Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[C:20]1([C:26]2([CH2:29][NH2:30])[CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>C(O)C>[C:20]1([C:26]2([CH2:29][NH:30][C:5]3[C:4]4[N:8]=[CH:9][N:10]([C:3]=4[N:2]=[CH:1][N:6]=3)[C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[CH2:27][CH2:28]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: NCC1(c2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: OC[C@H]1O[C@@H](n2cnc3c(NCC4(c5ccccc5)CC4)ncnc32)[C@H](O)[C@@H]1O
Yield: 77.5 %

Procedure:
A mixture of 6-chloropurine riboside (8.61 g, 30 mmol), (1-phenylcyclopropyl)methylamine (4.41 g, 30 mmol) and triethylamine (6.06 g, 60 mmol) are refluxed in stirring ethanol (300 mL) under N2 for 20 h. On cooling to 0° the product crystallized. Vacuum filtration and drying in vacuo gives N6-((1-phenylcyclopropyl)methyl)adenosine (9.24 g, 79%) as a very pale khaki solid m.p. 118°-23° C. Found: C, 59.58; H, 5.77; N, 17.49%. C20H23N5O4 calculated requires: C, 60.45; H, 5.79; N, 17.63%.
Reaction SMILES: C([O:4][C:5]1[C:15]2[CH2:14][CH2:13][CH2:12][C:11]([C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)=[CH:10][C:9]=2[CH:8]=[CH:7][C:6]=1[O:28][CH3:29])(C)C.[Cl-].[Al+3].[Cl-].[Cl-]>O>[CH3:29][O:28][C:6]1[C:5]([OH:4])=[C:15]2[CH2:14][CH2:13][CH2:12][C:11]([C:16]3[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=3)=[CH:10][C:9]2=[CH:8][CH:7]=1
Reactant: COc1cc(C2=Cc3ccc(OC)c(OC(C)C)c3CCC2)cc(OC)c1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: COc1ccc2c(c1O)CCCC(c1cc(OC)c(OC)c(OC)c1)=C2
Reaction time: 0.17 h
Yield: 41 %

Procedure:
41 (220 mg, 0.55 mmol) was dissolved in 15 mL of anhydrous dichlromethane under nitrogen at room temperature. Aluminium chloride (147 mg, 1.1 mmol) was added and the reaction mixture was stirred for 10 minutes. 10 mL of water was added and the product was extracted in dichloromethane (2×20 mL) and the combined organic phases were dried over anhydrous sodium sulfate, evaporated under reduced pressure purified by column chromatography. The product 3, 81 mg (41% yield) was obtained in 10% ethylacetate in hexanes. Rf. 0.54 (60:40 Hex:EA).
Reaction SMILES: [Na:1].[N:2]1[C:10]([NH2:11])=[C:9]2[C:5]([N:6](C3(OC[C@H](OCP(O)(O)=O)[C@H]3O)O)[CH:7]=[N:8]2)=[N:4][CH:3]=1.N1C(N)=C2C(N([C:35]3([O:52][CH2:51][C@H:38]([O:39][CH2:40][P:41]([O:47]C(C)C)([O:43]C(C)C)=[O:42])[CH2:37]3)[OH:36])C=N2)=NC=1>>[Na:1].[N:2]1([C:35]2([O:52][CH2:51][C@H:38]([O:39][CH2:40][P:41]([OH:47])([OH:43])=[O:42])[CH2:37]2)[OH:36])[C:10]([NH2:11])=[C:9]2[C:5](=[N:6][CH:7]=[N:8]2)[N:4]=[CH:3]1
Reactant: CC(C)OP(=O)(CO[C@H]1COC(O)(n2cnc3c(N)ncnc32)C1)OC(C)C
Reactant: Nc1ncnc2c1ncn2C1(O)OC[C@H](OCP(=O)(O)O)[C@H]1O
Agent: [Na]
Product: Nc1c2ncnc-2ncn1C1(O)C[C@@H](OCP(=O)(O)O)CO1
Yield: 43 %

