Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[Si](C)(C)C.C([O:8][P:9]([CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:31]3[C:32]4[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=4[S:34][C:30]=3[CH:29]=[C:28]3[C:23]=2[CH:24]=[CH:25][CH:26]=[CH:27]3)=[CH:18][CH:17]=1)(=[O:13])[O:10]CC)C>C(Cl)Cl>[CH:38]1[C:32]2[C:31]3[C:22]([C:19]4[CH:20]=[CH:21][C:16]([O:15][CH2:14][P:9](=[O:8])([OH:10])[OH:13])=[CH:17][CH:18]=4)=[C:23]4[C:28](=[CH:29][C:30]=3[S:34][C:33]=2[CH:35]=[CH:36][CH:37]=1)[CH:27]=[CH:26][CH:25]=[CH:24]4
Reactant: CCOP(=O)(COc1ccc(-c2c3ccccc3cc3sc4ccccc4c23)cc1)OCC
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: O=P(O)(O)COc1ccc(-c2c3ccccc3cc3sc4ccccc4c23)cc1
Reaction time: 1 h
Yield: 84.5 %

Procedure:
Iodotrimethylsilane (0.78 mL, 5.49 mmol) was added to a 0-5° C., stirred solution of [4-(benzo[b]naphtho [2,3-d]thiophen-11-yl)-phenoxymethyl]-phosphonic acid diethyl ester (0.871 g, 1.83 mmol) in methylene chloride (24 mL) under a try N2 atmosphere over a period of 10 min. After 1 h, the solution was quenched with water (0.6 mL), 10% aqueous sodium carbonate (100 mL) was added and mixture was washed with methylene chloride. The aqueous layer was acidified with 10% aqueous HCl. The solid was filtered and recrystallized from methanol (75 mL) to provide the title compound as a white solid (0.65 g, 85%): mp 240-242° C.: MS (EI): [M+], 420; Anal. Calc. for C23H17O4PS: C, 65.17, H, 4.08, N, 0.00. Found: C, 63.95, H, 3.89, N, 0.41.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][C:9]#[CH:10])SC)#[N:2].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][S:18][CH2:19][CH2:20][NH2:21]>>[C:1]([NH:3][C:4]([NH:7][CH2:8][C:9]#[CH:10])=[N:21][CH2:20][CH2:19][S:18][CH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=1)#[N:2]
Reactant: C#CCN=C(NC#N)SC
Reactant: NCCSCc1ccccn1
Product: C#CCNC(=NCCSCc1ccccn1)NC#N

Procedure:
The product of Step A is reacted with about an equimolar amount of 2-[(2-pyridyl)methylthio]ethylamine in a nonreactive solvent to give after workup, the title product.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36](O)=[O:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1>>[CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][N:6]([C:36]([C:31]3[C:30]([C:27]4[CH:26]=[CH:25][C:24]([F:23])=[CH:29][CH:28]=4)=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:37])[C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CC(C)C[C@@H]21
Reactant: O=C(O)c1ccccc1-c1ccc(F)cc1
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2CC(C)C[C@H]2CN1C(=O)c1ccccc1-c1ccc(F)cc1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with commercially available 4′-fluoro-biphenyl-2-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:36][C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:40]([O:39][C:37](=[O:38])[CH2:36][O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1)([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(O)c4)nc4ccccc34)ccc21
Reactant: CC(C)OC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)COc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1

