Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][C:12]1([CH3:37])[CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[C:18]2[CH:17]=[C:16]([Se:24][C:25]#[C:26][C:27]3[CH:36]=[CH:35][C:30]([C:31](OC)=[O:32])=[CH:29][CH:28]=3)[CH:15]=[CH:14][C:13]1=2.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[CH3:11][C:12]1([CH3:37])[CH2:21][CH2:20][C:19]([CH3:22])([CH3:23])[C:18]2[CH:17]=[C:16]([Se:24][CH2:25][CH2:26][C:27]3[CH:36]=[CH:35][C:30]([CH2:31][OH:32])=[CH:29][CH:28]=3)[CH:15]=[CH:14][C:13]1=2
Reactant: COC(=O)c1ccc(C#C[Se]c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC1(C)CCC(C)(C)c2cc([Se]CCc3ccc(CO)cc3)ccc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
A 1M solution of diisobutylaluminium hydride in toluene (4 ml, 4 mmol) is added dropwise, at 0° C., to a solution of methyl 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)-benzoate obtained according to Example 4 (750 mg, 1.8 mmol), in toluene (20 ml) The solution is stirred for 4 h at 0° C. and is then treated with a double potassium sodium tartrate solution, filtered and taken up in a mixture of ethyl ether and water. The organic phase is washed with water, dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. 418 mg (60%) of a colourless oil are obtained.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([CH2:17][OH:18])[O:14][N:13]=2)=[CH:8][CH:7]=1.C(N(CC)CC)C.O>C(Cl)Cl>[N:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([CH2:17][O:18][S:2]([CH3:1])(=[O:4])=[O:3])[O:14][N:13]=2)=[CH:10][CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1nc(-c2ccncc2)no1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCc1nc(-c2ccncc2)no1
Reaction time: 0.17 h

Procedure:
Methanesulfonyl chloride (0.50 ml, 6.50 mmol) was added to a stirred solution of (3-pyridin-4-yl-[1,2,4]oxadiazol-5-yl)methanol (1 g, 5.65 mmol) and triethylamine (0.953 ml, 6.78 mmol) in CH2Cl2 (30 ml) at 0° C. After 10 min, water (20 ml) was added and the aqueous phase extracted with CH2Cl2 (20 ml). The combined organic phases were dried (MgSO4) and evaporated to afford the title compound: RT=2.32 min; m/z (ES+)=256.0 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccccc1C=Cc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1ccccc1CCc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Reaction time: 3 h
Yield: 107.5 %

Procedure:
To a solution of 4-tert-butyl-2-[5-{2-(2-ethoxycarbonylphenyl)ethenyl}benzofuran-2-yl]thiazole (250 mg) in methanol (20.0 ml), 10% palladium on carbon (140 mg) was added. The mixture was hydrogenated for 3 hours (3.0-2.3 atm). The catalyst was removed by filtration and washed with methanol. The filtrate was evaporated under reduced pressure to give 4-tert-butyl-2-[5-{2-(2-ethoxycarbonylphenyl)ethyl}benzofuran-2-yl]thiazole (270 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[CH:11][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[NH2:21][C:22]1[S:23][C:24]([CH3:27])=[CH:25][N:26]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O>[CH3:27][C:24]1[S:23][C:22]([NH:21][C:2]2[N:7]=[C:6]([S:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])=[CH:11][CH:10]=3)[CH:5]=[N:4][CH:3]=2)=[N:26][CH:25]=1
Reactant: O=C(Nc1ccc(Sc2cncc(Cl)n2)cc1)C1CC1
Reactant: Cc1cnc(N)s1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cnc(Nc2cncc(Sc3ccc(NC(=O)C4CC4)cc3)n2)s1
Yield: 13.5 %

