Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)([CH2:9][CH2:10][C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)[O:4][C:3]1=[O:25].[SH:26][C:27]1[S:28][CH:29]=[CH:30][N:31]=1.C(N(CC)CC)C>CN(C=O)C>[CH:20]1([C:5]2([CH2:9][CH2:10][C:11]#[C:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)[O:4][C:3](=[O:25])[C:2]([S:26][C:27]3[S:28][CH:29]=[CH:30][N:31]=3)=[C:7]([OH:8])[CH2:6]2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Sc1nccs1
Reactant: O=C1CC(CCC#Cc2cccc(O)c2)(C2CCCC2)OC(=O)C1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1OC(CCC#Cc2cccc(O)c2)(C2CCCC2)CC(O)=C1Sc1nccs1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 10.6 %

Procedure:
To a solution of 3-chloro-6-cyclopentyl-6-[4-(3-hydroxy-phenyl)-but-3-ynyl]-dihydro-pyran-2,4-dione (216 mg, 0.6 mmol) from Step 5 below and 2-mercaptothiazole (141 mg, 1.2 mmol) in DMF (6 mL) was added triethylamine (0.15 mL, 1.2 mmol). The reaction was stirred at 50° C. for 2.5 hours and then quenched with 10 mL of saturated ammonium chloride. The mixture was further acidified to a pH of 1-2 with 1 N HCl. To this mixture was added 10 mL CH2Cl2 and the layers were separated. The aqueous was extracted with 2×10 mL CH2Cl2, and the organic layers were combined. After drying the organic layer over MgSO4, the solids were filtered away and the liquid was concentrated to an oil. The oil was chromatographed on silica to yield the desired product (28 mg, 11% yield). 1H NMR (CDCl3) δ: 1.09-1.58 (m, 8H), 1.93-2.05 (m, 3H), 2.58-2.82 (m, 4H), 6.59 (d, J=6.82 Hz, 2H), 6.65 (d, J=7.58 Hz, 1H), 6.96-7.00 (m, 1H), 7.32 (d, J=3.28 Hz, 1H), 7.46 (d, J=3.28 Hz, 1H). MS (ESI): 440 (M−H).
Reaction SMILES: C(Cl)([O:6]C(F)F)C(F)(F)F.CN[C:13]1(C2C=CC=CC=2Cl)[C:18](=O)CCC[CH2:14]1.CC1C=CC=C(C)C=1NC1SCCCN=1.C[C@@:43]12[C@H:52]3[CH2:53][CH2:54][C@:55]4([CH3:62])[C:59](=[O:60])[C@H:58](F)[CH2:57][C@H:56]4[C@@H:51]3[CH2:50][CH:49]=[C:48]1[CH2:47]CCC2>C(O)C>[CH3:47][C:48]1[CH2:43][CH2:52][C@@H:51]([C:56]([CH3:57])=[CH2:55])[CH2:50][CH:49]=1.[C:59]([O:60][CH:13]([CH3:18])[CH3:14])(=[O:6])[CH2:58][CH2:57][CH2:56][CH2:51][CH2:50][CH2:49][CH2:48][CH2:43][CH2:52][CH2:53][CH2:54][CH2:55][CH3:62]
Reactant: FC(F)OC(Cl)C(F)(F)F
Reactant: C[C@]12CCCCC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)[C@H](F)C[C@@H]12
Reactant: CNC1(c2ccccc2Cl)CCCCC1=O
Agent: Cc1cccc(C)c1NC1=NCCCS1
Solvent: CCO
Product: C=C(C)[C@H]1CC=C(C)CC1
Product: CCCCCCCCCCCCCC(=O)OC(C)C

