Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[CH3:10][O:11][C:12](=[O:16])[C:13]([CH3:15])=[CH2:14].C1(C(N)C2CCCCC2)CCCCC1>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].C1([B-](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.O1CCOCC1>[CH3:10][O:11][C:12](=[O:16])/[C:13](/[CH3:15])=[CH:14]/[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9]
Reactant: C=C(C)C(=O)OC
Reactant: Cc1cccc(C)c1Cl
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: NC(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: COC(=O)/C(C)=C/c1c(C)cccc1C
Yield: 75.8 %

Procedure:
A 30-ml four-necked flask was equipped with a stirrer, a thermometer and a reflux condenser. 0.703 g (5 mmol) of 2-chloro-meta-xylene, 1.001 g (10 mmol) of methylmethacrylate, 0.034 g (0.038 mmol) of tris(dibenzylideneacetone)dipalladium (0), 1.074 g (5.5 mmol) of dicyclohexylmethylamine and 5 ml of 1,4-dioxane were weighed in the flask, followed by stirring. Further, 0.078 g (0.15 mmol) of tri-tert-butylphosphonium tetraphenylborate obtained in Example A-1 was weighed in air and added into the flask. The flask was purged with argon, followed by stirring at 120° C. for 37 hours. After the completion of the reaction, 5 ml of toluene and 10 ml of saturated sodium chloride solution were added, followed by separation. The organic phase was purified by column chromatography to afford 0.774 g of (E)-3-(2,6-dimethylphenyl)-2-methylacrylic acid methyl ester (yield: 76 mol % based on 2-chloro-meta-xylene). The identification of the product was made by 1H-NMR and 13C-NMR.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[C:5]([F:9])=[CH:4][C:3]=1[F:10].CN([CH:14]=[O:15])C.C([Li])CCC>CCOCC>[Br:8][C:6]1[C:5]([F:9])=[CH:4][C:3]([F:10])=[C:2]([CH:7]=1)[CH:14]=[O:15]
Reactant: Fc1cc(F)c(Br)cc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1cc(Br)c(F)cc1F
Yield: 61.3 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 27 for the preparation of I-27a above, 1,5-dibromo-2,4-difluorobenzene (3 g, 11.07 mmol) in dry ether was reacted with DMF (1.05 mL, 14.39 mmol) and n-butyl lithium (6.08 ml, 11.56 mmol to afford the crude product. Purification by column chromatography on silica gel (2% ethyl acetate in hexane) afforded 1.5 g of the product (61% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](=O)[NH:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C1C=CC=CC=1)C.O=P(Cl)(Cl)[Cl:32]>>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([Cl:32])=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]cnc2c1CCN(Cc1ccccc1)C2
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: Clc1ncnc2c1CCN(Cc1ccccc1)C2
Temperature: 80 °C

Procedure:
To a mixture of 7-benzyl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-one 3a (1.0 g, 4.14 mmol) and N,N-diethylaniline (0.37 g, 2.48 mmol) was slowly added POCl3 (12 mL). The mixture was heated to 80° C. for 20 h. After evaporation of the excess of POCl3, the residue was poured into ice, dichloromethane was added and the mixture was made basic (pH=11) with solid Na2CO3. The product was extracted with dichloromethane, dried, and concentrated. Flash column chromatography with 20% ethyl acetate:hexane gave 0.46 g of 7-benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine 4a as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.[Br:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20](Br)[CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:17][C:18]1[CH:19]=[C:20]([C:9]2[CH:10]=[CH:11][C:6]3[NH:5][C:4](=[O:15])[O:3][C:2]([CH3:16])([CH3:1])[C:7]=3[CH:8]=2)[CH:21]=[C:22]([F:24])[CH:23]=1
Reactant: Fc1cc(Br)cc(Br)c1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(Br)c3)cc21
Temperature: 85 °C
Yield: 40 %