Procedure:
To a solution of N-(4-(6-chloropyrazin-2-ylthio)phenyl)cyclopropanecarboxamide (0.82 mmol) and 2-amino-5-methylthiazole (0.86 mmol) in 1,4-dioxan (3 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.05 mmol), tris(dibenzylideneacetone)dipalladium (0.03 mmol) and sodium carbonate (1.15 mmol) were added. The resulting solution was heated at 120° C. in the microwave (175W, 25 psi) for 3 h. Water (10 mL) and ethyl acetate (10 mL) were added and the layers separated. The aqueous layer was extracted further with ethyl acetate (2×10 mL), the combined organic layers dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography eluting with MeOH:CH2Cl2 (1:20) to give the title compound (42.5 mg, 14%) as a light brown solid; 1H NMR (400 MHz, DMSO-d6) δ 0.81 (4H, m), 1.82 (1H, m), 2.16 (3H, s), 3.32 masked signal, 6.99 (1H, m), 7.58 (2H, m), 7.76 (2H, m), 7.84 (1H, s), 8.04 (1H, s), 10.49 (1H, s), 11.50 (1H, br s); MS (ES+): m/e=384.48 (100%).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2ccc(Cl)cc2)c1Br
Yield: 93 %

Procedure:
4-Chloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 4-chlorobenzenesulfonyl chloride according to the procedures described in Example 25b. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a yellow powder, m.p. 145-150° C., yield 93%.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([CH:23]=[CH:24][C:25]#[N:26])[CH:17]=[CH:16]2>C(O)C.C(Cl)(Cl)Cl.[OH-].[Pd+2].[OH-].[C]>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([CH2:23][CH2:24][C:25]#[N:26])[CH:17]=[CH:16]2
Reactant: N#CC=Cc1ccc2cc(CN3C(=O)c4ccccc4C3=O)ccc2n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: N#CCCc1ccc2cc(CN3C(=O)c4ccccc4C3=O)ccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.6 %

Procedure:
The compound (574.4 mg) obtained in Example 119-6 was dissolved in ethanol (20 ml) and chloroform (10 ml). Then, the solution was added with 20% palladium hydroxide-carbon (172.3 mg) and then stirred at room temperature for 16 hours under a hydrogen atmosphere. After the reaction, the solution was filtrated through Celite and the solvent was then distilled off under reduced pressure. The residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (101.9 mg) as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[N:5][C:4]2[S:8][C:9]3[CH2:14][CH:13]([CH2:15][C:16]([O-:18])=[O:17])[CH2:12][CH2:11][C:10]=3[C:3]1=2.[C:19]([C:21]1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1>[CH2:19]([O:17][C:16](=[O:18])[CH2:15][C:13]1[CH:12]=[CH:11][C:10]2[C:3]3[C:2](=[O:1])[NH:7][CH:6]=[N:5][C:4]=3[S:8][C:9]=2[CH:14]=1)[CH3:21]
Reactant: O=C([O-])CC1CCc2c(sc3nc[nH]c(=O)c23)C1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc2c(c1)sc1nc[nH]c(=O)c12
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 36.1 %

