Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O1CCCC1>[CH2:4]([N:11]1[CH2:16][CH2:15][C:14]([CH3:1])([OH:17])[CH2:13][CH2:12]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C[Mg]Br
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: C1CCOC1
Product: CC1(O)CCN(Cc2ccccc2)CC1
Reaction time: 1 h

Procedure:
Under nitrogen atmosphere, methylmagnesium bromide (3.0M solution in diethyl ether, 10.8 mL) was diluted with tetrahydrofuran (110 mL) with cooling on an ice bath. To the solution, was added dropwise a solution of 1-benzyl-4-piperidinone (5.6 g) in tetrahydrofuran (40 mL), and the mixture was stirred for 1 hr.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](=[C:18]([S:28]([CH3:31])(=[O:30])=[O:29])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)C.O1CCCC1.[Fe]>[NH2:25][C:21]1[CH:20]=[C:19]([C:18](=[C:16]2[CH2:15][N:14]([CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:17]2)[S:28]([CH3:31])(=[O:30])=[O:29])[CH:24]=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)C(=C1CN(C(c2ccccc2)c2ccccc2)C1)c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CS(=O)(=O)C(=C1CN(C(c2ccccc2)c2ccccc2)C1)c1cccc(N)c1
Temperature: 25 °C
Yield: 53.7 %

Procedure:
A mixture of 0.34 g of 1-benzhydryl-3-[(methylsulfonyl)(3-nitrophenyl)methylene]azetidine, 16 cm3 of 1 N hydrochloric acid in 8 cm3 of ethanol and 16 cm3 of tetrahydrofuran is heated under reflux. 0.17 g of iron powder is added and the reflux is maintained for 3 hours. The mixture is then cooled to room temperature and the insoluble matter is filtered off. The solution is taken up in 10 cm3 of 1 N sodium hydroxide and 50 cm3 of a saturated aqueous sodium chloride solution. The aqueous phase is extracted with 3 times 40 cm of dichloromethane, the extracts are combined, dried over sodium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (50/50 by volume) as eluent, collecting 20 cm3 fractions. Fractions 13 to 31 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 15 cm3 of ethyl ether. 0.17 g of 3-[(3-aminophenyl)(methylsulfonyl)methylene]-1-benzhydrylazetidine is obtained melting at 197° C. [NMR spectrum in DMSO-d6, T=300K, δ in ppm (250 MHz): 2.95 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.75 (1H, s, NCH), 5.25 (2H, s, NH2), 6.55 (3H, m, 3CH arom.), 7.05 (1H, t, J=7 Hz, CH arom.), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t, J=7 Hz, 4CH arom.), 7.45 (4H, d, J=7 Hz, 4CH arom.)].
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>C(O)C.O1CCOCC1>[ClH:23].[ClH:23].[CH3:21][C:19]1[CH:18]=[C:17]([CH3:22])[N:16]=[C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:20]=1
Reactant: Cc1cc(C)nc(NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1cc(C)nc(NC2CCNCC2)n1

Procedure:
A solution of 4-(4,6-dimethyl-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.47 g, 4.80 mmol) in ethanol (20 mL) and 4 M HCl in dioxane (40 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 207.3 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([CH:25]3[S:29][CH2:28][CH2:27][S:26]3)([CH3:24])[CH3:23])[CH:19]=[CH:18][C:17]=2[O:30][CH3:31])[C@@H:9]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=O)(C)(C)C.[ClH:38].CO>CCOC(C)=O>[ClH:38].[ClH:38].[CH3:31][O:30][C:17]1[CH:18]=[CH:19][C:20]([C:22]([CH:25]2[S:26][CH2:27][CH2:28][S:29]2)([CH3:24])[CH3:23])=[CH:21][C:16]=1[CH2:15][NH:14][C@H:10]1[CH2:11][CH2:12][CH2:13][NH:8][C@H:9]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1ccc(C(C)(C)C2SCCS2)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(C(C)(C)C2SCCS2)cc1CN[C@H]1CCCN[C@H]1c1ccccc1