Procedure:
A mixture of (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid (2.22 g, 10 mmol), 1,3-dibromo-5-fluorobenzene (3.05 g, 12 mmol), tetrakis(triphenylphosphine)palladium (0) (0.6 g, 0.52 mmol), and sodium carbonate (2.2 g, 21 mmol) in a mixture of DME and water (70 mL/15 mL) was degassed to remove the oxygen and then heated at 85° C. under a blanket of nitrogen for 3 hours. The reaction mixture was cooled to ambient temperature and quenched with a saturated aqueous ammonium chloride solution (20 mL). Ethyl acetate (100 mL) was added and organic layer was separated. The aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine and dried with MgSO4. The solvent was removed in vacuo and the residue was purified by a silica gel flash chromatography (hexane:ethyl acetate/1:1) to give 6-(3-bromo-5-fluorophenyl)-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one as a white solid (1.4 g, 40%): mp 182-183° C.; 1H-NMR (DMSO-d6) δ 10.36 (s, 1H, D2O exchangeable), 7.78 (s, 1H), 7.58-7.65 (m, 3H), 7.49 (dd, 1H, J=8.3, 1.8 Hz), 6.96 (d, 1H, J=8.5 Hz), 1.69 (s, 6H); 19F-NMR (DMSO-d6) δ −112.46 (m, 1F); MS (CI) m/z 352 ([M+H]+, 78%), 350 ([M+H]+, 75%). Anal. Calcd. For C16H13BrFNO2: C, 54.88; H, 3.74; N, 4.00. Found: C, 54.83; H, 3.82; N, 3.95.
Reaction SMILES: [CH:1]1([C:7](=O)[CH2:8][CH2:9][C:10]2[N:11]=[C:12]3[CH:18]=[CH:17][N:16]([S:19]([C:22]4[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=4)(=[O:21])=[O:20])[C:13]3=[N:14][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O(C1C=CC(P2(=S)SP(=S)(C3C=CC(OC4C=CC=CC=4)=CC=3)S2)=CC=1)C1C=CC=CC=1.N1C=CN=CC=1>C1COCC1.CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH:1]1([C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][N:16]([S:19]([C:22]5[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=5)(=[O:21])=[O:20])[C:13]=4[N:14]=[CH:15][C:10]3=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CCC(=O)C4CCCCC4)cnc32)cc1
Agent: O=C([O-])O
Agent: S=P1(c2ccc(Oc3ccccc3)cc2)SP(=S)(c2ccc(Oc3ccccc3)cc2)S1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: c1cnccn1
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2ccc(C4CCCCC4)n23)cc1
Reaction time: 6 h

Procedure:
To a solution of 1-cyclohexyl-3-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)propan-1-one (0.050 g, 0.12 mmol) in THF (2 mL) was added 2,4-bis(4-phenoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (0.071 g, 0.13 mmol, TCI). After about 6 h at ambient temperature, the reaction mixture was diluted with EtOAc (50 mL) and NaHCO3 (50 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of 40-90% EtOAc in heptanes to provide 8-cyclohexyl-3-tosyl-3H-dipyrrolo[1,2-a:2;3′-e]pyrazine as a tan solid (0.020 g, 42%). LC/MS (Table 2, Method a) Rt=3.39 min; MS m/z: 394 (M+H)+.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:14]([CH:15]=[O:16])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:17][CH3:18])[CH:11]=2)[N:6]=1)([CH3:3])[CH3:2]>C1COCC1>[CH:1]([NH:4][C:5]1[C:14]([CH2:15][OH:16])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:17][CH3:18])[CH:11]=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc2nc(NC(C)C)c(C=O)cc2c1
Solvent: C1CCOC1
Product: COc1ccc2nc(NC(C)C)c(CO)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a stirred solution of 2-(isopropylamino)-6-methoxyquinoline-3-carbaldehyde SLA 28186 (1.55 g, 6.35 mmol) in THF (100 mL) in a 250 mL round-bottomed flask equipped with a magnetic stirrer was added sodium borohydride NaBH4 (0.24 g, 6.35 mmol) and the mixture was stirred for overnight at RT then cooled in an ice bath before quenching by addition of a 1 N aq. HCl solution (40 mL). After stirring for 15 min at that temperature, the mixture was basified to pH=9 with a 2 N aq. NaOH solution. THF was then removed at 40° C. under vacuum and the solution was extracted with CH2Cl2 (200 mL), washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under vacuum to give (2-(isopropylamino)-6-methoxyquinolin-3-yl)methanol SLA 28188 as an orange solid (1.45 g, 93% yield).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])=[CH:6][CH:5]=1.[CH3:25][N:26]([CH3:30])[C:27](Cl)=[S:28]>CN(C=O)C>[O:24]=[C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22](=[O:23])[N:14]1[CH2:13][CH2:12][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][C:27](=[S:28])[N:26]([CH3:30])[CH3:25])=[CH:5][CH:6]=1
Reactant: CN(C)C(=S)Cl
Reactant: O=C1c2ccccc2C(=O)N1CCCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=S)Oc1ccc(CCCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
A suspension of sodium hydride (60% in mineral oil, 0.44 g, 0.11 mmol) in anhydrous DMF (10 mL) was cooled to 0° C. and added to a solution of 2-[4-(4-hydroxyphenyl)-butyl]isoindole-1,3-dione 8 (2.95 g, 10 mmol) in DMF (15 mL). The mixture was stirred at 0° C. for 30 min and then at room temperature for an additional one hour. A solution of dimethylthiocarbamic acid chloride (1.35 g, 11 mmol) in DMF (10 mL) was then added. The reaction mixture was stirred at room temperature first for 16 h and then at 50° C. for 1 h, cooled back to room temperature and quenched with methanol (10 mL). The mixture was concentrated under vacuum and the residue was purified by flash silica gel column chromatography eluting with CH2Cl2/hexanes/EtOAc (10:1:0.2, v/v) to give the desired product 9 as a yellowish solid (2.27 g, 59% yield). 1H NMR (300 MHz, CDCl3) δ 1.72 (m, 4H), 2.67 (m, 2H), 3.33 (s, 3H), 3.45 (s, 3H), 3.71 (m, 2H), 6.95 (d, 2H), 7.18 (d, 2H), 7.70 (m, 2H), 7.84 (m, 2H). m/z (ESI): 383 [C21H22N2O3S+H]+.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[CH:32]=[CH:31][C:11]([O:12][C:13]2[CH:14]=[C:15]([CH:20]=[C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])=[CH:10][CH:9]=1)=[O:7])(=O)[CH3:2].S(Cl)(Cl)=O>C1(C)C=CC=CC=1.O>[CH2:24]([O:23][C:21]1[CH:20]=[C:15]([CH:14]=[C:13]([O:12][C:11]2[CH:31]=[CH:32][C:8]([C:6]3[O:7][C:1]([CH3:2])=[N:4][N:5]=3)=[CH:9][CH:10]=2)[CH:22]=1)[C:16]([O:18][CH3:19])=[O:17])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(Oc2ccc(C(=O)NNC(C)=O)cc2)c1
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(OCc2ccccc2)cc(Oc2ccc(-c3nnc(C)o3)cc2)c1
Yield: 97.8 %

