Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:28])[CH:20]=[CH:21][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:37](I)[CH3:38].[I+].C([N+](CCCC)(CCCC)CCCC)CCC>O>[C:1]1([CH:7]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]([CH2:37][CH3:38])[C:19](=[O:28])[CH:20]=[CH:21][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(C=Cc1cccnc1)NCCCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: CCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I+]
Solvent: O
Product: CCN(CCCCC1CCN(C(c2ccccc2)c2ccccc2)CC1)C(=O)C=Cc1cccnc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
10 g (22.0 mmol) N-[4-(1-diphenylmethylpiperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide (substance 104) are dissolved in 100 ml THE and added to 0.73 g (24.3 mmol) 80% NaH (heavy foaming) and stirred 20 minutes at RT. 2.1 ml (26.4 mmol) ethyl iodine are added dropwise and the mixture is stirred five hours at RT. 0.1 g tetrabutyl ammonium iodine are added and the batch is further stirred at RT overnight. Subsequently, 0.1 g (3 mmol) 80% NaH are added and this is heated at 50° C. for one hour under stirring. The batch is carefully hydrolyzed with 50 ml water after cooling to RT. The aqueous phase is extracted with 100 ml dichloromethane and the combined organic phases are washed with 50 ml water. The organic phase is concentrated in vacuum and the residue is chromatographically pre-purified twice over silica gel with CHCl3/CH3OH (95/5 to 90/10 and 98/2 to 95/5), subsequently further purified by flash chromatography with CHCl3/CH3OH (100/0 to 98/2) and crystallized three times from 20 ml 1-chlorobutane, 10 ml acetonitrile/diisopropyl ether (1/1) and 8 ml isopropanol/diisopropyl ether (1/1). Yellow crystals with a MP of 115-117° C. were recovered, yield. 1.1 g (10%).
Reaction SMILES: [CH2:1]([C:3]1[O:4][CH:5]=[C:6]([CH2:8]P(=O)([O-])[O-])[N:7]=1)[CH3:2].[H-].[Na+].[CH3:15][O:16][CH2:17][O:18][C:19]1[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:20]=1.O>O1CCCC1>[CH2:1]([C:3]1[O:4][CH:5]=[C:6](/[CH:8]=[CH:24]\[C:23]2[C:19]([O:18][CH2:17][O:16][CH3:15])=[N:20][N:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:22]=2)[N:7]=1)[CH3:2]
Reactant: COCOc1nn(-c2ccccc2)cc1C=O
Reactant: CCc1nc(CP(=O)([O-])[O-])co1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc(/C=C\c2cn(-c3ccccc3)nc2OCOC)co1
Reaction time: 0.5 h
Yield: 7.4 %

Procedure:
To a solution of diethyl ([(2-ethyl-1,3-oxazol-4-yl)methyl]phosphonate (2.97 g) in tetrahydrofuran (50 mL) was added sodium hydride (60% in oil, 0.48 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (2.32 g) was added to the reaction mixture and the mixture was heated under reflux for 1.5 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:9-3:7, v/v) to give 2-ethyl-4-{(Z)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-1,3-oxazole as a pale-yellow oil (0.24 g, yield 7.4%).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3](=O)[C:4]([CH3:7])([CH3:6])[CH3:5].P(Cl)(Cl)(Cl)=O.[NH2:15][C:16]1[N:17]=[N:18][C:19]([Cl:22])=[CH:20][CH:21]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:22][C:19]1[N:18]=[N:17][C:16]([N:15]=[C:3]([N:2]([CH3:9])[CH3:1])[C:4]([CH3:7])([CH3:6])[CH3:5])=[CH:21][CH:20]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: CN(C)C(=O)C(C)(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(C)C(=Nc1ccc(Cl)nn1)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 28.6 %