Procedure:
To a solution of Compound 82 (0.128 g) in EtOAc (5 ml) was added an excess amount of 10% HCl-MeOH (1 ml) for 8 hr. The resulting precipitate was collected and washed with EtOAc to give Compound 83 (0.069 g) as a colorless crystal.
Reaction SMILES: [CH3:1][CH:2]1[C:8]2=[C:9]3[C:13](=[CH:14][CH:15]=[C:7]2[O:6][CH2:5][CH2:4][N:3]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH:12][CH:11]=[CH:10]3.[H-].[Na+].[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](Cl)(=[O:34])=[O:33]>CN(C=O)C>[CH3:1][CH:2]1[C:8]2=[C:9]3[C:13](=[CH:14][CH:15]=[C:7]2[O:6][CH2:5][CH2:4][N:3]1[C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[N:12]([S:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH3:25])(=[O:34])=[O:33])[CH:11]=[CH:10]3
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: CC1c2c(ccc3[nH]ccc23)OCCN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1S(=O)(=O)n1ccc2c3c(ccc21)OCCN(C(=O)OC(C)(C)C)C3C
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
tert-Butyl 1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 42, 25 mg, 0.083 mmol) was dissolved in DMF (1 mL) and sodium hydride (60% in mineral oil, 4.0 mg, 0.17 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes before 2-methylbenzenesulfonyl chloride (22 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at room temperature overnight. The reaction was quenched by addition of water and the crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give tert-butyl 1-methyl-8-[(2-methylphenyl)sulfonyl]-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (21 mg) which was dissolved in DCM (1 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and the solvent was removed under reduced pressure. The crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH3CN) to give the title compound (1.1 mg) as a white solid. MS m/z 357 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]1.Cl>C(OCC)C.C(Cl)Cl>[NH:10]1[CH2:11][CH2:12][CH2:13][CH:8]([CH2:7][C:2]2[N:1]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCC(Cc2ncccn2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: c1cnc(CC2CCCNC2)nc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86 %

Procedure:
To a solution of tert-butyl 3-(pyrimidin-2-ylmethyl)piperidine-1-carboxylate (Preparation 70, 27.3 g, 98.4 mmol, 1 eq) in diethyl ether (160 mL) and DCM (50 mL) was added dropwise a 2M solution of hydrogen chloride in diethyl ether (246 mL, 492 mmol, 5 eq) while maintaining the internal temperature below 30° C. The reaction mixture was stirred at room temperature for 20 h. The solvent was decanted and fresh diethyl ether (300 mL) added. The solid was collected by filtration and washed with diethyl ether (3×100 mL) then dissolved in water (150 mL). The aqueous layer was washed with DCM (2×150 mL), basified with sodium hydroxide pellets to pH 13-14 and extracted with DCM (5×200 mL). The organic layer was separated, dried over sodium sulphate, filtered and concentrated under reduced pressure to afford title compound (15 g, 84.6 mmol, 86%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17]CC2C=CC=CC=2)=[CH:13][CH:12]=1)[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2]>C(O)C.ClCCl.[Pd]>[C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:9][OH:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CO)c1ccc(O)cc1
Reaction time: 8 h
Yield: 90.8 %

Procedure:
[(R)-1-(4-Benzyloxy-phenyl)-2-hydroxy-ethyl]-carbamic acid t-butyl ester (2.013 g, 5.87 mmol) and 10% Palladium on active carbon (0.300 g, 0.294 mmol) were mixed in ethanol (15 ml) and dichloromethane (5 ml). The hydrogenation was carried at 1 atmosphere at room temperature overnight. The catalyst was filtered out. The filtrate was concentrated to a white solid (1.350 g, 91% yield): 1H NMR (400 MHz, MeOD) δ ppm 7.36 (d, 2H), 6.97 (m, 2H), 3.83 (m, 1H), 3.54 (dt, J=3.2, 1.5 Hz, 2 H), 1.66 (m, 9H); LCMS (ESI) m/e 254.1 [(M+H), calcd. for C13H20NO4 254.3].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[H-].[Na+].Br[CH2:12][CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:12][CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1
Reactant: Sc1ccccc1Br
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccccc1SCCOC1CCCCO1
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a solution of 2-bromobenzenethiol (3.0 ml, 24.9 mmol) in N,N-dimethylformamide (50 ml) was added sodium hydride (60% in oil, 1.10 g, 27.5 mmol) under ice-cooling, and the mixture was stirred for 1 hr. To this reaction mixture was added 2-(2-bromoethoxy)tetrahydropyran (4.5 ml, 29.7 mmol) under ice-cooling, and the mixture was stirred at room temperature for 3 hr. Aqueous sodium carbonate solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate=10:1) to give 2-[2-(2-bromophenylsulfanyl)ethoxy]tetrahydropyran (7.91 g, yield 100%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:14])=[C:4]2[C:10]([N+:11]([O-])=O)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl[Sn]Cl.C([O-])([O-])=O.[Na+].[Na+]>Cl>[Br:1][C:2]1[C:3]([F:14])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1c[nH]c2ncc(Br)c(F)c12
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Product: Nc1c[nH]c2ncc(Br)c(F)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.2 %

