Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15](O)=[CH:16][C:17](=[O:20])[N:18]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:24]>>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([Cl:24])=[CH:16][C:17](=[O:20])[N:18]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)cc(O)c2c(=O)n(Cc3ccccc3)cnc21
Reactant: O=P(Cl)(Cl)Cl
Product: Cn1c(=O)cc(Cl)c2c(=O)n(Cc3ccccc3)cnc21
Yield: 94 %

Procedure:
3-Benzyl-5-hydroxy-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (1.1 g, 3.88 mmol) was dissolved in excess POCl3 (5 mL) and subjected to microwave irradiation at 70° C. for 30 minutes. The POCl3 was removed in vacuo and the residue dissolved in DCM then quickly washed with saturated sodium bicarbonate solution until neutral pH was observed. The organic layer was dried over MgSO4 and evaporated to dryness to give 1.5 g of the title compound as a reddish brown solid (94%). [M+H] calc'd for C15H12ClN3O, 302; found, 302.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@H:11]([CH2:42][C:43]([CH3:48])([CH3:47])[C:44](O)=[O:45])[CH2:10]2)=[CH:5][CH:4]=1.[CH3:49][NH:50][CH3:51]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=3)(=[O:34])=[O:33])[C@H:11]([CH2:42][C:43]([CH3:48])([CH3:47])[C:44]([N:50]([CH3:51])[CH3:49])=[O:45])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: CNC
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C(=O)N(C)C)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
According to general procedure D, 150 mg of 3-[(2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2,2-dimethyl-propionic acid (from example 65b) and dimethylamine are used to afford the title compound as a brown oil. Rf=0.45 (EtOAc-heptane 1:1); Rt=5.27.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([CH2:12][N:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][CH3:15])=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[Br:22].N1C=CC=CC=1.[OH-].[Na+].[CH2:31]([OH:34])[CH2:32][OH:33]>O>[NH2:2][C:3]1[C:11]([CH2:12][N:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][CH3:15])=[CH:10][C:6]([C:7]([O:33][CH2:32][CH2:31][OH:34])=[O:8])=[CH:5][C:4]=1[Br:22]
Reactant: OCCO
Reactant: CCN(Cc1cc(C(=O)Cl)cc(Br)c1N)C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CCN(Cc1cc(C(=O)OCCO)cc(Br)c1N)C1CCCCC1
Temperature: 105 °C

Procedure:
41 gm (0.1 mol) of 4-amino-3-bromo-5-(N-ethylcyclohexylaminomethyl)-benzoyl chloride hydrochloride were dissolved in 250 ml of ethylene glycol, and after addition of 17 gm (0.22 mol) of pyridine the solution was heated to 105° C. for one hour. After cooling to room temperature, the mixture was diluted with 1 liter of water. After addition of aqueous sodium hydroxide the mixture was extracted with ether, the ether extract was dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on silicagel (eluant: ethyl acetate). After evaporation of the eluate, a resin was obtained which was converted into crystals by trituration with petroleum ether. The crystals obtained were recrystallized from ethanol.
Reaction SMILES: [C:1]([C:5]1[O:10][C:9](=O)[CH:8]=[C:7]([OH:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH4+:13].[OH-]>C1(C)C=CC=CC=1>[C:1]([C:5]1[NH:13][C:9](=[O:10])[CH:8]=[C:7]([OH:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC(C)(C)c1cc(O)cc(=O)o1
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(O)cc(=O)[nH]1
Yield: 80 %

