])(=[O:35])[NH:31]1>>[CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([N:31]5[C@H:30]([CH3:29])[CH2:34][CH2:33][S:32]5(=[O:36])=[O:35])=[CH:23][C:22]=4[F:28])=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1
Reactant: C[C@@H]1CCS(=O)(=O)N1
Reactant: O=C(c1ccc(I)cc1F)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Product: C[C@@H]1CCS(=O)(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C3CC3)CC2)c(F)c1
Yield: 42.2 %

Procedure:
Using [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](2-fluoro-4-iodophenyl)methanone (491 mg) described in Preparation Example 164 and (R)-3-methylisothiazolidine 1,1-dioxide (135 mg) described in Preparation Example 2 and by the reaction and treatment in the same manner as in Example 1, the title compound (210 mg) was obtained.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:7]=2[O:6][CH:5]=1.[C-:15]#[N:16].[Na+]>>[CH3:14][O:13][C:12]1[C:7]2[O:6][CH:5]=[C:4]([CH2:3][CH2:2][C:15]#[N:16])[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: [C-]#N
Reactant: COc1cccc2c(CCBr)coc12
Agent: [Na+]
Product: COc1cccc2c(CCC#N)coc12
Yield: 97.2 %

Procedure:
This compound was prepared by the same method as for intermediate 27, using 2.87 g (11.25 mmol) of 3-(2-bromoethyl)-7-methoxybenzofuran and 1.1 g (22.5 mmol) of sodium cyanide, to afford 2.2 g (97%) of the title compound: MS (ESI) m/z 201 [M]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:17]=[C:16]([CH3:18])[NH:15][C:14]=1[CH:19]=O>C(O)(=O)C.CCO>[CH3:12][C:13]1[CH:17]=[C:16]([CH3:18])[NH:15][C:14]=1[CH:19]=[N:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: NNC(=O)c1ccc(O)cc1
Reactant: Cc1cc(C)c(C=O)[nH]1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(C)c(C=NNC(=O)c2ccc(O)cc2)[nH]1
Temperature: 25 °C
Yield: 85.5 %

Procedure:
To a solution of 4-hydroxy-benzoic acid hydrazide (0.3 g, 0.002 mol) and 3,5-dimethyl-pyrrole-2-carboxaldehyde (0.25 g, 0.002 mol) in abs. EtOH (10 mL), was added 1 drop of acetic acid. The reaction mixture was refluxed for 5 hours. The reaction mixture was cooling to room temperature and concentrated to remove solvent. The resulting residue was solidified by EtOAc to give grey solid 0.44 g, in 86% yield, mp: 261.2° C. 1H NMR (CD3OD) δ 8.12 (s, 1H), 7.79 (d, 2H), 6.88 (d, 2H), 5723 (s, 1H), 2.24 (s, 3H), 2.13 (s, 3H). 13C NMR (CD3OD) δ 166.5, 162.5, 139.4, 134.1, 130.5, 127.1, 124.9, 124.1, 116.3, 110.7, 12.9, 10.7. Anal. Calcd for C14H15N3O2: C, 65.35; H, 5.88; N, 16.33. Found: C, 65.52; H, 5.79; N, 16.30.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][NH:11][C:12](=[O:15])[CH2:13][CH3:14].OS(O)(=O)=O.[N+:21]([O-])([OH:23])=[O:22].O>[N+](C)([O-])=O>[N+:21]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][CH:2]([CH2:10][NH:11][C:12](=[O:15])[CH2:13][CH3:14])[CH2:3]2)([O-:23])=[O:22]
Reactant: O=[N+]([O-])O
Reactant: CCC(=O)NCC1Cc2ccccc2C1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C[N+](=O)[O-]
Product: CCC(=O)NCC1Cc2ccc([N+](=O)[O-])cc2C1
Temperature: 5 °C
Reaction time: 0.75 h
Yield: 96 %

Procedure:
N-Indan-2-ylmethyl-propionamide (4.00 g, 19.7 mmol) was dissolved in nitromethane (60 mL) and added to a mixture of concentrated H2SO4 (19 mL), concentrated nitric acid (1.4 mL) and water (3.2 mL) cooled to 5° C. After stirring for 45 min, the reaction solution was poured into water, extracted with ethyl acetate and the organic phase separated and dried over MgSO4. The filtered solution was concentrated to give a brown oil (4.67 g, 96%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:6][CH:5]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:29](Br)[CH:30]=[CH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl>CN(C=O)C>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][N:13]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:29]/[CH:30]=[CH:31]/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(OCCNS(C)(=O)=O)cc1
Reactant: BrCC=Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCN(C/C=C/c2ccccc2)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.1 %

Procedure:
To a solution of 4-(2-methanesulfonylamino-ethoxy)-benzoic acid methyl ester (62 mg, 0.23 mmol) in DMF (10 mL) at 0° C. was added sodium bis(trimethylsilyl)amide (1.0M in THF, 0.24 mL, 0.24 mmol) dropwise. After 20 minutes, cinnamyl bromide (51 mg, 0.26 mmol) was added and the reaction was stirred at room temperature for 2 h. Aqueous 1N HCl was added and the product was extracted into EtOAc. The organic solution was washed with 1N HCl (3×) followed by brine. The organic solution was dried (Na2SO4), filtered, and concentrated. Radial chromatography (20% EtOAc in hexanes) provided trans4-{2-[methanesulfonyl-(3-phenyl-allyl)-amino]-ethoxy}-benzoic acid methyl ester (70 mg). 1NMR (400 MHz, CDCl3) δ 7.97 (d, 2H), 7.35-7.23 (m, 5H), 6.88 (d, 2H), 6.58 (d, 1H), 6.18 (m, 1H), 4.20 (t, 2H), 4.12 (d, 2H), 3.88 (s, 3H), 3.68 (t, 2H), 2.95 (s, 3H).