Procedure:
This compound was prepared as described for 3a, using 19 (70 mg, 0.23 mmol) as a starting material. Compound 3e (38 mg, 0.11 mmol) was obtained as a colorless solid, in 43% yield, which was characterized as follows:
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:31](OC)=[O:32])=[CH:20][C:21]([CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:22][CH:23]=2)=[CH:14][CH:13]=1>ClCCl>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:20][C:19]=2[CH2:31][OH:32])=[CH:14][CH:13]=1
Reactant: COC(=O)c1cc(CCN2CCCC2)ccc1-c1ccc(Cl)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: OCc1cc(CCN2CCCC2)ccc1-c1ccc(Cl)cc1
Reaction time: 0.33 h

Procedure:
Diisobutylaluminum hydride (1M in hexanes, 7.8 mL) was added to a solution of EXAMPLE 53D (0.89 g) in dichloromethane (30 mL) at 0° C., and the reaction was stirred for 20 minutes. The reaction was quenched by the slow addition of methanol, and then poured into 1M aqueous NaOH (50 mL). The mixture was extracted twice with ethyl acetate, and extracts were combined, washed with brine, dried over Na2SO4, filtered, and concentrated.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([O:20][C:21]([F:24])([F:23])[F:22])[CH:19]=1)[CH2:15][OH:16].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([O:20][C:21]([F:22])([F:23])[F:24])[CH:19]=1)[CH:15]=[O:16]
Reactant: OCc1cc(Cl)cc(OC(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=Cc1cc(Cl)cc(OC(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 94.7 %

Procedure:
A solution of DMSO (16.1 g, 205.9 mmol) in anhydrous CH2Cl2 (300 mL) was cooled to −78° C. Oxalyl chloride (13.1 g, 103.0 mmol) was added slowly via a syringe (gas evolution was observed). The resulting solution was stirred at −78° C. for 15 minutes. A solution of 3-chloro-5-trifluoromethoxybenzyl alcohol (21.2 g, 93.6 mmol; see step (v) above) in CH2Cl2 (200 mL) was added via an addition funnel over a period of 15 minutes. The cloudy solution was stirred at −78° C. for 40 minutes and DIPEA (60.5 g, 468.0 mmol) was added via an addition funnel over 10 minutes. The resulting homogeneous solution was stirred at −78° C. for 1.5 hours, then warmed to room temperature and stirred 18 hours. The crude solution was concentrated in vacuo, the residue diluted with EtOAc and washed with H2O (1×), 2N HCl (1×), brine (1×), aqueous NaHCO3 (1×) and brine (1×). The organics were dried (Na2SO4), filtered and concentrated in vacuo to give the crude sub-title compound (19.9 g, 95%) which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[CH:4][C:3]=1I.N.[CH3:16][N:17]1CCCC1=O>>[NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[CH:4][C:3]=1[C:16]#[N:17]
Reactant: CN1CCCC1=O
Reactant: Cc1cc(-n2cncn2)cc(I)c1N
Agent: N
Product: Cc1cc(-n2cncn2)cc(C#N)c1N

Procedure:
A mixture of 1-(4-amino-3-iodo-5-methyl-phenyl)-1,2,4-triazole (14.23 g) and cuprous cyanide (5.94 g) was heated at 120° in N-methylpyrrolidone (32 cm3) for 2.5 hours. The cooled mixture was poured into ammonia solution (100 cm3 ; S.G. 0.880) and the resulting solution was extracted with chloroform:methanol, 19:1 (3×150 cm3). The combined and dried (MgSO4) organic extracts were filtered and evaporated in vacuo (0.5 mm) to afford an oil which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with ethyl acetate:methanol, 19:1. Combination and evaporation of appropriate fractions gave an oil which crystallised on trituration with ether to give the title compound, m.p. 231°-3° (2.8 g).
Reaction SMILES: C([S:4][CH2:5][CH2:6][CH2:7][CH:8]([C:20]([O:22]C)=[O:21])[O:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15]C)=[O:14])(=O)C.[OH-].[Na+].Cl>C1COCC1>[C:20]([CH:8]([O:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([OH:15])=[O:14])[CH2:7][CH2:6][CH2:5][SH:4])([OH:22])=[O:21]
Reactant: COC(=O)c1cccc(OC(CCCSC(C)=O)C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cccc(OC(CCCS)C(=O)O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.4 %

