Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][N:27]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]1[S:15][CH:16]([CH2:19][C:20]([O:22]CC)=[O:21])[CH2:17][N:18]=1)=[CH:10]2)[CH3:3].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:28][N:27]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]1[S:15][CH:16]([CH2:19][C:20]([OH:22])=[O:21])[CH2:17][N:18]=1)=[CH:10]2)[CH3:1]
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cn4)cc(OC(C)C)c3[nH]2)S1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Temperature: 50 °C
Reaction time: 3 h
Yield: 89.5 %

Procedure:
A mixture of ethyl {2-[7-(1-methylethoxy)-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (980 mg), tetrahydrofuran (10 mL), ethanol (10 mL) and 1M aqueous sodium hydroxide solution (10 mL) was stirred at 50° C. for 3 h. Water and 1M hydrochloric acid (10 mL) were added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The residual crystals were washed with ethyl acetate and hexane to give the title compound (830 mg, 89%) as brown crystals. MS 490 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[S:17][C:6]2=[N:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([OH:11])=[C:5]2[CH:4]=1)[CH3:2].[H-].[Na+].[C:20]([N:39]1[C:43]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[C:50]2[CH:57]=[CH:56][C:53]([CH2:54]Br)=[CH:52][CH:51]=2)=[N:42][N:41]=[N:40]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C=O)C>[CH2:1]([C:3]1[S:17][C:6]2[N:7]([CH2:54][C:53]3[CH:52]=[CH:51][C:50]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[C:43]4[N:39]([C:20]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:40]=[N:41][N:42]=4)=[CH:57][CH:56]=3)[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)c1cnc2sc(CC)cc2c1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c2sc(CC)cc2c1=O
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 76.9 %

Procedure:
To a solution of ethyl 2-ethyl-4-hydroxy-thieno[2,3-b]pyridine-5-carboxylate (1.00 g, 4 mmol) in 20 ml of DMF) was added sodium hydride (60% dispersion in oil, 160 mg) and the mixture was stirred for 10 minutes. To the reaction mixture was added 4-[2'-(N-trityltetrazol-5-yl)phenyl]benzyl bromide (2.23 g, 4 mmol) and the mixture was heated at 90° C. for 1 hour with stirring. The reaction mixture was poured into water followed by extraction with ethyl acetate. The organic layer was washed with water, dried (MgSO4), and evaporated to dryness. The resulting residue was purified by flash column chromatography on silica gel. The column was eluted with ethyl acetate/dichloromethane (1:1) to give 2.24 g (77%) of the title compound as white crystals.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:13]=[C:14](S(C)=O)[NH:15][C:16](=[O:21])[C:17]=2[C:18]([NH2:20])=[O:19])[CH:8]=[CH:9][CH:10]=1)=[O:4].[NH2:25][CH2:26][C:27]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.CN1C(=O)CCC1>C(OCC)(=O)C>[NH2:33][C:27]1([CH2:26][NH:25][C:14]2[NH:15][C:16](=[O:21])[C:17]([C:18]([NH2:20])=[O:19])=[C:12]([NH:11][C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([C:3](=[O:4])[NH:2][CH3:1])[CH:6]=3)[N:13]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NCC1(N)CCCCC1
Reactant: CNC(=O)c1cccc(Nc2nc(S(C)=O)[nH]c(=O)c2C(N)=O)c1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CNC(=O)c1cccc(Nc2nc(NCC3(N)CCCCC3)[nH]c(=O)c2C(N)=O)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
A mixture of 4-{[3-(methylcarbamoyl)phenyl]amino}-2-(methylsulfinyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide (Preparation Example 311) (234 mg), 1-(aminomethyl)cyclohexaneamine (172 mg) and NMP (2 mL) was stirred at 80° C. for 30 minutes. After cooling, the reaction liquid was diluted with ethyl acetate, and the precipitated solid was collected by filtration. This solid was heated with ethanol-water and washed to give 2-{[(1-aminocyclohexyl)methyl]amino}-4-{[3-(methylcarbamoyl)phenyl]amino}-6-oxo-1,6-dihydropyrimidine-5-carboxamide (215 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:16](=[O:19])[NH:17][N:18]=2)[C:5]([CH3:15])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][N:29]=1.O>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:3]2[N:4]([C:16](=[O:19])[N:17]([CH2:27][C:28]3[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][N:29]=3)[N:18]=2)[C:5]([CH3:15])=[CH:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1
Reactant: N#Cc1ccc(CCl)nc1
Reactant: Cc1cc(-c2ccc(Cl)cc2)c(Br)c2n[nH]c(=O)n12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(Cl)cc2)c(Br)c2nn(Cc3ccc(C#N)cn3)c(=O)n12
Temperature: 70 °C
Reaction time: 1 h
Yield: 110 %