Procedure:
5-bromo-4-fluoro-3-nitro-1H-pyrrolo[2,3-b]pyridine (2.0 g, 7.7 mmol) was placed in 6M HCl (30 mL) at room temperature. SnCl2 (7.29 g, 38.5 mmol) was then added, and the reaction was stirred for 30 minutes at room temperature. The reaction was then cooled to 0° C. and a saturated aqueous solution of Na2CO3 was added to raise the pH to 8. The reaction was then extracted with DCM (with minimal MeOH to aid solubility). The combined organic fractions were dried, filtered, and concentrated to give the crude product 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.50 g, 28.2% yield), which was used without purification.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:8]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:9]=3[S:10][CH:11]=2)=[CH:4][CH:3]=1.[C:20]([O:24][CH3:25])(=[O:23])[CH:21]=[CH2:22].C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl.O.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>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:8]2[C:7]([O:6][C:5]3[CH:18]=[CH:19][C:2](/[CH:22]=[CH:21]/[C:20]([O:24][CH3:25])=[O:23])=[CH:3][CH:4]=3)=[CH:11][S:10][C:9]=2[CH:12]=1
Reactant: C=CC(=O)OC
Reactant: COc1ccc2c(Oc3ccc(Br)cc3)csc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)/C=C/c1ccc(Oc2csc3cc(OC)ccc23)cc1
Temperature: 120 °C
Yield: 61.1 %

Procedure:
To a microwave vial, 3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene (500 mg, 1.49 mmol), methyl acrylate (770 mg, 8.95 mmol), and Pd(PPh3)2Cl2 (157 mg, 0.22 mmol) were suspended in DMF (12 mL) and triethylamine (1.039 mL, 7.46 mmol). The reaction was heated for 60 min at 120° C. under microwave irradiation. The reaction mixture was diluted with DCM and water. The organic layer was collected (phase separator) and concentrated to obtain the crude product. The crude material was purified by column chromatography (SiO2, 1-20% EtOAc/Heptane) to afford (E)-methyl 3-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (311 ms, 0.91 mmol, 61% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm=1.46 (s, 3 H), 3.73 (s, 3 H), 6.28 (d, J=16.17 Hz, 1 H), 6.59 (s, 1 H), 6.90 (dd, J=8.59, 2.02 Hz, 1 H), 7.00 (d, J=8.59 Hz, 2 H), 7.21 (d, J=2.02 Hz, 1 H), 7.37-7.48 (m, 3 H), 7.59 (d, J=16.17 Hz, 1 H), LC/MS (m/z, MH+): 341.1.
Reaction SMILES: C(O)(=O)C(O)=O.[CH2:7]([N:10]1[CH2:15][CH2:14][C:13]2([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([O:29]C)[C:23]=3[O:22][C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:12][CH2:11]1)[C:8]#[CH:9].[ClH:31].N1C=CC=CC=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O.N1C=CC=CC=1>[Cl:31][CH:9]=[CH:8][CH2:7][N:10]1[CH2:15][CH2:14][C:13]2([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:29])[C:23]=3[O:22][C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:12][CH2:11]1
Reactant: C#CCN1CCC2(CC1)c1ccccc1Oc1c(OC)cccc12
Reactant: Cl
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: Oc1cccc2c1Oc1ccccc1C21CCN(CC=CCl)CC1
Temperature: 200 °C

Procedure:
A mixture of 1'-(prop-2-ynyl)-4-methoxyxanthene-9-spiro-4'-piperidine hydrogen oxalate (1.3 g.) and pyridine hydrochloride prepared from pyridine (9 ml.) and concentrated hydrochloric acid (10 ml.) is heated at 200° C. for 10 minutes. The mixture is cooled and water (20 ml.) added. The solution is basified with dilute sodium carbonate solution and extracted with ether. The ether extract is washed with water, dried with MgSO4 and evaporated to dryness. The solid residue is recrystallised from ethyl acetatepetroleum ether (b.p. 80°-100° C.) to give 1'-(3-chloro-prop-2-enyl)-4-hydroxyxanthene-9-spiro-4'-piperidine, m.p. 153°-155° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1.O[CH2:21][C@H:22]([NH:32][S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[N+:42]([O-:44])=[O:43])(=[O:35])=[O:34])[C@@H:23]1[CH2:27][C@@H:26]([CH2:28][CH2:29][CH3:30])[C:25](=[O:31])[O:24]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[N+:42]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[S:33]([N@:32]1[CH2:21][CH:22]1[C@H:23]1[O:24][C:25](=[O:31])[C@H:26]([CH2:28][CH2:29][CH3:30])[CH2:27]1)(=[O:35])=[O:34])([O-:44])=[O:43]
Reactant: CCC[C@@H]1C[C@@H]([C@H](CO)NS(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCC[C@@H]1C[C@@H](C2C[N@@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Reaction time: 0.17 h
Yield: 73.2 %