Procedure:
A suspension of tert-butyl 5-(2-(3-hydroxyphenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (120 mg, 0.26 mmol), isopropyl 2-chloroacetate (45 mL, 0.36 mmol), K2CO3 (125 μL, 0.24 mmol), in DMF (5 mL) stirred at RT for 2 h. Concentrated in vacuo to afford the crude tert-butyl 5-(2-(3-(2-isopropoxy-2-oxoethoxy)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate ( ). (0.26 mmol)
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@@H:12]([OH:21])[CH2:11][CH2:10]4)[C@H:7]([CH2:22]C=C)[CH2:6][C:5]=2[CH:4]=1.[F:25][C:26]([F:47])([C:43]([F:46])([F:45])[F:44])[CH2:27][CH2:28][CH2:29][CH:30]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH:41]=[CH2:42])[C:31]([O:33]CC)=[O:32]>>[OH:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@@H:12]([OH:21])[CH2:11][CH2:10]4)[C@H:7]([CH2:22][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH:30]([CH2:29][CH2:28][CH2:27][C:26]([F:25])([F:47])[C:43]([F:44])([F:45])[F:46])[C:31]([OH:33])=[O:32])[CH2:6][C:5]=2[CH:4]=1
Reactant: C=CC[C@@H]1Cc2cc(OC)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Reactant: C=CCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O)[C@H]3[C@@H]1CC[C@@H]2O

Procedure:
Starting with the 3-methoxy-7α-(2-propenyl)estra-1,3,5(10)-trien-17β-ol prepared in Example 13 and ethyl 2-(4,4,5,5,5-pentafluoropentyl)-8-nonenoate prepared separately, the same procedure as shown in Example 13 was repeated to give 10-[3,17β-dihydroxyestra-1,3,5(10)-trien-7α-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoic acid.
Reaction SMILES: [Li].C[Cu]C.O1CCC[CH2:6]1.[CH2:10]([O:17][C:18]1[CH:23]=[C:22]([C:24]([CH3:32])([CH3:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:21]=[CH:20][C:19]=1[C:33]1[CH2:38][CH2:37][CH2:36][C:35](=[O:39])[CH:34]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+]>CCOCC>[CH2:10]([O:17][C:18]1[CH:23]=[C:22]([C:24]([CH3:31])([CH3:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:21]=[CH:20][C:19]=1[C:33]1([CH3:6])[CH2:38][CH2:37][CH2:36][C:35](=[O:39])[CH2:34]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCCCCCC(C)(C)c1ccc(C2=CC(=O)CCC2)c(OCc2ccccc2)c1
Reactant: C1CCOC1
Agent: C[Cu]C
Agent: [Cl-]
Agent: [Li]
Solvent: CCOCC
Product: CCCCCCC(C)(C)c1ccc(C2(C)CCCC(=O)C2)c(OCc2ccccc2)c1
Reaction time: 0.5 h

Procedure:
To a -10° C. to -5° C. solution of 4.17 mmoles of dimethylcopper lithium in 10 ml. of tetrahydrofuran was slowly added 5.60 g. (1.39 mmoles) of 3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]cyclohex-2-enone in 5 ml. of tetrahydrofuran. The reaction mixture was stirred for 30 minutes longer and was then added to 100 ml. of saturated ammonium chloride and 100 ml. of ether. After stirring for 10 minutes the quenched reaction was extracted with 200 ml. of ether. The ether extract was washed with 100 ml. of saturated sodium chloride, dried over magnesium sulfate and evaporated to an oil. The oil was purified via preparative layer chromatography on three 20 cm.×20 cm.×2 mm. silica gel plates eluted with 2:1 cyclohexane:ether to yield 282 mg. (48%) (higher Rf) of the title compound, as an oil, and 211 mg. (36%) (lower Rf) of 3-[ 2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-1-methylcyclohex-2-en-1-ol, as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:18]([CH3:19])[C:17]3[C:12](=[N:13][C:14]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:15][CH:16]=3)[N:11]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:10]2=[O:33])=[CH:5][CH:4]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:18]([CH3:19])[C:17]3[CH:16]=[N:15][C:14]([N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:34](=[O:36])[CH3:35])=[N:13][C:12]=3[N:11]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:10]2=[O:33])=[CH:5][CH:4]=1
Reactant: COc1ccc(N2C(=O)N(c3ccccc3)c3nc(Nc4ccccc4)ncc3C2C)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1ccc(N2C(=O)N(c3ccccc3)c3nc(N(C(C)=O)c4ccccc4)ncc3C2C)cc1
Temperature: 90 °C