Procedure:
36 g of N,N-dimethylpivalamide was dissolved in 85 ml of toluene; under ice cooling conditions, 11.3 ml of phosphorus oxychloride was added drop by drop, followed by stirring at room temperature for 24 hours. To this solution, 12.0 g of 3-amino-6-chloropyridazine was added, followed by stirring at 60-70° C. for 24 hours. After cooling, ethyl acetate was added; the mixture was washed with a 2 N aqueous solution of sodium hydroxide and saline, dried over sodium a sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane:ethyl acetate:triethylamine (50:50:2). The desired fraction was collected to yield 6.38 g of N2-(6-chloropyridazin-3-yl)-N1,N1-dimethylpivalamidine. The filtrate was purified by silica gel column chromatography to yield 6.07 g of the amidine. 12.5 g of the amidine derivative obtained was dissolved in 60 ml of methanol; a solution of 4.31 g of hydroxylamine hydrochloride in 40 ml of methanol was added, followed by stirring at room temperature for 2 hours. The methanol was concentrated to half volume under reduced pressure; the crystal precipitated was collected by filtration, washed with water and ethyl ether and dried to yield 10.44 g of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.[Cl:7][C:8]1[CH:13]=[C:12]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[O:25][CH2:26][C@@H:27]([NH:29][CH3:30])[CH3:28])[N:18]=[CH:17][N:16]=2)[CH:11]=[CH:10][C:9]=1[OH:31]>>[Cl:7][C:8]1[CH:13]=[C:12]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[O:25][CH2:26][C@@H:27]([N:29]([CH3:30])[C:4](=[O:6])[CH2:3][O:2][CH3:1])[CH3:28])[N:18]=[CH:17][N:16]=2)[CH:11]=[CH:10][C:9]=1[OH:31]
Reactant: CN[C@@H](C)COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Reactant: COCC(=O)O
Product: COCC(=O)N(C)[C@@H](C)COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Yield: 49 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using methoxyacetic acid and 2-chloro-4-[(5-{[(2S)-2-(methylamino)propyl]oxy}quinazolin-4-yl)amino]phenol (obtained as described in Example 56, preparation of starting materials) to give N-[(1S)-2-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)-1-methylethyl]-2-methoxy-N-methylacetamide in 49% yield; Mass spectrum MH+ 429.2.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([O:18][C:19]2[C:20]([CH3:26])=[N:21][N:22]([CH3:25])[C:23]=2[CH3:24])[CH:17]=1)[C:13]#[N:14].N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:24][C:23]1[N:22]([CH3:25])[N:21]=[C:20]([CH3:26])[C:19]=1[O:18][C:16]1[CH:15]=[C:12]([CH:11]=[C:10]([Cl:9])[CH:17]=1)[C:13]#[N:14]
Reactant: Cc1nn(C)c(C)c1Oc1cc(Cl)cc(C#N)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nn(C)c(CBr)c1Oc1cc(Cl)cc(C#N)c1
Temperature: 25 °C
Yield: 52.5 %

Procedure:
N-Bromosuccinimide (340 mg, 1.90 mmol) was added to a stirred solution of the pyrazole of Example 112 (500 mg, 1.90 mmol) in carbon tetrachloride (10 ml) and azobisisobutyronitrile (20 mg) at room temperature under nitrogen. The reaction was heated under reflux for 1 hour, cooled to room temperature and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel eluting with pentane:ethyl acetate (80:20, by volume) to provide the title compound (340 mg) as a white solid, m.p. 76-78° C.
Reaction SMILES: [F-].[K+].Cl[C:4]1[C:9]([S:10]([N:13]([C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:24])[C:14]2[C:19]([O:20][CH3:21])=[N:18][C:17]([CH3:22])=[CH:16][N:15]=2)(=[O:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:30][O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)=[O:33].C(OCC)(=O)C>O.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>[CH2:26]([O:25][C:23]([N:13]([C:14]1[C:19]([O:20][CH3:21])=[N:18][C:17]([CH3:22])=[CH:16][N:15]=1)[S:10]([C:9]1[C:4]([C:37]2[CH:38]=[CH:39][C:34]([C:32]([O:31][CH3:30])=[O:33])=[CH:35][CH:36]=2)=[N:5][CH:6]=[CH:7][CH:8]=1)(=[O:12])=[O:11])=[O:24])[CH:27]([CH3:29])[CH3:28]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(-c2ncccc2S(=O)(=O)N(C(=O)OCC(C)C)c2ncc(C)nc2OC)cc1
Yield: 82.6 %

