Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1)=[O:5])C>C1COCC1.[OH-].[Na+]>[C:11]1([C:9]2[N:10]=[C:6]([C:4]([OH:5])=[O:3])[S:7][CH:8]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1nc(-c2ccccc2)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1nc(-c2ccccc2)cs1

Procedure:
Ethyl-4-phenylthiazole-2-carboxylate (300 mg) was stirred overnight in a mixture of THF (4 mL) and 1N aqueous NaOH (1 mL) for 18 hours. The THF was removed under reduced pressure and the aqueous solution was acidified with 4N HCl, extracted with CH2Cl2, dried over Na2SO4 and concentrate to obtain 4-phenylthiazole-2-carboxylic acid which was used as is in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Si:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH3:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:30][C:31]([SH:34])([Cl:33])[Cl:32]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([Si:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([CH3:15])[CH2:9][N:10]2[C:14]([S:34][C:31]([Cl:33])([Cl:32])[Cl:30])=[N:13][CH:12]=[N:11]2)=[CH:6][CH:7]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: C[Si](Cn1cncn1)(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[Si](Cn1ncnc1SC(Cl)(Cl)Cl)(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 2 h
Yield: 59.6 %

Procedure:
To a solution of 4.0 g (0.013 mol) of bis(4-fluorophenyl)methyl(1H-1,2,4-triazol-1-ylmethyl)silane and 2.0 mL (0.014 mol) of triethylamine in 50 mL of methylene chloride at 6° was added 1.4 mL (0.013 mol) of perchloromethylmercaptan over 2 minutes. The reaction temperature rose 6°. The dark solution was stirred at 25° for 2 hours, then diluted with methylene chloride, washed with water and brine, and evaporated to give 3.6 g of the title compound as an oil: ir (neat) 3100, 3020, 2960, 1590, 1500; nmr (CDCl3) δ 0.7 (3H, s), 4.4 (2H, s), 7.1 (4H, t), 7.5 (4H, dd), 8.1 (1H, s); mass spectrum: m/e 464.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=1)[CH2:5]2.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[N:6]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:16][CH:15]=2)[CH2:5]3)[CH2:30][CH2:29]1
Reactant: CN1CCNCC1
Reactant: O=C1c2ccc(Br)cc2CN1CCc1ccc(Oc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CN1CCN(c2ccc3c(c2)CN(CCc2ccc(Oc4ccccc4)cc2)C3=O)CC1
Yield: 29.4 %

Procedure:
A mixture of 5-bromo-2-[2-(4-phenoxy-phenyl)-ethyl]-2,3-dihydro-isoindol-1-one (0.128 g, 0.31 mmol), 1-methyl piperazine (0.046 mL, 0.41 mmol), Pd2.dba3 (0.009 g, 0.01 mmol), BINAP (0.012 g, 0.02 mmol), and sodium tertiary-butoxide (0.048 g, 0.5 mmol) in toluene (3 mL) was heated to reflux for 3 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-(4-Methyl-piperazin-1-yl)-2-[2-(4-phenoxy-phenyl)-ethyl]-2,3-dihydro-isoindol-1-one (0.039 g, 29%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.36 (s, 3H), 2.58 (m, 4H), 2.94 (t, 2H), 3.32 (m, 4H), 3.81 (t, 2H), 4.16 (s, 2H), 6.82-7.35 (m, 1H), 7.69 (d, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([O:33][CH3:34])=[CH:15][CH:16]=[C:17]2[C:22]=1[NH:21][C:20](=[O:23])[CH:19]=[C:18]2[NH:24][C:25]1[C:30]([Cl:31])=[CH:29][N:28]=[CH:27][C:26]=1[Cl:32]>CS(C)=O>[Cl:32][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([Cl:31])[C:25]=1[NH:24][C:18]1[C:17]2[C:22](=[C:13]([O:12][CH2:11][CH2:10][CH2:9][N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[C:14]([O:33][CH3:34])=[CH:15][CH:16]=2)[NH:21][C:20](=[O:23])[CH:19]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCBr
Solvent: CS(C)=O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCN1CCN(C)CC1
Reaction time: 15 h

