Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([Si:7]([CH3:26])([CH3:25])[O:8][C@H:9]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]2[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]([S:23][CH3:24])[N:16]=2)[CH2:10]1)([CH3:6])([CH3:5])[CH3:4].[CH3:27][C:28](OC(C)=O)=[O:29].O.NN>CN(C=O)C>[NH2:22][C:21]1[C:20]2[CH:19]=[N:18][C:17]([S:23][CH3:24])=[N:16][C:15]=2[N:14]([C@H:11]2[CH2:12][CH2:13][C@H:9]([O:8][Si:7]([C:3]([CH3:6])([CH3:5])[CH3:4])([CH3:26])[CH3:25])[CH2:10]2)[C:28](=[O:29])[CH:27]=1
Reactant: CSc1ncc(C#N)c(N[C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)C2)n1
Reactant: CC(=O)OC(C)=O
Agent: NN
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ncc2c(N)cc(=O)n([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)C3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 108.7 %

Procedure:
Sodium hydride (60% suspension in mineral oil, 303 mg, 7.59 mmol) was added in one portion, under argon atmosphere, to a mixture of 4-[trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamino]-2-methylsulfanyl-pyrimidine-5-carbonitrile (658 mg, 1.81 mmol) in anhydrous DMF (10 mL) and the resulting mixture was stirred at RT for 30 min. Anhydrous Ac2O (2.56 mL, 27.1 mmol) was added dropwise, over a period of 35 min, and the reaction mixture was stirred for additional 10 min. The resulting mixture was quenched with NH4Cl (sat'd aq, 50 mL), and extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×10 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was dissolved in MeOH (15 mL), and hydrazine hydrate (0.877 mL, 18.08 mmol) was added dropwise. The resulting mixture was heated at 85° C. in a microwave reactor for 50 min. The solvent was evaporated under reduced pressure and water was added to the residue. The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (3×10 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (DCM/MeOH) to afford 800 mg of 5-amino-8-[trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:15])[N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:5]=[CH:6][C:7]=1Cl.[CH3:16][OH:17].[OH-].[K+]>CCCCCC.C(OCC)C>[Cl:1][C:2]1[C:3](=[O:15])[N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:5]=[CH:6][C:7]=1[O:17][CH3:16]
Reactant: CO
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1cnn(C2CCCCO2)c(=O)c1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
4,5-Dichloro-2-(tetrahydro-2H-pyran-2-yl)-3(2H)-pyridazinone from the previous step and 17 L of methanol were added to a 50 L round bottomed flask equipped with a glycol cooling jacket and a mechanical stirrer. The resulting solution was cooled to 0° C. and 87% KOH (1172 g 18.17 moles) was added in portions over approximately 1 h. The mixture exothermed to 40° C. Following the addition the mixture was allowed to stir an additional 3 h at ambient temperature. The reaction mixture was partitioned with 12 L of ethyl acetate and 12 L of H2O. The aqueous layer was extracted with ethyl acetate (2×4 L). The combined organic layers were washed with brine (2×10 L) and dried (MgSO4). The organic solution was clarified by filtration and concentrated to give a dark semi-solid. The crude material was equally divided and added to two 22 L flasks. The material was suspended in 12 L hexane/diethyl ether (2:1 ratio). The washed material was vacuum filtered on a Buchner funnel and air dried overnight to give 3,406 g (77% over 2 steps) of 4-chloro-5-methoxy-2-(tetrahydro-2H-pyran-2-yl)-3(2H)-pyridazinone as a dark tan solid suitable for further transformations. The product was purified by recrystallization from ethyl acetate/cyclohexane to give a white solid, mp=118°-120° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=O)=[C:9]3[N:8]=[C:7]([S:16][CH3:17])[CH:6]=2)[CH2:3][CH2:2]1.[NH:18]1[CH2:24][C:22](=[O:23])[NH:21][C:19]1=[O:20].N1CCCCC1>C(O)C>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:24]4/[C:22](=[O:23])[NH:21][C:19](=[O:20])[NH:18]/4)=[C:9]3[N:8]=[C:7]([S:16][CH3:17])[CH:6]=2)[CH2:3][CH2:2]1
Reactant: O=C1CNC(=O)N1
Reactant: CSc1cc(NC2CC2)n2ncc(C=O)c2n1
Solvent: CCO
Solvent: C1CCNCC1
Product: CSc1cc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Temperature: 80 °C
Yield: 90 %

