Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].Cl[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23]>>[OH:25][C:22]([CH3:24])([CH3:23])[CH2:21][CH2:20][CH2:19][CH2:18][N:11]1[C:12](=[O:14])[C:13]2[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:6]=[N:7][C:8]=2[N:9]([CH3:16])[C:10]1=[O:15]
Reactant: CCCCn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CC(C)(O)CCCCCl
Product: CCCCn1cnc2c1c(=O)n(CCCCC(C)(C)O)c(=O)n2C

Procedure:
The title compound was prepared by using 7-butyl-3-methylxanthine and 1-chloro-5-hydroxy-5-methylhexane as starting materials. C17H28N4O3 (molecular weight=336.4); the oily product was characterized and identified by NMR mass-spectroscopy.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:6])([CH3:5])[CH3:4].C(N(CC)CC)C.Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16]>CCOCC>[CH3:4][C:3]([NH2:6])([CH3:5])[CH2:2][NH:1][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CC(C)(N)CN
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)NCC(C)(C)N
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.9 %

Procedure:
To a mixture of 88.2 g (1 mol) of 1,2-diamino-2-methylpropane, 50 ml of triethylamine and 500 ml of diethyl ether was added dropwise to a solution of 27.1 g (0.25 mol) of ethyl chloroformate in 100 mL of ether. The reaction mixture was stirred for 16 hours at 25° C. and filtered. Evaporation of the filtrate to dryness gave 38 g (95%) of product which was identified by NMR and IR spectroscopy.
Reaction SMILES: [CH3:1][Li].[CH2:3]([O:10][CH:11]1[CH2:16][CH2:15][CH2:14][C:13]2([O:20][CH2:19][CH2:18][O:17]2)[C:12]1([CH3:26])[CH2:21][CH2:22][CH2:23][CH:24]=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CCOCC>[CH2:3]([O:10][CH:11]1[CH2:16][CH2:15][CH2:14][C:13]2([O:17][CH2:18][CH2:19][O:20]2)[C:12]1([CH3:26])[CH2:21][CH2:22][CH2:23][CH:24]([OH:25])[CH3:1])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC1(CCCC=O)C(OCc2ccccc2)CCCC12OCCO2
Reactant: [Li]C
Solvent: CCOCC
Product: CC(O)CCCC1(C)C(OCc2ccccc2)CCCC12OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
Methyllithium (63.3 ml, 0.0918 mol, 1.45 M in ether) is added dropwise to a solution of the aldehyde (2S*, 3R*)-3-benzyloxy-1,1-ethylenedioxy-2-methyl-2-(4'-oxobutyl)-cyclohexane (25.4 g, 0.0765 mol) in ether (1000 ml) at 0° C. in a nitrogen atmosphere. The cooling bath is removed and the mixture is stirred for 0.5 hours at ambient temperature. The mixture is then poured into a cold saturated sodium chloride solution (500 ml). The ether phase is separated and the aqueous phase is extracted with ether (3×100 ml). The ether phases are combined, dried (MgSO4) and the solvent is removed at reduced pressure. The crude product (27.1 g) is chromatographed on SilicAR CC-7 (300 g, Millinckrodt) in hexane. Elution with 10% ethyl acetate/hexane gives (2S*, 3R*)-3-benzyloxy-1,1-ethylenedioxy-2-methyl-2-(4'-hydroxypentyl)-cyclohexane as a colorless oil (25.8 g, 97%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:12]=[C:11]([CH:13]([OH:18])[CH2:14][CH2:15][CH2:16]O)[C:10]2[C:5](=[C:6]([C:19]([F:22])([F:21])[F:20])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:23][C:2]([F:24])([F:1])[C:3]1[CH:12]=[C:11]([CH:13]2[CH2:14][CH2:15][CH2:16][O:18]2)[C:10]2[C:5](=[C:6]([C:19]([F:20])([F:21])[F:22])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: OCCCC(O)c1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: FC(F)(F)c1cc(C2CCCO2)c2cccc(C(F)(F)F)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.2 %

