Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:4]1[S:5][CH:6]=[C:7]([C:9](=[O:12])[CH2:10]Br)[N:8]=1)[CH3:3].C(=O)([O-])O.[K+].Cl.[C:19]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:30]([NH2:32])[CH3:31])=[CH:25][CH:24]=1)([O:21][CH3:22])=[O:20]>CC(C)=O>[C:19]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([NH:32][CH2:10][CH:9]([OH:12])[C:7]2[N:8]=[C:4]([N:2]([CH3:3])[CH3:1])[S:5][CH:6]=2)=[CH2:31])=[CH:25][CH:24]=1)([O:21][CH3:22])=[O:20]
Reactant: CN(C)c1nc(C(=O)CBr)cs1
Reactant: COC(=O)c1ccc(CC(C)N)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(Cc1ccc(C(=O)OC)cc1)NCC(O)c1csc(N(C)C)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5 g of 2-(N,N-dimethylamino)-4-bromoacetyl-thiazole in 250 ml of acetone are heated to reflux with 10 g of potassium hydrogen carbonate and 9.5 g of 2-(4-carbomethoxyphenyl)-1-methylethylamine-hydrochloride for 3 hours. After the reaction mixture has been cooled the inorganic products are removed by filtration, and the filtrate is concentrated in a rotary evaporator. The resulting oil residue is taken up in 150 ml of absolute methanol and, at 0°-5° C., 1.75 g of sodium borohydride are added in small portions. The mixture is then stirred at 0°-5° C. for one hour and at room temperature for 24 hours. Then ice-water are added to the reaction mixture, and it is acidified with concentrated hydrochloric acid, made alkaline with ammonia, while cooling in ice, and extracted with methylene chloride. The extract is dried over sodium sulphate, concentrated and purified on a silica gel column using ethyl acetate/methanol =8:2 as eluant.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.C([N:48]1[CH:52]=[C:51]([CH2:53][CH2:54][NH2:55])[N:50]=[CH:49]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[NH:48]1[CH:52]=[C:51]([CH2:53][CH2:54][NH:55][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[C:14]([C:17]5[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=5)[CH:15]=4)[NH:10][N:9]=3)[N:7]=2)[N:50]=[CH:49]1
Reactant: NCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Product: Cn1cc(-c2cc3c(-c4cccc(NCCc5c[nH]cn5)n4)n[nH]c3cn2)cn1
Yield: 37.6 %

Procedure:
Following the procedures as described in Example 189, 3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and 2-(1-trityl-1H-imidazol-4-yl)-ethylamine were reacted. The product was deprotected to give 217 as a white solid (37.6% over two steps). 1H NMR (400 MHz, DMSO) δ 9.01 (s, 1H), 8.62 (s, 1H), 8.26 (s, 1H), 8.03 (s, 1H), 7.88 (s, 1H), 7.56 (s, 1H), 7.49 (d, J=8.1 Hz, 1H), 7.34 (d, J=7.4 Hz, 1H), 6.86 (s, 1H), 6.80 (s, 1H), 6.49 (d, J=8.3 Hz, 1H), 3.88 (s, 3H), 3.78-3.70 (m, 2H), 2.92 (t, J=7.5 Hz, 2H), 2.54 (s, 1H). LC/MS: m/z 386.1 [M+1]
Reaction SMILES: [CH:1]([N:4]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17]CC)=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:32][CH2:33][C:34]2[CH:35]=[C:36]([NH2:39])[NH:37][N:38]=2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1.C[Al](C)C.C(Cl)Cl.CCOCC>C1(C)C=CC=CC=1>[CH3:31][O:30][C:28]1[CH:27]=[C:26]([CH2:32][CH2:33][C:34]2[CH:35]=[C:36]([NH:39][C:15](=[O:17])[C:14]3[CH:13]=[CH:12][C:11]([N:7]4[CH2:8][CH2:9][CH2:10][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:5][CH2:6]4)=[CH:21][CH:20]=3)[NH:37][N:38]=2)[CH:25]=[C:24]([O:23][CH3:22])[CH:29]=1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: CCOC(=O)c1ccc(N2CCCN(C(C)C)CC2)cc1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCCN(C(C)C)CC4)cc3)[nH]n2)cc(OC)c1
Yield: 42.9 %