Procedure:
A mixture of 6-(tert-butyl)-4-hydroxy-2H-pyran-2-one (38 g, 168 mmol) and aq. NH4OH (150 mL, 30%) in dry toluene (200 mL) was heated at reflux for 1 h. The resulting mixture was concentrated and purified by CC (PE/EA=5/1) to give compound 17a (22.5 g, 80%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9]1([C:15]2[O:16][C:17](=O)[CH2:18][N:19]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>C(O)(=O)C>[C:15]([NH:19][CH2:18][C:17]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1)(=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccccc1S
Reactant: O=C1CN=C(c2ccccc2)O1
Solvent: CC(=O)O
Solvent: O
Product: O=C(NCc1nc2ccccc2s1)c1ccccc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
2-Aminothiophenol (1.2 ml) is added to a solution of 2-phenyl-4,5-dihydro-1,3-oxazol-5-one (1.8 g) in acetic acid (14 ml), and the mixture is stirred for one hour while heating it at 40° C. Water is added to the reaction mixture, and the resulting precipitate is filtered off to give 2-(benzoylaminomethyl)benzothiazole (0.75 g) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:19]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:20]([C:22]2([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]2)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](I)[S:17][C:10]=12.[CH3:35][C:36]([N:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)([C:38]#[CH:39])[CH3:37]>>[F:1][C:2]1[CH:3]=[C:4]([N:19]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:20]([C:22]2([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]2)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:39]#[C:38][C:36]([CH3:37])([N:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)[CH3:35])[S:17][C:10]=12
Reactant: C#CC(C)(C)N1CCCCC1
Reactant: NC(=O)C1(C(=O)N(c2ccc(F)cc2)c2ccc(Oc3ccnc4cc(I)sc34)c(F)c2)CC1
Product: CC(C)(C#Cc1cc2nccc(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccc(F)cc4)cc3F)c2s1)N1CCCCC1
Yield: 38.5 %

Procedure:
Prepared from N-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Example 12, Step A, 20 mg, 0.0338 mmol) and 1-(2-methylbut-3-yn-2-yl)piperidine (10.2 mg, 0.0676 mmol) using the procedure described for Example 6, Step B. The crude was purified by preparative TLC (1 mm thickness, Rf=0.34) eluting with 10% MeOH/DCM. A second purification by preparative TLC was conducted (0.5 mm thickness, Rf=0.49), eluting with 15% MeOH in EtOAc, in order to obtain product of adequate purity. The product was obtained as a beige powder (8 mg, 38%). HPLC: 98% purity (254 nm); LCMS (APCI−): 100% purity, 220 nm, m/z 613 (M−1) detected; 1H NMR (400 MHz, CDCl3) δ 10.04 (s, 1H), 8.48 (d, J=6 Hz, 1H), 8.15 (s, 1H), 7.74 (m, 1H), 7.55 (s, 1H), 7.45 (m, 2H), 7.24 (m, 2H), 7.07 (t, J=9 Hz, 2H), 6.50 (d, J=6 Hz, 1H), 2.66 (br s, 4H), 1.81 (m, 2H), 1.64 (m, 6H), 1.51 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[C:7](O)=[C:6]([I:9])[CH:5]=[C:4]([CH:10]([OH:12])[CH3:11])[N:3]=1.[H-].[Na+].[CH2:15](Br)[CH:16]=[CH2:17].C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[C:7]([CH2:17][CH:16]=[CH2:15])=[C:6]([I:9])[CH:5]=[C:4]([CH:10]([OH:12])[CH3:11])[N:3]=1
Reactant: CC(O)c1cc(I)c(O)c(Cl)n1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCc1c(I)cc(C(C)O)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A solution of 2-chloro-3-hydroxy-4-iodo-6-(1-hydroxyethyl)-pyridine (3.6 g, 12 mmol) in 24 mL of N,N-dimethylformamide at 0° C. is treated with 480 mg (60% in oil, 12 mmol) of sodium hydride and stirred at room temperature for 1 h. The reaction is treated with 1.14 g (13.2 mmol) of allyl bromide and stirred for 2 h. The mixture is poured into 125 mL of ethyl acetate and washed with 4×50 mL of saturated sodium chloride, 2×25 mL of 50% saturated sodium carbonate and dried over potassium carbonate. The dried organics are concentrated in vacuo, diluted with 20 mL of hexanes, and chilled to -15° C. The solid is filtered to provide 3.61 g (89%) of 2-chloro-3-(1-propen-3-yl)-4-iodo-6-(1-hydroxyethyl)-pyridine.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:18][CH:17]=2)[C:13](=[O:35])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:36]([O-])=O)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[H][H]>CO.[Pd]>[NH2:36][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:14]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:18][CH:17]=1)[C:13]2=[O:35]
Reactant: CCCCc1nc2ccc([N+](=O)[O-])cc2c(=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCCc1nc2ccc(N)cc2c(=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
0.11 g (0.21 mmol) of 2-butyl-3-[(2'-(t-butoxycarbonyl)biphen-4-yl)methyl]-6-nitroquinazolin-3(1H)-one (Example 27) was suspended in 7.5 mL of MeOH and hydrogenated over 55 mg of 10% Pd/C under an atmospheric pressure hydrogen blanket. After 1 hour the reaction mixture was filtered through celite and the filtrate concentrated in vacuo. The residue was purified by flash chromatography over silica gel eluting with 50% EtOAc/hexane to give a white foam. 1H-NMR (CDCl3): 0.94 (t, 3H, J=7. Hz), 1.23 (s, 9H), 1.41 (m, 2H), 1.79 (m, 2H), 2.74 (3 line m, 2H, J=7.7 Hz), 5.44 (bs, 2H), 7.05-7.57 (m, 10H), 7.77 (d, J=7.5 Hz).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[C:10](Cl)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([NH:5][C:6]1[CH:11]=[C:10]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Nc1cc(Cl)ncn1
Reactant: COc1ccc(N)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(Nc2cc(NC(C)(C)C)ncn2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 48 %