Procedure:
To a stirring solution of 8-bromo-7-(4-chlorophenyl)-5-methyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (40 mg, 0.11 mmol) in DMF (0.25 mL) at room temperature under argon was added K2CO3 (50 mg, 0.36 mmol), followed by 6-(chloromethyl)nicotinonitrile (20 mg, 0.13 mmol). The reaction mixture was stirred at 70° C. for 1 h. The reaction mixture was cooled to room temperature, water (2 mL) and EtOAc (5 mL) were added. The layers were separated. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure to obtain 55 mg of the title compound as a yellow solid. HPLC/MS: retention time=3.55 min, [M+H]+=454.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH3:11][O:12][C:13](=[O:29])[C@@H:14]([NH2:28])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1>>[CH3:11][O:12][C:13](=[O:29])[C@@H:14]([NH:28][C:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[O:10])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1ccc(Br)cn1
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1ccc(Br)cn1
Yield: 87.6 %

Procedure:
3-Biphenyl-4-yl-(2S)-[(5-bromo-pyridine-2-carbonyl)-amino]-propionic acid methyl ester (1.5 g, 90%) was prepared by following general procedure A from commercially available 5-bromo picolinic acid (0.9 g, 4.7 mmol) and (2S)-amino-3-biphenyl-4-yl-propionic acid methyl ester (1.0 g, 3.9 mmol).
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH2:17]([NH:24][CH3:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.O>CS(C)=O>[CH2:17]([N:24]([CH3:25])[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Reactant: CNCc1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)c1ccc2[nH]c(=O)c(N(C)Cc3ccccc3)nc2c1
Temperature: 85 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (500 mg, 2.10 mmol) in DMSO (6 mL) was added benzyl(methyl)amine (305 mg, 2.52 mmol), and DIEA (542 mg, 4.19 mmol). The resulting solution was stirred for 2 h at 85° C., then water (50 mL) was added, causing a precipitate to form which was collected by filtration to afford methyl 3-(benzyl(methyl)amino)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a yellow solid (0.55 g, 81%).
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@H:8]([C:10](=[O:23])[NH:11][C:12]1[CH:13]=[CH:14][C:15]2[NH:16][C:17](=[O:22])[NH:18][CH2:19][C:20]=2[N:21]=1)[CH3:9])(C)(C)C.[ClH:26]>>[ClH:26].[CH3:6][NH:7][C@@H:8]([CH3:9])[C:10]([NH:11][C:12]1[CH:13]=[CH:14][C:15]2[NH:16][C:17](=[O:22])[NH:18][CH2:19][C:20]=2[N:21]=1)=[O:23]
Reactant: C[C@@H](C(=O)Nc1ccc2c(n1)CNC(=O)N2)N(C)C(=O)OC(C)(C)C
Agent: Cl
Product: CN[C@@H](C)C(=O)Nc1ccc2c(n1)CNC(=O)N2