Procedure:
A solution of methyl 3-(4-acetylthio-1-methoxycarbonylbutoxy)benzoate XV (8.00 g, 23.5 mmol) in THF (60 mL) was deoxygenated by bubbling N2 through the solution for 1 hour. To the solution was added deoxygenated 3 N NaOH (47 mL, 141 mmol) and the mixture was stirred for 24 hours at room temperature under N2. The mixture was acidified with 1 N HCl and extracted with EtOAc (3×300 mL). The organic extracts were washed with water (300 mL) and brine (300 mL), dried over MGSO4, filtered, and concentrated. The residual oil was dissolved in ether and the solution was concentrated to afford 3-(1-carboxy-4-mercaptobutoxy)-benzoic acid (4.40 g, 16.3 mmol, 69%) as a white solid: 1H NMR (CDCl3) δ1.40 (t, J=7.9 Hz, 1H), 1.83-1.99 (m, 2H), 2.11-2.22 (m, 2H), 2.63 (m, 2H), 4.76 (dd, J=7.3, 5.0 Hz, 1H), 7.23 (m, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.49 (m, 1H), 7.72 (d, J=7.7 Hz, 1H); 13C NMR (CDCl3) δ24.1, 29.6, 31.2, 75.5, 114.8, 122.1, 123.9, 129.9, 130.5, 157.6, 171.8, 177.1. Elemental analysis calculated for C12H14O5S: C, 53.32; H, 5.22; S, 11.86. Found: C, 53.04; H, 5.38; S, 11.58.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8](B(O)O)=[CH:9][C:4]=2[O:3][CH2:2]1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([C:26](SC2C=CC=CC=2)=[O:27])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>C1COCC1.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].S1C=CC=C1C([O-])=O.[Cu+]>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)=[O:27])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Sc2ccccc2)CC1
Reactant: OB(O)c1ccc2c(c1)OCO2
Agent: [Cu+]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc3c(c2)OCO3)CC1
Yield: 92.5 %

Procedure:
To a mixture of benzo[d][1,3]dioxol-5-ylboronic acid (0.39 g, 2.30 mmol), ligand TFP (0.07 g, 0.3 mmol), Pd2dba3 (0.14 g, 0.16 mmol), copper (I) thiophene-2-carboxylate (0.45 g, 2.4 mmol) was added a solution of 4-phenylsulfanylcarbonyl-piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 1.6 mmol) in 10 mL of THF while purging with N2 at 50° C. After 18 hours the reaction mixture was diluted with ethyl acetate, filtered through celite then concentrated in vacuo. Purification by flash chromatography gave the title compound (0.52 g, 1.48 mmol). MS (ESI) m/z 333.8 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 1.52 min.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:17]=[CH:16][C:6]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Br[CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:11][CH:10]=2)=[CH:16][CH:17]=1
Reactant: Oc1ccc(CNc2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)C(C)Br
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)Oc1ccc(CNc2ccc(Cl)cc2)cc1
Yield: 73.5 %