Procedure:
N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(4-propan-2-yl-1,4-diazepan-1-yl)benzamide was prepared using the same procedure as for Example 159, but starting from ethyl 4-(4-isopropyl-1,4-diazepan-1-yl)benzoate (0.212 g, 0.73 mmol), 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.181 g, 0.73 mmol) and a 2M solution of trimethylaluminium (0.913 ml, 1.83 mmol) in toluene. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford a gum which solidified on trituration with DCM/Ether to afford the title compound (0.154 g, 42.9%) as a cream solid.
Reaction SMILES: C([NH:8][C@H:9]([C:11](O)=[O:12])[CH3:10])(OC(C)(C)C)=O.[ClH:14].[NH2:15][N:16]1[C:22](=[O:23])[CH:21]([CH3:24])[C:20]2[CH:25]=[CH:26][CH:27]=[CH:28][C:19]=2[C:18]2[CH:29]=[CH:30][CH:31]=[CH:32][C:17]1=2>>[ClH:14].[NH2:8][C@H:9]([C:11]([NH:15][N:16]1[C:22](=[O:23])[CH:21]([CH3:24])[C:20]2[CH:25]=[CH:26][CH:27]=[CH:28][C:19]=2[C:18]2[CH:29]=[CH:30][CH:31]=[CH:32][C:17]1=2)=[O:12])[CH3:10]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC1C(=O)N(N)c2ccccc2-c2ccccc21
Agent: Cl
Product: CC1C(=O)N(NC(=O)[C@H](C)N)c2ccccc2-c2ccccc21

Procedure:
Following General Procedure D and using N-Boc-L-alanine (Aldrich) and 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 1), the title compound was prepared.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([NH:13][C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[N:3]=1.[NH2:21][C@@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]1[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].C(N(CC)CC)C>CC(N(C)C)=O.CCOC(C)=O>[C:31]([O:30][C:29]([NH:28][C@H:23]1[CH2:24][CH2:25][CH2:26][CH2:27][C@H:22]1[NH:21][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([NH:13][C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[N:3]=1)=[O:35])([CH3:34])([CH3:32])[CH3:33]
Reactant: COC(=O)c1c(C)nc(Cl)nc1Nc1cccc(C)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C)nc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cccc(C)c1
Yield: 62.2 %

Procedure:
A solution of methyl 2-chloro-4-methyl-6-(m-tolylamino)pyrimidine-5-carboxylate (1.2 g, 4.11 mmol), tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (0.882 g, 4.11 mmol) and triethylamine (1.720 mL, 12.34 mmol) in DMA (10 mL) was heated at 90° C. for 4 h. The solution was then diluted with EtOAc, washed with brine and water. The organic extract was dried and concentrated under reduced pressure to give a light yellow residue; white crystals were formed upon triturating with ACN (5 mL). The resultant solid was filtered, washed with ACN, and dried to give the title compound as white solid (1.2 g, 62%). [M+H] calc'd for C25H35N5O4, 470. found, 470.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15]([CH3:17])[C:5]([O:6][CH:7]([C:10]2[NH:11][CH2:12][CH2:13][N:14]=2)[CH2:8]C)=[C:4]([CH3:18])[C:3]=1[N+:19]([O-])=O>C(O)C>[BrH:1].[NH:14]1[CH2:13][CH2:12][N:11]=[C:10]1[CH:7]([O:6][C:5]1[C:4]([CH3:18])=[C:3]([NH2:19])[CH:2]=[CH:16][C:15]=1[CH3:17])[CH3:8]
Reactant: CCC(Oc1c(C)cc(Br)c([N+](=O)[O-])c1C)C1=NCCN1
Solvent: CCO
Product: Br
Product: Cc1ccc(N)c(C)c1OC(C)C1=NCCN1
Yield: 85.8 %

Procedure:
The title product of Example 6 (14.8 g) was hydrogenated in ethanol using 10% palladium on carbon as catalyst. Insolubles were removed by filtration and the filtrate was concentrated to an oil which solidified upon standing. The solid was triturated with diethyl ether and collected by filtration, giving the debrominated title compound (11.2 g) as a hydrated hydrobromide salt. Structure assignment was supported by nmr and infrared spectra and by elemental analysis.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[C:8]([O:12][C:13](=[O:17])[CH2:14][CH2:15][NH2:16])([CH3:11])([CH3:10])[CH3:9].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([N:49]=[C:50]=[S:51])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.C(NCC)C>>[C:8]([O:12][C:13](=[O:17])[CH2:14][CH2:15][N:16]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[C:50]([NH2:49])=[S:51])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)CCN
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCNCC
Product: CC(C)(C)OC(=O)CCN(C(N)=S)C1CCCC1