Procedure:
2.95 ml of a solution of diethyl azodicarboxylate in toluene (40%) (6.48 mmol) was added to a solution of 2.01 g of N-{(S)-2-hydroxy-1-[(2S,4R)-5-oxo-4-propyltetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfonamide obtained in Example (116f) (5.4 mmol) and 1.7 g of triphenylphosphine (6.48 mmol) in tetrahydrofuran (54 ml) under ice-cooling over five minutes, and the mixture was stirred at the same temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: toluene/acetone=5/1) to obtain 1.4 g of the title compound (yield: 74%).
Reaction SMILES: [C:1]([CH:5]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH:10]2[N:6]1[CH2:7][CH2:8][CH2:9]2)([O:3]C)=O.N(C[C@@H]1CCCN1)[C:20]1C=CC=C[CH:21]=1.[Cl-].[Mg+2].[Cl-].C([Mg]Br)C>C1COCC1.CCOCC>[C:1]([CH:5]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH:10]2[N:6]1[CH2:7][CH2:8][CH2:9]2)(=[O:3])[CH2:20][CH3:21]
Reactant: COC(=O)C1N(c2ccccc2)CC2CCCN21
Reactant: c1ccc(NC[C@@H]2CCCN2)cc1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(=O)C1N(c2ccccc2)CC2CCCN21
Temperature: -70 °C
Yield: 28 %

Procedure:
2-Carbomethoxy-3-phenyl-1,3-diazabicyclo[3,3,0]octane prepared from 1.76 g of (S)-2-(anilinomethyl)pyrrolidine, as described in Example 8, was dissolved in 50 ml of THF, then admixed with 1.05 g of anhydrous magnesium chloride and refluxed by heating for 10 minutes. To the mixture cooled to -70° C., was added dropwise an ether solution containing 1.46 equivalents of ethylmagnesium bromide. The resulting mixture was treated as described in Example 12 to obtain 694 mg (28%) of 2-propionyl-3-phenyl-1,3-diazabicyclo[3,3,0]octane. NMR peaks: δ(ppm)=1.0 (3H, triplet), 1.4-2.1 (4H, multiplet), 2.1-2.6 (2H, multiplet), 2.6-3.3 (3H, multiplet), 3.5-3.9 (2H, multiplet), 4.2 (1H, singlet), 6.1-7.1 (5H, multiplet).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4](O)[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:4]1[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:2]([CH3:1])[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c(-c2ccccc2)c(O)nc2nccn12
Product: Cc1c(-c2ccccc2)c(Cl)nc2nccn12

Procedure:
250 mg of the product of step 1 and 10 ml POCl3 are heated to 100° C. for 1 h. The excess POCl3 is removed by distillation and the residue is treated with ice and diluted with dichloromethane. The phases are separated, the aqueous layer is extracted twice with dichloromethane, the combined organic layers are dried over Na2SO4 and concentrated to give the crude product.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][NH2:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:18][CH:19]([C:23](=O)[CH3:24])[C:20](=O)[CH3:21]>C(O)C>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[C:23]([CH3:24])=[C:19]([F:18])[C:20]([CH3:21])=[N:17]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NNc1ccccc1OCc1ccccc1
Reactant: CC(=O)C(F)C(C)=O
Agent: Cl
Solvent: CCO
Product: Cc1nn(-c2ccccc2OCc2ccccc2)c(C)c1F
Yield: 70.6 %

Procedure:
500 mg of 2-benzyloxyphenyl hydrazine hydrochloride and 251 mg of 3-fluoropentane-2,4-dione were added to 12 ml of ethanol, and heated at reflux for 1.5 hours. The reaction solution was concentrated under reduced pressure as it is and purified using silica gel column chromatography (hexane:ethyl acetate=6:1 to 5:1) to yield 417 mg of the title compound.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:14]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1>[Cl:13][C:10]1[CH:11]=[N:12][C:2]([CH3:14])=[C:3]([CH:9]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CB1OB(C)OB(C)O1
Reactant: CCOC(=O)c1cc(Cl)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cc(Cl)cnc1C
Temperature: 25 °C
Yield: 37958.3 %