Procedure:
The mice were anesthetized with Isoflurane, and then were given an intramuscular injection of 0.1 mL solution of ketamine (50 mg/kg) and xylazine (10 mg/kg). Approximately 10 minutes after the i.m. injection (after the mice could not turn over when placed on their backs), the mice were treated with 3.7 μL of a 10 mg/mL fluasterone:ethanol:limonene:isopropyl myristate solution to give a dose of 1.5 mg/kg. The mice were anesthetized and on their backs for approximately 30 minutes after application of fluasterone:ethanol:limonene:isopropyl myristate solution. One hour after the application of fluasterone solution, 2 μg of TPA dissolved in 0.2 mL of acetone was applied to the shaved area on the back of each mouse.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][F:21]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH2:19][CH2:20][F:21]
Reactant: O=[N+]([O-])c1ccc(Br)c(O)c1
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Br)c(OCCF)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Intermediate 16A (475 mg, 2.179 mmol) was dissolved in DMF (1 mL) and to this solution was added potassium carbonate (903 mg, 6.54 mmol) and 1-bromo-2-fluoroethane (415 mg, 3.27 mmol). The reaction mixture was stirred at 100° C. for 3 hours, cooled, diluted with water (20 mL) and then extracted with EtOAc (2×20 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Intermediate 16B was obtained as a pale yellow semi-solid (570 mg, 2.159 mmol, 99% yield). MS (ES): m/z=199.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.47-4.51 (m, 1 H) 4.55-4.59 (m, 1 H) 4.73-4.78 (m, 1 H) 4.85-4.91 (m, 1 H) 7.77-7.83 (m, 1 H) 7.91 (d, J=2.51 Hz, 1 H) 7.94 (d, J=8.53 Hz, 1 H).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]1([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH:20]([F:22])[F:21])[C:13](O)=[O:14])[CH2:7][CH2:6]1>C1(C)C=CC=CC=1>[CH:5]1([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH:20]([F:22])[F:21])[C:13]([Cl:3])=[O:14])[CH2:7][CH2:6]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(OC(F)F)c(OCC2CC2)c1
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Yield: 100 %

Procedure:
Thionyl chloride (25 ml, 344 mmol) was added dropwise to a solution of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (12 g, 48 mmol) in toluene (100 ml) and the reaction mixture was heated to reflux for 2 hours, then the solvent was evaporated to dryness under vacuum and the residue was used without further purification (13.2 g, 48 mmol, 100% yield).
Reaction SMILES: [C:1]([C:4]1[NH:8][N:7]=[C:6]([O:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:5]=1[CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)(=O)[CH3:2].[C:25]([NH:33][NH2:34])(=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>C1(C)C(C)=CC=CC=1>[CH:20]1([C:5]2[C:6]([O:9][S:10]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)(=[O:12])=[O:11])=[N:7][N:8]3[C:4]=2[C:1]([CH3:2])=[N:34][N:33]=[C:25]3[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(=O)c1[nH]nc(OS(=O)(=O)c2ccc(C)cc2)c1C1CCCC1
Reactant: NNC(=O)c1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: Cc1ccccc1C
Solvent: c1ccc(-c2ccccc2)cc1
Product: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4ccccc4)nnc(C)c3c2C2CCCC2)cc1
Temperature: 180 °C

Procedure:
Toluene-4-sulfonic acid 5-acetyl-4-cyclopentyl-1H-pyrazol-3-yl ester (0.65 g, 1.87 mmol) and benzhydrazide (0.28 g, 1.1 molar eq) were stirred together in xylene (20 ml) at reflux for 2.5 h. The solvent was reduced to ˜5 ml and Dowtherm A (20 ml) was added and the reaction mixture was heated at 180° C. for 2 h. The mixture was cooled and poured directly onto a column of silica gel, and the Dowtherm was eluted off with dichloromethane before eluting the product off with 3-6% ethyl acetate in dichloromethane (UV detection). Toluene-4-sulfonic acid 3-cyclopentyl-4-methyl-7-phenylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester was obtained as a light brown solid (0.62 g). 1H NMR (360 MHz, CDCl3) δ 1.73-2.07 (8H, m), 2.49 (3H, s), 2.91 (3H, s), 3.48 (1H, m), 7.26-7.61 (5H, m), 7.93-7.97 (2H, m), 8.13-8.15 (2H, d, J=8.7 Hz); MS (ES+) m/e 449 [MH]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:15]=[C:14]([OH:16])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:17])[CH:12]=2)[N:7]=1)=O)C.[NH3:18]>CO>[OH:16][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:17])[CH:12]=2)[N:7]=[C:6]([C:4]([NH2:18])=[O:3])[N:15]=1
Reactant: CCOC(=O)c1nc(O)c2cc(O)ccc2n1
Reactant: N
Solvent: CO
Product: NC(=O)c1nc(O)c2cc(O)ccc2n1
Reaction time: 3 h