Procedure:
(4-Oxo-3,4,5,6,7,8-hexahydro[1]benzothieno[2,3-d]pyrimidin-7-yl)acetate (5 g, 17.10 mmol, from step 2) was added to DDQ (9.71 g, 42.76 mmol, 2.5 equiv) in 1,4-dioxane (50 mL) solution under argon. The reaction mixture was heated to 90° C. for 15 h. The mixture was then allowed to cool to rt and the brown solid precipitated from solution. The solid was filtered and washed with 1,4-dioxane (2×30 mL). The filtrate was concentrated in vacuo. Saturated aqueous NaHCO3 (150 mL) was then slowly poured into the concentrated filtrate at 0° C. The mixture was stirred at 0° C. for 10 min then extracted with DCM (3×300 mL). The combined organic layer was washed with saturated aqueous NaHCO3 (100 mL), brine (30 mL) and dried (Na2SO4), then concentrated in vacuo. Ethyl ether (2×15 mL) was used to triturated the product. After drying, 1.78 g (6.18 mmol, 35%) of the desired product was obtained as a brown solid and it was used without further purification. 1H-NMR (CD3OD) δ 8.46 (d, J=8.1 Hz, 1H), 8.18 (s, 1H), 7.84 (s, 1H), 7.43 (d, J=8.2 Hz, 1H), 4.14 (q, 2H), 3.79 (s, 2H), 1.25 (t, 3H), LCMS RT=2.52 min, [M+H]+=289
Reaction SMILES: C1(C2C=CC(C[NH:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15](F)=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=3)=CC=2)CC1.[CH3:25][C:26]1([CH3:37])[C:34]2[C:29](=[CH:30][C:31]([CH:35]=O)=[CH:32][CH:33]=2)[CH2:28][CH2:27]1.FC(F)(F)C1C=C(CCN)C=CC=1.[BH4-].[Na+]>>[CH3:25][C:26]1([CH3:37])[C:34]2[C:29](=[CH:30][C:31]([CH2:35][NH:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([F:20])([F:21])[F:22])[CH:13]=3)=[CH:32][CH:33]=2)[CH2:28][CH2:27]1
Reactant: CC1(C)CCc2cc(C=O)ccc21
Reactant: Fc1ccc(CCNCc2ccc(C3CC3)cc2)cc1C(F)(F)F
Agent: NCCc1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Product: CC1(C)CCc2cc(CNCCc3cccc(C(F)(F)F)c3)ccc21
Yield: 97 %

Procedure:
The title compound was synthesized in analogy to (4-cyclopropylbenzyl)-[2-(4-fluoro-3-trifluoromethylphenyl)-ethyl]-amine (described in example S53) using 1,1-dimethylindan-5-carbaldehyde (100 mg, 0.57 mmol), 2-(3-trifluoromethylphenyl)-ethylamine (109 mg, 0.57 mmol) and sodium borohydride (33 mg, 0.86 mmol). The desired product (194 mg, 97%) was isolated without further purification as a colorless oil. MS (ISP) 348.4 (M+H)+.
Reaction SMILES: [CH2:1]([C@H:8]1[O:10][C@@H:9]1[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:14]1([NH2:17])[CH2:16][CH2:15]1.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>C(Cl)Cl.ClC1C=CC=CC=1>[CH:14]1([NH:17][C:11]([C@@H:9]2[C@@H:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[O:10]2)=[O:13])[CH2:16][CH2:15]1
Reactant: O=C(O)[C@H]1O[C@@H]1Cc1ccccc1
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: Clc1ccccc1
Solvent: ClCCl
Product: O=C(NC1CC1)[C@H]1O[C@@H]1Cc1ccccc1
Temperature: 5 °C
Reaction time: 14 h
Yield: 62.1 %

Procedure:
(2S,3R)-3-Benzyl-2-oxiranecarboxylic acid (66 mg) and a chlorobenzene solution (2 ml) of cyclopropylamine (23.2 mg, 1.1 equivalents) were mixed, and the mixture was cooled to 5° C. A methylene chloride solution (2 ml) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.5 equivalents) was gradually added, and the mixture was stirred at room temperature for 14 hours. Saturated aqueous solution of sodium hydrogencarbonate (5 ml) was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate (10 ml). The organic layer was washed with 1 N hydrochloric acid (5 ml) and water (5 ml) in order, and the solvent was evaporated away under reduced pressure to obtain the title compound as a brown oil (50 mg, yield: 62%).
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.C(N)C1C=CC=CC=1.[N+:22]([CH3:25])([O-:24])=[O:23]>O>[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH:25][N+:22]([O-:24])=[O:23])=[CH:8][CH:7]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(Cl)cc1
Solvent: NCc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])C=Cc1ccc(Cl)cc1
Temperature: 78 °C
Reaction time: 2 h

