Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:18]=[C:17]([C:19]([NH2:21])=[O:20])[O:16][N:15]=2)=[CH:10][CH:9]=1)(C)(C)C.N1C=CC=CC=1.O>C1COCC1>[OH:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:18]=[C:17]([C:19]([NH2:21])=[O:20])[O:16][N:15]=2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(-c2cc(C(N)=O)on2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: NC(=O)c1cc(-c2ccc(CO)cc2)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
A mixture of 3-[4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 18; 800 mg, 2.4 mmol) in THF (8 mL) and HF/pyridine (70%; 0.25 mL) was stirred at room temperature. After 30 min, an addition portion of THF (8 mL) was added and the mixture was stirred for 5 h. H2O was added and the mixture was extracted four times with CHCl3/CH3OH (7:3). The organic layers were dried (Na2SO4), filtered and evaporated to give 3-(4-hydroxymethyl-phenyl)-isoxazole-5-carboxylic acid amide (300 mg, 57%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Br:15][CH2:16][S:17](Br)(=[O:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[Br:15][CH2:16][S:17]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:19])=[O:18]
Reactant: CCCCCCC=CCCCCCC
Reactant: O=S(=O)(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCCCCCC=CCCCCCCS(=O)(=O)CBr
Yield: 100.7 %

Procedure:
A mixture of 7-tetradecene (3.92 g) and bromomethanesulfonyl bromide (7.14 g) in methylene chloride (8 mL) was irradiated at -15° C. with an ultraviolet lamp for 2 hours. A small amount of solid potassium carbonate was added and then removed by filtration. The reaction mixture was diluted with methylene chloride (100 mL) and triethylamine (3.0 g) was added. The reaction mixture was heated on a steam bath for 1 hour. The reaction mixture was washed with dilute HCl and water. The methylene chloride layer was separated, dried over anhydrous magnesium sulfate and the methylene chloride removed in vacuo to give 7.1 g (100% yield) of oily 7-tetradecenyl bromomethyl sulfone which was characterized by IR and NMR spectroscopy.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.[C:12](OC)(=[O:17])[C:13]([O:15]C)=[O:14].C[O-].[Na+]>CO>[OH:17]/[C:12](=[C:3]1/[CH2:2][O:1][C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]/1=[O:11])/[C:13]([OH:15])=[O:14]
Reactant: COC(=O)C(=O)OC
Reactant: O=C1CCOc2ccccc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)/C(O)=C1\COc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
To a solution of 4-chromanone (6.1097 g, 40.0 mmol) and dimethyl oxalate (5.759 g, 48.28 mmol) in methanol (50 ml), a solution of 0.5M sodium methoxide (96.9 ml, 48.28 mmol) was added dropwise at RT under N2 over 20 min. The colorless solution turned to yellow. The solution was stirred at RT under N2 overnight. After 16 h, the reaction solution was removed under reduced pressure. The residue was diluted with EA, washed with H2O and brine, dried over MgSO4. After filtration, the solvent was removed under reduced pressure to yield crude product methyl ester of (2Z)-hydroxy(4-oxo-2H-1-benzopyran-3(4H)-ylidene)ethanoic acid (8.9096 g, 95.2%) after dried under vacuum.
Reaction SMILES: [Cl-].[C:2]1([CH2:12][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH:38]([C:40]1[N:41]=[C:42]([CH:45]2[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH2:46]2)[S:43][CH:44]=1)=O.[Cl-].[NH4+]>O1CCCC1>[C:2]1(/[CH:12]=[CH:38]\[C:40]2[N:41]=[C:42]([CH:45]3[CH2:46][CH2:47][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:49][CH2:50]3)[S:43][CH:44]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc([P+](Cc2cccc3ccccc23)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=O)cs2)CC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(/C=C\c3cccc4ccccc34)cs2)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Under argon, (1-naphthylmethyl)triphenylphosphonium chloride (2.96 g) is dissolved in 20 ml of tetrahydrofuran and cooled to 0° C., and potassium tert.