Procedure:
3-(1-Cyclopentyl-thioureido)-propionic acid tert-butyl ester was prepared using general procedure D with cyclopentanone, beta-alanine tert-butyl ester hydrochloride, sodium triacetoxyborohydride, Fmoc isothiocyanate, and diethyl amine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].[CH3:32][S:33](Cl)(=[O:35])=[O:34]>>[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])=[C:3]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:4]=2)[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)Nc1ccc(N2CCCNCC2)cc1NS(=O)(=O)c1ccccc1

Procedure:
N-{5-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}benzenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}benzenesulfonamide (0.075 g, 0.16 mmol) and, methanesulfonyl chloride (0.017 mL, 0.22 mmole) to give 41.6 mg of a light purple solid; Anal. (C24H27ClN4O3S×1.3H2O) C, H, N, S.; M+ 425.4 Calcd 425.12.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([N:9]2[C:17]3[C:12](=[C:13]([O:18][Si](C(C)C)(C(C)C)C(C)C)[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)[CH:6]=[CH:5][N:4]=1.[F:29][C:30]([F:35])([F:34])[CH2:31]OC.CN1[C:41](=[O:42])[CH2:40]CC1>>[F:35][C:30]([F:29])([F:34])[CH2:31][CH:41]([OH:42])[CH2:40][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[CH:11]=[CH:10][N:9]2[C:7]1[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=1
Reactant: COCC(F)(F)F
Reactant: CSc1nccc(-n2ccc3c(O[Si](C(C)C)(C(C)C)C(C)C)cccc32)n1
Reactant: CN1CCCC1=O
Product: CSc1nccc(-n2ccc3c(OCC(O)CC(F)(F)F)cccc32)n1
Temperature: 25 °C

Procedure:
1-(2-methylsulfanyl-pyrimidin-4-yl)-4-triisopropylsilanyloxy-1H-indole (1.25 g) was mixed with 1,1,1-trifluoro-2-methoxy-ethane (2.5 g) and H2CO3 (2.68 g) in NMP (5 mL) at 110° C. for 30 min, cooled to RT, quenched with water, extracted into DCM, and the filtrate purified on a column with hexane to EtOAc/hexane. The fractions collected yielded an oil which was triturated with water to precipitate a solid, which was filtered and dried to yield 4,4,4-tri-fluoro-1-[1-(2-methylsulfanyl-pyrimidin-4-yl)-1H-indol-4-yloxy]-butan-2-ol (1.5 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:6]=[N:7][C:8]([CH2:14][CH3:15])=[C:9]([CH2:11][C:12]#[N:13])[CH:10]=1.Cl.N[C:19]1[C:24]([F:25])=[C:23]([F:26])[CH:22]=[C:21]([F:27])[C:20]=1[SH:28]>>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:6]=[N:7][C:8]([CH2:14][CH3:15])=[C:9]([CH2:11][C:12]2[S:28][C:20]3[C:21]([F:27])=[CH:22][C:23]([F:26])=[C:24]([F:25])[C:19]=3[N:13]=2)[CH:10]=1
Reactant: CCc1ncc(CC(=O)OC)cc1CC#N
Reactant: Nc1c(F)c(F)cc(F)c1S
Agent: Cl
Product: CCc1ncc(CC(=O)OC)cc1Cc1nc2c(F)c(F)cc(F)c2s1
Temperature: 120 °C
Yield: 78.6 %