Procedure:
To 1066.8 g of acetic acid were added 200.14 g (1.356 mol) of 4-chlorobenzaldehyde, and 153.4 g (1.429 mol) of benzylamine, and the added components were dissolved in the acid. This solution was heated to 78° C., and 325.7 g (5.336 mol) of nitromethane was dropwise added thereto at 78 to 80° C. over 2 hours and 50 minutes. Thereafter, the solution was stirred at about 79° C. for 40 minutes. Next, 1016 g of water was dropwise added thereto at about 50° C. over 2 hours and 25 minutes. The mixture was cooled to about 10° C. and was stirred at 6 to 10° C. for 1 hour and 50 minutes. The obtained crystals were filtrated, and washed with 1016.2 g of water. The wet crystals were dissolved into 572.8 g of toluene at about 50° C. The resultant was separated into two phases, and the water phase thereof was removed. The remaining phase was washed with 330.8 g of water. By HPLC, 803.24 g of the toluene phase was analyzed. As a result, the phase contained 253.8 g of 4-chloro-β-nitrostyrene. The yield thereof was 97.1%.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][C:9]1([CH2:23][CH2:24][OH:25])[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2>N1C=CC=CC=1>[CH3:1][S:2]([O:25][CH2:24][CH2:23][C:9]1([CH2:8][CH2:7][O:6][S:2]([CH3:1])(=[O:4])=[O:3])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[O:16][C:17]2[C:22]1=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCC1(CCO)c2ccccc2Oc2ccccc21
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCC1(CCOS(C)(=O)=O)c2ccccc2Oc2ccccc21
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A mixture of 9,9-bis(2'-vinyloxyethyl)xanthene (57 g.) (prepared as in Example 2), water (400 ml.) and concentrated hydrochloric acid (15 ml.) is heated on the steambath with vigorous stirring for 5 hours. The cooled mixture is extracted three times with ether and the combined extracts are dried over MgSO4 and evaporated to dryness. The solid residue is recrystallised from chloroform-light petroleum (b.p. 60°-80° C.) to give 9,9-bis(2'-hydroxyethyl)xanthene, m.p. 144°-145° C. Methanesulphonyl chloride (588 mg.) is added dropwise over 5 minutes at 5° C. to a solution of 9,9-bis(2'-hydroxyethyl)xanthene (0.54 g.) in dry pyridine (5 ml.) with stirring. The mixture is allowed to stand at room temperature for 20 hours and is then poured into a mixture of 3N hydrocholoric acid (20 ml.) and ice (10 g.), and the resulting mixture is extracted with ethyl acetate. The ethyl acetate extract is washed with 3N hydrochloric acid and water, dried over MgSO4, and evaporated to dryness. The solid residue is recrystallised from acetone-light petroleum (b.p. 60°-80° C.) to give 9,9-bis(2'-methanesulphonyloxyethyl)-xanthene, m.p. 121°-122° C.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH2:7][CH2:8][C:9]1[C:14]([CH2:15][OH:16])=[C:13]([CH3:17])[CH:12]=[CH:11][N:10]=1.O>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[OH:16][CH2:15][C:14]1[C:9]([CH2:8][NH:7][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[N:10][CH:11]=[CH:12][C:13]=1[CH3:17]
Reactant: Cc1ccnc(CN)c1CO
Reactant: CC(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccnc(CNC(=O)C(C)C)c1CO
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of isobutyryl chloride (29 μL, 0.276 mmol) in DCM (0.20 mL) was added to a vigorously stirred mixture of (2-aminomethyl-4-methyl-pyridin-3-yl)-methanol (30 mg, 0.20 mmol) in DCM (1.0 mL) and aqueous Na2CO3 (1 M, 1 mL) at 0° C. After stirring for 30 min at 0° C., DCM (10 mL) and water (1 mL) was added, and the aqueous layer was extracted with DCM (1×10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with MeOH/DCM 1:20) to give the title compound. MS (m/z): 223.0 [M+H+].
Reaction SMILES: [C:1]([C:4]1([CH2:11][CH:12]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:9][CH2:8][CH2:7][CH2:6]C1=O)(=[O:3])C.[OH:26]O>C(O)(C)(C)C.S(=O)(=O)(O)O>[C:22]([O:21][C:19]([CH:12]([CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:11][C:4]1([C:1]([OH:26])=[O:3])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: OO
Reactant: COCCOCC(CC1(C(C)=O)CCCCC1=O)C(=O)OC(C)(C)C
Agent: O=S(=O)(O)O
Solvent: CC(C)(C)O
Product: COCCOCC(CC1(C(=O)O)CCCC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 105.9 %