Procedure:
1-Methylpiperazine (0.5 mL, 4.5 mmol) was added to a solution of 8-(3-bromopropoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (150 mg, 0.32 mmol) and DMSO (2 mL) at room temperature. After 15 h, the reaction was placed under vacuum (˜0.1 Torr, 24h) to remove the excess amine. The resulting solution was purified by reverse-phase HPLC to give 4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-8-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-2(1H)-one. 1H NMR (400 MHz, DMSO-d6, bis HCl salt): δ 12.01 (br, 2H), 10.80 (br, 1H), 9.21 (s, 1H), 8.79 (s, 2H), 8.01 (d, 1H), 7.15 (d, 1H), 4.94 (s, 1H), 4.04 (t, 2H), 3.95 (s, 3H), 3.90-3.60 (br m, 4H), 3.60-3.34 (br m, 6H), 2.82 (s, 3H), 2.25 (m, 2H); MS (ESI): 492.3.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][OH:12])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.O>CS(C)=O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1CO
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)c1ccccc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
To a solution of (2-tert-butylphenyl)methanol (935 mg) in DMSO (20 mL) were added triethylamine (4.81 mL) and sulfur trioxide pyridine complex (3.02 g). The reaction mixture was stirred at room temperature for 1 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (780 mg).
Reaction SMILES: [ClH:1].[CH3:2][CH:3]1[CH:8]2[C:9]([CH:11]([CH3:13])[CH3:12])=[CH:10][CH:5]([CH:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:7]2)[N:4]1CC1C=CC=CC=1.[H][H]>[Pd].C(O)C>[ClH:1].[CH3:2][CH:3]1[CH:8]2[C:9]([CH:11]([CH3:12])[CH3:13])=[CH:10][CH:5]([CH:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:7]2)[NH:4]1
Reactant: CCOC(=O)C1CC2C(C(C)C)=CC1N(Cc1ccccc1)C2C
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1CC2C(C(C)C)=CC1NC2C
Yield: 100.8 %

Procedure:
A mixture of ethyl 3-methyl-8-isopropyl-2-(phenylmethyl)-2-azabicyclo[2.2.2]oct-7-ene-6-carboxylate hydrochloride (23.2 g, 63.8 mmol), ethanol (200 mL) and 10% palladium on carbon (2.3 g) was placed on a Parr hydrogenator at 44 psi of hydrogen pressure for 4 hours. The catalyst was removed by filtration and the solvent was concentrated in vacuo to afford 17.6 g (100%) of ethyl 3-methyl-8-isopropyl-2-azabicyclo[2.2.2]oct-7-ene-6-carboxylate hydrochloride as a white solid.
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[C:8]([NH2:11])[N:9]=[CH:10][C:5]=2[S:4][CH:3]=1.B([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([OH:20])=[O:19])(O)O>>[NH2:11][C:8]1[N:9]=[CH:10][C:5]2[S:4][CH:3]=[C:2]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([OH:20])=[O:19])[C:6]=2[N:7]=1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: Nc1ncc2scc(Br)c2n1
Product: Nc1ncc2scc(-c3cccc(C(=O)O)c3)c2n1
Yield: 56.3 %

Procedure:
3-(2-Aminothieno[3,2-d]pyrimidin-7-yl)benzoic acid (800 mg, 56% yield) was prepared in the same manner as Step 6 of Example 1 using 7-bromothieno[3,2-d]pyrimidin-2-amine (1.2 g, 5.24 mmol) and 3-boronobenzoic acid (870 mg, 5.24 mmol).
Reaction SMILES: [NH3:1].[CH3:2][O:3][C:4]1[CH:12]=[C:11]([Br:13])[C:10]([S:14](Cl)(=[O:16])=[O:15])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]>>[CH3:2][O:3][C:4]1[CH:12]=[C:11]([Br:13])[C:10]([S:14](=[O:16])(=[O:15])[NH2:1])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COc1cc(Br)c(S(=O)(=O)Cl)cc1C(=O)O
Reactant: N
Product: COc1cc(Br)c(S(N)(=O)=O)cc1C(=O)O
Reaction time: 1 h
Yield: 85 %

