Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:4]([CH3:16])=[N:3]1.[Cl:17][C:18]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:1][N:2]1[C:6]([O:7][C:20]2[CH:21]=[CH:22][N:23]=[C:18]([Cl:17])[N:19]=2)=[C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:4]([CH3:16])=[N:3]1
Reactant: Clc1ccnc(Cl)n1
Reactant: Cc1nn(C)c(O)c1Sc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1nn(C)c(Oc2ccnc(Cl)n2)c1Sc1ccccc1Cl
Yield: 76.2 %

Procedure:
A mixture of 2.4 g (10 mmol) of 1,3-dimethyl-4-(2-chlorophenylthio)-5-hydroxypyrazole, 1.5 g (10 mmol) of 2,4-dichloropyrimidine and 1.5 g (11 mmol) of potassium carbonate was refluxed for 1 hour in 10 ml of acetonitrile. After completing the reaction, the reaction mixture was poured into water, extracted with ethyl acetate and dried. Then the organic layer was concentrated. The residue was purified by means of silica gel column chromatography (developing solution: ethyl acetate-hexane (3:1 v/v)) to give 2.8 g of 1,3-dimethyl-4-(2-chlorophenylthio)-5-(2-chloropyrimidine-4-yloxy)pyrazole
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[S:5][CH3:6])#[N:2].[NH:9]([C:11]1[N:12]=[N:13][C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:15]([CH3:17])[N:16]=1)[NH2:10]>C(Cl)Cl.CO>[NH2:2][C:1]1[N:9]([C:11]2[N:12]=[N:13][C:14]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:15]([CH3:17])[N:16]=2)[N:10]=[C:4]([S:5][CH3:6])[N:3]=1
Reactant: Cc1nc(NN)nnc1-c1ccccc1
Reactant: CSC(=NC#N)SC
Solvent: CO
Solvent: ClCCl
Product: CSc1nc(N)n(-c2nnc(-c3ccccc3)c(C)n2)n1
Reaction time: 40 h
Yield: 89.2 %

Procedure:
A solution of dimethyl N-cyanodithioimidocarbonate (2.65 g) in methylene chloride (15 ml) was added to a solution of 3-hydrazino-5-methyl-6-phenyl-1,2,4-triazine (3.52 g) in methanol (20 ml) and stirring was continued for 40 hours at room temperature. The resultant precipitates were collected by filtration, washed with methanol, and dried to give 3-(5-amino-3-methylthio-1,2,4-triazol-1-yl)-5-methyl-6-phenyl-1,2,4-triazine (4.67 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH2:10]([Mg]Br)[CH3:11].B(F)(F)F.CCOCC>C(OCC)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH2:9])[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: N#Cc1ccc(Br)cn1
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: FB(F)F
Solvent: CCOCC
Product: NC1(c2ccc(Br)cn2)CC1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
5-bromopicolinonitrile (D9) (43.6 g, 0.238 mol) was suspended in diethyl ether (1.3 L) and the resulting mixture was cooled to −78° C. Titanium (IV) isopropoxide (74.4 g, 0.262 mol) was added dropwise and the reaction mixture was stirred for 5 min. Ethylmagnesium bromide 1M in diethyl ether (525 ml, 0.525 mol) was added dropwise and the resulting reaction mixture was stirred for 30 mins at −78° C. The reaction mixture was allowed to warm to room temperature for 1 hour then boron trifluoride etherate (107 ml) was added dropwise. After stirred at room temperature for 2 hours, the reaction was quenched with 1M HCl (1.5 L). The aqueous layer was washed with diethyl ether (1 L) and then basified (pH=9) with 2N NaOH (1.25 L). The resulting mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4 and evaporated in vacuo. The residue was purified by column chromatography eluting with a mixture petroleum ether/ethyl acetate 1:1. Collected fractions after solvent evaporation afforded the title compound (D10) (15.7 g) as a grey solid.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([O:26]CC)=[O:25])=[CH:18][CH:17]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C1COCC1.CCO>[CH2:1]([C:5]1[C:6]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25])=[CH:18][CH:17]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2ccccc2c(Oc2ccc(/C=C/C(=O)OCC)cc2)c1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCc1cc2ccccc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccc(F)cc1
Yield: 77.1 %