-butoxide (757 mg) is added, whereupon the colour of the solution changes to dark-red. After 10 min of stirring, tert-butyl 4-(4-formyl-1,3-thiazol-2-yl)piperidine-1-carboxylate (1.00 g) is added. The mixture is stirred at 0° C. for another 30 min and then slowly warmed to room temperature. After a further 20 min, saturated ammonium chloride solution is added, and the aqueous phase is separated off. After extraction of the aqueous phase with ethyl acetate, the combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. After chromatographic purification, this gives tert-butyl 4-{4-[(Z)-2-(naphthalen-1-yl)ethenyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (1.2 g, Z isomer).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7](O)[CH:6]=[CH:5]2.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(=O)C.[Na+]>C(O)C.C1(C)C(C)=CC=CC=1>[C:14]1([NH:13][C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[CH:8]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccccc1
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CCO
Solvent: O
Product: Brc1ccc2cc(Nc3ccccc3)ccc2c1
Temperature: 85 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
Xylene was distilled from a mixture of 6-bromo-2-naphthol (16.4 g., 0.0735 mol.), aniline (25 ml, 0.274 mol.), xylene (25 ml), and p-toluene sulfonic acid monohydrate (2.7 g., 0.014 mol.) until the reaction temperature reached 190° C. The mixture was held at this temperature for 5 hours, and then cooled to 85° C. Sodium acetate (3.7 g.) and ethanol (100 ml) were added and the mixture was heated to reflux. The solution was cooled to 5° C. and the resulting slurry was filtered. The solids were washed with cold ethanol (50 ml). The air-dried solids (19.5 g.) were reslurried in hot water (150 ml) and filtered to give a gray solid, 19.3 g, 88% yield, m.p. 126.2-128.3° C. Two successive recrystalizations from heptane-ethyl acetate (19:1) gave a sample for analysis, m.p. 131-133° C. Mass Spec: m/z 297, 299 (M+). Analysis: Calculated for C16H12NBr: C, 64.45; H, 4.06; N, 4.70, Br, 26.80. Found: C, 64.36; H, 4.02; N, 4.67; Br, 27.04.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]([NH2:17])=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16].[N:19]([O-])=O.[Na+]>C(O)(=O)C.C(OCC)(=O)C.O>[Br:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[CH:6][C:5]2[N:17]=[N:19][NH:18][C:4]=2[CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1cc(Br)c(Oc2ccc(F)cc2F)cc1N
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Fc1ccc(Oc2cc3nn[nH]c3cc2Br)c(F)c1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
A solution of 4-bromo-5-(2,4-difluorophenoxy)benzene-1,2-diamine (0.071 g, 0.22 mmol) in acetic acid (0.4 mL) was treated with water (1.1 mL) followed by sodium nitrite (0.078 g, 1.1 mmol) and stirred at 20° C. for 30 min. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with saturated sodium bicarbonate (2×) and brine, dried with magnesium sulfate, filtered, and concentrated to give a crude brown oil. Purification by flash column chromatography (100% hexanes to 60% EtOAc/hexanes) gave the desired product (57 mg, 78%) as a yellow solid. LCMS calculated for C12H7BrF2N3O (M+H)+: m/z=326.0, 328.0. found: 325.9, 327.9.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:29]([N:25]1[CH2:24][CH2:23][CH:22]([N:21]([CH3:28])[C:19](=[O:20])[CH2:18][O:17][C:4]2[N:3]=[C:2]([CH3:1])[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:6]([CH3:16])[N:5]=2)[CH2:27][CH2:26]1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Product: Cc1nc(OCC(=O)N(C)C2CCN(C(=O)c3ccccc3)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 31 and benzoyl chloride in the same manner as in Example 32.
Reaction SMILES: [OH:1][N:2]=[C:3]([Cl:17])[C@H:4]1[C@H:8]([CH2:9][O:10][CH3:11])[O:7][C:6]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[O:5]1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C>CCOCC>[CH3:11][O:10][CH2:9][C@@H:8]1[O:7][C:6]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[O:5][C@H:4]1[C:3]([Cl:17])=[N:2][O:1][S:19]([CH3:18])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: COC[C@@H]1OC2(CCCCC2)O[C@H]1C(Cl)=NO
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC[C@@H]1OC2(CCCCC2)O[C@H]1C(Cl)=NOS(C)(=O)=O
Reaction time: 0.5 h
Yield: 49 %