Procedure:
A mixture of 5-cyanomethyl-6-ethyl-pyridin-3-yl-acetic acid methyl ester (0.51 g, 2.34 mmol), 2-amino-3,4,6-trifluorothiophenol hydrochloride (0.54 g, 2.53 mmol) and BHT (10 mg) in a sealed reaction vessel is heated to 120° C. for 9 h. After cooling to room temperatue, the resulting slurry is adsorbed onto silica gel and purified by flash column chromatography (10-30% ethyl acetate in hexanes) to give 6-ethyl-5-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyridin-3-yl-acetic acid-methyl ester as a yellow oil (0.70 g, 79%): Rf 0.36 (50% ethyl acetate in n-heptane), 1H NMR (CDCl3, 300 MHz) δ 8.46 (s, 1 H), 7.64 (s, 1 H), 7.08-6.97 (m, 1 H), 4.50 (s, 2 H), 3.72 (s, 3 H), 3.65 (s, 2 H), 2.90 (q, J=7.4 Hz, 2 H), 1.29 (t, J=7.4 Hz, 3 H); ESI-LCMS m/z calcd for C18H15F3N2O2S: 380.1; found 381.0 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[C:12]([Cl:22])[C:11]=2[CH:10]=[CH:9]1.[NH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28]>>[ClH:22].[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[C:12]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])[C:11]=2[CH:10]=[CH:9]1
Reactant: Cc1ccccc1-n1ccc2c(Cl)nc3c(C)cccc3c21
Reactant: NCCCCO
Product: Cc1ccccc1-n1ccc2c(NCCCCO)nc3c(C)cccc3c21
Product: Cl
Yield: 62 %

Procedure:
1-(2-methylphenyl)4 -chloro-6-methylpyrrolo[3,2-c]quinoline (1.0 g, 3,26 mmol) was dissolved in 4-aminobutanol (3.0 g) and stirred for 6 hoursat 170°. Chromatography (silica gel, 2% methanolic ammonia in dichloromethane), conversion to the hydrochloride and recrystallisation from ethanol/ether gave 1-(2-methylphenyl)-4-(4-hydroxybutylamino)-6-methylpyrrolo[3,2-c]quinolinehydrochloride (0.8 g), m.p. 176°-178°.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6](O)=[CH:5][CH:4]=1.C(Cl)Cl.C(N([CH2:20][CH3:21])CC)C.CS(Cl)(=O)=O.CC(C)=O.[I-:31].[Na+]>>[I:31][CH2:20][CH2:21][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:11])([F:10])[F:1])=[CH:4][CH:5]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: [I-]
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: FC(F)(F)c1ccc(CCI)cc1
Reaction time: 3 h
Yield: 96.3 %

Procedure:
To 4-(trifluoromethyl)phenyl alcohol (5.0 g, 0.026 mol) in methylene chloride (30 mL, 0.5 mol) at 0° C. was added triethylamine (5.13 mL, 0.0368 mol) followed by methanesulfonyl chloride (3.92 g, 0.0342 mol). After stirring from 0° C. to room temperature for 3 hours, the reaction mixture was washed with 1N HCl, saturated NaHCO3, water, brine and dried over anhydrous sodium sulfate. To the crude product in acetone (50 mL, 0.7 mol) was added sodium iodide (5.9 g, 0.039 mol). The reaction mixture was stirred at 55° C. overnight, filtered and the solid washed with acetone. The filtrate was concentrated, dissolved in Et2O (100 mL), washed with water, brine and dried over anhydrous sodium sulfate to give 7.51 g of brown liquid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:12]([O:14][C:15]([CH:17]1[CH2:22][CH2:21][CH:20](O)[CH2:19][CH2:18]1)=[O:16])[CH3:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:12]([O:14][C:15]([C@H:17]1[CH2:22][CH2:21][C@@H:20]([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=3[C:10]([I:11])=[CH:9]2)[CH2:19][CH2:18]1)=[O:16])[CH3:13]
Reactant: CCOC(=O)C1CCC(O)CC1
Reactant: Clc1ncnc2[nH]cc(I)c12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CC[C@@H](n2cc(I)c3c(Cl)ncnc32)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Into the THF (5 mL) solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (prepared according to: L. B. Townsend et al., J. Med. Chem. 1990, 33 (7), 1984-92) (140 mg, 0.500 mmol), 4-hydroxycyclohexanecarboxylic acid ethyl ester (104 mg, 0.600 mmol; Aldrich, cis/trans mixture), and PPh3 (263 mg, 1.00 mmol) was added DIAD (203 mg, 1.00 mmol) dropwise at 0° C. under N2 over 5 min. The reaction was then stirred at rt for 2 days. After that time, the solvent was evaporated, and the residue was purified by chromatography on silica gel, eluting with 200 mL of 5%, 10%, 20% and 30% EtOAc/hexane to obtain cis-4-(4-chloro-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclohexanecarboxylic acid ethyl ester as a white solid, which was further purified by HPLC. 1H NMR (CDCl3, 400 MHz): δ=1.32 (t, 3H, J=7.2 Hz), 1.74-1.78 (m, 2H), 1.88-1.98 (m, 4H), 2.33-2.36 (m, 2H), 2.75-2.77 (m, 1H), 4.23 (q, 2H, J=7.2 Hz), 4.73-4.81 (m, 1H), 7.45 (s, 1H), 8.60 (s, 1 H). MS (ES+): 433.9/435.9 [MH+]. HPLC: tR=4.0 min (polar—5 min).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([CH3:13])[N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:49][CH2:50][C:51]([N:53]1[CH2:58][CH2:57][CH:56]([NH:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[Cl:66])[CH2:55][CH2:54]1)=[O:52]>CN(C=O)C.O>[Cl:66][C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=1[NH:59][CH:56]1[CH2:55][CH2:54][N:53]([C:51](=[O:52])[CH2:50][NH:49][C:14]([C:10]2[CH:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:12]([CH3:13])[N:11]=2)=[O:16])[CH2:58][CH2:57]1
Reactant: Cn1nc(C(=O)O)cc1-c1ccccc1O
Reactant: NCC(=O)N1CCC(Nc2ccccc2Cl)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1nc(C(=O)NCC(=O)N2CCC(Nc3ccccc3Cl)CC2)cc1-c1ccccc1O
Reaction time: 8 h
Yield: 40.2 %