Procedure:
4,6-Dihydroxy-quinazoline-2-carboxylic acid ethyl ester (11 mmol) is dissolved in methanol (50 ml) containing ammonia (4N). The mixture is stirred for 3 hours and the solid material formed is filtered off. A pale powder with mp. 305° C. (decomposition) is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH3:11])[C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[O:18]([CH2:25][C:26](Cl)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C(Cl)Cl>[CH3:11][NH:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([NH:1][C:26](=[O:27])[CH2:25][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:3]=1[C:4]#[N:5]
Reactant: O=C(Cl)COc1ccccc1
Reactant: CNc1cccc(N)c1C#N
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CNc1cccc(NC(=O)COc2ccccc2)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-6-(methylamino)benzonitrile (3.3 g) in methylene chloride (50 ml) is added pyridine (3.6 ml), and thereto is added dropwise phenoxyacetyl chloride (6.2 ml) which is cooled in an ice bath. The mixture is stirred at room temperature for 1 hour, and thereafter, water is added thereto, and the mixture is extracted with methylene chloride. The organic layer is dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The resulting crude crystals are recrystallized from ethanol to give the title compound (1.4 g) having the following physical properties.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>O1CCCC1.C(N(CC)CC)C>[CH3:40][C:30]1[CH:35]=[CH:34][C:33]([S:36]([N:23]2[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C:17]3[CH:26]=[CH:27][C:14]([NH:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:15][CH:16]=3)[CH2:21][CH2:22]2)(=[O:38])=[O:37])=[CH:32][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N2CCN(C(=O)c3ccc(Nc4ccnc5cc(C(F)(F)F)ccc45)cc3)CC2)cc1
Yield: 90.2 %

Procedure:
To a suspension of 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine (2 g, 0.005 mol) in 20 ml of tetrahydrofuran and 0.5 ml of triethylamine is added a solution of p-toluenesulfonyl chloride (0.95 g, 0.005 mol) in 10 ml of tetrahydrofuran dropwise over a 15 minute period, under nitrogen. After complete addition, the resultant solution is stirred at room temperature for 1 hour. This is quenched in cold water and extracted with methylene chloride (2×, 50 ml). The methylene chloride solution is washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to a yellow solid. This, after re-crystallization from methanol, gives 2.5 g (90%) of white crystalline 1-[(4-methylphenyl)sulfonyl]-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine with melting point 215°-217° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15][CH2:16][C:17]([C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([Br:29])[CH:25]=2)[CH:20]=1)=[O:18])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].COC(=O)[C@@H:33]1C[C@H](C#N)C[N:34]1C(OC(C)(C)C)=O>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:33]#[N:34])[CH2:10][CH:9]1[C:13]([O:15][CH2:16][C:17]([C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([Br:29])[CH:25]=2)[CH:20]=1)=[O:18])=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1C[C@H](C#N)CN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)OCC(=O)c1ccc2cc(Br)ccc2c1
Product: CC(C)(C)OC(=O)N1CC(C#N)CC1C(=O)OCC(=O)c1ccc2cc(Br)ccc2c1

Procedure:
Title compound was prepared according to the method employed to prepare pyrrolidine-1,2-dicarboxylic acid 2-[2-(6-bromo-naphthalen-2-yl)-2-oxo-ethyl]ester 1-tert-butyl ester in Example CL, substituting pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester with N-Boc-cis-4-cyano-L-proline methyl ester (643 mg, 67%)
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]([C:5](F)=[O:6])[C:3]=1[C:14](F)=[O:15].FC1(F)C2C(=C(F)C(F)=C(F)C=2F)C(=O)[O:19]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]2[C:5](=[O:19])[O:6][C:14](=[O:15])[C:3]=12
Reactant: O=C(F)c1c(F)c(F)c(F)c(F)c1C(=O)F
Reactant: O=C1OC(F)(F)c2c(F)c(F)c(F)c(F)c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Yield: 91.5 %