Procedure:
Methyl-[(S)-1-(2-oxo-1,2,3,4-tetrahydro-pyrido[3,2-d]pyrimidin-6-ylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (67 mg, 0.19 mmol) was treated with HCl according to the General procedure 3 to afford the title compound (27 mg).
Reaction SMILES: B(O)(O)O.[OH:5]O.S(=O)(=O)(O)O.[F:12][C:13]1[CH:14]=[C:15]([N+:23]([O-:25])=[O:24])[C:16]([OH:22])=[C:17](C(=O)C)[CH:18]=1>O1CCCC1.O>[F:12][C:13]1[CH:18]=[C:17]([OH:5])[C:16]([OH:22])=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=1
Reactant: OO
Reactant: CC(=O)c1cc(F)cc([N+](=O)[O-])c1O
Agent: O=S(=O)(O)O
Agent: OB(O)O
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cc(F)cc(O)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
Boric acid (20.45 g, 330.7 mmol), and hydrogen peroxide (35%, 36.8 mL) in tetrahydrofuran (150 ml) was treated with concentrated sulfuric acid (15 ml) and the mixture was stirred at rt for 30 min. 1-(5-Fluoro-2-hydroxy-3-nitrophenyl)ethanone (15 g, 75.4 mmol) in tetrahydrofuran (45 ml) was added and reaction heated for 48 h at 75° C. The reaction mixture was cooled to rt, diluted with water and extracted with DCM (3×500 ml). The combined organic phases were dried on magnesium sulphate, evaporated and the residue was subjected to column chromatography on silica gel using a 20%-80% EtOAc: 40-60 petroleum ether gradient to provide the desired compound (6.55 g, 50%), a 5:1 mixture of desired product and 1-(5-fluoro-2-hydroxy-3-nitrophenyl)ethanone (4 g) and recovered 1-(5-fluoro-2-hydroxy-3-nitrophenyl)ethanone (1.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([OH:23])[C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].Br[CH2:27][C:28]#[N:29]>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([O:23][CH2:27][C:28]#[N:29])[C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#CCBr
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](O)c2ccc(F)c(Cl)c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCC#N)c2ccc(F)c(Cl)c2)C1
Temperature: -40 °C
Reaction time: 1 h
Yield: 113.2 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(3-chloro-4-fluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (5.1 g, 15 mmol) in CH3CN (150 mL), NaH (1.8 g, 45 mmol) was added at 0° C. The mixture was stirring for 1 hour. Then the mixture was cooled to −40° C., the bromoacetonitrile (5.4 g, 45 mmol) was added dropwise. The mixture was allowed to warm to 0° C. gradually. The addition of NaH and bromoacetonitrile was repeated three times. The mixture was quenched with H2O and exacted with CH2Cl2. The organic layer was dried over Na2SO4 and concentrate to get the crude (R)-tert-butyl 3-((R)-(3-chloro-4-fluorophenyl)(cyanomethoxy)methyl)piperidine-1-carboxylate (6.5 g, 100%).
Reaction SMILES: [N:1]([C:4](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([P:18]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[OH:17])=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[N+]=[N-].[H][H].C(Cl)(Cl)Cl.CO>CO.[Pd]>[C:26]([O:25][P:18]([CH:16]([OH:17])[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH:4]([C:5]([O:7][CH3:8])=[O:6])[NH2:1])=[CH:11][CH:12]=1)([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])([CH3:27])([CH3:28])[CH3:29]
Reactant: [H][H]
Reactant: COC(=O)C(=Cc1ccc(C(O)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1)N=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)C(N)Cc1ccc(C(O)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1
Yield: 92 %

Procedure:
A solution of 7 (1.25 g, 2.85 mmol) in MeOH (50 mL) was hydrogenated in a Parr apparatus over 10% Pd.C (200 mg) under 40 psi H2. The hydrogen was replenished after 10 minutes. The reaction was terminated after 3 hours, and catalyst removed by filtration. Evaporation of solvent yielded 8 as a clear, colorless syrup, 1.17 g (100% crude yield). Silica gel chromatography [CHCl3 :MeOH(25:1)] provided pure 8 (92%).
Reaction SMILES: [N:1]([CH:4]([CH3:27])[CH2:5][O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[O:14][C:15]3[CH:21]=[C:20]([O:22][CH2:23][CH:24]4[CH2:26][CH2:25]4)[CH:19]=[CH:18][C:16]=3[CH:17]=2)[CH2:9][CH2:8]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[CH:24]1([CH2:23][O:22][C:20]2[CH:19]=[CH:18][C:16]3[CH:17]=[C:13]([C@H:10]4[CH2:11][CH2:12][C@H:7]([O:6][CH2:5][CH:4]([NH2:1])[CH3:27])[CH2:8][CH2:9]4)[O:14][C:15]=3[CH:21]=2)[CH2:26][CH2:25]1
Reactant: CC(CO[C@H]1CC[C@H](c2cc3ccc(OCC4CC4)cc3o2)CC1)N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(N)CO[C@H]1CC[C@H](c2cc3ccc(OCC4CC4)cc3o2)CC1
Temperature: 25 °C