Procedure:
To a solution of 0.256 g of sodium in 30 ml of ethanol is added 2 g of 4-(4-chloroanilinomethyl)phenol, and 2.02 g of ethyl 2-bromopropionate is further added dropwise at room temperature. The mixture is thereafter refluxed under heating for 5.5 hours. The ethanol is distilled off from the reaction mixture, 20 ml of water is added to the residue, and the diluted residue is extracted with ether. The extract is washed twice with a saturated aqueous solution of sodium chloride and then dried. After distilling off the solvent from the dried extract, the residue (2.9 g) is purified by column chromatography, using 60 g of silica gel and chloroform as a developer, to give 2.1 g of ethyl 2-[4-(4-chloroanilinomethyl)phenoxy]propionate as an oily product.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:23]=[CH:22][CH:21]=[CH:20][C:9]=1[CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.O.[OH-].[Na+]>C1COCC1>[F:7][C:8]1[CH:23]=[CH:22][CH:21]=[CH:20][C:9]=1[CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1
Reactant: N#Cc1ccc(OCc2ccccc2F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(OCc2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
To a LiAlH4 (6.50 g, 171.9 mmol) suspension in THF (500 mL) was added dropwise a THF (40 mL) solution of 4-(2-fluorobenzyloxy)benzonitrile (13.00 g, 57.3 mmol) at 0° C. The mixture was stirred at room temperature (16 h) and H2O (5.4 mL) was added dropwise at 0° C. followed by an aqueous NaOH solution (2.7 mL, 15% w/w), and then H2O (5.4 mL). The mixture was stirred at room temperature (2 h), and the precipitate filtered and washed with CH2Cl2. The filtrate was concentrated in vacuo to obtain a colorless oil (8.00 g, 64%): Rf=0.00 (hexanes/EtOAc 911); IR (hydrochloride salt, nujol) 3081, 1608, 1519, 1457, 1380, 1300, 1240, 1181, 1051, 967, 836, 754, 558 cm−1; 1H NMR (CDCl3) δ 1.63 (br 5, NH2), 3.80 (s, CH2NH2), 5.12 (s, CH2O), 6.96 (d, J=9.0 Hz, 2 ArH), 7.05-7.34 (m, 5 ArH), 7.50 (td, J=1.5, 7.5 Hz, 1 ArH).
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][C:15]2[N:16]([CH3:24])[N:17]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:19]=2)=[O:13])=[CH:7][CH:6]=1)C.[OH-].[Na+].Cl>C(O)C.C(OCC)(=O)C>[C:20]([C:18]1[CH:19]=[C:15]([NH:14][C:12](=[O:13])[NH:11][C:8]2[CH:7]=[CH:6][C:5]([C:4]([OH:25])=[O:3])=[CH:10][CH:9]=2)[N:16]([CH3:24])[N:17]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOC(=O)c1ccc(NC(=O)Nc2cc(C(C)(C)C)nn2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1ccc(C(=O)O)cc1
Temperature: 80 °C

Procedure:
To a suspension of 4-[3-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-ureido]benzoic acid ethyl ester (0.24 g, 0.71 mmol) in ethanol (4 mL) is added 1 N aq. NaOH solution (2 mL) and the mixture is heated at 80° C. for 2 hours. Then, 1 N HCl is added until pH 6 and the mixture is diluted with ethyl acetate. The organic phase is washed once with aqueous sodium chloride solution and dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 0.19 g (0.59 mmol), 83% as white solid. ES+(m/z) 317 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[CH:12]([OH:15])S[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].I([O-])(=O)(=O)=[O:17].[Na+]>CO.O.[Ru](Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[CH:12]([OH:15])[O:17][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1C(O)SCN1c1ccc(Cl)c(Cl)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1C(O)OCN1c1ccc(Cl)c(Cl)c1
Reaction time: 2 h
Yield: 21 %

Procedure:
A stirred solution of 3-(3,4-dichlorophenyl)-5-hydroxythiazolidin4-one (264 mg, prepared as in Example 1 of WO 94/13652) in methanol (5 ml) was treated with a solution of sodium periodate (852 mg) in water (10 ml). More methanol (5 ml) was added to redissolve the cloudy precipitate which formed. Ruthenium trichioride (10 mg) was added, whereupon the solution turned brown, became warm and a precipitate slowly formed. The resultant slurry was stirred for 2 hours, then water (30 ml) was added and the mixture extracted with ethyl acetate (3×20 ml). The combined ethyl acetate extracts were washed with saturated aqueous sodium sulfite solution (2×20 ml), water (3×20 ml) and brine (20 ml), then dried (MgSO4). Evaporation of the solvent under reduced pressure gave a yellow oil, which was purified by silica-gel chromatography, eluting with ethyl acetate/hexane mixtures, then by high-pressure silica-gel chromatography, eluting with 60% ethyl acetate/hexane, to give the title compound as a white solid (52 mg).
Reaction SMILES: C([O:8][N:9]1[C:13](=[O:14])[CH2:12][C@@H:11]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:10]1=[O:31])C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][N:9]1[C:13](=[O:14])[CH2:12][C@H:11]([NH:15][S:16]([C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)(=[O:18])=[O:17])[C:10]1=[O:31]
Reactant: O=C1C[C@@H](NS(=O)(=O)c2ccc(-c3ccccc3)cc2)C(=O)N1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C1C[C@H](NS(=O)(=O)c2ccc(-c3ccccc3)cc2)C(=O)N1O