Procedure:
A solution of potassium fluoride (7.0 g) in water (150 ml) was added to a solution of 2-chloro-N-isobutoxycarbonyl-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (8.3 g), 4-methoxycarbonylphenylboronic acid (7.9 g) and tetrakis(triphenylphosphine)palladium(0) (1.0 g) in toluene (150 ml) and the mixture was heated under reflux under argon for 18 hours. Ethyl acetate (150 ml) was added and the organic phase was separated. The solution was washed with 2M sodium hydroxide solution (100 ml) and water (250 ml) and then dried (MgSO4). Volatile material was removed by evaporation and the residue was triturated with ethyl acetate/hexane (1:3 v/v) to give N-(isobutoxycarbonyl)-2-(4-methoxycarbonylphenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)-pyridine-3-sulphonamide (8.5 g), m.p. 134°-136° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]([O:10]C)=[O:9])[N:5]=[C:4]2[S:12][CH:13]=[CH:14][C:3]=12.[Li+].[OH-]>>[OH:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]=[C:4]2[S:12][CH:13]=[CH:14][C:3]=12
Reactant: COC(=O)c1cc(O)c2ccsc2n1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1cc(O)c2ccsc2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A sample of methyl 4-hydroxythieno[2,3-b]pyridine-6- carboxylate is hydrolyzed by the addition of 2.5 equivalent of aqueous lM LiOH and stirred for 16 hours at RT. The aqueous reaction mixture is extracted 2x with ethyl acetate and acidified to pH 2.0 with aqueous lN HCl. The resulting precipitate is filtered, washed with water and dried to give 4-hydroxythieno[2,3-b]pyridine-6-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH:5]([O:18][C:19]([C:21]1[N:22]2[CH:25]([S:26][CH2:27][C:28]=1[CH:29](Br)[CH:30]=O)[CH:24]([NH:33][C:34](=[O:45])[CH2:35][S:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([Cl:44])[CH:38]=1)[C:23]2=[O:46])=[O:20])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>O.O1CCCC1>[NH2:1][C:2]1[S:3][C:29]([C:28]2[CH2:27][S:26][CH:25]3[N:22]([C:23](=[O:46])[CH:24]3[NH:33][C:34](=[O:45])[CH2:35][S:36][C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([Cl:44])[CH:38]=3)[C:21]=2[C:19]([O:18][CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:20])=[CH:30][N:4]=1
Reactant: NC(N)=S
Reactant: O=CC(Br)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)CSc3ccc(Cl)c(Cl)c3)C2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)CSc4ccc(Cl)c(Cl)c4)C3SC2)s1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of thiourea (0.054 g) in distilled water (1 cc) is added to a solution of 2-benzhydryloxycarbonyl-3-(1-bromo-2-oxoethyl)-7-(3,4-dichlorophenylthio)acetamido-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (mixture of the diastereoisomers at the substituent in the 3-position) (0.5 g) in tetrahydrofuran (10 cc), and the reaction mixture is then stirred for 17 hours at 25° C. before being poured into a mixture of distilled water (250 cc), a saturated solution of sodium bicarbonate (60 cc) and ethyl acetate (60 cc). The organic phase is washed with distilled water (3×30 cc) and then with a saturated solution of sodium chloride (30 cc) and dried over magnesium sulphate. The residue obtained after concentration of the solvent to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. is chromatographed on a column (height: 28 cm, diameter: 2 cm) of silica gel (0.04-0.063 mm), elution being carried out under a pressure of 0.5 bar (50 kPa) with a 30/70 by volume mixture of cyclohexane and ethyl acetate, and 15 cc fractions being collected. Fractions 7 to 10, containing the pure product, are combined and concentrated under reduced pressure (30 mm Hg; 4 kPa) at 30° C. to give 3-(2-aminothiazol-5-yl)-2-benzhydryloxycarbonyl-7-(3,4-dichlorophenylthio)acetamido-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.29 g) in the form of a hard, pale yellow foam.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:13]2[CH2:26][CH2:25][N:16]3[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=4[C:23]([F:24])=[C:15]3[C:14]2=[O:27])=[N:8][CH:9]=[CH:10][C:11]=1Cl)(=[O:3])[CH3:2].[B:28]1(B2OC(C)(C)C(C)(C)O2)[O:32]C(C)(C)C(C)(C)[O:29]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])(=O)C.[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:13]2[CH2:26][CH2:25][N:16]3[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=4[C:23]([F:24])=[C:15]3[C:14]2=[O:27])=[N:8][CH:9]=[CH:10][C:11]=1[B:28]([OH:32])[OH:29])(=[O:3])[CH3:2]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: CC(=O)OCc1c(Cl)ccnc1N1CCn2c3c(c(F)c2C1=O)CCCC3
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c3c(c(F)c2C1=O)CCCC3
Temperature: 65 °C
Yield: 67.1 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 231b (600 mg, 1.53 mmol), Pin2B2 (1.94 g, 7.65 mmol), PdCl2(dppf) (65 mg, 0.080 mmol), X-Phos (73 mg, 0.15 mmol), potassium acetate (304 mg, 3.1 mmol), and dioxane (30 mL). After three cycles of vacuum/argon flush, the mixture was heated at 65° C. for 5 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was washed with petroleum ether to afford 231c (412 mg, 67%) as yellow solid. MS-ESI: [M+H]+ 402.1
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:18]([O-])=O)=[C:13]([CH:17]=1)[C:14]([NH2:16])=[O:15])C1C=CC=CC=1.NC1C=CC(O)=CC=1F>>[NH2:18][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:17][C:13]=1[C:14]([NH2:16])=[O:15]
Reactant: NC(=O)c1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: Nc1ccc(O)cc1F
Product: NC(=O)c1cc(O)ccc1N
Yield: 17.6 %