Procedure:
To a solution of 2-acetyl-2-[2-(tert-butoxycarbonyl)-3-(2-methoxyethoxy)propyl]cyclohexanone (see Preparations 5 and 11) (50 m9, 0.14 mmol) in tert-butanol (0.5 ml) was added a 30% aqueous hydrogen peroxide solution (0.02 ml, 0.168 mmol) and concentrated sulphuric acid (one drop) at room temperature. The mixture was stirred at room temperature for 4 hours, partitioned between dichloromethane (10 ml) and water (10 ml), and the layers separated. The aqueous layer was extracted with dichloromethane (2×10 ml), the combined organic extracts dried over magnesium sulphate, filtered and concentrated under reduced pressure to give the title compound, (49 mg). Rf. 0.36 (silica, ethyl acetate). 1H-NMR (300 MHz, CDCl3) =1.43 (s, 9H), 1.43-1.60 (m, 2H), 1.61-1.65 (m, 4H), 1.78 (dd, 1H), 2.0 (dd, 1H), 2.08-2.20 (m, 2H), 2.59-2.70 (m, 1H), 3.38 (s, 3H), 3.48-3.65 (m, 6H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[N:10][N:9]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([CH2:20][C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[CH2:27][CH2:28]2)=[O:22])[N:11]=[N:10][N:9]=1
Reactant: Brc1ccccc1-c1nnn[nH]1
Reactant: O=C(CCl)N1CCN(c2ccc(Cl)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Cn1nnnc1-c1ccccc1Br)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-(2-Bromo-phenyl)-1H-tetrazole (0.374 g, 1.66 mmol) was taken in dry DMF (15 mL) and dry potassium carbonate (800 mg) and KI (20 mg) was added to it and stirred at rt for 1 h under nitrogen. 2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone (500 mg, 1.8 mmol) in DMF (5 mL) was then added to the mixture through a syringe. The reaction was then heated at 140° C. for 14 h, cooled and quenched with water and extracted with ethyl acetate. Drying of the organic layer with Na2SO4 followed by concentration afforded material that was further purified by flash column chromatography (ethyl acetate/pet ether): 1H NMR (300 MHz, CDCl3): δ 7.90 (d, 1H), 7.74 (d, 1H), 7.45 (t, 1H), 7.35 (t, 1H), 7.25 (d, 2H), 6.87 (d, 2H), 5.65 (s, 2H), 3.84 (m, 2H), 3.73 (m, 2H), 3.20 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:26]=[CH:25][C:6]([O:7][C:8]2[CH:24]=[CH:23][C:11]([O:12][CH:13]([CH3:22])[CH:14]([OH:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C(Cl)Cl.O.[CH:33](O)=[O:34]>>[F:1][C:2]([F:27])([F:28])[C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:24]=[CH:23][C:11]([O:12][CH:13]([CH3:22])[CH:14]([O:21][CH:33]=[O:34])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)CC(O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: O=CO
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CC(OC=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Yield: 60 %

Procedure:
4 g of ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-hydroxypentanoate in formic acid were heated to 60° C. for 6 hours and to 65° C. for an additional 3 hours (approx. 80% complete reaction) Methylene chloride and H2O were added to the mixture after transferring to a separation funnel. The methylene chloride layer was washed with water, NaHCO3, water and brine, dried over MgSO4 and its volume reduced to 3.8 g. The product was purified by silica gel chromatography (hexane/ethyl acetate) and identified as the above methyl formoyloxypentanoate ester with an overall yield of 60%.
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][N:9]([CH3:29])[C@H:10]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[F:28])[C:11]([O:13][C@H](C1C=CC=CC=1)C)=[O:12]>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:8][N:9]([CH3:29])[C@H:10]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[F:28])[C:11]([OH:13])=[O:12]
Reactant: C[C@H](OC(=O)[C@@H](c1ccccc1F)N(C)C)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CN(C)[C@@H](C(=O)O)c1ccccc1F
Reaction time: 4 h
Yield: 84.7 %