Procedure:
N-[1-(benzyloxy)-2,5-dioxo-3-(R)-pyrrolidinyl][1,1′-biphenyl]4-sulfonamide was hydrogenated over 10% Pd on charcoal in ethanol+10% AcOH under normal atmospteric pressure in the standard hydrogenation apparatus and the reaction progress was monitored by TLC. Then,the catalysator was filtered,washed with ethanol and the title compound was purified by silica gel chromatography (EtOAc+10% MeOH+1% AcOH)
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+].[C:22]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:25])[CH:23]=[CH2:24]>CN(C=O)C.O.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:27]([O:26][C:22](=[O:25])[CH:23]=[CH:24][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: O=Cc1ccc(Br)cc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C=Cc1ccc(C=O)cc1
Temperature: 100 °C
Yield: 63.8 %

Procedure:
A solution of 4-bromo benzaldehyde (2 g, 10.8 mmol) in DMF (50 ml) and triethylamine (3.4 ml, 27 mmol) was degassed flushing N2 for 30 min. PPh3 (141 mg, 0.54 mmol), Pd(OAc)2 (48.4 mg, 0.21 mmol), NaHCO3 (1.84 g, 21.6 mmol) and tert-butyl acrylate (1.58 ml, 10.8 mmol) were added and the resulting mixture was heated to reflux for 3 h. Additional Pd(OAc)2 (24 mg) was added and the mixture was heated to 100° C. for 1 h. The solution was diluted with H2O and extracted with Et2O. The organic layer was dried over Na2SO4 and the solvent was evaporated under vacuo to give the crude product that was triturated in isopropyl ether to give 1.6 g of 3-(4-formyl-phenyl)-acrylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH:13]([CH:14]=O)[CH:12]2[CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9]3)=[CH:4][CH:3]=1.C1(=O)NC(=O)C=C1.ClC1C=CC(N)=CC=1.N1C=CC=CC=1.Cl.[CH3:45][O:46][NH2:47]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[CH:13]([CH:14]=[N:47][O:46][CH3:45])[CH:12]2[CH2:11][N:10]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:9]3)=[CH:6][CH:7]=1
Reactant: CON
Reactant: CC(C)(C)OC(=O)N1CC2C(C=O)C2(c2ccc(Cl)cc2)C1
Agent: Cl
Agent: Nc1ccc(Cl)cc1
Agent: O=C1C=CC(=O)N1
Solvent: CCO
Solvent: c1ccncc1
Product: CON=CC1C2CN(C(=O)OC(C)(C)C)CC12c1ccc(Cl)cc1
Yield: 63 %

Procedure:
To a solution of tert-butyl 1-(4-chlorophenyl)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (609 mg, 1.99 mmol, prepared from maleimide and 4-chloroaniline according to the methods described in WO 2009141412 and WO 2008074716), in ethanol (10 mL) under nitrogen atmosphere, were added pyridine (0.8 mL, 9.9 mmol) and O-methylhydroxylamine hydrochloride (332.4 mg, 3.98 mmol). The reaction mixture was refluxed for 5 h. After completion of the reaction as confirmed by TLC, the solvent was evaporated. The crude compound was extracted with ethyl acetate (20 mL). The organic layer was separated, washed with 5% HCl (5 mL), water (10 mL), dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 2:3 EtOAc:Pet Ether) to afford pure tert-butyl 1-(4-chlorophenyl)-6-((methoxyimino)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (430 mg, 63%) as a viscous oil as mixture of isomers.
Reaction SMILES: BrC1C=C(N=C=S)C=CC=1.BrC1C=C(NC(N)=S)C=CC=1.NC1[S:24][C:25]2[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:26]=2[N:27]=1>>[NH2:27][C:26]1[CH:28]=[C:29]([Br:32])[CH:30]=[CH:31][C:25]=1[SH:24]
Reactant: Nc1nc2cc(Br)ccc2s1
Agent: NC(=S)Nc1cccc(Br)c1
Agent: S=C=Nc1cccc(Br)c1
Product: Nc1cc(Br)ccc1S
Yield: 21.1 %