Procedure:
50 mg of N-tert-butyl-6-chloropyrimidin-4-amine, 39 mg of p-anisidine, 104 mg of CsCO3, 1.2 mg of Pd(OAc)2 and 3 mg of BINAP were taken in a screw cap vial under argron in 2 mL of dry toluene and the vial obtained was kept in a heating block at 150° C. for 12 hours. The mixture obtained was cool to r.t. and purification was carried out by column chromatography using 30% EtOAc in PE. N4-tert-Butyl-N6-(4-methoxyphenyl)pyrimidine-4,6-diamine was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH:11]([OH:12])[CH:10]([C:13]2[C:14](=[O:26])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=[CH:17][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:27]#[N:28])[CH:8]=2)[O:3]1.P(=O)(O)(O)[OH:31]>>[CH3:1][C:2]1([CH3:29])[CH:11]([OH:12])[CH:10]([C:13]2[C:14](=[O:26])[N:15]([CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:16]=[CH:17][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:27](=[O:31])[NH2:28])[CH:8]=2)[O:3]1
Reactant: CC1(C)Oc2ccc(C#N)cc2C(c2cccn(Cc3ccccc3)c2=O)C1O
Reactant: O=P(O)(O)O
Product: CC1(C)Oc2ccc(C(N)=O)cc2C(c2cccn(Cc3ccccc3)c2=O)C1O

Procedure:
A mixture of 1 g of 2,2-dimethyl-4-(1-benzyl-1,2-dihydro-2-oxo-3-pyridyl)-6-cyano-3-chromanol and 10 ml of 85 percent phosphoric acid is warmed to 100° for 2 hours. After cooling and working up in the customary manner, there is obtained 2,2-dimethyl-4- (1-benzyl-1,2-dihydro-2-oxo-3-pyridyl)-6-carbamoyl -3-chromanol, m.p. 230°-235°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8]Br)[CH:7]=1.[CH3:10][S-:11].[Na+]>CCO>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][S:11][CH3:10])[CH:7]=1
Reactant: BrCc1cncc(Br)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCO
Product: CSCc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 91.7 %

Procedure:
3-Bromo-5-bromomethyl-pyridine (7.5 g, 30 mmol) is dissolved in EtOH (200 mL). The solution is cooled down to 0° C. Sodium thiomethoxide (3.1 g, 45 mmol) is added slowly and the reaction mixture is stirred for 16 hrs. Then the solvent is removed, water and EtOAc are added. The aqueous layer is separated and extracted with EtOAc. Organic layers are combined and concentrated to give 6.0 g of the 3-bromo-5-methylsulfanylmethyl-pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:22]=1.N1C=CC=CC=1.[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[CH2:34][C:35](Cl)=[O:36]>C(Cl)Cl>[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[CH2:34][C:35]([N:19]1[CH2:18][CH2:17][C:16](=[C:15]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]3[CH:22]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]2=3)[CH2:21][CH2:20]1)=[O:36]
Reactant: Clc1ccc2c(c1)CCc1cccnc1C2=C1CCNCC1
Reactant: O=C(Cl)Cc1cccs1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cc1cccs1)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1