Procedure:
Ethyl ester (168) (0.25 g, 0.53 mmol) was saponified with 1 N NaOH in THF and EtOH to give 0.18 g (79%) of the title compound (169) as a white solid. mp 169-170° C. 1H NMR (400 MHz, CH3OH-d4): δ 0.78 (t, J=7.3 Hz, 3H), 1.15-1.28 (m, 2H), 1.40-1.50 (m, 2H), 2.60 (t, J=7.9 Hz, 2H), 6.27 (d, J=16.0 Hz, 1H), 6.56 (d, J=8.6 Hz, 2H), 7.01 (t, J=8.7 Hz, 2H), 7.12-7.22 (m, 2H), 7.32-7.42 (m, 3H), 7.46-7.56 (m, 2H), 7.70-7.80 (m, 2H), 7.90 (d, J=8.2 Hz, 1H). LCMS (ESI): m/z 441 (M+H)+, m/z 439 (M−H)−. Anal. Calc for C29H25FO3.0.1H2O: C, 78.75; H, 5.74. Found: C, 78.85; H, 5.64.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[CH:8]1([N:11]2[C:15]3[C:16]([O:34][C@@H:35]([C@H:37]4[CH2:41][NH:40][C:39](=[O:42])[CH2:38]4)[CH3:36])=[N:17][C:18]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[C:22]([O:32][CH3:33])[CH:21]=4)=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH2:10][CH2:9]1.C(N(CC)CC)C.C(OC(=O)C)(=O)C>C(Cl)Cl>[C:3]([N:29]1[CH2:30][CH2:31][N:26]([C:23]2[CH:24]=[CH:25][C:20]([C:18]3[N:17]=[C:16]([O:34][C@@H:35]([C@H:37]4[CH2:41][NH:40][C:39](=[O:42])[CH2:38]4)[CH3:36])[C:15]4[N:11]([CH:8]5[CH2:10][CH2:9]5)[CH:12]=[N:13][C:14]=4[CH:19]=3)=[CH:21][C:22]=2[O:32][CH3:33])[CH2:27][CH2:28]1)(=[O:4])[CH3:2]
Reactant: COc1cc(-c2cc3ncn(C4CC4)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)ccc1N1CCNCC1
Reactant: O=C(O)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(-c2cc3ncn(C4CC4)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)ccc1N1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an appropriate sized vial the trifluoroacetic acid salt of (R)-4-((R)-1-((3-cyclopropyl-6-(3-methoxy-4-(piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one: 3.51 (80 mg, 0.085 mmol) and triethylamine (52 mg, 0.51 mmol) were dissolved in DCM (4 mL). To this mixture acetic anhydride (10.5 mg, 0.1 mmol) was added and the mixture was stirred at room temperature for 30 min. After reaction was complete the solution was concentrated under reduced pressure and the residue was purified via prep HPLC (2-65% acetonitrile in water, 0.1% trifluoroacteic acid buffer) to provide (R)-4-((R)-1-((6-(4-(4-acetylpiperazin-1-yl)-3-methoxyphenyl)-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one: 3.52 as its trifluoroacetic acid salt.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[CH3:18][O:19][C:20]1[CH:32]=[CH:31][C:23]([O:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:22][CH:21]=1>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:28]1[CH2:27][CH2:26][CH:25]([O:24][C:23]2[CH:31]=[CH:32][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[CH2:30][CH2:29]1)=[O:9])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: COc1ccc(OC2CCNCC2)cc1
Product: COc1ccc(OC2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)CC2)cc1
Yield: 73 %