Procedure:
1,290 ml of 22° Be. ammonia is placed in a 3 liter flask fitted with an agitator and a thermometer. It is cooled, and 805 g of 2-methoxy-4-bromo-5-chlorosulphonyl-benzoic acid is added in stages between 0° and +10° C. The reaction medium is agitated for 1 hour at about +10° C. then the solution is filtered with charcoal. The filtrate is diluted with 300 ml of water and the acid precipitated by adding hydrochloric acid (density 1.18). The precipitate is drained, washed with water and dried in an oven at 50° C. 645 g (85%) of product is obtained, melting at 256° C.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH2:17][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[CH:15]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:28]([O:30][CH2:31][C:32]([Cl:35])([Cl:34])[Cl:33])=[O:29]>O.CCOC(C)=O>[Cl:33][C:32]([Cl:35])([Cl:34])[CH2:31][O:30][C:28](=[O:29])[NH:10][C:8]1[N:7]([C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH2:17][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[CH:15]=2)[N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:9]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(N)n(-c2cnn(CCOC3CCCCO3)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cnn(CCOC3CCCCO3)c2)n1
Reaction time: 0.17 h
Yield: 63 %

Procedure:
To a mixture of Intermediate 108a (1.29 g, 3.87 mmol) in water (5 mL) and EtOAc (13 mL) was added NaOH (310 mg, 7.74 mmol). After 10 min stirring, 2,2,2-trichloroethyl chloroformate (640 μL, 4.65 mmol) was added and the reaction mixture was stirred at RT for 1 h. The aqueous layer was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-75% EtOAc in cyclohexane, to afford the title compound (1.24 g, 63%). LCMS (Method 4): Rt 3.92 min, m/z 508, 510 [MH+].
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][CH2:4][C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:8]=2[CH:9]=1.[BH4-].[Na+].O>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].[Pd].ClCCl>[NH2:14][C:11]1[CH:12]=[CH:13][C:7]2[O:6][C:5]([CH2:4][CH2:3][C:2]([F:18])([F:1])[F:17])=[CH:9][C:8]=2[CH:10]=1
Reactant: O=[N+]([O-])c1ccc2oc(CCC(F)(F)F)cc2c1
Agent: [Pd]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [BH4-]
Solvent: ClCCl
Solvent: O
Product: Nc1ccc2oc(CCC(F)(F)F)cc2c1

Procedure:
A mixture of 2.4 g (9.2 mmol) of 2-(3,3,3-trifluoropropyl)-5-nitrobenzofuran, 0.65 g (17 mmol) of sodium borohydride, 45 mg of Adogen 464 and 0.38 g of 10% palladium on carbon containing 50% of water is stirred for 5 hours in 95 ml of dichloromethane and 48 ml of water, then it is filtered on silica and the silica is rinsed with ethanol. The filtrate is then concentrated under reduced pressure and coevaporated with toluene. After chromatography of the residue on a silica column using a 0-30% mixture of ethyl acetate in cyclohexane, 2.0 g of product are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=2)[C:10]2[N:14]([CH3:15])[C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Li+].[OH-].CCOC(C)=O.Cl>O1CCOCC1.O>[Cl:8][C:6]1[CH:5]=[C:4]([N:9]([CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)[C:10]2[N:14]([CH3:15])[C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[N:11]=2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COC(=O)c1ccc(CN(c2cc(Cl)cc(Cl)c2)c2nc3ccccc3n2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c(N(Cc2ccc(C(=O)O)cc2)c2cc(Cl)cc(Cl)c2)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the title compound of Example 223 Step B (0.2 mmol, 85 mg) in 1.6 mL of dioxane was added a solution of LiOH (0.8 mmol, 19 mg) in 0.8 mL of H2O. The reaction was allowed to stir at ambient temperature overnight. The crude reaction mixture was poured into pH 7 buffer/EtOAc, which was acidified with 2 N HCl until two clear layers formed after agitation. The organic phase was collected and the aqueous phase was extracted twice with EtOAc. The combined organic phase was dried over MgSO4, then concentrated under reduced pressure to afford the product as a white foam. MS (ESI): m/z 426 (M+H). HPLC A: 1.79 min.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH2:9])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].[Cl:11][C:12]1[C:13]([CH3:22])=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1>>[C:1]([C:4]1[S:8][C:7]([NH:9][S:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([Cl:11])[C:13]=2[CH3:22])(=[O:19])=[O:20])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)c1sc(N)nc1C
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: CC(=O)c1sc(NS(=O)(=O)c2cccc(Cl)c2C)nc1C