Procedure:
To a suspension of (±)-3-(4-methoxy-phenyl)-4-methyl-1-phenyl-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (500 mg, 1.14 mmol) (from Example 1g supra) in pyridine (1 mL) (Fisher) was added acetic anhydride (1.0 mL) followed by addition of 4-(dimethylamino)pyridine (25 mg) (Aldrich) in one portion. The reaction mixture was heated to 90° C. for 5 hours until no starting material was detectable by TLC analysis. The reaction mixture was quenched with water and extracted with ethyl acetate (3×50 mL). The combined organic extracts were successively washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product which was purified by flash chromatography to give (±)-N-[6-(4-methoxy-phenyl)-5-methyl-7-oxo-8-phenyl-5,6,7,8-tetrahydro-pyrimido[4,5-d]pyrimidin-2-yl]-N-phenyl-acetamide. (Yield 373 mg, 68.0%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9].C1(C)C=CC=CC=1.C([O:19][C:20](=O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])C.[OH-].[Na+]>C(OCC)(=O)C.O>[CH3:9][N:5]1[CH2:6][CH2:7][CH2:8][CH:4]1[CH2:3][CH2:2][NH:1][C:20](=[O:19])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCC(=O)OCC
Reactant: CN1CCCC1CCN
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCC(=O)NCCC1CCCN1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.5 %

Procedure:
Toluene (1.0 ml), dried using MS 4A, was mixed with 1.48 ml of a n-hexane solution of 15% Me3Al. With the mixture being cooled in an ice-methanol bath, 0.25 ml (1.16 mmols) of 2-(2-aminoethyl)-1-methylpyrrolidine was added dropwise over about 2 minutes. After stirring for 20 minutes, the temperature was raised to room temperature, and 0.5 ml of a toluene solution of 0.2 g (1.16 mmols) of caprylic acid ethyl ester was added dropwise over 1 minute. After stirring for 2 hours at 70° C., the mixture was cooled with ice, and 10 ml of 1N NaOH was added dropwise. The mixture was stirred for 10 minutes, and water and ethyl acetate were added. Then, the mixture was separated into respective layers, and the organic layer was washed twice with 20 ml of a saturated aqueous solution of sodium chloride. After this layer was dried over anhydrous magnesium sulfate, it was concentrated under reduced pressure on a 30° C. water bath to obtain the captioned compound (yield 0.22 g). This compound was subjected to silica gel column chromatography (mobile phase: CHCl3:MeOH (19:1→9:1)) for purification. NMR and mass spectrum confirmed the purified compound to have the following structure:
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22])[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:23]2[CH2:26][CH2:25][CH2:24]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:27]([OH:29])[CH3:28].[ClH:30]>ClCCl>[ClH:30].[CH2:27]([O:29][C:21](=[NH:22])[CH2:20][CH2:19][CH2:18][CH2:17][N:14]1[CH2:13][CH2:12][N:11]([C:9]2[CH:8]=[C:7]([CH:23]3[CH2:26][CH2:25][CH2:24]3)[N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[N:10]=2)[CH2:16][CH2:15]1)[CH3:28]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCC#N)CC2)n1
Reactant: CCO
Agent: Cl
Solvent: ClCCl
Product: CCOC(=N)CCCCN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1.5 g of 5-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-pentanenitrile (4.22 mmol) were dissolved in 40 ml of dichloromethane and 0.4 g of dry ethanol (8.7 mmol). Gaseous hydrochloric acid was introduced into the solution until saturation at 0° C. The reaction was stirred for 15 h at room temperature and concentrated to dryness. The resulting crude product (2.18 g) was directly used in the next reaction step.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[NH2:13][C:14]1[S:15][C:16]([S:19][CH2:20][C:21]2[O:22][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:24][N:25]=2)=[CH:17][N:18]=1.[CH3:30][CH:31]([N:33]1[CH2:38][CH2:37][CH:36]([C:39](O)=[O:40])[CH2:35][CH2:34]1)[CH3:32].CN(C)C=O>CN(C)C1C=CN=CC=1.O.C(Cl)Cl>[CH3:27][C:26]([C:23]1[O:22][C:21]([CH2:20][S:19][C:16]2[S:15][C:14]([NH:13][C:39]([CH:36]3[CH2:37][CH2:38][N:33]([CH:31]([CH3:32])[CH3:30])[CH2:34][CH2:35]3)=[O:40])=[N:18][CH:17]=2)=[N:25][CH:24]=1)([CH3:29])[CH3:28]
Reactant: CC(C)(C)c1cnc(CSc2cnc(N)s2)o1
Reactant: CC(C)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)N1CCC(C(=O)Nc2ncc(SCc3ncc(C(C)(C)C)o3)s2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.0 g, 5.2 mmol, 2 eq) was added to a mixture of 2-amino-5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]thiazole (0.7 g, 2.6 mmol, 1 eq), 1-(1-methylethyl)-4-piperidine carboxylic acid (0.78 g, 3.9 mmol, 1.5 eq), 4-(dimethylamino)pyridine (0.16 g, 1.3 mmol, 0.5 eq), N,N-dimethylformamide (2.6 mL) and CH2Cl2 (7.8 mL). The reaction mixture was stirred at rt for 1 h, diluted with 30 mL of water and extracted with ethyl acetate (2×70 mL). The organic extracts were dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography on silica gel eluting with a gradient of 5-10% triethylamine in ethyl acetate. The material was recrystallized from ethanol and water to provide 0.93 g (85%) of N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]-methyl]thio]-2-thiazolyl]-1-(1-methylethyl)-4-piperidinecarboxamide as a yellowish solid. MS: 423 [M+H]+; HPLC: 100% at 3.15 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][NH:13][C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[O:15])=[N:2]1.C(N(C(C)C)CC)(C)C.[Cl:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([Cl:41])[CH:40]=1)[C:35](Cl)=[O:36]>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][NH:13][C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:35](=[O:36])[C:34]3[CH:33]=[C:32]([Cl:31])[CH:40]=[C:39]([Cl:41])[CH:38]=3)[CH2:17]2)=[O:15])=[N:2]1
Reactant: O=C(NCCNc1nsc2ccccc12)C1CCCNC1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCNc1nsc2ccccc12)C1CCCN(C(=O)c2cc(Cl)cc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.1 %