Procedure:
The above product 7-(cyclopropylamino)-5-(methylthio)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde was dissolved in 20.0 mL ethanol, added hydantoin (2.82 g, 28.17 mmol) and piperidine (2.70 mL). The reaction was heated to 80° C. for overnight. Cooled the reaction mixture and yellow precipitate was filtered, washed with ethanol, dried to yield (Z)-5-((7-(cyclopropylamino)-5-(methylthio) pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione 4.18 g (90% yield). LCMS (M+1=331)
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)CBr>CN.CO>[Br:8][C:9]1[CH:16]=[C:15]([CH:14]=[CH:11][CH:10]=1)[CH2:7][CH2:6][NH2:3]
Reactant: CCN(CC)CC
Reactant: BrCc1cccc(Br)c1
Agent: CN
Solvent: CO
Product: NCCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 63.2 %

Procedure:
Triethylamine (19.2 g; 100.5 mmol) was dissolved in 40% solution of methylamine in methanol (150 ml). While the resultant solution was stirred in an ice bath, a solution of 3-bromobenzylbromide (25.1 g; 100.5 mmol) in methanol (40 ml) was added dropwise. After completion of the addition, the mixture was removed from the ice bath, and stirred for 15 hours at room temperature. Methanol and excess methylamine were evaporated under reduced pressure, and the residue was taken up in a mixture of ether and 2N hydrochloric acid (100 ml-100 ml). The aqueous layer was alkalinized with aqueous sodium hydroxide solution, and the mixture was extracted with chloroform (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, to thereby yield 12.7 g of the target compound as a yellow-orange oily substance (yield: 63.2%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH:17]([NH:19][CH:20]=[O:21])[CH3:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][O:23][C:24]1[N:29]=[C:28]([O:30][CH3:31])[C:27](B(O)O)=[CH:26][N:25]=1>>[CH3:22][O:23][C:24]1[N:29]=[C:28]([O:30][CH3:31])[C:27]([C:2]2[CH:3]=[C:4]([N:8]3[C:12]4[CH:13]=[CH:14][C:15]([CH:17]([NH:19][CH:20]=[O:21])[CH3:18])=[CH:16][C:11]=4[N:10]=[CH:9]3)[CH:5]=[CH:6][CH:7]=2)=[CH:26][N:25]=1
Reactant: CC(NC=O)c1ccc2c(c1)ncn2-c1cccc(Br)c1
Reactant: COc1ncc(B(O)O)c(OC)n1
Product: COc1ncc(-c2cccc(-n3cnc4cc(C(C)NC=O)ccc43)c2)c(OC)n1
Yield: 81 %

Procedure:
This was prepared analogously from N-{1-[1-(3-bromo-phenyl)-1H-benzoimidazol-5-yl]-ethyl}-formamide and 2,4-dimethoxypyrimidine-5-boronic acid in 81% yield. LC-ESI-HRMS of [M+H]+ shows 404.1729 Da. Calc. 404.172265 Da. dev. 1.6 ppm.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH2:12])[CH:5]=[N:4][CH:3]=1.O=[C:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.[BH4-].[Na+].C(=O)([O-])O.[Na+]>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].CO.ClCCl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:5]=[N:4][CH:3]=1
Reactant: Nc1cccc2cncc(Cl)c12
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccc3cncc(Cl)c23)CC1
Temperature: 25 °C
Reaction time: 138 h
Yield: 21.8 %

Procedure:
According to the method of Example 103, Step A, a mixture of Intermediate 90 (121 mg), tert-butyl 4-oxo-1-piperidinecarboxylate (274 mg), titanium tetraisopropoxide (0.41 ml) and dichloromethane (7 ml) was stirred at room temperature for 138 hours. The reaction mixture was added with sodium borohydride (114 mg) and methanol (1 ml) and stirred for 1.5 hours with ice cooling. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate (10 ml) with ice cooling and extracted twice with ethyl acetate (15 ml for each time). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain the title compound (53.5 mg).
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.Cl.[CH3:12]O>O1CCOCC1>[OH:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:12])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(O)n1
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1cccc(O)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 90 %