Procedure:
Into a 500 ml glass reactor equipped with a reflux condenser and a stirrer, 100 g (0.413 mol) of the mixture (1:1) of the 3,4,5,6-tetrafluorophthaloyldifluoride and the 3,3,4,5,6,7-hexafluoro-1-[3H]-isobenzofuranone of Example 2, 43.8 g (0.413 mol) of sodium carbonate and 200 g of xylene were charged, and the mixture was reacted at 130° C. for 3 hours with vigorous stirring. Then, the inorganic substance was removed by filtration, and the residue was subjected to distillation to obtain 83.1 g of tetrafluorophthalic anhydride. The yield was 91.5%.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:15][CH:16]([CH2:20][CH2:21][CH2:22]C)[C:17](Cl)=O>C1(C)C=CC=CC=1>[Cl:15][CH:16]([C:17]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([F:12])([F:13])[F:14])[C:2]=2[N:1]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCC(Cl)C(=O)Cl
Reactant: Nc1c(C(=O)O)cccc1C(F)(F)F
Solvent: Cc1ccccc1
Product: CCCC(Cl)c1nc2c(C(F)(F)F)cccc2c(=O)o1
Yield: 55 %

Procedure:
A mixture of 10.25 g of 2-amino-3-trifluoromethylbenzoic acid, 20 ml of toluene and 20.3 g of 2-chlorohexanoic acid chloride [prepared according to J. Org. CHem., Vol. 40 (1975), p. 23420] was refluxed for one hour and then toluene and excess acid chloride were removed by distillation. The residue was chromatographed over silica gel and eluted with methylene chloride and then by chromatography under pressure. Elution with a 1-1 ethyl acetate-petroleum ether (b.p.=60°-80° C.) mixture yielded 8.4 g of 2-(1-chlorobutyl)-8-trifluoromethyl-4H-3,1-benzoxazine-4-one in the form of an oil which was used as is for the next step.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH2:10][OH:11])=[CH:4][CH:3]=1.[CH3:17][C:18]1([CH3:26])[C:20]([CH3:22])([CH3:21])[CH:19]1[C:23](Cl)=[O:24].N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH2:10][O:11][C:23]([CH:19]2[C:20]([CH3:22])([CH3:21])[C:18]2([CH3:26])[CH3:17])=[O:24])=[CH:4][CH:3]=1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Reactant: OCc1cccc(Oc2ccc(F)cc2)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)C(C(=O)OCc2cccc(Oc3ccc(F)cc3)c2)C1(C)C
Yield: 81.8 %

Procedure:
5.05 g (0.0232 mol) of 3-(4-fluoro-phenoxy)-benzyl alcohol and 3.72 g (0.0232 mol) of 2,2,3,3-tetramethylcyclopropanecarboxylic acid chloride were dissolved in 100 ml of anhydrous toluene, and 2.3 g of pyridine, dissolved in 50 ml of anhydrous toluene, were added dropwise at 20°-25° C., while stirring. The reaction mixture was then stirred for a further 3 hours at 25° C. It was poured into 150 ml of water, to which 10 ml of concentrated hydrochloric acid had been added, and the organic phase was separated off and washed again with 100 ml of water. The toluene phase was then dried over sodium sulphate and the solvent was distilled off under a waterpump vacuum. Last residues of solvent were removed by brief incipient distillation at a bath temperature of 60° C./1 mm Hg. 6.5 g (81.9% of theory) of 2,2,3,3-tetramethyl-cyclopropanecarboxylic acid 3-(4-fluorophenoxy)-benzyl ester were obtained as a yellow oil with a refractive index nD20 of 1.5348.
Reaction SMILES: [Sn:1]([Cl:3])[Cl:2].[C:4]([CH2:7][C:8](=[O:10])[CH3:9])(=O)[CH3:5].C([Br:19])(=O)C1C=CC=CC=1>C(OCC)C>[CH3:5][C:4]([Sn:1]([Br:19])([Cl:3])[Cl:2])=[CH:7][C:8](=[O:10])[CH3:9]
Reactant: Cl[Sn]Cl
Reactant: O=C(Br)c1ccccc1
Reactant: CC(=O)CC(C)=O
Solvent: CCOCC
Product: CC(=O)C=C(C)[Sn](Cl)(Cl)Br
Yield: 64.8 %