Procedure:
To a solution of 1.0 gm (3.22 mmole) of 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta [1,2-b]pyridin-11-ylidene) piperidine and 0.29 mL of pyridine in 20 mL of dry CH2Cl2 at 0° C. and under an argon atmosphere was added dropwise 0.438 mL (3.55 mmol) of 2-thiopheneacetyl chloride. After 30 minutes the mixture was washed with 1.0N aqueous NaOH and then brine. The organic portion was dried over Na2SO4, filtered and converted in vacuo to provide a residue which was purified via flash chromatography (3% MeOH in CH2Cl2) and treated with activated carbon to provide the title compound as a glass.
Reaction SMILES: [OH:1][NH:2][CH:3]([CH2:13][S:14]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]#[C:30][C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)=[CH:25][N:24]=2)[CH2:19][CH2:18]1)(=[O:16])=[O:15])[CH2:4][CH2:5][CH2:6][C:7]1[N:12]=[CH:11][CH:10]=[CH:9][N:8]=1.C1C[O:39][CH2:38]C1>>[OH:1][N:2]([CH:3]([CH2:13][S:14]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]#[C:30][C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)=[CH:25][N:24]=2)[CH2:19][CH2:18]1)(=[O:16])=[O:15])[CH2:4][CH2:5][CH2:6][C:7]1[N:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH:38]=[O:39]
Reactant: O=S(=O)(CC(CCCc1ncccn1)NO)N1CCN(c2ccc(C#Cc3cccs3)cn2)CC1
Reactant: C1CCOC1
Product: O=CN(O)C(CCCc1ncccn1)CS(=O)(=O)N1CCN(c2ccc(C#Cc3cccs3)cn2)CC1
Temperature: 40 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
and a solution of 2-[4-(hydroxyamino)-5-({4-[5-(thien-2-ylethynyl)pyridin-2-yl]piperazin-1-yl}sulfonyl)pentyl]pyrimidine (84 mg, 0.16 mmol) in THF (8 mL) was then added. The reaction was brought to RT and stirred for one hour. Volatiles were then removed in vacuo, and the residue azeotroped with toluene (2×5 mL). The residue was then dissolved in MeOH (10 mL) and heated to 40° C. for one hour. The solution was then cooled to RT and concentrated in vacuo. The residue was then purified by flash chromatography (silica gel, 10% MeOH in EtOAc) to give the title compound as an off-white foam (87 mg, 0.16 mmol, 54%).
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]([NH2:7])=[S:6])=[S:3].[CH2:8](Br)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>COCCO>[CH2:8]([SH:3]=[C:2]([NH:4][C:5]([NH2:7])=[S:6])[NH2:1])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: NC(=S)NC(N)=S
Reactant: CCCCCCCCBr
Solvent: COCCO
Product: CCCCCCCC[SH]=C(N)NC(N)=S
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The S-octyldithiobiuret was prepared as follows: To 135 g of dithiobiuret in 300 ml ethyleneglycol monomethyl ether were added 210 g of n-octyl bromide dropwise at 70°C. After 12 hours the solvent was distilled off at 12 mm. The residue was dissolved in toluene and hexane was added after which the mixture was cooled at 0°C. The solvent was decanted from the semicrystalline precipitate which was dissolved again in glacial acetic acid. The solution was poured on icewater and stirred for 2 hours. The solid was filtered, stirred with hexane in a beaker until it had completely crystallized, filtered and dried. The product had a melting point of 75°-77°C.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([O:10][CH:11]([CH3:15])[C:12](Cl)=[O:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>O1CCCC1>[C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([O:10][CH:11]([CH3:15])[C:12]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OC(C)C(=O)Cl)cc1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OC(C)C(=O)N2CCOCC2)cc1

Procedure:
7.5 g (30 mmol) of 2-[(4-tolylsulfonyl)oxy]-propionyl chloride are dissolved in 15 ml of tetrahydrofuran in a flask. 6.5 g (80 mmol) of morpholine are then slowly added dropwise at 0°-5° C., with stirring and simultaneous cooling. The mixture is then subsequently stirred at 0° C., poured onto ice and extracted with diethyl ether. The organic phase is separated off, dried with Na2SO4 and concentrated in a rotary vacuum evaporator. The light yellow residue is separated on a silica gel column (eluting agent: hexane/ethyl acetate 1:1). White crystals of melting point 75°-77° C. then result.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3]1.[BH4-].[Na+].Cl>CO>[OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:3]1
Reactant: CCOC(=O)C1CCC(=O)C=C1c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C1CCC(O)C=C1c1ccccc1
Reaction time: 0.75 h
Yield: 99.8 %