Procedure:
To a stirring solution of Methyl 3-[4-(2-acetylhydrazinecarbonyl)phenoxy]-5-(benzyloxy)benzoate (32 g) (Intermediate 9) in dry toluene was added thionyl chloride (10.5 g) drop wise at room temperature under nitrogen atmosphere. The reaction was refluxed and monitored by TLC. After completion of the reaction, reaction mixture was diluted with water and extracted with EtOAc. All organic layers were combined and washed with saturated sodium bicarbonate solution, water, and brine, dried over anhydrous sodium sulphate, filtered and concentrated under vacuum to get crude pale yellow solid (30 g). The crude compound was purified by solvent trituration.
Reaction SMILES: CO[C:3](=[O:15])[C:4]([CH3:14])([CH3:13])[CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1.[C:16](#[N:18])[CH3:17].[H-].[Na+]>C1(C)C=CC=CC=1>[CH3:14][C:4]([CH3:13])([CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)[C:3](=[O:15])[CH2:17][C:16]#[N:18]
Reactant: CC#N
Reactant: COC(=O)C(C)(C)COC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(COC1CCCCO1)C(=O)CC#N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 101.4 %

Procedure:
A solution of 129 g (0.60 mol) of 2,2-dimethyl-3-(tetrahydro-pyran-2-yloxy)-propionic acid methyl ester and 44 mL (0.84 mol) of acetonitrile in toluene (250 mL) is added dropwise to the refluxing suspension of 33 g (0.84 mol) of sodium hydride (60% in mineral oil) in toluene (600 mL) over a period of 2 h. After the addition, the reaction mixture is stirred at reflux for 3 h. Additional 16.7 g (0.42 mol) of sodium hydride (60% dispersion in mineral oil) and 22 mL (0.42 mol) of acetonitrile are added to the reaction mixture and the refluxing is continued for another 1.5 h. After this time, the reaction mixture is cooled to room temperature and ice water (˜0.8 L) is added. The layers are separated and the aqueous layer is neutralized to pH ˜6-7 by adding 1M aqueous HCl solution. The aqueous layer is extracted with ethyl acetate (3×0.8 L). The organic layers are combined, washed with brine (1.5 L), dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure to yield 137 g of 4,4-dimethyl-3-oxo-5-(tetrahydro-pyran-2-yloxy)-pentanenitrile as a brown oil, which is used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (6H, s), 1.10 (6H, s), 1.4-1.7 (6H, m), 3.3 (1H, m), 3.35 (1H, d), 3.4 (1H, m), 3.6 (1H, d), 3.7 (1H, m), 4.2 (1H, s); 4.55 (1H, t).
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][C:10](=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[CH3:9][C:10]1[NH:7][C:1]2[C:6]([C:11]=1[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:5][CH:4]=[CH:3][CH:2]=2
Reactant: NNc1ccccc1
Reactant: CCCCCC(C)=O
Product: CCCCc1c(C)[nH]c2ccccc12
Yield: 38 %