Procedure:
The title compound was prepared from 5-acetyl-2-amino-4-methylthiazole and 3-chloro-2-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (10.8 mg) with purity >90%. LCMS (pos) m/z 345.0.
Reaction SMILES: CC[O-].[Na+].[C:5]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:6][SH:7].Br[C:13]1[N:14]=[C:15]([CH3:28])[N:16]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:17]=1[CH:18]=O.CCCCCC>C(O)C>[CH3:28][C:15]1[N:16]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:25])[CH3:27])[C:17]2[CH:18]=[C:6]([C:5]([O:9][CH2:10][CH3:11])=[O:8])[S:7][C:13]=2[N:14]=1
Reactant: CCOC(=O)CS
Reactant: Cc1nc(Br)c(C=O)n1COCC[Si](C)(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)c1cc2c(nc(C)n2COCC[Si](C)(C)C)s1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
2.68 M Sodium ethylate was dissolved in ethanol (50 ml) and a solution (25 ml) of ethyl thioglycolate in ethanol was added. Thereto was added a solution (150 ml) of 4-bromo-2-methyl-1-(2-(trimethylsilyl)ethoxymethyl)imidazol-5-carboxaldehyde (3.16 g) in ethanol and the mixture was stirred at 80° C. for 2 hr. The solvent was evaporated under reduced pressure and water was added. The mixture was extracted twice with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was obtained by silica gel column chromatography (hexane/ethyl acetate=9/1). Hexane was added to the purified product and crystals were collected by filtration to give the objective compound (765 mg) as pale-brown crystals.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.O>O1CCCC1>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)NCCNc1ccccc1[N+](=O)[O-]

Procedure:
A mixture of 1-fluoro-2-nitrobenzene (2 g, 14.2 mmol), tert-butyl 2-aminoethylcarbamate (2.7 g, 17.0 mmol) and triethylamine (1.7 g, 2.4 mmol) in tetrahydrofuran was refluxed for 7 h. After cooling to rt 100 mL of water was added and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with brine (150 mL), dried over anhydrous sodium sulfate and filtered. The solvent was removed and the product was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:8][CH2:7][N:6]1[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4].COC(C)(C)C>O>[CH2:9]([N:6]1[CH2:7][CH2:8][CH:5]1[C:3]([OH:4])=[O:2])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)C1CCN1Cc1ccccc1
Solvent: COC(C)(C)C
Solvent: O
Product: O=C(O)C1CCN1Cc1ccccc1
Temperature: 40 °C
Reaction time: 14 h