Procedure:
N-(2-(Benzo[d]isothiazol-3-ylamino)ethyl)piperidine-3-carboxamide (75 mg, 0.24 mmol) was dissolved in anhydrous dichloromethane (5 mL) with diisopropylethylamine (38 μL, 0.27 mmol). The solution was cooled on an ice-water bath and then a solution of 3,5-dichlorobenzoyl chloride (57 mg, 0.27 mmol) in dichloromethane (0.5 mL) was added dropwise. The reaction mixture was allowed to stir overnight while warming to room temperature. The solution was washed with saturated sodium bicarbonate solution and brine, then dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. Purification by column chromatography, on silica gel, eluting with a mixture of 25% ethyl acetate in hexanes and selected fractions were combined and concentrated under reduced pressure to yield N-(2-(benzo[d]isothiazol-3-ylamino)ethyl)-1-(3,5-dichlorobenzoyl)piperidine-3-carboxamide (23 mg). 1H NMR (300 MHz, CDCl3): 7.8 (m, 1H), 7.5 (m, 1H), 7.3 (m, 2H), 7.1 (m, 1H), 6.3 (m, 1H), 3.7 (m, 4H), 3.3 (m, 2H), 2.5 (m, 1H), 1.8 (m, 1H), 1.6 (m, 3H) 1.1 ppm (m, 1H). MW=477 confirmed by LC-MS, tr=3.93 min (Method Y) MH+=478.
Reaction SMILES: [CH3:1][N:2]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=S)[C:20]1[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:23]([OH:30])=[C:22]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:21]=1)[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:13][O:14][C:8]=2[CH:7]=1.[H-].[Na+].C(I)C.[N:41]#[C:42][NH2:43]>O1CCCC1>[C:42]([NH:43][C:19](=[N:18][CH2:17][CH2:16][CH2:15][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:13][O:14][C:8]=2[CH:7]=1)[C:20]1[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:23]([OH:30])=[C:22]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:21]=1)#[N:41]
Reactant: CN(CCCNC(=S)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)CCOc1ccc2c(c1)OCO2
Reactant: N#CN
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCI
Product: CN(CCCN=C(NC#N)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)CCOc1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
To a solution of N-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl]amino]propyl]-3,5-di-tert-butyl-4-hydroxybenzothioamide (1.0 g) obtained in Example 60 in dry tetrahydrofuran was added sodium hydride (0.16 g) at 0° C. under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 1 hour. To the mixture was added ethyl iodide (0.31 g), followed by stirring at room temperature for 2 hours. The mixture was again cooled to 0° C., and cyanamide (0.84 g) was added thereto, followed by stirring at room temperature for 15 hours. After completion of the reaction, the mixture was poured into ice-water, and the product was extracted with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; chloroform-methanol, 99:1) to afford 0.70 g (69%) of the title compound as pale yellow crystals. mp 129-130° C. NMR (CDCl3) (200 MHz) δ: 1.45 (18H, s), 1.6-2.1 (2H, m), 2.20 (3H, s), 2.6-3.0 (4H, m), 3.6-3.8 (2H, m), 3.83 (2H, t, J=5.7 Hz), 5.56 (1H, s), 5.84 (2H, s), 5.8-6.8 (3H, m), 7.48 (2H, s), 8.44 (1H, brs)
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][CH:7]([C:11]1[CH:16]=[CH:15][C:14](OCCN(CC)CC)=[CH:13][CH:12]=1)[CH2:8][CH2:9][CH3:10])=[O:5])#[N:2].C1([C@@H](N)CCC)C=CC=CC=1>>[C:1]([CH2:3][C:4]([NH:6][C@H:7]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:8][CH2:9][CH3:10])=[O:5])#[N:2]
Reactant: CCCC(NC(=O)CC#N)c1ccc(OCCN(CC)CC)cc1
Agent: CCC[C@H](N)c1ccccc1
Product: CCC[C@H](NC(=O)CC#N)c1ccccc1
Yield: 58 %