Procedure:
To a stirred solution of 5-(2-hydroxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid (0.13 g, 0.0006 mol) in DMF (2 mL) was added DIPEA (0.308 g, 0.00234 mol), HOBt (0.101 g, 0.00075 mol) and EDCI.HCl (0.143 g, 0.00075 mol) at ambient temperature. After 5 minutes 2-amino-1-[4-(2-chloro-phenylamino)-piperidin-1-yl]-ethanone hydrochloride (0.181 g, 0.00060 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and recrystallized from ethyl acetate to afford 0.113 g (41%) of 5-(2-hydroxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 468.18 (M+1)+, 96.98%. 1H NMR (DMSO-d6): δ 10.2 (s, 1H), 8.7 (t, 1H), 7.7 (d, 1H), 7.4 (s, 1H), 7.1 (m, 3H), 6.8 (m, 3H), 6.6 (m, 1H), 4.9 (m, 1H), 4.3 (d, 1H), 4.1 (m, 4H), 3.9 (m, 1H), 3.6 (m, 1H), 3.1 (m, 1H), 2.7 (m, 1H), 1.9 (m, 2H), 1.4 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:8]=2[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:19]OS(OC)(=O)=O.C([O-])([O-])=O.[K+].[K+]>C(C(CC)=O)C>[CH3:19][O:10][C:9](=[O:11])[C:8]1[C:12]([CH3:16])=[CH:13][CH:14]=[CH:15][C:7]=1[O:6][C:5]1[CH:17]=[CH:18][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: Cc1cccc(Oc2ccc(F)cc2)c1C(=O)O
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(=O)CC
Product: COC(=O)c1c(C)cccc1Oc1ccc(F)cc1
Reaction time: 18 h
Yield: 97.8 %

Procedure:
A mixture of 2-(4-fluoro-phenoxy)-6-methyl-benzoic acid (21.6 mmol, 5.32 g), dimethylsulfate (43.2 mmol, 4.2 mL), K2CO3 (43.2 mmol, 6 g), and diethyl ketone (80 mL) was refluxed with stirring for 18 h before it was concentrated in vacuo. To the residue was added water (50 mL) and the mixture was extracted with ethyl acetate (1×100 mL). The organic phase was dried over MgSO4 and concentrated in vacuo to give the title compound as a tan oil (5.5 g); 1H NMR (CDCl3, 200 MHz): δ=7.20 (t, 1H), 6.92 to 7.04 (m, 5H), 6.66 (d, 1H), 3.84 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[N:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[Br:12]Br>N1C=CC=CC=1.[Cl-].[Na+].O>[Br:12][C:9]1[C:8]([OH:11])=[CH:7][CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[N:10]=1
Reactant: CC(C)(C)c1ccc(O)cn1
Reactant: BrBr
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(O)c(Br)n1
Reaction time: 1 h