Procedure:
This compound was prepared from 5-benzyloxy-2-nitrobenzamide (2.7 g, 56 mmol) in the manner described for 4-amino-3-fluorophenol, affording 1.5 g (99%) of 2-amino-5-hydroxybenzamide. 1H-NMR (CDCl3) δ 7.41 (d, J=8.1 Hz, 1H), 7.16 (dd, J=8.1, 1.6 Hz, 1H), 7.13 (d, J=1, 6 Hz, 1H), 3.93 (s, 3H); MS GC-MS (M+=211, RT=6.15 min).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([C:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=5)[CH:23]=[CH:22][C:20]=4[N:21]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3].C(N(CC)CC)C.Cl[S:40]([CH2:43][CH2:44][CH2:45][C:46]([O:48][CH3:49])=[O:47])(=[O:42])=[O:41]>C(Cl)Cl>[CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([C:26]5[CH2:27][CH2:28][N:29]([S:40]([CH2:43][CH2:44][CH2:45][C:46]([O:48][CH3:49])=[O:47])(=[O:42])=[O:41])[CH2:30][CH:31]=5)[CH:23]=[CH:22][C:20]=4[N:21]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: COC(=O)CCCS(=O)(=O)Cl
Reactant: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCNCC5)cc4s3)CC2)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCN(S(=O)(=O)CCCC(=O)OC)CC5)cc4s3)CC2)nc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 67.4 %

Procedure:
To a solution of 2-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)-6-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d]thiazole (60 mg, 0.138 mmol) and triethylamine (0.039 mL, 0.275 mmol) in CH2Cl2 (1.5 mL) at 0° C. was added methyl 4-(chlorosulfonyl)butanoate (41.5 mg, 0.207 mmol). Upon completion of addition, the reaction mixture was stirred at 0° C. for 15 min. At the conclusion of this period, the reaction mixture was allowed to warm to rt, where it stirred for 1 hr. After this time, the reaction mixture was quenched with saturated aq NaHCO3 (3 mL) and then extracted with CH2Cl2 (3×2 mL). The combined organic layers were washed with brine (2 mL), dried (Na2SO4), filtered, and concentrated to yield the crude product. The crude product was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 50% EtOAc) to afford Compound 5B (56 mg, 0.093 mmol, 68% yield). 1H NMR (500 MHz, chloroform-d) ppm 8.21 (2H, br. s.), 7.62-7.66 (2H, m), 7.37-7.42 (1H, m), 6.06-6.10 (1H, m), 5.43-5.51 (1H, m), 4.18-4.29 (2H, m), 4.00-4.06 (2H, m), 3.67-3.82 (4H, m), 3.60 (2H, t, J=5.6 Hz), 3.07-3.14 (2H, m), 2.65-2.72 (2H, m), 2.54 (2H, t, J=7.0 Hz), 2.43 (2H, t, J=7.6 Hz), 2.12-2.26 (4H, m), 1.92-2.05 (2H, m), 1.50-1.65 (3H, m), 0.96 (3H, t, J=7.3 Hz). LC/MS (m/z)=600 (M+H)+.
Reaction SMILES: [CH3:1][SiH:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH2:8])=[CH:5][CH:4]=1.[CH3:12][SiH:13]([O:16][CH3:17])[O:14][CH3:15].C1(C)C=CC=CC=1>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl.C(O)(C)C>[CH3:11][SiH:2]([CH3:1])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][CH2:8][CH2:12][SiH:13]([O:16][CH3:17])[O:14][CH3:15])=[CH:5][CH:4]=1
Reactant: CO[SiH](C)OC
Reactant: C=Cc1ccc([SiH](C)C)cc1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CO[SiH](CCCc1ccc([SiH](C)C)cc1)OC
Temperature: 50 °C
Yield: 4.1 %