Procedure:
39.8 g (0.21 mol) of tin(II) chloride and 21.0 g (0.21 mol) of acetylacetone in 200 ml of diethyl ether were placed in a reactor. 38.8 g (0.21 mol) of benzoyl bromide were metered in over 15 min at room temperature, with stirring, a rise in temperature to the reflux point being recorded. After a postreaction time of 1 h at the reflux temperature, the mixture was cooled and the crystalline precipitate was separated off. 48 g (65% of theory) of 1-methylbut-1-en-3-onyltin bromide dichloride (BrCl2Sn--C(CH3)=CH--CO--CH3) were isolated.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:5]=2[N:6]=1.[CH3:13][C@H:14]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:15][O:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(CC)C(C)C)(C)C.CN(C=O)C>O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([N:20]3[CH2:19][CH2:18][CH:17]([O:16][CH2:15][C@@H:14]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH3:13])[CH2:22][CH2:21]3)=[N:6][C:5]=2[CH:7]=1
Reactant: C[C@@H](COC1CCNCC1)NC(=O)OC(C)(C)C
Reactant: COc1ccc2sc(Cl)nc2c1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2sc(N3CCC(OC[C@H](C)NC(=O)OC(C)(C)C)CC3)nc2c1
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 64.3 %

Procedure:
A mixture of 2-chloro-5-methoxy-1,3-benzothiazole (143 mg), tert-butyl [(1S)-1-methyl-2-(piperidin-4-yloxy)ethyl]carbamate (186 mg), N,N-diisopropylethylamine (93 mg) and DMF (3 mL) was stirred at 150° C. for 1.5 hr under microwave irradiation. Water was added to the reaction mixture, and the obtained mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (194 mg).
Reaction SMILES: CS([O:5][CH:6]([CH3:35])[CH:7]([N:9]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:11]=[N:10]1)[CH3:8])(=O)=O.[OH-].[K+]>CO.O1CCCC1>[OH:5][CH:6]([CH3:35])[CH:7]([N:9]1[C:13](=[O:14])[N:12]([C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)[CH2:25][CH2:26]3)=[CH:19][CH:20]=2)[CH:11]=[N:10]1)[CH3:8]
Reactant: COc1ccc(N2CCN(c3ccc(-n4cnn(C(C)C(C)OS(C)(=O)=O)c4=O)cc3)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(N2CCN(c3ccc(-n4cnn(C(C)C(C)O)c4=O)cc3)CC2)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
According to the precedure described in Nakamura et al. (J.A.C.S. 1985, 107 p2138), intermediate 5d (0.001 mol) was added to a solution of KOH (0.03 g) in CH3OH (7 ml) and tetrahydrofuran (3 ml). The mixture was stirred at 100° C. for 4 hours, yielding [S—(R*,R*)]-2,4-dihydro-2-(2-hydroxy-1-methylpropyl)-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one (interm. 5c).
Reaction SMILES: [Cl-].[Cl-].[CH2:3]([C:6]1([Zr+2:11][C:12]2([CH2:17][CH2:18][CH3:19])[CH:16]=[CH:15][CH:14]=[CH:13]2)[CH:10]=[CH:9][CH:8]=[CH:7]1)[CH2:4][CH3:5].C([Sn]([F:33])(CCCC)CCCC)CCC.CCCCC>ClCCl>[F-:33].[F-:33].[CH2:17]([C:12]1([Zr+2:11][C:6]2([CH2:3][CH2:4][CH3:5])[CH:10]=[CH:9][CH:8]=[CH:7]2)[CH:16]=[CH:15][CH:14]=[CH:13]1)[CH2:18][CH3:19]
Reactant: CCCC[Sn](F)(CCCC)CCCC
Agent: CCCC1([Zr+2]C2(CCC)C=CC=C2)C=CC=C1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCCCC
Product: [F-]
Temperature: -35 °C
Reaction time: 1 h