Procedure:
A mixture of ethyl 2,5-dichloronicotinate (step 1, 10 g, 0.045 mol), tetrakis(triphenylphoshine)palladium (5.2 g, 4.5 mmol), trimethylboroxine (5.65 g, 0.045 mmol) and potassium carbonate (18.66 g, 0.16 mmol) in 1,4-dioxane (contain 10% water, 100 ml) was refluxed for 7 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature and poured into water. The aqueous mixture was extracted with ethyl acetate. The organic extracts were dried over sodium sulfate and concentrated. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (50/1 to 20/1) to afford 3.41 g (38%) of the title compound:
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[S:10][C:11]([CH3:18])=[C:12]([C:14]([O:16][CH3:17])=[O:15])[N:13]=1>O1CCOCC1>[CH3:18][C:11]1[S:10][CH:9]=[N:13][C:12]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1nc(N)sc1C
Agent: CC(C)(C)ON=O
Solvent: C1COCCO1
Product: COC(=O)c1ncsc1C
Temperature: 60 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
To a solution of tert-butyl nitrite (24 mL, 202 mmol) in 1,4-dioxane (180 mL) was added a mixture of methyl 2-amino-5-methyl-1,3-thiazole-4-carboxylate (6.83 g, 40.0 mmol) in 1,4-dioxane (70 mL). The solution was stirred at 60° C. for 1 hour. After cooling to room temperature, the solvent was evaporated. The crude oil was purified by flash chromatography (0-20% EtOAc/hexanes), affording methyl 5-methyl-1,3-thiazole-4-carboxylate (3.95 g, 63%). The product was used for the next step without any further purification.
Reaction SMILES: [NH4+].[OH:2][C:3]([CH3:12])([CH2:8][C:9]([O-:11])=[O:10])[CH2:4][C:5]([NH2:7])=[O:6]>O>[OH:2][C:3]([CH3:12])([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][C:5]([NH2:7])=[O:6]
Reactant: CC(O)(CC(N)=O)CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: CC(O)(CC(N)=O)CC(=O)O

Procedure:
1.79 g. (0.01 moles) of 3-hydroxy-3-methylglutaric acid monoamide, ammonium salt is dissolved in 50 ml of water and the solution is passed through a 100 ml column of Dowex 50 (H30 ) resin. The eluate is evaporated to dryness and the resulting residue dissolved in 100 ml of methanol containing 5 g. of hydrogen chloride. After 24 hours at room temperature the reaction mixture is evaporated to dryness under vacuum. The resulting residue is dissolved in 50 ml of water and the solution passed through a 50 ml column of Dowex 2 in the formate form. The column is eluted with 200 ml of water which is collected and evaporated under vacuum to afford 3-hydroxy-3-methylglutaric acid monoamide, methyl ester.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH:13]1([NH2:16])[CH2:15][CH2:14]1>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:16][CH:13]2[CH2:15][CH2:14]2)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: NC1CC1
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Solvent: CN(C)C=O
Product: Cc1csc2c(NC3CC3)nc(Cl)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.7 %

Procedure:
In DMF was dissolved 700 mg (3.2 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine, and then an aqueous solution of 428 mg (7.5 mmol) of cyclopropylamine was added dropwise to the resulting solution under ice cooling over 5 minutes. The reaction mixture was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for one hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/6) to give 780 mg (yield: 95.4%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[C:11]([OH:15])=[C:10]([CH3:16])[CH:9]=2)[N:4]=1.O[CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[F:18][C:2]([F:17])([F:1])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[C:11]([O:15][CH2:20][CH2:21][CH2:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[C:10]([CH3:16])[CH:9]=2)[N:4]=1
Reactant: OCCCCc1cccnc1
Reactant: Cc1cc(-c2noc(C(F)(F)F)n2)cc(C)c1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(-c2noc(C(F)(F)F)n2)cc(C)c1OCCCCc1cccnc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.2 %

Procedure:
To a suspension of 0.44 g (1.8 mmol) of 4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenol, 0.25 g (1.66 mmol) of 3-(4-hydroxybutyl)-pyridine, and 0.52 g (1.99 mmol) of triphenylphosphine in 30 ml of methylene chloride under nitrogen at 0° C. was added dropwise a solution of 0.35 g (1.97 mmol of DEAD in methylene chloride, and the resulting mixture was allowed to warm to room temperature. After adding 70 mg of triphenylphosphine, the mixture was stirred at room temperature for 2 days. The solution was concentrated in vacuo and the residue was purifed by MPLC (26 id Kieselgel 60 column; hexane/ethyl acetate 3:1) to yield 0.56 g (86.1%) of 3-[4-[4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]-butyl]-pyridine, as a pale yellow oil.