Procedure:
(2R,3S)—N-hydroxy-3-(methoxymethyl)-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (35.6 g, 135.0 mmol) was dissolved in Et2O (600 mL) and cooled in an ice bath. Methanesulfonyl chloride (10.49 ml, 135.0 mmol) was added, followed by dropwise addition of triethylamine (18.82 ml, 135.0 mmol). The reaction was stirred for 30 minutes and then filtered and concentrated. The residue was purified on 1 Kg SiO2 (1 to 5% EtOAc in CH2Cl2) to afford (2R,3S)-3-(methoxymethyl)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (22.6 g, 66.12 mmol, 48.98% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:11][CH2:12][NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=O.CC(C)([O-])C.[K+]>C1COCC1.C(OCC)(=O)C>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([N:13]2[CH2:12][CH2:11][C:5]3([CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)[C:3]2=[O:2])=[N:15][CH:16]=1
Reactant: COC(=O)C1(CCNc2ccc(Br)cn2)CCOCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1N(c2ccc(Br)cn2)CCC12CCOCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 46 %

Procedure:
To a solution of 4-[2-(5-bromo-pyridin-2-ylamino)-ethyl]-tetrahydro-pyran-4-carboxylic acid methyl ester in THF (15 mL) was added a solution of potassium t-butoxide (1 M in THF) (3.5 eq), and allowed to stir at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (15 mL), quenched with brine (2 mL). The aqueous layer was extracted with ethyl acetate (2×15 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. Purification over silica gel eluting with methanol in dichloromethane (0-10%) afforded 0.4 g (46%) of title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([OH:11])[CH3:10].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].O>ClCCl>[S:20]([O:11][CH:9]([CH3:10])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])(=[O:22])(=[O:21])[CH3:19]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)Cc1ccccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(Cc1ccccc1F)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
Under a nitrogen atmosphere, to a mixture of 2.15 g (14.0 mmol) of (+)-1-(2-fluorophenyl)-propan-2-ol and 2.34 ml (16.8 mmol) of triethylamine in 10 ml of dichloromethane, 1.19 ml (15.4 mmol) of methanesulfonyl chloride was added at 0° C. The resulting mixture was stirred overnight at room temperature and then treated with water and extracted 3 times with dichloromethane. The combined organic layer was then washed with water, solvent was distilled off and the residue was purified by silica gel chromatography, giving 2.68 g of the title compound. (Yield: 82%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5](N)[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=[O:8].C(O)(=O)C.N([O-])=O.[Na+].[BrH:23]>O>[Br:23][C:5]1[CH:4]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Br
Reactant: Nc1cc(C(F)(F)F)ccc1C(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc(C(F)(F)F)cc1Br
Temperature: -10 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
205 g (1 mol) of 4-(trifluoromethyl)anthranilic acid, 600 ml of glacial acetic acid and 400 ml of 47% hydrobromic acid are introduced successively into a three-liter round-bottomed flask. After dissolution, the reaction mixture is cooled to -10° C., diluted with 400 ml of water and then treated dropwise with a solution of 69 g (1 mol) of sodium nitrite in 200 ml of water while maintaining the temperature below 0° C. When the addition is finished, the reaction mixture is stirred at 0° C. for 2 hours. This solution is run in dropwise into a six-liter reactor containing 143.5 g (1 mol) of cuprous bromide in 500 ml of 47% hydrobromic acid maintained at 60° C. When the addition is finished, the reaction mixture is stirred at 60° C. for one hour, cooled to room temperature and then poured into two liters of ice-cold water. The precipitate which forms is filtered on sintered glass, washed with water and then dried under a stream of air. There is thus obtained 216 g (yield: 80%) of 2-bromo-4-(trifluoromethyl)benzoic acid in the form of a solid melting at 118.5° C.
Reaction SMILES: [C:1]1([C:7]23[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH:11]2[CH2:10][O:9][NH:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Ni]>[NH2:8][C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:11]([CH2:10][OH:9])[CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CC2CONC2(c2ccccc2)C1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(CO)C(N)(c2ccccc2)C1
Yield: 0.1 %

Procedure:
tert-Butyl 6a-phenyl-3,3a,4,6-tetrahydro-1H-pyrrolo[3,4-c]isoxazole-5-carboxylate (142 mg, 489.04 mmol) is dissolved in methanol (10 mL). The solution is put through a flow hydrogenator with the Raney/Ni catalyst bed at 1 atmosphere H2 pressure and at 20° C., with a flow rate of 1 mL/min. Wash the bed with 10 mL more of MeOH after all the original solution has passed through. Remove the solvent under reduced pressure to obtain the title compound as a clear oil (168 mg, 117%) EI/MS (m/e): 293.3 (M+H).
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])[CH:10]=2)[O:5][CH:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:3]1.[C:26](=[N:32][Si](C)(C)C)=[N:27][Si](C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:15]([C:14]1[CH:13]=[C:12]([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[O:5][CH:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:3]/[C:2]/3=[N:32]/[C:26]#[N:27])[CH:19]=[CH:18][CH:17]=1)#[N:16]
Reactant: N#Cc1cccc(-c2ccc3c(c2)C(=O)CC(c2ccccn2)O3)c1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1/CC(c2ccccn2)Oc2ccc(-c3cccc(C#N)c3)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 190.3 %