Procedure:
To a straw yellow solution of bis(propylcyclopentadienyl)zirconium dichloride [(PrCp)2ZrCl2] (1.00 g, 2.66 mmol, 1.00 eq.) in dichloromethane (10 mL) was added tributyltin fluoride (1.72 g, 5.57 mmol, 2.10 eq.). The reaction rapidly lightened, turning almost colorless. The reaction was stirred 1 h and was then filtered to give a colorless solution and a small amount of white solid. The solution was evaporated in vacuo, leaving a damp, white solid. Pentane (10 mL) was added and the mixture was cooled to −35° C. The mixture was filtered, and resulting white solid was washed with pentane (3×3 mL) cooled to −35° C. The white solid was dried in vacuo to yield 0.75 g (82%). 1H NMR(CD2Cl2): δ 0.92 (t, 6H, CH2CH2CH3), 1.56 (m, 4H, CH2CH2CH3), 2.44 (t, 4H, CH2CH2CH3), 6.05 (m, 4H, ring-H), 6.30 (m, 4H, ring-H). 19F NMR(CD2Cl2): δ 20.4 (s).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[C:10]([S-:12])#[N:11].[K+].BrBr>CC(O)=O>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[S:12][C:10]([NH2:11])=[N:9][C:6]2=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cn1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: COc1ccc2nc(N)sc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 6-methoxypyridin-3-amine (2.5 g, 20 mmol) in 5 mL of AcOH was slowly added to a solution of KSCN in 50 mL of AcOH with vigorously stirring at 0 C, followed by a solution of bromine in 3 mL of AcOH. The mixture was stirring at 0 C for 1 h and slowly warmed to rt and stirring was continued for 30 min at rt. Solid was collected via filtration and washed with AcOH (2×20 mL), and partitioned between EtOAc (100 mL) and NaHCO3 (sat. 80 mL). Organic phase was dried over MgSO4 and filtered and the filtrate was concentrated to afford 5-methoxythiazolo[5,4-b]pyridin-2-amine (WZ02129) as a tan solid (2.5 g, 69%). MS (ESI) m/z 182 (M+H+).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:39]=[CH:38][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35](O)=[O:36])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:40]([CH2:42][NH2:43])[OH:41]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][C:35]([NH:43][CH2:42][CH2:40][OH:41])=[O:36])=[CH:31][CH:32]=2)=[CH:38][CH:39]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCC(=O)O)cc2)cc1
Reactant: NCCO
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCC(=O)NCCO)cc2)cc1

Procedure:
The product from Example 104A and ethanolamine were processed as described in Example 147 to provide the title compound. 1H NMR (500 MHz, DMSO-D6) δ8.95 (s, 1 H), 7.78 (t, 1 H), 7.26 (m, 6 H), 7.19 (m, 3 H), 7.04 (t, 1 H), 6.97 (m, 2 H), 6.87 (m, 4 H), 4.03 (d, 4 H), 3.35 (m, 2 H), 3.10 (dd, 2 H), 2.91 (s, 3 H), 2.78 (t, 2 H), 2.39 (s, 3 H), 2.36 (m, 2 H); MS (ESI+) m/z 588 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH:5]([O:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][CH2:2][CH2:3][CH2:4][CH:5]([O:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)CCCC(CCCN)Oc1cccnc1
Product: CCOC(=O)CCCC(CCCNS(=O)(=O)c1ccc(Cl)cc1)Oc1cccnc1

Procedure:
Ethyl 8-amino-5-(3-pyridyloxy)-octanoate is condensed with p-chlorophenylsulfonyl chloride according to methodology previously described to yield ethyl 8-(p-chlorophenylsulfonamido)-5-(3-pyridyloxy)-octanoate which is purified by chromatography on silica gel using 7:3 ethyl acetate, hexane as eluent; 1H NMR (CDCl3): delta 8.26 (br,1H), 8.20 (br,4H), 5.23 (t,1H), 4.28 (m,1H), 4.08 (q,2H).