Procedure:
Prepared in analogy to Example 1 from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 4-(4-methoxy-phenoxy)-piperidine. The crude material was purified by reversed phase HPLC (acetonitrile/water) to yield the title compound as an amorphous white solid (yield 73%). MS (m/e): 448.2 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[S:9](Cl)(=[O:11])=[O:10].[OH:13][CH2:14][P:15](=[O:24])([O:20][CH:21]([CH3:23])[CH3:22])[O:16][CH:17]([CH3:19])[CH3:18].C(N(CC)CC)C>CCOCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[S:9]([O:13][CH2:14][P:15](=[O:24])([O:16][CH:17]([CH3:19])[CH3:18])[O:20][CH:21]([CH3:23])[CH3:22])(=[O:10])=[O:11]
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Cl
Reactant: CC(C)OP(=O)(CO)OC(C)C
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1cccc(Cl)c1S(=O)(=O)OCP(=O)(OC(C)C)OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
A solution of 21.7 g of 2-chloro-6-methylbenzenesulfonyl chloride dissolved in 40 ml of ether was added dropwise over 90 minutes to a mixture of 20.6 g of diisopropyl P-(hydroxymethyl)-phosphonate, (Example 17), 80 ml of ether, and 15.4 ml of triethylamine. The addition was mildly exothermic and the reaction was cooled using a cool water bath (no ice). The reaction was allowed to stir overnight at room temperature and then was diluted with 300 ml of ethyl acetate, washed with three 100 ml portions of water, the organic phase dried with magnesium sulfate, filtered and concentrated under reduced pressure to yield 34.0 g of the desired product as a yellow oil.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:15]([CH3:17])=[C:14]([CH3:18])[N:13]=[C:12](OC3C=CC=CC=3)[C:11]=2[N:10]=[C:9]1[CH2:26][CH2:27][CH3:28])(=[O:4])=[O:3].C([O-])(=O)C.[NH4+:33]>>[CH3:1][S:2]([CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:15]([CH3:17])=[C:14]([CH3:18])[N:13]=[C:12]([NH2:33])[C:11]=2[N:10]=[C:9]1[CH2:26][CH2:27][CH3:28])(=[O:4])=[O:3]
Reactant: [NH4+]
Reactant: CCCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCCS(C)(=O)=O
Agent: CC(=O)[O-]
Product: CCCc1nc2c(N)nc(C)c(C)c2n1CCCS(C)(=O)=O
Yield: 67.2 %

Procedure:
Using the general method of Example 89 Part H, 1-[3-(methanesulfonyl)propyl]-6,7-dimethyl-4-phenoxy-2-propyl-1H-imidazo[4,5-c]pyridine (2.1 g, 5.23 mmol) was reacted with ammonium acetate (25 g) and purified to provide 1.14 g of 1-[3-(methanesulfonyl)propyl]-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-4-amine as white needles, mp 153.5-155.0 C. 1H NMR (300 MHz, CDCl3) 67 4.83 (br s, 2H), 4.48-4.42 (m, 2H), 3.07 (t, J=7.1 Hz, 2H), 2.95 (s, 3H), 2.82-2.77 (m, 2H), 2.45-2.25 (m, 2H), 1.94-1.81 (m, 2H), 1.07 (t, J=7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 153.2, 148.3, 147.1, 138.9, 125.4, 104.0, 51.2, 42.9, 41.3, 29.5, 24.3, 22.1, 21.5, 14.0, 13.1; MS (APCI) m/z 325 (M+H)+; Anal. Calcd for C15H24O2N4S: C, 55.53; H, 7.46; N, 17.27; S, 9.87. Found: C, 55.53; H 7.44; N, 17.27; S, 9.90.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])([O-])=O.[SH-].CO>O>[NH2:1][C:4]1[C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Agent: [SH-]
Solvent: O
Solvent: CO
Product: Nc1cccc(C(=O)O)c1[N+](=O)[O-]