Procedure:
To a solution of 3-(4-oxo-2-(pyridin-2-yl)chroman-6-yl)benzonitrile (50 mg, 0.15 mmol) in DCM (2 mL) was added TiCl4 (1 mL, 1 M in CH2Cl2) dropwise within 15 minutes at room temperature. After stirring for 1 h, N,N′-methanediylidenebis(1,1,1-trimethylsilanamine) (0.07 mL, 0.31 mmol) was added dropwise. The mixture was stirred at room temperature overnight and poured into ice-water (25 g). The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic layer was dried and concentrated to give crude (Z)—N-(6-(3-cyanophenyl)-2-(pyridin-2-yl)chroman-4-ylidene)cyanamide (100 mg, crude).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]([C:8]1([C:11]([OH:13])=O)[CH2:10][CH2:9]1)([CH3:7])[CH2:5][NH2:6].C[Si](C)(C)N[Si](C)(C)C.CO>C(#N)C>[NH2:3][C:4]1([CH3:7])[C:8]2([CH2:10][CH2:9]2)[C:11](=[O:13])[NH:6][CH2:5]1
Reactant: CC(N)(CN)C1(C(=O)O)CC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: CC#N
Solvent: CO
Product: CC1(N)CNC(=O)C12CC2
Temperature: 100 °C

Procedure:
To a solution (70 mL) of the crude 1-(1,2-diamino-1-methyl ethyl)-1-cyclopropanecarboxylic acid dihydrochloride (800 mg, 3.46 mmol) in acetonitrile was added 1,1,1,3,3,3-hexamethyldisilazane (7.38 mL, 34.6 mmol), and the mixture was heated under reflux in an oil bath at 100° C. for 4 hours under nitrogen atmosphere. The mixture was cooled to room temperature, and after adding methanol (70 mL), the solvent was removed by distillation under reduced pressure to obtain crude 7-amino-7-methyl-5-azaspiro[2.4]heptan-4-one as a pale brown gummy solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][CH2:7][O:8][CH2:9][C:10](OCC)=[O:11])[CH3:2].CC(C)([O-])C.[K+].O1CCCC1.Cl>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:5]1[CH2:6][CH2:7][O:8][CH2:9][C:10]1=[O:11])=[O:15])[CH3:2]
Reactant: CCOC(=O)CCCOCC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCOCC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.5 %

Procedure:
A solution of 4-ethoxycarbonylmethoxybutyric acid ethyl ester (90%, 15.0 g, 61.9 mmol) in toluene (300 mL) was stirred at room temperature and treated over 5 min with a solution of potassium tert-butoxide in tetrahydrofuran (1.0 M, 74.2 mL, 74.2 mmol). The mixture was stirred at room temperature for 24 h, then was poured into 1 N hydrochloric acid. The phases were separated, and the aqueous phase was extracted with ether. The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (5% ethyl acetate/hexanes) to provide the product as a pale yellow liquid (5.06 g, 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[O:7])=[C:4]([CH3:17])[CH:3]=1.C(NC(C)C)(C)C.[Li]C(CC)C.C=O.[C:32](=O)=[O:33].CC(C)=O>C1COCC1.C(Cl)Cl.CO>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[O:7])=[C:4]([CH2:17][CH2:32][OH:33])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(=O)NC1CCOCC1
Reactant: O=C=O
Agent: C=O
Agent: [Li]C(C)CC
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Solvent: CC(C)=O
Product: O=C(NC1CCOCC1)c1ccc(Cl)cc1CCO
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 54 %