Procedure:
To a stirred solution of 6-(1,1-dimethylethyl)-3-pyridinol, (3.8 g) in pyridine (150 ml) was added bromine (1.29 ml), diluted in pyridine, dropwise at 20 C. The reaction mixture was allowed to stir at 25-30 C. for 1 h. The reaction had gone to completion by tlc. It was poured into brine and extracted with ethyl acetate. The organics were dried over sodium sulphate and concentrated under reduced pressure. The crude material was subjected to flash chromatography using a 0-5% gradient of ethyl acetate in hexane to give the title compound, 2.9 g
Reaction SMILES: [OH:1][CH:2]([CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1>>[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:5][CH2:6]2)=[CH:31][CH:30]=1
Reactant: CCCCCCCCCCCCCCCCOCC(O)CN1CCNCC1
Reactant: Fc1ccc(CCl)cc1
Product: CCCCCCCCCCCCCCCCOCC(O)CN1CCN(Cc2ccc(F)cc2)CC1

Procedure:
Following the procedure of Example 5, 1-(2-hydroxy-3-n-hexadecyloxypropyl)-piperizine was reacted with 4-fluorobenzyl chloride to form 1-(4-fluorobenzyl)-4-(2-hydroxy-3-n-hexadecyloxypropyl)-piperazine, mp 242° C. (dec).
Reaction SMILES: [F:1][C:2]1([F:57])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18]CC4C=CC(OC)=CC=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH2:42][O:43][CH3:44])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:45]([F:56])[C:46]2[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:48][CH:47]=2)[CH2:4][CH2:3]1.FC1(F)CCC(C2C3C(OCC4C=CC(OC)=CC=4)CC(C)(C)CC=3N=C(C3CCN(C4N=CC(C(O)C(C)C)=CN=4)CC3)C=2C(F)C2C=CC(C(F)(F)F)=CC=2)CC1>>[F:57][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:31][CH2:32][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH2:42][O:43][CH3:44])=[CH:38][N:37]=4)[CH2:34][CH2:35]3)[C:9]=2[CH:45]([F:56])[C:46]2[CH:47]=[CH:48][C:49]([C:52]([F:53])([F:55])[F:54])=[CH:50][CH:51]=2)[CH2:6][CH2:7]1
Reactant: COCc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(OCc3ccc(OC)cc3)CC(C)(C)C4)CC2)nc1
Agent: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(C(O)C(C)C)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Product: COCc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1
Yield: 94.8 %

Procedure:
Reactions similar to those of Example 24 were performed except for using 42 mg (0.053 mmol) of 4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 22 instead of 4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-{1-[5-(1-hydroxy-2-methylpropyl)pyrimidin-2-yl]piperidin-4-yl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline to provide 34 mg of the title compound as a foam (yield: 96%).
Reaction SMILES: C[OH:2].Cl.Cl.Cl.[CH2:6]([NH:14][C:15]([NH:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[NH:19])=[NH:16])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH3:28][C:29]([CH3:31])=[O:30]>>[C:29]([OH:2])(=[O:30])[CH3:31].[CH2:6]([NH:14][C:15]1[NH:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[N:19][C:29]([CH3:31])([CH3:28])[N:16]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCNC(=N)NC(=N)NCCCCCCC
Reactant: CO
Reactant: CC(C)=O
Agent: Cl
Product: CC(=O)O
Product: CCCCCCCCNC1=NC(C)(C)N=C(NCCCCCCC)N1

Procedure:
100 ml of methanol, 80 ml of acetone and 0.5 ml of concentrated hydrochloric acid were added to 8.0 g (20.8 mmol) of N1-octyl-N5-heptyl-biguanide dihydrochloride. The mixture was refluxed for 64 hours, and the solvent was distilled off under reduced pressure. To the residue were added 100 ml of ethanol, 60 ml of water and 8.5 ml of 5N sodium hydroxide, and the mixture was refluxed for 1 hour, concentrated under reduced pressure, and extracted with ethyl acetate. The extract was washed with water, and 1.3 g of acetic acid was added thereto. The solvent was distilled off under reduced pressure, and the residue was dried well, and recrystallized from methyl ethyl ketone to obtain 4.1 g of colorless crystals having a melting point of 82 to 84° C.