Procedure:
Phenylhydrazine was reacted with heptan-2-one in the same way as in Example 2. 2-Methyl-3-butylindole was formed in a yield of 38%.
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[F:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](Cl)=[O:11].Cl.N1C=CC=CC=1>N1C=CC=CC=1>[F:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH:5][NH:4][C:3]([NH:2][CH3:1])=[S:6])=[O:11]
Reactant: O=C(Cl)c1ccccc1F
Reactant: CNC(=S)NN
Agent: Cl
Solvent: c1ccncc1
Product: CNC(=S)NNC(=O)c1ccccc1F

Procedure:
To a stirred room temperature solution of 4-methylthiosemicarbazide (10.5 g, 1.00×10-1 mole) and pyridine (250 ml), 2-fluorobenzoyl chloride (11.9 ml, 1.00×10-1 mole) was added dropwise. After stirring overnight at room temperature the excess pyridine was evaporated at reduced pressure first on a rotary evaporator and then at high vacuum. This afforded a mixture of the desired product and pyridine hydrochloride which is used without further purification in the subsequent cyclization step.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.[CH3:12][C:13]([CH3:15])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH3:12][CH:13]([N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1)[CH3:15]
Reactant: CC(C)=O
Reactant: CCOC(=O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)C1CCN(C(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 93.3 %

Procedure:
Ethyl isonipecotate (3.2 g, 20 mmol, 1 eq) was combined with acetone (5.8 g, 100 mmol, 5 eq), sodium triacetoxyborohydride (10.5 g, 50 mmol, 2.5 eq) and 1,2-dichloroethane (200 mL). The reaction mixture was stirred at rt for 72 h. Saturated aqueous NaHCO3 was added, and the mixture was extracted with CH2Cl2. The organic extracts were dried, filtered through a silica gel pad, and concentrated in vacuo to provide 3.72 g (93%) of ethyl 1-(1-methylethyl)-4-piperidine carboxylate as a colorless liquid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[O:23][CH3:24].FC1C=CC(NC2CCN(C(OC(C)(C)C)=O)CC2)=CC=1>>[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)=[CH:18][C:17]=1[O:23][CH3:24]
Reactant: COc1cc(N)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)(C)OC(=O)N1CCC(Nc2ccc(F)cc2)CC1
Product: COc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1F

Procedure:
The title compound was prepared from 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate and 4-fluoro-3-methoxyaniline using a method similar to that described for D1.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C[O-].[Na+].[C:13]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>CO>[CH2:1]([CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13]([O:21][CH2:22][CH3:23])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCCCCCCCBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCC(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Yield: 66.2 %

Procedure:
n-Octylbromide (193 g, 1 m) was slowly added to a mixture of 25% sodium methoxide solution (216 g, 1 m), diethyl malonate (160 g, 1 m) and methanol (1 l) with stirring at room temperature. The resulting mixture was refluxed until neutral to litmus (about 24 hours). The solvent was stripped off and the residue was filtered and washed with chloroform. The filtrate was evaporated to remove chloroform and the residue was vacuum-distilled to yield diethyl n-octylmalonate (180 g, 66%) bp 105°-115° C./0.5-0.7 mm.
Reaction SMILES: [Na].[O-]CC.[Na+].[C:6]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(O)C>[CH2:17]([CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6]([O:14][CH2:15][CH3:16])=[O:13])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCCCCCCCBr
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCCCCCCCC(C(=O)OCC)C(=O)OCC
Yield: 85 %

Procedure:
200 ml of ethanol was put in a 1-liter four-necked flask, 7.6 g of metal sodium cut into pieces was put therein portionwise to prepare sodium ethoxide. To this were added dropwise 54.6 g of diethyl malonate and then 63.9 g of octyl bromide. Thereafter, the mixture was refluxed for 3 hours. Then, the most part of ethanol was distilled away under the atmospheric pressure, 200 ml of water was added, and the mixture was extracted with 250 ml of ether. The ether solution was dried over sodium sulfate, ether was distilled away, and the residue was distilled under reduced pressure to give 72.1 g of a colorless oily substance (b.p. 111° C./2 mmHg). Yield 85%.
Reaction SMILES: [CH2:1]([C:8]1[S:9][CH:10]=[C:11]([C:13](O)=[O:14])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:1]([C:8]1[S:9][CH:10]=[C:11]([CH2:13][OH:14])[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1csc(Cc2ccccc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1csc(Cc2ccccc2)n1