Procedure:
In one non-limiting reaction scheme, dinitrobenzoic acid may be reacted with about one to about five equivalents of an alkali hydrosulfide in a methanol:water mixture at reflux temperature for about 20 to about 40 minutes to produce an aminonitrobenzoic acid. As is described in the Example below, 2,6-dinitrobenzoic acid may be allowed to react with about three equivalents of sodium hydrosulfide in a methanol:water mixture at reflux temperature for about 30 minutes to produce 2-amino-6-nitrobenzoic acid. In some non-limiting embodiments, three equivalents of sodium hydrosulfide may be reacted with one equivalent of the sodium salt of 2,6-dinitrobenzoic acid in refluxing methanol/water followed by acidification.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(=[O:4])=[O:3].C(N(CC)CC)C.[C:21]([C:25]1[N:30]=[CH:29][C:28]([C:31]2[N:32]([C:52](Cl)=[O:53])[C:33]([C:45]3[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=3)([CH3:44])[C:34]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=3)([CH3:36])[N:35]=2)=[C:27]([O:55][CH2:56][CH3:57])[CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>C(Cl)Cl>[C:21]([C:25]1[N:30]=[CH:29][C:28]([C:31]2[N:32]([C:52]([N:11]3[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH2:9][CH2:10]3)=[O:53])[C@@:33]([C:45]3[CH:46]=[CH:47][C:48]([Cl:51])=[CH:49][CH:50]=3)([CH3:44])[C@@:34]([C:37]3[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=3)([CH3:36])[N:35]=2)=[C:27]([O:55][CH2:56][CH3:57])[CH:26]=1)([CH3:22])([CH3:23])[CH3:24]
Reactant: CS(=O)(=O)CCCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-(3-Methanesulfonyl-propyl)-piperazine (30 mg, 0.11 mmol, prepared as described in Fotouhi, N. et al. WO 2005110996) was suspended in 5 mL of methylene chloride and cooled to 0° C. Triethylamine was added followed by drop wise addition of rac-(4S*,5R*)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride in 2 mL of methylene chloride. The mixture was stirred at room temperature for 30 min and then taken up in methylene chloride and washed successively with 10% sodium hydrogen carbonate and water. The methylene chloride phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography on silica gel eluting with methylene chloride/methanol (95:5) gave rac-[(4S*,5R*)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-[4-(3-methanesulfonyl-propyl)-piperazin-1-yl]-methanone as a white solid (16 mg). HR-MS (ES, m/z) calculated for C37H48N5O4SCl2 [(M+H)+] 728.2799, observed 728.2793.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:39](Cl)([O:41]C(=O)OC(Cl)(Cl)Cl)Cl.[F:50][C:51]1[CH:52]=[C:53]([CH:57]=[CH:58][CH:59]=1)[CH:54]([OH:56])[CH3:55]>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:39](=[O:41])[O:56][CH:54]([C:53]1[CH:57]=[CH:58][CH:59]=[C:51]([F:50])[CH:52]=1)[CH3:55]
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(O)c1cccc(F)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OC(C)c4cccc(F)c4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Yield: 33.3 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (98 mg) was added to toluene/triethylamine=10/1 (10 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (150 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-fluoro-α-methylbenzyl alcohol (70 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (49 mg, yield 31%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[OH:9].C(=O)([O-])[O-].[K+].[K+].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([Cl:24])=[CH:19][N:18]=1>O1CCCC1>[Cl:16][C:17]1[N:22]=[C:21]([NH:2][C@@H:3]2[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]2[OH:9])[C:20]([Cl:24])=[CH:19][N:18]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reaction time: 3 h
Yield: 49.8 %