Procedure:
To a solution of 6-hydroxypicolinic acid (13.0 g, 93.5 mmol) in methanol (150 mL) at room temperature was added HCl in dioxane (4N, 10 mL). The resulting mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated to give methyl 6-hydroxypicolinate (13 g, 90%) as a white solid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][Si:8]([CH2:11][CH2:12][O:13][CH2:14]Cl)([CH3:10])[CH3:9].[CH3:16][O:17][N:18]([CH3:39])[C:19]([CH:21]1[CH2:24][CH:23]([CH2:25][C:26]2[NH:30][C:29]3[CH:31]=[CH:32][C:33]([C:35]([F:38])([F:37])[F:36])=[CH:34][C:28]=3[N:27]=2)[CH2:22]1)=[O:20]>CN(C=O)C.O.[Cl-].[Na+].O>[CH3:16][O:17][N:18]([CH3:39])[C:19]([CH:21]1[CH2:22][CH:23]([CH2:25][C:26]2[N:30]([CH2:14][O:13][CH2:12][CH2:11][Si:8]([CH3:10])([CH3:9])[CH3:7])[C:29]3[CH:31]=[CH:32][C:33]([C:35]([F:38])([F:37])[F:36])=[CH:34][C:28]=3[N:27]=2)[CH2:24]1)=[O:20]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CON(C)C(=O)C1CC(Cc2nc3cc(C(F)(F)F)ccc3[nH]2)C1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CC(Cc2nc3cc(C(F)(F)F)ccc3n2COCC[Si](C)(C)C)C1
Reaction time: 8 h

Procedure:
K2CO3 (381 mg, 2.76 mmol), followed by SEM-Cl (430 μl, 2.43 mmol) was added to a solution of the N-methoxy-N-methyl-3-{[5-(trifluoromethyl)-1H-1,3-benzodiazol-2-yl]methyl}cyclobutane-1-carboxamide (754 mg, 2.21 mmol) in DMF (10 ml) at RT and stirred overnight. The reaction was monitored by LCMS. The reaction mixture was diluted with water (3 ml), brine (30 ml) and then extracted with EtOAc (2×50 ml). This was dried over Na2SO4, filtered and evaporated to give a clear orange oil. Purification by silica gel column chromatography, eluting with EtOAc:heptanes (1:1-1) gave the desired products as a beige oils as a single regioisomer (217 mg, 21%); MS (ESI+) for C22H32F3N3O3Si m/z 472.55 [M+H]+; HPLC purity 99% (ret. time, 2.37 min); 1H NMR (250 MHz, CHLOROFORM-d) δH ppm −0.31-0.22 (9 H, m), 0.83-1.00 (2 H, m), 2.03-2.25 (2 H, m), 2.30-2.74 (2 H, m), 2.85-3.14 (3 H, m), 3.18 (3 H, s), 3.32-3.60 (3 H, m), 3.61-3.72 (3 H, m), 5.52 (2 H, s), 7.51 (1 H, dd, J=8.38, 1.22 Hz), 7.70 (1 H, s), 7.79 (1 H, d, J=8.53 Hz) and as a mixture of regioisomers (280 mg, 27%); C22H32F3N3O3Si m/z 472.55 [M+H]+; HPLC purity 72% & 21% (ret. time, 2.39 & 2.36 min); 1H NMR (250 MHz, CHLOROFORM-d) δ ppm −0.08-0.01 (9 H, m), 0.81-0.99 (2 H, m), 1.94-2.24 (2 H, m), 2.38-2.74 (2 H, m), 2.90-3.14 (3 H, m), 3.14-3.22 (3 H, m), 3.33-3.63 (3 H, m), 3.63-3.70 (3 H, m), 5.40-5.64 (2 H, m), 7.40-7.74 (2 H, m), 7.75-8.14 (1 H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@H:20]([C:22]([OH:24])=O)[CH3:21])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:48][C:49]1([C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH2:53][CH2:52][CH2:51][CH2:50]1.Cl.C(N1CCCCC1)C>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@H:20]([C:22]([CH:50]1[CH2:51][CH2:52][CH2:53][C:49]1([NH2:48])[C:54]([O:56][CH2:57][CH3:58])=[O:55])=[O:24])[CH3:21])=[O:18])[CH2:13][CH:14]([CH3:15])[CH3:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)C(=O)O
Reactant: CCOC(=O)C1(N)CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C1(N)CCCC1C(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: -5 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of benzyloxycarbonylleucyl-alanine (6.72 g, 20 mmoles) in dimethylformamide (70 ml) was added N-hydroxysuccinimide (2.3 g. 20 mmoles) and on cooling to -5° C. N,N'-dicyclohexyl-carbodiimide (4.4 g) was admixed. After 1 hour of stirring and cooling (-5° C.) there was added a dimethylformamide (40 ml) solution of ethyl 1-amino-1-cyclopentanecarboxylate liberated from its hydrochloride (3.86 g, 20 mmoles) with N-ethylpiperidine (2.8 ml) and the reaction mixture was stirred for further 2 hours at room temperature. After subsequent 12 hours of standing, the N,N'-dicyclohexylurea precipitate was filtered off, washed with dimethylformamide and the filtrate was evaporated. The residue was dissolved in an ethyl acetate-water mixture and the organic phase was shaken successively with 1M hydrochloric acid, water, 5% sodium hydrogencarbonate and water, dried over anhydrous sodium sulfate and evaporated. The residue was crystallized from ethyl acetate (25 ml) and petroleum ether (200 ml) to give 7.6 g (80%) of the title compound, m.p. 102° to 104° C., after similar recrystallization 104° to 106° C. [α]D20 -35.9° (c 0.2, methanol).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22](O)(=[O:24])=[O:23])[C:17]=2[N:26]([C:33](=[O:37])[CH2:34][CH2:35][CH3:36])[C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[CH:12]=[C:13]([CH3:15])[CH:14]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:39].CCOCC>ClCCl>[CH3:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([Cl:39])(=[O:24])=[O:23])[C:17]=2[N:26]([C:33](=[O:37])[CH2:34][CH2:35][CH3:36])[C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[CH:12]=[C:13]([CH3:15])[CH:14]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCCC(=O)N(C(=O)C(F)(F)F)c1c(-c2cc(C)cc(C)c2)cccc1S(=O)(=O)O
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)N(C(=O)C(F)(F)F)c1c(-c2cc(C)cc(C)c2)cccc1S(=O)(=O)Cl
Temperature: 25 °C