Procedure:
The title compound was prepared by using a similar procedure as described for the preparation of 29 except that (S)-1-phenylbutylamine was used instead of 1-(4-(2-(diethylamino)ethoxy)phenyl)butan-1-amine (25). This produced crude product which was purified by flash silica gel column chromatography, eluting with 7:3 hexanes/ethyl acetate, to give 39 (375 mg, 58%) as a white solid: MS (ES+) m/z 217.1.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[NH:8][C:4]=2[CH:3]=1.[H-].[Na+].[N+]([C:17]1[O:21][C:20]([CH:22]=[O:23])=[CH:19][CH:18]=1)([O-])=O.O>O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([S:9][C:17]3[O:21][C:20]([CH:22]=[O:23])=[CH:19][CH:18]=3)[NH:8][C:4]=2[CH:3]=1
Reactant: Sc1nc2ccc(Cl)cc2[nH]1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(Sc2nc3ccc(Cl)cc3[nH]2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
Aldehyde intermediate preparation: 5-Chloro-2-mercaptobenzimidazole (1.5 g, 8.12 mmol) dissolved in 10 ml of anhydrous tetrahydrofuran is added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil, 0.325 g, 8.12 mmol) in anhydrous tetrahydrofuran (20 ml) at 10° C. over a 15 minute period. The reaction mixture is stirred for 2 hours at room temperature. Then 5-nitro-2-furaldehyde (1.146 g, 8.12 mmol) dissolved in 20 ml of anhydrous tetrahydrofuran is added dropwise over a 15 minute period and the reaction mixture is stirred at room temperature for an additional 16 hour period. The reaction mixture is then poured into 300 ml of water and extracted twice with 150 ml of ethyl acetate. The combined organic extracts are dried over MgSO4 and concentrated under reduced pressure. The residue is purified on a silica gel column (120 g) eluted with a mixture of cyclohexane and ethyl acetate (80/20, v/v) to yield 1.9 g of 5-(6-chloro-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde. Yield=88%. Analytical LC/MS (method B): retention time=3.40 min., m/z=278.95/1Cl (positive ion mode).
Reaction SMILES: [C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:23](Cl)=[N:24][C:25]5[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=5[CH3:32])[CH2:19][CH2:18]4)[S:15][CH:16]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:34]>ClCCl>[C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:23](=[NH:34])[NH:24][C:25]5[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=5[CH3:32])[CH2:19][CH2:18]4)[S:15][CH:16]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C)c(N=C(Cl)N2CCC(c3nc(C4=NOC(c5ccccc5)C4)cs3)CC2)c1
Reactant: N
Solvent: ClCCl
Product: Cc1ccc(C)c(NC(=N)N2CCC(c3nc(C4=NOC(c5ccccc5)C4)cs3)CC2)c1
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
A mixture of 4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]-N-(2,5-dimethylphenyl)-1-piperidinecarboximidoyl chloride (i.e. the product of Step B) (0.300 g, 0.63 mmol) in dichloromethane (4 mL) was added dropwise to a solution of ammonia in mathanol (7M, 10 ml) which was cooled to 0° C. The reaction mixture was stirred for 2 minutes, concentrated under reduced pressure, and the resulting tan solid portioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic layer was dried and concentrated under reduced pressure to give of the title, a compound of the present invention, compound as a foamy white solid (0.25 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[N:10]=1)[C:5](Cl)=[O:6].[Li+].[BH4-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:8]=[C:9]([Cl:11])[N:10]=1
Reactant: O=C(Cl)c1cc(Cl)nc(Cl)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc(Cl)nc(Cl)c1
Temperature: 0 °C