Procedure:
A solution of 2-[trans-4-(2-azidopropoxy)cyclohexyl]-6-(cyclopropylmethoxy)-1-benzofuran (397 mg) and triphenylphosphine (564 mg) in THF (4 mL)/water (2 mL) was stirred at 60° C. overnight. The reaction mixture was allowed to cool to room temperature, and extracted with ethyl acetate and water. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate/methanol) to give the title compound (373 mg).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:40][O:41][CH3:42])[C:10]([NH:12][CH:13]2[C:38](=[O:39])[N:15]3[C:16]([C:22]([O:24][CH:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])=[C:17]([CH:20]=[O:21])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].C(N(CC)CC)C.C(OCC)(=O)C>O1CCCC1>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:40][O:41][CH3:42])[C:10]([NH:12][CH:13]2[C:38](=[O:39])[N:15]3[CH:16]([C:22]([O:24][CH:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[C:17]([CH:20]=[O:21])=[CH:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=O)CS[C@H]12)c1csc(NC=O)n1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(C=O)=CS[C@H]12)c1csc(NC=O)n1
Yield: 82.7 %

Procedure:
A solution of benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-formyl-3-cephem-4-carboxylate (syn isomer) (3 g) and triethylamine (0.45 g) in tetrahydrofuran (30 ml) was stirred at ambient temperature for 40 minutes. To the reaction mixture was added ethyl acetate (50 ml) and washed with 3% hydrochloric acid and brine. The organic solution was dried over magnesium sulfate and evaporated. The residue was pulverized in diisopropyl ether to give benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-formyl-2-cephem-4-carboxylate (syn isomer) (2.48 g).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][CH2:6][C:7](=[O:19])[CH:8]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])C#N)C.S(=O)(=O)(O)O.O>C(O)(=O)C>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[CH2:8][C:7](=[O:19])[CH2:6][CH2:5][C:4]([OH:20])=[O:3]
Reactant: CCOC(=O)CCC(=O)C(C#N)c1ccc(Cl)cc1Cl
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CCC(=O)Cc1ccc(Cl)cc1Cl
Yield: 80 %

Procedure:
A 1-liter 1-neck R.B. flask was charged with 156.61 g (0.50 Mol) of ethyl-5-(2',4'-dichlorophenyl)-5-cyano-4-ketopentanoate, 153 ml of concentrated sulfuric acid, 153 ml of water, and 440 ml of glacial acetic acid. The reaction mixture was stirred and refluxed for 24 hours. l g, 80% yield) was obtained as a viscous dark-colored oil.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH3:32])[CH2:8][CH2:9][CH2:10][C:11]([CH3:31])(O)[C:12]#[C:13][C:14]#[C:15][C:16]([CH3:29])(O)[CH2:17][CH2:18][CH2:19][CH:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH3:3]>[Pd].CCCCCCC>[CH3:26][CH:24]([CH2:23][CH2:22][CH2:21][CH:20]([CH2:19][CH2:18][CH2:17][CH:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH:11]([CH2:10][CH2:9][CH2:8][CH:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1])[CH3:32])[CH3:31])[CH3:29])[CH3:27])[CH3:25]
Reactant: CC(C)CCCC(C)CCCC(C)(O)C#CC#CC(C)(O)CCCC(C)CCCC(C)C
Agent: [Pd]
Solvent: CCCCCCC
Product: CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C
Yield: 85.8 %

Procedure:
To 100 ml of n-heptane was dissolved 50 g of 2,6,10,15,19,23-hexamethyltetracosa-11,13-diyne-10,15-diol which was prepared in the same manner as in example 5 and 2.5 g of 3 % palladium on active carbon was added. The mixture was hydrogenated at 50° C under a hydrogen pressure of 3 ~ 5 kg/cm2. The product was subjected to dehydration, hydrogenation and distillation in the same manner as in example 4 to give 40.6 g of squalane.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@H:9]([CH2:10]I)[CH2:8][CH2:7][N:6]1[C@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])=[O:4].C([O-])([O-])=O.[K+].[K+].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(#N)C>[CH3:1][O:2][C:3]([C@@H:5]1[C@H:9]([CH2:10][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH2:8][CH2:7][N:6]1[C@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])=[O:4]
Reactant: C1COCCN1
Reactant: COC(=O)[C@@H]1[C@H](CI)CCN1[C@@H](C)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)[C@@H]1[C@H](CN2CCOCC2)CCN1[C@@H](C)c1ccccc1
Temperature: 50 °C
Reaction time: 62 h