Procedure:
To a solution of 1.8 g (3.3 mmol) of the N,N-diethylethanamine salt of 2-[(3',5'-dimethyl)-2-[(1-oxobutyl)(trifluoroacetyl)amino][1,1-biphenyl]-3-sulphonic acid in 10 ml of dichloromethane are added, at room temperature under nitrogen, 1.37 g (6.6 mmol) of phosphorus pentachloride, the mixture is heated at the reflux temperature for 4 hours and the reaction medium is then allowed to cool to room temperature, 100 ml of ether are poured in and the mixture is filtered then concentrated under reduced pressure. The residue thus obtained is purified by chromatography on a florisil™ column, eluting with dichloromethane.
Reaction SMILES: C(N=C(N)N)#N.C(O)(=O)C.C(O)(=O)C.C(N)=N.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][C:20]=1[N+:28]([O-])=O>[Ni].CO>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=1[NH2:28]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Ni]
Agent: N#CN=C(N)N
Agent: N=CN
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ccc(Cl)c(N)c1

Procedure:
3 g of dicyanodiamide, 3 g of acetic acid, 2 g of Raney nickel (60%, aqueous), and 120 ml of methanol are introduced in an autoclave equipped with gas introduction stirrer. Under a hydrogen pressure of 4 bar and a temperature of 25° C., the dicyanodiamide is hydrogenated to the formamidine acetate. 40.8 g of 1-chloro-2,4-dinitrobenzene are then added to the autoclave, and the hydrogenation is carried out at a pressure of 10 bar and a temperature of 60° C. The hydrogenation time is 11/4 hours. 1-Chloro-2,4-diaminobenzene, 98% pure (analysed as 1-Chloro-2,4-acetamidobenzene by liquid chromatography), is obtained in quantitative yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]#[N:11])=[CH:4][CH:3]=1.CSC.Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][NH2:11])=[CH:6][CH:7]=1
Reactant: N#CCOc1ccc(Br)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CSC
Product: NCCOc1ccc(Br)cc1
Reaction time: 0.08 h