Procedure:
21.02 g of N-Benzylazetidine-2-carboxylic acid methyl ester, 592 g of t-butyl methyl ether and 40 g of water are mixed at 20 to 25° C. and then 1.41 g of enzyme (Chirazyme L-2) was added thereto and the resulting solution was heated to 40° C. and stirred for 14 hours. Settled solution was separated into an aqueous phase and an organic phase. The aqueous phase was washed twice with t-butyl methyl ether to yield an aqueous solution of optically active N-benzylazetidine-2-carboxylic acid and a combined organic phase of N-benzylazetidine-2-carboxylic acid methyl ester. Results of the same analysis as in the Example 1 is shown in Table 7.
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:8]=[C:7]([N+]([O-])=O)[CH:6]=[CH:5][N+:4]=1[O-:12].[CH2:13]([OH:16])[CH2:14][CH3:15]>>[CH3:2][C:3]1[CH:8]=[C:7]([O:16][CH2:13][CH2:14][CH3:15])[CH:6]=[CH:5][N+:4]=1[O-:12]
Reactant: CCCO
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Agent: [Na]
Product: CCCOc1cc[n+]([O-])c(C)c1

Procedure:
To a solution of sodium n-propoxide solution prepared by dissolving sodium (1.7 g) in n-propanol (200 ml) was added to a hot solution of 2-methyl-4-nitropyridine-1-oxide (5.2 g) in n-propanol (210 ml). The mixture was stirred for ten minutes, then n-propanol was evaporated off. To the residue was added chloroform under ice-cooling, and insoluble materials were removed by means of celite filtration. From the resultant solution was removed chloroform by evaporation. The residue was subjected to a silica-gel column chromatography, followed by elution with 10% methanol-chloroform to yield 2-methyl-4-propoxypyridine-1-oxide (4.7 g) as an oily substance.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH2:2][CH3:3].[CH3:7][O:8][N:9]=[C:10]([C:13]1[CH2:14][N:15]([OH:19])[CH2:16][CH2:17][CH:18]=1)[C:11]#[N:12]>C1(C)C=CC=CC=1>[CH3:7][O:8][N:9]=[C:10]([C:13]1[CH2:14][N:15]([O:19][C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[O:6])[CH2:16][CH2:17][CH:18]=1)[C:11]#[N:12]
Reactant: CCCN=C=O
Reactant: CON=C(C#N)C1=CCCN(O)C1
Solvent: Cc1ccccc1
Product: CCCNC(=O)ON1CCC=C(C(C#N)=NOC)C1
Reaction time: 2 h
Yield: 55.6 %

Procedure:
Propyl isocyanate (0.23 g, 0.00275 moles) was added to a solution of α-(methoxyimino)-α-(1-hydroxy-1,2,5,6-tetrahydropyridin-3-yl)acetonitrile (E2) (0.45 g, 0.0025 moles ) in dry toluene (20 ml) with stirring. The mixture was kept at ambient temperature for 2 hrs then evaporated to dryness. The resulting residue crystallised from ethyl acetate/60-80 petrol. Recrystallisation from the same solvent system gave the title compound (E8) as a white crystalline solid (0.37 g, 56%) m.p. 95°-6° C.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1>O1CCCC1>[OH:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(NC(=O)c2ccccc2)cn1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(O)nc1)c1ccccc1
Temperature: 180 °C
Yield: 53.4 %

Procedure:
N-(6-Methoxy-pyridin-3-yl)-benzamide (2.38 g, 10.4 mmol) was dissolved in a mixture of tetrahydrofuran and diethyl ether. HCl-gas was bubbled into the solution for 5 minutes. More diethyl ether was added and the white precipitate was collected by suction, washed twice with diethyl ether and heated in a kugelrohr apparatus at 180° C. for 0.5 hours. The solid material was crystallised from methanol:water, washed twice with water and dried overnight in a vacuum oven, yielding the title compound (1.19 g, 53% yield) as a grey solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]([SH:15])[CH2:13][SH:14])[CH:6]=[C:7]([O:10][CH3:11])[C:8]=1[OH:9].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH:21]=O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1C=CC=CC=1>C1C=CC=CC=1.O>[CH3:29][O:28][C:24]1[CH:23]=[C:20]([CH:21]2[S:15][CH:12]([C:5]3[CH:6]=[C:7]([O:10][CH3:11])[C:8]([OH:9])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:13][S:14]2)[CH:19]=[C:18]([O:17][CH3:16])[C:25]=1[O:26][CH3:27]
Reactant: COc1cc(C(S)CS)cc(OC)c1O
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Solvent: O
Product: COc1cc(C2CSC(c3cc(OC)c(OC)c(OC)c3)S2)cc(OC)c1O