Procedure:
325 mg Of 4-dimethylsilylstyrene, 212 mg of methyldimethoxysilane, and 83 mg of toluene were placed in a glass reaction vessel and 0.001 ml of an isopropyl alcohol solution of chloroplatinic acid (platinum content: 0.39 Wt. %) was added to this mixture. The reaction tube was sealed with Teflon tape and heated for 0.5 hours in an oil bath at 50° C. When the tube contents were analyzed by GC-MS following cooling, the conversion rate of 4-dimethylsilylstyrene was 12.7% and (4-(dimethylsilyl) phenethyl)methyldimethoxysilane was produced at a yield of 4.1%. The yield of (α-(4-(dimethylsilyl)phenyl)ethyl)methyldimethoxysilane was 3.3%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]Br.[C:6]([C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][CH:25]=[CH:24]3)=[O:19])=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7]>>[C:6]([C:10]1[CH:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[N:26]([CH2:4][CH2:3][O:2][CH3:1])[CH:25]=[CH:24]3)=[O:19])=[CH:14][CH:15]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: COCCBr
Reactant: CC(C)(C)c1ccc(/C=C/C(=O)Nc2ccc3[nH]ccc3c2)cc1
Product: COCCn1ccc2cc(NC(=O)/C=C/c3ccc(C(C)(C)C)cc3)ccc21

Procedure:
Analogous to the procedure used to prepare Example 70, 2-bromoethyl methyl ether (140 mg, 1.0 mmol, Aldrich) and (2E)-3-[4-(tert-butyl)phenyl]-N-indol-5-ylprop-2-enamide, Example 161, (320 mg, 0.01 mmol) provided, after purification by silica gel chromatography (65:35 hexane:EtOAc), the title compound as a pale yellow solid. MP 138° C. MS (ESI, pos. ion) m/z: 377 (M+1).
Reaction SMILES: [CH:1]1([C:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:26])[N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:16][CH:15]=2)([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=2)O)[CH2:3][CH2:2]1.[BrH:27].O>C(O)(=O)C>[Br:27][CH2:3][CH2:2][CH:1]=[C:4]([C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:26])[N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:16][CH:15]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1
Reactant: CCN(CC)C(=O)c1ccc(C(O)(c2cccc(OC)c2)C2CC2)cc1
Reactant: Br
Solvent: CC(=O)O
Solvent: O
Product: CCN(CC)C(=O)c1ccc(C(=CCCBr)c2cccc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
1-Cyclopropyl-1-(4-diethylcarbamoylphenyl)-1-(3-methoxyphenyl)Methanol (90.9 mg) was dissolved in acetic acid (1.8 ml), added with 48% hydrobromic acid (1.8 ml) with ice cooling and stirred at room temperature for 1.5 hours. The reaction mixture was added with water (5 ml) and extracted twice with dichloromethane (5 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to obtain 102 mg of the title compound. Yield: 95%.
Reaction SMILES: [CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[NH:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[N:10]2[C:25]2[C:26]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:22]=[CH:23][CH:24]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Brc1cccc2ccccc12
Reactant: CC1(C)NN(C2CCCCCCC2)C1=O
Product: CC1(C)C(=O)N(C2CCCCCCC2)N1c1cccc2ccccc12

Procedure:
2-Cyclooctyl-4,4-dimethyl-1,2-diazetidin-3-one and 1-bromonaphtalene were used for a similar reaction and treatment as Example 181, and the title compound was obtained as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[CH3:11][C:12]1[O:13][C:14]([CH3:21])=[CH:15][C:16]=1[S:17](Cl)(=[O:19])=[O:18]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:17]([C:16]1[CH:15]=[C:14]([CH3:21])[O:13][C:12]=1[CH3:11])(=[O:19])=[O:18]
Reactant: Cc1cc(S(=O)(=O)Cl)c(C)o1
Reactant: Cc1noc(N)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(S(=O)(=O)Nc2onc(C)c2Br)c(C)o1