Procedure:
To a solution of [(4-bromophenyl)oxy]acetonitrile (3.07 g; 14.5 mmol; step 1 above) in anhyd THF (10 mL) at 0° C. was added BH3.DMS (18.1 mL of a 2M solution in THF; 36.2 mmol), dropwise over 5 min. The mixture was heated under reflux for 1.5 h, cooled, and 2M HCl (ca. 50 mL) was slowly added. The acidic mixture was extracted with Et2O (×2) and the extracts set aside. NaOH pellets were added to the aqueous residue until ca. pH 14, and the whole was extracted with Et2O (×3). Combined extracts of the basic mixture were washed (brine), dried over Na2SO4, and concentrated in vacuo, affording the first batch of title compound as a pale yellow liquid. The reserved Et2O extracts (from acidic mixture) were concentrated in vacuo, the residue was heated at near reflux in 15 wt % NaOH (aq) for 15 min, cooled, and extracted with CH2Cl2 (×3). Combined organics were washed (brine) and concentrated in vacuo. The residue was slurried in 4M HCl and insoluble material was removed by filtration. The filtrate was extracted with Et2O (×2), pH was adjusted to ca. pH 14 by addition of NaOH pellets and extracted with Et2O (×5). Combined extracts from the basic mixture were washed (brine), dried over Na2SO4, filtered and concentrated in vacuo, affording a second batch of the title compound, which was combined with the first batch. LC/MS (method D) 1.15 min, m/z 216 (M+H, 79Br), 218 (M+H, 81Br).
Reaction SMILES: C([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[CH3:15])[C:8](/[CH:16]=[CH:17]/[C:18]([O:20]CC)=[O:19])=[CH:7][C:6]=1[CH:23]([CH3:25])[CH3:24])(=O)C.[OH-].[K+].O.Cl>C(O)C>[CH:23]([C:6]1[CH:7]=[C:8](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])[C:9]2[C:14]([C:5]=1[OH:4])=[C:13]([CH3:15])[CH:12]=[CH:11][CH:10]=2)([CH3:25])[CH3:24]
Reactant: CCOC(=O)/C=C/c1cc(C(C)C)c(OC(C)=O)c2c(C)cccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cccc2c(/C=C/C(=O)O)cc(C(C)C)c(O)c12
Temperature: 0 °C
Yield: 47.9 %

Procedure:
0.5 g of ethyl (E)-3-(4-acetoxy-3-isopropyl-5-methyl-1-naphthyl)propenoate was dissolved in 50 ml of ethanol, to which a potassium hydroxide aqueous solution (potassium hydroxide 1.6 g/water 10 ml) was added, followed by refluxing for 30 minutes. The solution was cooled to 0° C. and water was added. Dilute hydrochloric acid was added to make the aqueous phase acidic and extracted with ethyl acetate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (40% ethyl acetate/hexane) and the resultant crystals were recrystallized from a mixed solvent of isopropyl ether and ethyl acetate (1:1) and washed with isopropyl ether and hexane (3:7) to obtain 0.19 g of the titled compound as yellow needle.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][CH2:7][C:8]1([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:16]2[C:11](=[CH:12][C:13]([C:17]#[N:18])=[CH:14][CH:15]=2)[CH2:10][O:9]1>CC(C)=O.Cl>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:8]2([CH2:7][CH2:6][CH:2]=[O:1])[C:16]3[C:11](=[CH:12][C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:24][CH:23]=1
Reactant: N#Cc1ccc2c(c1)COC2(CCC1OCCO1)c1ccc(F)cc1
Agent: Cl
Solvent: CC(C)=O
Product: N#Cc1ccc2c(c1)COC2(CCC=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 107.3 %

Procedure:
1-(2-[1, 3]-dioxolan-2-yl-ethyl)-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran-5-carbonitrile (6 g) was dissolved in a mixture of acetone (100 mL) and aqueous HCl (5N, 30 mL). The reaction mixture was stirred at room temperature for 60 h, and concentrated to remove acetone. The aqueous solution was extracted with ethyl acetate (40 mL), and concentrated to give a crude oil. It was dissolved in acetone (80 mL) and aqueous HCl (5N, 25 mL), stirred for 3 h, and concentrated to remove acetone. The aqueous solution was extracted with ethyl acetate (40 mL), washed with water, and concentrated to give the pure product 7 (5.6 g). 1H NMR (CDCl3, δ): 2.22-2.64 (M, 4H), 5.14 (s, 2H), 6.94-7.06 (m, 2H), 7.40-7.63 (m, 5H), 9.70 (s, 1H).
Reaction SMILES: [CH:1]([S:3](N1CC(C2C=CC3C4N=C(C5N(C(C)C)N=CN=5)SC=4CCOC=3C=2)C1)(=[O:5])=[O:4])=[CH2:2].Cl.[F:33][C:34]1([F:38])[CH2:37][NH:36][CH2:35]1>C(Cl)Cl>[CH:1]([S:3]([N:36]1[CH2:37][C:34]([F:38])([F:33])[CH2:35]1)(=[O:5])=[O:4])=[CH2:2]
Reactant: FC1(F)CNC1
Reactant: C=CS(=O)(=O)N1CC(c2ccc3c(c2)OCCc2sc(-c4ncnn4C(C)C)nc2-3)C1
Agent: Cl
Solvent: ClCCl
Product: C=CS(=O)(=O)N1CC(F)(F)C1