Procedure:
Tetrahydrofuran (100 mL) was added to racemic trans-2-amino-cyclohexanol hydrochloride (4.28 g, 28.2 mmol) and potassium carbonate (12.1 g, 88 mmol). The mixture was cooled at 0° C. before 2,4,5-trichloropyrimidine (2 mL, 17.4 mmol) was added. After 3 hours, the mixture was partitioned between water and ethyl acetate, the aq. layer was extracted and the combined extracts were dried and conc. in vacuo. The crude product was taken up in ethyl acetate and washed with 10% w/v citric acid, then with sodium bicarbonate, dried over sodium sulfate and conc. in vacuo to give rel-(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexanol (2.27 g, 50%) as a white solid. m.p.=139-142° C.; LCMS (m/e) 262 (M+1); 1H-NMR (DMSO-d6, 400 MHz) δ 8.12 (s, 1H), 7.45 (m, 1H), 68 (m, 1H), 3.81 (m, 1H), 3.55 (m, 1H), 1.92 (m, 1H), 1.81 (m, 1H), 1.67 (m, 2H), 1.41 (m, 1H), 1.26 (m, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]#N.[OH-:14].[Na+].[OH2:16]>C(O)C>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([OH:16])=[O:14]
Reactant: N#CCc1ccccc1CCCO
Reactant: O
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)Cc1ccccc1CCCO

Procedure:
A solution of [2-(3-hydroxypropyl)phenyl]acetonitrile (52.5 g., 0.30 mole) and sodium hydroxide (40 g., 1.0 mole) in water (200 ml.) and ethanol (600 ml.) is heated at reflux for 18 hours. The solution is concentrated in vacuo to about half-volume. Water (600 ml.) is added and the resulting solution is acidified with 6N hydrochloric acid. The precipitated product acid is taken up in ether, washed with water, and dried over magnesium sulfate. The ether is evaporated in vacuo to afford [2-(3-hydroxypropyl)phenyl]acetic acid.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([NH2:20])[CH:17]([CH3:19])[CH3:18].[H][H]>C(O)C.CCOCC.[Pd]>[CH2:16]([NH:20][CH2:12][C:11]1[CH:14]=[CH:15][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: CC(C)CN
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOCC
Product: CC(C)CNCc1ccc(Oc2ccccc2)cc1
Yield: 93 %

Procedure:
4-Phenoxybenzaldehyde (10.0 g, 0.05 mmol), excess isobutylamine and 1.0 g of 10% Pd/O in 200 mL of ethanol were stirred under an inert atmosphere for 16 hours followed by an atmosphere of hydrogen for 16 hours. After removal of the catalyst by filtration through Celite®, the filtrate was concentrated under reduced pressure to give the crude product as an oil. The oil was dissolved in ether and precipitated by treatment with anhydrous HCl. The solid was filtered, washed with ether, and partitioned between ethyl acetate and 1M NaOH. The ethyl acetate solution was washed with brine, dried over Na2SO4, and evaporated to give the title compound in 93% yield.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:7][NH:8][C:9]([NH2:11])=[S:10])=[N:4][O:5][N:6]=1.[O-]CC.[Na+].[C:16]([CH2:18][C:19](OCC)=[O:20])#[N:17]>>[NH2:17][C:16]1[N:8]([CH2:7][C:3]2[C:2]([CH3:1])=[N:6][O:5][N:4]=2)[C:9](=[S:10])[NH:11][C:19](=[O:20])[CH:18]=1
Reactant: Cc1nonc1CNC(N)=S
Reactant: CCOC(=O)CC#N
Agent: CC[O-]
Agent: [Na+]
Product: Cc1nonc1Cn1c(N)cc(=O)[nH]c1=S
Yield: 57.5 %

Procedure:
The title compound was prepared in accordance with the general method described in Example 12(b) by using 1-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]thiourea (0.55 g, 3.2 mmol, obtained from Example 16(a)), sodium ethoxide (21% w/v, 3.1 mL, 9.5 mmol) and ethyl cyanoacetate (1.0 mL, 9.5 mmol) which provided the title compound (0.44 g, 58% yield).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])(=[O:21])=[O:20])[CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:29](C=P(CCCC)(CCCC)CCCC)#N.CO>C1(C)C=CC=CC=1>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]([CH3:29])[S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])(=[O:21])=[O:20])[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CCCCP(=CC#N)(CCCC)CCCC
Reactant: Cc1ccccc1S(=O)(=O)N[C@H]1CC[C@H](C(=O)N2CCN(C(C)C)CC2)CC1
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1ccccc1S(=O)(=O)N(C)[C@H]1CC[C@H](C(=O)N2CCN(C(C)C)CC2)CC1