Procedure:
2-Benzyl-4-thiazolecarboxylic acid is converted to the methyl ester and the ester is reduced with lithium aluminium hydride in tetrahydrofurann to give 2-benzyl-4-hydroxymethylthiazole. Using this compound as the starting material in the procedure of Example 1 gives N-methyl-N'-[2-((2-benzyl-4-thiazolyl)methylthio)ethyl]-thiourea.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[NH2:23][C@H:24]([C:32]([OH:34])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([NH:23][C@H:24]([C:32]([OH:34])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:16])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.7 %

Procedure:
A solution of 0.223 g (0.001 mol) of N-benzyloxycarbonylalanine (Z-Ala), 0.08 g (0.001 mol) of pyridine and 0.256 g (0.001 mol) of DSC in 10 ml of dimethylformamide (DMF) was stirred at ambient temperature. After silica gel TLC. showed that Z-Ala (the free acid form) disappeared in the solution, the reaction solution was admixed with ethyl acetate and washed with aqueous 4% NaHCO3, with 1 N-HCl and with a saturated aqueous solution of sodium chloride. The solution so treated was then distilled to remove the ethyl acetate, leaving a solid residue. This residue was admixed with a solution of 0.165 g (0.001 mol) of phenylalanine (Phe-OH) and 0.101 g (0.001 mol) of triethylamine in 20 ml of DMF, and the admixture so obtained was stirred at ambient temperature for 24 hours. Subsequently, the resultant reaction mixture was admixed with ethyl acetate, washed with aqueous 4% NaHCO3, with 1 N-HCl and with a saturated aqueous solution of sodium chloride to remove the liberated N-hydroxysuccinimide, followed by drying over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was distilled to remove the solvent, affording a colorless crystalline substance. Recrystallization of this crystalline substance from methylene chloride-ethyl ether gave 0.321 g of N-benzyloxycarbonylalanyl-phenylalanine (Z-Ala-Phe-OH) as a colorless crystalline substance. Yield 86%.
Reaction SMILES: [H][H].[C:3]([NH:6][C:7](=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:5])[CH3:4]>CO>[C:3]([NH:6][C@H:7]([C:8]([OH:10])=[O:9])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:5])[CH3:4]
Reactant: [H][H]
Reactant: CC(=O)NC(=Cc1ccccc1)C(=O)O
Solvent: CO
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 0.5 h

Procedure:
The organic inorganic composite material 2-13 (50 mg) and 2 mg (4.9 mmol) of bis(cyclooctadiene)rhodium (I) tetrafluoroborate were stirred in 3 ml of methanol at room temperature for 30 minutes in a hydrogen atmosphere of 1 atm. 105 mg (0.51 mmol) of α-(acetoamido)cinnamic acid was added to the resulting mixture, and reaction was conducted at room temperature for 30 minutes. Thus, N-acetyl-phenylalanine was obtained. An enantiomer excess of D-form determined by HPLC analysis (Chirace AD-H, manufactured by Daicel) was 97% e.e.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.[F:10][C:11]1[C:16](B(O)O)=[CH:15][CH:14]=[CH:13][N:12]=1.ClCCl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[F:10][C:11]1[C:16]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[CH:3]=2)=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: OB(O)c1cccnc1F
Reactant: Cc1nc(N)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(N)cc(-c2cccnc2F)n1
Temperature: 110 °C
Reaction time: 8 h
Yield: 24.4 %

Procedure:
A mixture of 6-chloro-2-methyl-4-pyrimidinamine (SynChem, Inc., Des Plaines, Ill.) (0.500 g, 3.48 mmol), 2-fluoropyridin-3-ylboronic acid (0.589 g, 4.18 mmol), PdCl2 (dppf) complex with dichloromethane (0.199 g, 0.244 mmol) and 2 M Na2CO3 (aq., 5.22 mL, 10.45 mmol) in dioxane (17 mL) was stirred at 110° C. overnight. After cooling to RT, water was added and the mixture was filtered through Celite® (diatomaceous earth). The mixture was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica gel column (40 g), eluting with a gradient of 0% to 5% MeOH in CH2Cl2, to provide 6-(2-fluoro-3-pyridinyl)-2-methyl-4-pyrimidinamine (0.173 g, 0.85 mmol, 24% yield) as an off-white solid. m/z (ESI, +ve) 205.1 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 8.52-8.62 (m, 1H); 8.27-8.34 (m, 1H); 7.44-7.61 (m, 2H); 7.00 (br. s., 1H); 6.75-6.83 (m, 1H); 2.39 (s, 3H).