Procedure:
The title compound was prepared by a similar procedure to 8-(1-ethenesulfonyl-azetidin-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene using 3,3-difluoroazetidine hydrochloride salt. 1-Ethenesulfonyl-3,3-difluoro-azetidine was isolated as a light brown oil after flash chromatography (SiO2, DCM) (171 mg, 61%). 1H NMR δ (ppm) (CDCl3): 6.56 (1H, dd, J=16.56, 9.83 Hz), 6.40 (1H, d, J=16.59 Hz), 6.20 (1H, d, J=9.83 Hz), 4.32-4.17 (4H, m)
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]1[CH2:13][C@@H:12]([CH3:14])[CH2:11][N:10](CC2C=CC=CC=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>[OH-].[OH-].[Pd+2].CCO>[C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]1[CH2:13][C@@H:12]([CH3:14])[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1C[C@@H](NC(=O)OC(C)(C)C)CN(Cc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: C[C@H]1CNC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 89.6 %

Procedure:
To ((3R,5R)-1-benzyl-5-methyl-piperidin-3-yl)-carbamic acid tert-butyl ester (prepared as described in WO2004014893) (4.6 g, 15.11 mmol) Pd(OH)2 on carbon (0.46 g) and EtOH (80 mL) were added and the reaction mixture stirred at RT under 1 atm of H2. After 3 hours the palladium was filtered off and the solvent was evaporated. The remaining oil was dried under high vacuum to give 2.9 g of ((3R,5R)-5-methyl-piperidin-3-yl)-carbamic acid tert-butyl ester as an off-white crystalline solid (89% yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:12]Cl>C(Cl)(Cl)(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11][Cl:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCl
Reactant: CC(C)(C)c1ccc(S)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1ccc(SCl)cc1
Yield: 94.2 %

Procedure:
To a mixture of 332 grams (2.0 moles) of 4-(tert-butyl)thiophenol and 800 ml of carbon tetrachloride was slowly added with stirring and cooling a solution of 150 grams (2.0+ moles) of chlorine in 600 ml of carbon tetrachloride at 0° C. After chlorine addition was complete the mixture was stirred at 0°-10° C. for two hours, hydrogen chloride and carbon tetrachloride removed in vacuo and the residue was distilled in a one-foot packed column to give 378 grams of 4-(tert-butyl)phenylsulfenyl chloride, b.p. 95°-97°/1.0 mm (yield 94%).
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13](=[O:15])[CH3:14])[CH:7]=[CH:8][C:9]=1[OH:10].[O-]CC.[Na+].[C:20](OCC)(=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22].Cl>C(O)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13](=[O:15])[CH2:14][C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: CCOC(=O)C(=O)OCC
Reactant: COc1cc(C=CC(C)=O)ccc1O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)C=Cc1ccc(O)c(OC)c1
Reaction time: 0.17 h
Yield: 63.2 %

Procedure:
Sodium metal (1.8 g, 0.078 mole) is dissolved in absolute ethanol (50 ml) under an inert atmosphere. An ethanolic solution of 1-(3'-methoxy-4'-hydroxyphenyl)-1-butene-3-one (5.00 g, 0.026 mole) is then added slowly to the sodium ethoxide solution. The mixture is stirred for 10 minutes, after which diethyl oxalate (3.80 g, 0.026 mole) is added. The reaction is stirred at room temperature for 5 hours and then acidified with concentrated HCl. The mixture is then stirred at 0° C. for 1 hour. The precipitate is collected and dried to afford 4.8 g of ethyl 6-(3'-methoxy-4'-hydroxyphenyl)-2,4-dioxo-5-hexenoate; 63% yield; mp=97°-98° C.