Procedure:
2,6-Dichloro-isonicotinoyl chloride (11-1, 2.31 g, 11.0 mmol) was dissolved in 20 mL of anhydrous THF in an oven dried flask under N2. The solution was cooled to 0° C. and LiBH4 (2 M solution in THF, 3.29 mL, 6.59 mmol) was added dropwise. After 1 hour the reaction was quenched by the addition of 1M HCl. After 10 minutes the mixture was diluted with saturated NaHCO3 (aq). The aqueous phase was extracted 3× with DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated to afford 11-2 as a white solid. 1H NMR (CDCl3) δ 7.30 (s, 2H), 4.75 (d, 2H), 2.15 (t, 1H). MS [M+H]+=178.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[C:12]([CH3:19])[CH:11]=1.C(=O)([O-])[O-].[Tl+2]>C1(C)C=CC=CC=1.C(Cl)Cl.CCCCCC.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>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][C:12]=2[CH3:19])[N:3]=1
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: Brc1cccc(Br)n1
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: [Tl+2]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCCCCC
Product: Cc1cc(F)ccc1-c1cccc(Br)n1
Yield: 74.4 %

Procedure:
In a 100 ml round-bottomed flask, 7.92 g (33.4 mmol) of 2,6-dibromopyridine was dissolved in 50 ml of anhydrous toluene forming a clear, colorless solution. 4-fluoro-2-methylbenzene boronic acid (5.09 g, 33.1 mmol) produced in step A was added forming a white suspension. Thallium carbonate (17.45 g, 37.2 mmol) was added followed by a catalytic amount (150 mg) of Pd(PPh3)4. The mixture was heated to reflux overnight, cooled, and filtered over a pad of silica gel. The silica was washed with CH2Cl2 and the filtrate was evaporated to afford a white solid. The solid was dissolved in a minimal amount of 50% CH2Cl2/hexane and chromatographed on a short column of silica gel using 30% CH2Cl2/hexane to afford 6.55 g (74%) of the 2-bromo-6-(4-fluoro-2-methylphenyl)pyridine as a white solid.