Procedure:
A mixture of (R)—((S)-1-phenylethyl) 2-(dimethylamino)-2-(2-fluorophenyl)acetate TFA salt (1.25 g, 3.01 mmol) and 20% Pd(OH)2/C (0.125 g) in ethanol (30 mL) was hydrogenated at room temperature and atmospheric pressure (H2 balloon) for 4 hours. The solution was then purged with Ar, filtered through diatomaceous earth (CELITE®), and concentrated in vacuo. This gave the title compound as a colorless solid (0.503 g, 98%). 1H NMR (400 MHz, CD3OD) δ 7.53-7.63 (m, 2H), 7.33-7.38 (m, 2H), 5.36 (s, 1H), 2.86 (s, 6H). LCMS: Anal. Calcd. for C10H12FNO2: 197; found: 198 (M+H)+.
Reaction SMILES: N#N.Br[C:4]1[CH:18]=[CH:17][C:7]2[N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[N:9]=[N:10][C:6]=2[CH:5]=1.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[N:8]1[C:7]2[CH:17]=[CH:18][C:4]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])=[CH:5][C:6]=2[N:10]=[N:9]1
Reactant: Brc1ccc2c(c1)nnn2C1CCCCO1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: N#N
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc2c(c1)nnn2C1CCCCO1
Temperature: 80 °C
Yield: 97 %

Procedure:
A 100-mL round-bottom flask equipped with a magnetic stir bar, a rubber septum and N2 inlet was charged with 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d][1,2,3]triazole (3.5 g, 12.4 mmol), Pd(Ph3P)2Cl2 (0.87 g, 1.24 mmol), CuI (0.47 g, 0.48 mmol), and triethylamine (62 mL). This mixture was degassed with three vacuum/N2 cycles. Trimethylsilylacetylene (3.5 mL, 24.8 mmol) was added, and the mixture was heated at 80° C. for 4 h. The reaction was monitored by LCMS. Upon completion, the reaction mixture was cooled down to room temperature, filtered through Celite, washed with ethyl acetate (100 mL), and concentrated. The crude product was purified on a silica gel column eluting with 5% ethyl acetate in hexanes to afford the title compound as a pale yellow oil (3.6 g). LCMS: 216 [(M-THP+H)+H]+.
Reaction SMILES: [C:1]1([CH:7]2[C:11]3([CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[O:10][C:9](=[O:17])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:18][C:19]1[N:24]=[C:23](Cl)[CH:22]=[CH:21][N:20]=1.[H-].[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C.C(Cl)Cl>[Cl:18][C:19]1[N:24]=[C:23]([N:8]2[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]3([CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)[O:10][C:9]2=[O:17])[CH:22]=[CH:21][N:20]=1
Reactant: O=C1NC(c2ccccc2)C2(CCOCC2)O1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1OC2(CCOCC2)C(c2ccccc2)N1c1ccnc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
To a mixture of 4-phenyl-1,8-dioxa-3-azaspiro[4.5]decan-2-one (300 mg, 1.286 mmol) and 2,4-dichloropyrimidine (192 mg, 1.286 mmol) in DMF (7 mL) under argon was added NaH (60% wt., 67.9 mg, 2.83 mmol) in two portions. The mixture was stirred for ˜1 hour. The reaction mixture was carefully poured into ice-coiled 0.25N aqueous HCl solution. DCM and aqueous NaHCO3 solution were added. The separated aqueous layer was extracted with DCM (3×) and ethyl acetate (1×). The organic layers (DCM and ethyl acetate containing layers independently) were washed with brine, dried over Na2SO4 and filtered off. The organic layers were combined and concentrated under reduced pressure providing crude 3-(2-chloropyrimidin-4-yl)-4-phenyl-1,8-dioxa-3-azaspiro[4.5]decan-2-one (330 mg) as a yellowish liquid, which was directly used in the next reaction without further purification. LCMS m/z 346.1 (M+H)+, Rt 0.83 min.