Procedure:
A mixture of (2S,3R)-3-iodomethyl-1-((S)-1-phenyl-ethyl)-pyrrolidine-2-carboxylic acid methyl ester (Step 5.5) (7.07 mmol), K2CO3 (21.22 mmol) and morpholine (10.61 mmol) in acetonitrile (24 mL) was stirred at 50° C. for 62 h. The reaction mixture was poured onto ice water and extracted with EtOAc (3×). The combined organic layers were successively washed with water and brine, dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a yellow oil. HPLC: tR=2.56 min (method A); ESI-MS: [M+H]+ 333.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[NH:12][C:11]2=[O:19])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[C:22]1([CH:21]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:4]2[CH2:3][CH2:2][N:1]([CH2:7][CH2:8][CH2:9][N:10]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[NH:12][C:11]3=[O:19])[CH2:6][CH2:5]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: O=c1[nH]c2ccccc2n1CCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=c1[nH]c2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 13 parts of 1,3-dihydro-1-[3-(1-piperazinyl)propyl]-2H-benzimidazol-2-one, 12.4 parts of 1,1'-(bromomethylene)bis[benzene], 6.6 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. After cooling to room temperature, water is added and the layers are separated. The organic layer is dried, filtered and evaporated. The residue is crystallized from a mixture of 2,2'-oxybispropane and a small amount of 2-propanol, yielding 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 153° C.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([Cl:30])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:20]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:19]1[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:13][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[CH:29]=[C:28]([Cl:30])[S:27][C:17]=2[N:18]=1
Reactant: NCCc1ccc2c(c1)OCCO2
Reactant: Clc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Product: Clc1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-2-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:17]=1)[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.[Na]>C(Cl)Cl.CC(O)C>[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:1][CH2:2][C:3]2[CH:4]=[C:5]([CH:15]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:17]=2)[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)NCc1cc(CN)cc(Oc2ccc(F)cc2)c1
Reactant: O=Cc1ccc(F)cc1
Agent: [Na]
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1cc(CNCc2ccc(F)cc2)cc(Oc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 66.7 %

Procedure:
To a solution of tert-butyl 3-(aminomethyl)-5-(4-fluorophenoxy)benzylcarbamate (1.37 g, 3.96 mmol) in CH2Cl2 (15 mL) and 2-propanol (15 mL) was added 4-fluorobenzaldehyde (0.42 mL, 3.96 mmol). The reaction mixture was stirred at rt. under nitrogen for 40 min, and then treated with sodium triacetoxyhydroborate (1.76 g, 8.31 mmol). The resulting mixture was stirred at rt for 2 h. The reaction mixture was concentrated and the residue was partitioned between saturated NaHCO3 solution and ethyl acetate. The organic layer (clear solution) was washed with brine and dried over MgSO4. The filtrate was concentrated. The sample was purified by flash chromatography. Elution with 0-35% of ethyl acetate in CH2Cl2 gave the product as viscous oil (1.2 g, 67%). 1H NMR (CD3OD): δ 7.35-7.32 (m, 2H), 7.13-6.99 (m, 7H), 6.87 (s, 1H), 6.80 (s, 1H), 4.20 (s, 2H), 3.70 (s, 2H), 1.44 (s, 9H); MS (ESI): (M−H)−=513.1.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][CH2:17][C:18]3[C:19]([CH:34]4[CH2:36][CH2:35]4)=[N:20][C:21]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)=[N:22][CH:23]=3)[CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[CH:34]1([C:19]2[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:13]=[C:14]4[C:9]([CH:8]=[CH:7][N:6]4[CH2:5][C:4]([OH:37])=[O:3])=[CH:10][CH:11]=3)=[CH:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=3)[N:20]=2)[CH2:36][CH2:35]1
Reactant: CCOC(=O)Cn1ccc2ccc(OCCc3cnc(-c4ccc(C(F)(F)F)cc4)nc3C3CC3)cc21
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cn1ccc2ccc(OCCc3cnc(-c4ccc(C(F)(F)F)cc4)nc3C3CC3)cc21

Procedure:
In analogy to the procedure described in example 5 g], (6-{2-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-ethoxy}-indol-1-yl)-acetic acid ethyl ester was treated with LiOH to obtain the title compound as yellow solid.