Procedure:
A solution of 1-(2,8-bis(trifluoromethyl)-4-quinolinyl)-4-hydroxybutanol (176 mg, 0.5 mmol) in CH2Cl2 (5 mL) was treated with p-toluenesulphonyl chloride (102 mg, 0.55 mmol) and triethylamine (0.084 mL, 0.6 mmol) and stirred at room temperature for 16 h. The mixture was poured into saturated NaHCO3 solution (10 mL), extracted with CH2Cl2 (2×10 mL) and the combined organic phase dried (MgSO4), concentrated in vacuo, purified by chromatography [SiO2, heptane-EtOAc (95:5)] and the resulting solid triturated with cold hexane and filtered to give the title compound (111 mg, 66%) as a white solid: mp 61.0-61.7° C.; IR νmax (Nujol)/cm−1 3096, 2924, 2854, 1603, 1585, 1516, 1463, 1431, 1308, 1178, 1100, 1086 and 775; NMR δH (400 MHz, CDCl3) 1.79-1.86 (1H, m), 2.00-2.16 (2H, m), 2.63-2.71 (1H, m), 4.08 (1H, q, J 7.3 Hz), 4.24-4.29 (1H, m), 5.63 (1H, t, J 7.3 Hz), 7.72 (1H, t, J 7.7 Hz), 7.99 (1H, s), and 8.14-8.18 (2H, m).
Reaction SMILES: [ClH:1].[C:2]([C:4]1[CH:5]=[C:6]([CH:23]=[C:24]([O:26][CH3:27])[N:25]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[O:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[C:12](F)[CH:11]=1)=[O:8])#[N:3].C(OC(N1CCO[C@@H](C2C=CC(N)=C([Cl:48])C=2)C1)=O)(C)(C)C>>[ClH:48].[Cl:1][C:11]1[CH:12]=[C:13]([C@@H:16]2[O:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:14]=[CH:15][C:10]=1[NH:9][C:7](=[O:8])[C:6]1[CH:23]=[C:24]([O:26][CH3:27])[N:25]=[C:4]([C:2]#[N:3])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)c(Cl)c2)C1
Reactant: COc1cc(C(=O)Nc2ccc([C@H]3CNCCO3)c(F)c2)cc(C#N)n1
Agent: Cl
Product: COc1cc(C(=O)Nc2ccc([C@H]3CNCCO3)cc2Cl)cc(C#N)n1

Procedure:
In analogy to example 83, step a) using 2-Cyano-6-methoxy-isonicotinic acid (described in example 107) instead of 2-(trifluoromethyl)-4-pyridinecarboxylic acid (CAS 131747-41-6) and (−)-(S)-2-(4-Amino-3-chloro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (described in example 29a) instead of (+)-(R)-2-(4-Amino-2-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2]1.[OH:18]S(O)(=O)=O.N#N>>[CH:2]([OH:18])([OH:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=S(=O)(O)O
Reactant: CCCCCCCCCCCCCCC1CO1
Agent: N#N
Product: CCCCCCCCCCCCCCCC(O)O
Yield: 95 %

Procedure:
120 grams of random, internal epoxyhexadecane was placed in a glass-lined autoclave with 40 ml. of 10% H2SO4. The mixture was heated to 150° C. for 3 hours under 300 psi N2. Upon cooling, the product solidified in the autoclave. The aqueous portion was decanted, and the solid was dissolved in hot hexane. The solution was dried over anhydrous, MgSO4, filtered, and cooled. The resulting crystals were removed by filtration to yield approximately 95% of pure random, internal vicinal hexadecane diol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](O)=[N:8][C:9]2[C:14]([C:15]=1[CH3:16])=[CH:13][CH:12]=[C:11]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=2)=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:24].C([O-])(O)=O.[Na+]>O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:24])=[N:8][C:9]2[C:14]([C:15]=1[CH3:16])=[CH:13][CH:12]=[C:11]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=2)=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(O)nc2cc(C(C)(C)C)ccc2c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1c(Cl)nc2cc(C(C)(C)C)ccc2c1C
Temperature: 150 °C
Yield: 88 %

Procedure:
A mixture of 150 mg (0.52 mmol) 7-tert-butyl-2-hydroxy-4-methyl-quinoline-3-carboxylic acid ethyl ester and POCl3 (1 ml) was heated for 2 h at 150° C. Then the reaction solution was poured into iced water (15 ml) and made alkaline with a saturated aqueous NaHCO3 solution. It was then extracted with EE and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. 140 mg (0.46 mmol, 88%) 7-tert-butyl-2-chloro-4-methyl-quinoline-3-carboxylic acid ethyl ester were obtained as the residue, which was reacted further with no additional purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([O:10][CH3:11])[CH3:9])[CH:5]=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][C:14]=1[F:23].[OH-].[Li+]>CO.O>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([O:10][CH3:11])[CH3:9])[CH:5]=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][C:14]=1[F:23]
Reactant: COC(=O)c1ccc(F)c(-c2c(F)cc(C(C)OC)cc2F)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(C)c1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 6-[2,6-difluoro-4-(1-hydroxyethyl)phenyl]-5-fluoro-pyridine-2-carboxylate (1.21 mmol, 376 mg; penultimate intermediate en route to Intermediate 136) in N,N-dimethylformamide (50 mL) at 0° C. was added sodium hydride (60 mass % in mineral oil, 1.5 equiv., 1.81 mmol, 72.5 mg). The mixture was stirred for 2 minutes, then iodomethane (3.0 equiv., 3.62 mmol, 0.226 mL) was added. The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and concentrated. The residue was purified on silica eluted with 0 to 50% EtOAc in Heptane to provide methyl 6-(2,6-difluoro-4-(1-methoxyethyl)phenyl)-5-fluoropicolinate (392 mg, 63%). This ester was diluted with MeOH (15 mL) and water (5 mL) and lithium hydroxide (60 mg) was added. The mixture was stirred overnight at rt. The reaction was quenched by the addition of 1 N HCl(aq), then the mixture was diluted with EtOAc and washed with brine. The organic extracts were dried (Na2SO4) and concentrated in vacuo to provide the title compound (quant) which was used without purification.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.[H-].[Na+].[C:19]([O:23][C:24](=[O:27])[CH2:25]Br)([CH3:22])([CH3:21])[CH3:20].FC(F)(F)C(O)=O>O1CCCC1.CC#N.O>[CH3:20][C:19]([O:23][C:24](=[O:27])[CH2:25][N:7]1[C:6]2[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=[CH:11][C:5]=2[O:4][CH2:3][C:2]1=[O:1])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)c1ccc2c(c1)NC(=O)CO2
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)N(CC(=O)OC(C)(C)C)C(=O)CO2
Reaction time: 2 h
Yield: 96 %