Procedure:
The procedure of Referential Example 16 was repeated, except that 3-bromophenyl isothiocyanate (25.0 g) serving as a starting material was used, to thereby yield N-(3-bromophenyl)thiourea (19.4 g) as colorless crystals. Subsequently, The procedure of Referential Example 17 was repeated, to thereby yield 2-amino-5-bromobenzothiazole (1.21 g). Thereafter, The procedure of Referential Example 18 was repeated, to thereby yield the title compound (227 mg).
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[C:6]([CH3:11])=[CH:5][C:3]=1[OH:4].O[CH:13]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]>CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.C1(C)C=CC=CC=1>[CH3:11][C:6]1[C:7](=[O:10])[C:8]([CH3:9])=[C:2]([CH3:1])[C:3](=[O:4])[C:5]=1[CH:13]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: COc1ccc(C(O)CCCCC(=O)O)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: COc1ccc(C(CCCCC(=O)O)C2=C(C)C(=O)C(C)=C(C)C2=O)cc1
Temperature: 70 °C
Yield: 68.8 %

Procedure:
D-Camphor-10-sulfonic acid (0.1 g) was added to a toluene solution (60 ml) of 2,3,5-trimethylhydroquinone (3.1 g, 0.02 mole) and 6-hydroxy-6-(4-methoxyphenyl)hexanoic acid (5.0 g, 0.021 mole), and the mixture was heated at 70° C. for 20 hours, with stirring. The reaction solution was evaporated under reduced pressure, and tetrahydrofuran (50 ml) was added to dissolve the residue, followed by adding furthermore a 10% aqueous solution of ferric chloride and stirring at room temperature for 10 minutes. The reaction product was extracted with ethyl acetate, and the organic layer was washed with water, dried and then concentrated under reduced pressure. The residue was chromatographed on a silica gel column, and elution was performed with isopropyl ether to give 6-(3,5,6-trimethyl-1,4-benzoquinon -2-yl)-6-(4-methoxyphenyl)hexanoic acid (5.1 g, 76%). Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. By following the procedure of this Example, the Compound Nos. 23 to 34 and 68 were prepared.
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3]([OH:5])=[O:4].[CH3:7][C:8]([Si:11](Cl)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:10])[CH3:9].N1C=CN=C1>CN(C=O)C>[Si:11]([O:1][C@H:2]([CH3:6])[C:3]([OH:5])=[O:4])([C:8]([CH3:10])([CH3:9])[CH3:7])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[C@@H](O)C(=O)O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2R)-2-hydroxypropanoic acid (5 g) in DMF (20 ml) was added TBDPSCl (33.0 g) and imidazole (16.4 g). The reaction was then stirred overnight at RT. The reaction was partitioned between EtOAc (200 ml) and H2O (200 ml). The organics were recovered and washed with 10% citric acid (200 ml), H2O (200 ml) and finally brine (200 ml). The organics were then collected, dried (MgSO4) before being reduced in vacuo. The residue was dissolved in MeOH (200 ml), cooled in an ice bath and potassium carbonate (6.9 g) in H2O was added. After stirring at room temperature for 6 h the solvent was removed in vacuo and the residue diluted with H2O (100 ml). The pH was then adjusted to pH 4 with 10% citric acid, and the aqueous extracted three times with EtOAc (3×200 ml). The organics were collected dried MgSO4 before reducing in vacuo to give the subtitle compound as a colourless oil. Yield: 7.5 g
Reaction SMILES: [CH2:1]([O:3][C:4](Cl)=[O:5])[CH3:2].[C:7]1([N:13]2[CH2:17][CH2:16][C:15]([NH:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[N:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>O1CCCC1>[C:7]1([N:13]2[CH2:17][CH2:16][C:15]([N:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[C:4](=[O:5])[O:3][CH2:1][CH3:2])=[N:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)Cl
Reactant: c1ccc(N2CCC(Nc3cccnc3)=N2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)N(C1=NN(c2ccccc2)CC1)c1cccnc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Ethylchloroformate (0.75 ml) was added dropwise to a solution of 4,5-dihydro-1-phenyl-N-(3-pyridinyl)-1H-pyrazol-3-amine (1.66 g) and triethylamine (2.85 ml) in tetrahydrofuran (150 ml) at -45° under N2. The solution was allowed to warm to room temperature and stirred for 24 hours. The solution was filtered, evaporated to dryness, and the residue chromatographed on silica gel eluting with ethyl acetate in dichloromethane to give an oil which crystallised on triturating with ether. The solid was recrystallised from ether and petrol to give the title compound (0.66 g) mp 110°-12° (dec).