Procedure:
A mixture of 41 mg (0.1 mmol) N-{trans-4-[(4-isopropylpiperazin-1-yl)carbonyl]cyclohexyl}-2-methylbenzenesulfonamide (example 4), 72 mg (0.3 mmol) cyanomethylene tri-n-butylphosphorane and 32 mg (1 mmol) methanol in 2 mL toluene was heated for 16 h to 110° C. After evaporation methanol and DMF were added and the mixture was subjected to preparative HPLC purification on reversed phase eluting with a gradient of acetonitrile/water (0.1% NEt3). The combined product fractions were evaporated to dryness to yield 12.4 mg (29%) of the title compound. MS (m/e): 422.2 (MH+).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH2:10]([O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Br:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:20][CH:21]=2)=[N:3][CH:4]=1
Reactant: Fc1cc(Br)cnc1Br
Reactant: CCCCCCCCOc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc(-c2ncc(Br)cc2F)cc1
Yield: 70 %

Procedure:
12.74 g (50.00 mmol) of 2,5-dibromo-3-fluoropyridine, 12.51 g (50.00 mmol) of 4-octyloxybenzeneboronic acid, 0.58 g (0.50 mmol) of tetrakis(triphenylphosphine)palladium(0) and 10.60 g (100 mmol) of sodium carbonate are heated at 80° C. for 3 hours in 375 ml of toluene, 250 ml of ethanol and 125 ml of water. The mixture is subsequently partitioned between aqueous sodium chloride solution and ether, and the organic phase is washed with aqueous sodium chloride solution, dried over sodium sulfate, evaporated and purified by chromatography (silica gel/hexane : ethyl acetate =9:1), giving 13.31 g of 5-bromo-3-fluoro-2-(4-octyloxyphenyl)pyridine. ##STR15##
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:22])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[CH2:23]([OH:45])[C@H:24]1[O:29][C@H:28]([O:30][C@H:31]2[C@H:36]([OH:37])[C@@H:35]([OH:38])[C@H:34]([OH:39])[O:33][C@@H:32]2[CH2:40]O)[C@H:27]([OH:42])[C@@H:26]([OH:43])[C@@H:25]1[OH:44]>[Pd].CO>[CH2:6]([O:5][CH2:4][CH:3]([OH:22])[CH2:2][N:1]([C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:40][C@@H:32]([C@H:31]([C@@H:36]([C@@H:35]([CH2:34][OH:39])[OH:38])[OH:37])[O:30][C@H:28]1[O:29][C@H:24]([CH2:23][OH:45])[C@@H:25]([OH:44])[C@H:26]([OH:43])[C@H:27]1[OH:42])[OH:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCCCCCCOCC(O)CN
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: [Pd]
Solvent: CO
Product: CCCCCCCCCCCCCCCCOCC(O)CN(C[C@H](O)[C@@H](O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)[C@H](O)[C@H](O)CO)C(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 20 h
Yield: 48 %

Procedure:
A 1-liter eggplant type flask equipped with a reflux condenser was charged with 22.7 g (72 mmol) of 1-amino-3-hexadecyloxy-2-propanol, 23.5 g (69 mmol) of maltose and 350 g of methanol. After stirring the mixture for 20 hours at room temperature under a nitrogen atmosphere, it was heated and stirred at 80° C. for 1 hour. The thus-obtained solution was transferred to a 970-ml autoclave, and 2.26 g of palladium on carbon was added, thereby subjecting the solution to hydrogenolysis at 50° C. for 16 hours under a hydrogen pressure of 100 kg/cm2. The catalyst was removed by filtering the hot mixture, and the filtrate was allowed to cool to form crystals. The crystals were recrystallized again from methanol, thereby obtaining 15.2 g (yield: 33%) of the title compound (2Be) as a colorless solid.