Procedure:
1-(3,5-dimethoxy-4-hydroxyphenyl)-1,2-ethanedithiol (40) (2.10 g, 8.54 mmole), 3,4,5-trimethoxybenzaldehyde (24) (1.28 g, 6.57 mmole) and 0.857 g of pyridinium paratoluene sulfonate are added to 60 ml dry benzene and refluxed with Dean-Stark removal of the benzene-water azeotrope overnight. The benzene is removed in vacuo, and the remaining oil is extracted into 10% NaOH which was washed with diethylether. The basic layer is reacidified with 10% HCl and the desired product is extracted into ethyl acetate. The organic layer is dried over MgSO4, filtered, and evaporated in vacuo to an oil which is purified by flash column chromatography with 2:1 hex/ethyl acetate as eluent. The product mixture contains a 1.0/1.2 cis/trans ratio after the first recrystallization (1.287 g, 59%). The trans isomer is isolated after six additional recrystallizations from methanol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:2]=1.[C:13](O)(=[O:15])[CH3:14]>CO>[C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:3]1[CH2:4][CH2:5][CH2:6][NH:1][CH2:2]1)(=[O:15])[CH3:14]
Reactant: CC(=O)O
Reactant: OCCCC#Cc1cccnc1
Solvent: CO
Product: CC(=O)OCCCCCC1CCCNC1

Procedure:
A solution of 5-(3-pyridinyl)-4-pentyn-1-ol (4.99 g, 31.0 mmol) in acetic acid (150 mL) was hydrogenated over platinium (IV) oxide (1.4 g, 6.16 mmol) for 18 hours. The mixture was filtered through a Celite cartridge, washed through with acetic acid and evaporated in vacuo to give a yellow oil. This was loaded in methanol and eluted on an aminopropyl (NH2) cartridge (70 g) with methanol (400 ml). The solvent was evaporated in vacuo to give the title compound as a colourless oil which solidified after being under vacuum for 18 hours (7.4 g).
Reaction SMILES: Br[C:2]1[O:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=[O:10])[C:4]=2[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC1(C)C(C)(C)OB([C:26]2[CH:39]=[CH:38][C:29]([O:30][CH2:31][CH2:32][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:28][CH:27]=2)O1.C(=O)([O-])[O-].[K+].[K+].COCCOC>O>[C:12]1([C:3]2[C:4]3[C:9](=[O:10])[NH:8][CH:7]=[N:6][C:5]=3[O:11][C:2]=2[C:26]2[CH:27]=[CH:28][C:29]([O:30][CH2:31][CH2:32][N:33]3[CH2:34][CH2:35][CH2:36][CH2:37]3)=[CH:38][CH:39]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1(C)OB(c2ccc(OCCN3CCCC3)cc2)OC1(C)C
Reactant: O=c1[nH]cnc2oc(Br)c(-c3ccccc3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: O=c1[nH]cnc2oc(-c3ccc(OCCN4CCCC4)cc3)c(-c3ccccc3)c12
Temperature: 75 °C

Procedure:
Into a 16×100 mm vial sparged with argon was placed 6-bromo-5-phenylfuro[2,3-d]pyrimidin-4 (3H)-one 45 (250 mg, 0.859 mmol), 1-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)pyrrolidine (409 mg, 1.29 mmol), palladiumtetrakistriphenylphosphine (100 mg, 0.086 mmol), potassium carbonate (1.18 g, 8.59 mmol), DME (4 mL), and water (1 mL). The vial was capped and heated to 75° C. for 20 hours.