Procedure:
4-Chloro-2-methyl-N-(tetrahydro-pyran-4-yl)-benzamide (2.09 g, 8.24 mmol) and diisopropylamine (0.15 equiv. 1.24 mmol, 125 mg.) were dissolved in anhydrous THF (100 mL). The solution was cooled to −78° C. When cooled at −78° C. it becomes a white suspension. To this solution was added sec-BuLi (1.4 M, in cyclohexane; 13 mL, 18.5 mmol, 2.25 equiv.), the reaction mixture turns into orange color, stirred for 5 min, and then submerged into ice-water bath (0° C.) for 15 min, the reaction becomes a clear orange solution, re-cooled to −78° C. Powdered formaldehyde (1.48 g, 49.44 mmol, 36 equiv.) was added. The dry ice-acetone bath was replaced with an ice-water and stirring was continued for 30 min. The red-brown color faded away to a light yellow color. The reaction was quenched with water, diluted with EtOAc. The two layers were separated and the aqueous was extracted with EtOAc (2×10 mL). The combined EtOAc solution was washed with brine (20 mL). Then, the EtOAc solution was dried over anhydrous granular K2CO3, filtered, and concentrated in vacuo. The crude product showed 2 peaks at 2.348 min, MS 284; 2.150 min, MS 254 at 2.808 (SM). The compound was purified on a 70-g silica gel column eluted with 1-5 min. 0-2.5% MeOH in DCM to obtain 1.25 g (54% yield) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[Cl-].[Li+].C([Sn](CCCC)(CCCC)[C:47]1[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=1)CCC>COCCOC.C(Cl)(Cl)Cl.CO>[N:49]1[CH:50]=[CH:51][CH:52]=[C:47]([C:2]2[CH:3]=[C:4]3[CH2:10][C:9]4([CH:15]5[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]5)[CH2:11]4)[O:8][C:5]3=[N:6][CH:7]=2)[CH:48]=1
Reactant: Brc1cnc2c(c1)CC1(CN3CCC1CC3)O2
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Cl-]
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Solvent: CO
Product: c1cncc(-c2cnc3c(c2)CC2(CN4CCC2CC4)O3)c1
Yield: 37 %

Procedure:
A solution containing 5'-bromospiro[1-azabicyclo[2.2.2]octane-3,2'(3'H)-furo[2,3-b]pyridine] (158 mg, 0.535 mmol), tris(dibenzylidineacetone)dipalladium (0) (23 mg, 0.025 mmol), tri(o-tolyl)phosphine (66 mg, 0.217 mmol), lithium chloride (99 mg, 2.34 mmol), and 3-(tri-n-butylstannyl)pyridine (0.3 ml, approx. 0.3 g, approx. 0.82 mmol) in 1,2-dimethoxyethane (2 ml) was heated under reflux for 6 h. The solution was evaporated, and the residue was taken up in chloroform and filtered. The filtrate was evaporated then purified by HPLC using a gradient of 0-20% 1:1:2 7M methanolic ammonia:methanol:chloroform and chloroform to obtain the title compound (58 mg, 0.198 mmol, 37%) as a pale solid: electrospray MS (m/z, relative intensity) 294 ([MH]+, 80), 273 (100).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[N:17][CH:18]=3)[N:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[C:9]=2[CH2:27][CH3:28])=[CH:4][C:3]=1[F:29].C([Sn](CCCC)(CCCC)[C:35]1[N:36]=[CH:37][S:38][CH:39]=1)CCC.[Cl-].[Li+]>O1CCOCC1.C(OCC)(=O)C.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>[CH2:27]([C:9]1[C:10]([C:23]([F:26])([F:25])[F:24])=[N:11][N:12]([C:13]2[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[N:17][CH:18]=2)[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([C:35]2[N:36]=[CH:37][S:38][CH:39]=2)=[C:3]([F:29])[CH:4]=1)[CH3:28]
Reactant: CCc1c(C(F)(F)F)nn(-c2ccc(S(N)(=O)=O)nc2)c1-c1ccc(Br)c(F)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCc1c(C(F)(F)F)nn(-c2ccc(S(N)(=O)=O)nc2)c1-c1ccc(-c2cscn2)c(F)c1
Yield: 77.1 %

Procedure:
A mixture of 5-(5-(4-bromo-3-fluorophenyl)-4-ethyl-3-trifluoromethyl-1H-pyrazol-1-yl)-2-pyridinesulfonamide (450 mg, 0.912 mmol), 4-tributylstannyl-1,3-thiazol (410 mg, 1.095 mmol), tetrakis(triphenylphosphine)palladium (105 mg, 0.091 mmol), lithium chloride (97 mg, 2.281 mmol) in 1,4-dioxane (11 ml) was stirred at reflux for 17 h. After cooling, the mixture was diluted with ethyl acetate, washed with water. The organic layer was dried (MgSO4) and concentrated. This was purified on silica gel eluting with ethyl acetate/hexane (1:3/1:2) to afford 350 mg (77.1%) of the titled compound as a yellow solid.