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2,5-dimethyl-furan-3-sulfonamide was prepared by the method of Example 41 with 4-bromo-3-methyl-5-amino-isoxazole (2.0 mmoles, 0.35 g), NaH (5.0 mmoles, 200 mg), 2,5-dimethyl-furan-3-sulfonylchloride (2.4 mmoles, 0.47 g) and THF (9 ml). Flash chromatography (5% methanol/chloroform) followed by recrystallization from chloroform and hexanes provided 0.21 g (31%) of a light brown solid, m.p. 85.5-87° C.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH:5]=[C:6]([CH3:28])[CH:7]=[CH:8][CH2:9][C:10]1([C:13]2[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:19]=[C:18]3[C:14]=2[CH2:15][CH2:16][C:17]3([CH3:27])[CH3:26])[CH2:12][CH2:11]1)C>CO>[C:22]([C:20]1[CH:19]=[C:18]2[C:14]([CH2:15][CH2:16][C:17]2([CH3:27])[CH3:26])=[C:13]([C:10]2([CH2:9]/[CH:8]=[CH:7]/[C:6](/[CH3:28])=[CH:5]/[C:4]([OH:29])=[O:3])[CH2:11][CH2:12]2)[CH:21]=1)([CH3:23])([CH3:24])[CH3:25]
Reactant: CCOC(=O)C=C(C)C=CCC1(c2cc(C(C)(C)C)cc3c2CCC3(C)C)CC1
Solvent: CO
Product: CC(/C=C/CC1(c2cc(C(C)(C)C)cc3c2CCC3(C)C)CC1)=C\C(=O)O

Procedure:
The above ethyl ester 19 (37 mg, 0.09 mmol) in 2 mL MeOH was hydrolyzed as described for Example 1 to give the crude acid. The crude mixture was purified by HPLC (82% MeOH/18% 10 mmol NH4OAc+0.3% AcOH) to give 18 mg (55%) of pure (2E, 4E)-6-[1-(6-t-butyl-1,1-dimethyl-indan-4-yl)-cyclopropyl]-3-methyl-2,4-hexadienoic acid (20). 1H NMR (400 MHz, CDCl3) δ7.05 (d, J=1.5 Hz, 1H, aromatic), 7.02 (d, J=1.7 Hz, 1H, aromatic), 6.09 (dt, J=15.7 and 7.2 Hz, 1H, vinylic CH), 5.97 (d, J=15.7 Hz, 1H, vinylic CH), 5.66 (s, 1H, vinylic CH), 2.90 (t, J=7.2 Hz, 2H, allylic CH2), 2.34 (d, J=7.2 Hz, 2H, allylic CH2), 2.22 (s, 3H, aliphatic CH3), 1.91 (t, J=7.0 Hz, 2H, aliphatic CH2), 1.30 (s, 9H, aliphatic 3CH3), 1.25 (s, 6H, aliphatic 2CH3), 0.80 (dd, J=10.1, 6.2 Hz, 2H, aliphatic CH2), 0.71 (dd, J=10.2, 3.9 Hz, 2H, aliphatic CH2).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:6][O:7][C:8]2[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH2:20][CH2:21][C:22]3=[O:27])[CH2:5][CH2:4]1.C(N(C(C)C)CC)(C)C.[C:37](Cl)(=[O:41])[CH2:38][CH2:39][CH3:40]>ClCCl>[CH3:15][O:14][C:13]1[C:12]([O:16][CH3:17])=[CH:11][CH:10]=[C:9]([C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH2:20][CH2:21][C:22]3=[O:27])[C:8]=1[O:7][CH2:6][C:3]1([CH2:2][NH:1][C:37](=[O:41])[CH2:38][CH2:39][CH3:40])[CH2:4][CH2:5]1
Reactant: CCCC(=O)Cl
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CN)CC2)c1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC(=O)NCC1(COc2c(-c3cccc4c3CCC4=O)ccc(OC)c2OC)CC1

Procedure:
To a stirring solution of 4-[2-(1-Aminomethyl-cyclopropylmethoxy)-3,4-dimethoxy-phenyl]-indan-1-one (Compound 182) (100 mg, 0.272 mmol) in dichloromethane (10 mL), were added diisopropylethylamine (0.034 g, 0.272 mmol) and butyryl chloride (29 mg, 0.272 mmol) and the resultant reaction mixture was subjected to the conditions used in the preparation of compound 183 to afford the title compound as a solid.