Procedure:
To a stirred solution of ethyl 4-oxo-2-phenylcyclohex-2-enecarboxylate(500 mg, 2.05 mmol) in MeOH(10 ml) at 0° C., NaBH4(77.5 mg, 2.05 mmol) was added by portions. After stirring for 45 minutes, dil.HCl aq. was added to the reaction mixture and the solvent was evaporated under reduced pressure. The residue was added water and extracted with AcOEt. The organic layer was washed with water and brine, dried over MgSO4. Concentration of the organic layer afford 504 mg of ethyl 4-hydroxy-2-phenylcyclohex-2-enecarboxylate(y=100%) as a pale yellow crystal. 1H-NMR(ppm, 300 MHz, CDCl3) δ 7.23-7.34(5H, m), 6.10-6.22(1H, m), 4.30-4.50(1H, m), 3.90-4.08(1H, m), 3.72 and 3.64(1H, t and t, J=5.8 and 5.3 Hz), 1.60-2.30(4H, m), 1.00 and 1.10(3H, m).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH2:22][CH2:23][O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=1)=[O:5])[CH3:2].O1CCCC1>[Pd].C(O)C>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[C:17]([CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(-n2cnc3ccc(C=CCCOCc4ccccc4)cc32)nc1-c1cccc(Cl)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(-n2cnc3ccc(CCCCOCc4ccccc4)cc32)nc1-c1cccc(Cl)c1
Yield: 76.1 %

Procedure:
A mixture of 0.568 g of 2-[6-(-benzyloxy-but-1-enyl)-benzoimidazol-1-yl]-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid ethyl ester (I.41b), 5 mL of tetrahydrofuran, 5 mL of ethanol, and 0.30 g of 10% palladium on carbon catalyst was hydrogenated at 50 psi overnight. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol-dichloromethane (gradient 0:100-2:98) to give 0.434 g of 2-[6-(4-benzyloxy-butyl)-benzoimidazol-1-yl]-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid ethyl ester (I.41c) as white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][O:1][C:2]2[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=2)=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(O)cn1
Reactant: Clc1ccc(CBr)cc1
Product: O=[N+]([O-])c1ccc(OCc2ccc(Cl)cc2)cn1

Procedure:
The substituted amino-pyridine compounds of formula (I) wherein W is oxygen can be prepared by the reaction of a hydroxy-nitropyridine with a substituted phenalkyl halide to obtain the corresponding substituted nitro-pyridine which is reduced to the desired substituted amino-pyridine of formula (I). For example, the reaction of 5-hydroxy-2-nitropyridine and 4-chlorobenzyl bromide gives 5-(4-chlorobenzyloxy)-2-nitropyridine which is then reduced to 2-amino-5-(4-chlorobenzyloxy)-pyridine of formula I. Alternatively, the compounds of formula I can be prepared by the reaction of a halo-nitropyridine with a substituted phenalkyl alcohol or substituted phenalkyl thiol followed by reduction of the nitro group. For example, the reaction of 2-chloro-5-nitropyridine and 4-bromobenzyl alcohol gives 2-(4-bromobenzyloxy)-5-nitropyridine which is then reduced using, for example, iron powder to give 5-amino-2-(4-bromobenzyloxy)pyridine of formula (I).
Reaction SMILES: [OH:1][CH:2]([CH3:6])[C:3]([NH2:5])=[O:4].[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:7]([O:1][CH:2]([CH3:6])[C:3]([NH2:5])=[O:4])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(O)C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(OC(=O)c1ccccc1)C(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.6 %

Procedure:
To a solution of 2-hydroxypropionamide (10.8 g, 121 mmol) in pyridine (40 mL) was added benzoyl chloride (14.2 mL, 122 mmol) at 0° C. and the reaction mixture was allowed to warm up to room temperature. The resulting mixture was stirred at room temperature for 3 hours and the solvent was removed under reduced pressure to give a residue. To the residue an aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The extracts were washed with an 1N hydrochloric acid twice and brine. The organic solution was dried, and concentrated under reduced pressure. The obtained crude crystal was recrystallized from ethyl acetate-hexane to give a title compound (17.9 g, yield 77%).