Procedure:
Several smaller batches of ethyl 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate were combined. A solution of ethyl 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (4.1 g, 19.0 mmol) dissolved in 30 mL of anhydrous tetrahydrofuran was added drop-wise to a mixture of sodium hydride (60% by weight in mineral oil, 0.8 g, 20 mmol) suspended in 60 mL of anhydrous tetrahydrofuran under argon. The mixture was allowed to stir at room temperature for 10 minutes before t-butyl-2-bromoacetate (3.4 mL, 23 mmol) was added to the mixture and stirred vigorously for 2 hours. HPLC (Eclipse XDB-C18, 4.6×250 mm, 5 micron, 1-99% CH3CN/H2O with 0.1% trifluoroacetic acid) chromatogram indicated that all of the starting material (Rt=5.5 min) was consumed and only a single new product had formed (Rt=7.7 min). The reaction was quenched by adding 8 mL of a 4 M solution of hydrochloric acid in dioxane. After allowing the mixture to stir for one hour, all of the volatiles were removed by rotary evaporation to give ethyl 4-{2-[(1,1-dimethylethyl)oxy]-2-oxoethyl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (6.14 g, 18.0 mmol, 96%). MS (ES) m/e 280 [M−t-butyl C4H9]+.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].[C:9]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1)#[N:10].C(OCC)C>C(#N)C>[C:9]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][N:7]=[CH:6]2)=[CH:13][CH:12]=1)#[N:10]
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: N#Cc1ccc(CBr)cc1
Solvent: CC#N
Solvent: CCOCC
Product: N#Cc1ccc(Cn2cncc2[N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
A solution of 4-nitroimidazole (2,25 g, 19.9 mmol) and 4-cyanobenzyl bromide (3.90 g, 19.9 mmol) in acetonitrile (10 ml) was stirred at 50° C. for 72 hrs. The reaction was allowed to cool to room temperature and diethyl ether (70 ml) was added. The precipitate was removed by filtration and the filtrate partitioned between EtOAc and NaHCO3 solution. The organic extract was dried (MgSO4) and the solvent evaporated in vacuo. The residue was chromatographed (SiO2, 5% MeOH in CH2Cl2) to afford a solid that was triturated with hot ethanol, and washed with diethyl ether, to afford the product as an off white solid.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[CH:21][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)=O.[C:29]([CH2:32][C:33](=O)[CH3:34])(=[O:31])[CH3:30]>C(O)(=O)C>[C:29]([C:32]1[C:33]([CH3:34])=[N:6][C:7]2[C:8]([C:9]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)=[CH:21][C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=2)(=[O:31])[CH3:30]
Reactant: CC(=O)CC(C)=O
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1ccc(-c2c(C(C)=O)c(C)nc3cc(OC)c(OC)cc23)cc1OC
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 81.4 %

Procedure:
Conc. sulfuric acid (0.185 ml ) was added to a mixture of 2-amino-4,5,3',4'-tetramethoxybenzophenone (10.0 g), acetylacetone (3.78 g) and acetic acid (75 ml), and the mixture was stirred at 100° C. for 2.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was poured into water and made alkaline with 2N sodium hydroxide, and extracted with chloroform. The chloroform layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform-ethanol (20:1, v/v) gave 3-acetyl-4-(3,4-dimethoxyphenyl )-6,7-dimethoxy-2-methyl-quinoline (9.78 g, 82%). This compound was recrystallized from dichloromethane-ethanol to give colorless prisms, mp. 210°-211° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Br[CH2:11][CH2:12][O:13][CH3:14].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:14][O:13][CH2:12][CH2:11][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cccc(C=O)c1

Procedure:
1.0 g of 3-hydroxybenzaldehyde, 1.1 g of 1-bromo-2-methoxyethane, and 10.7 g of Cs2CO3 were stirred at 40° C. in 10 ml of DMF (anhydrous) for 4 hours. The mixture was diluted with 100 ml of water and extracted twice with, in each case, 50 ml of EA. The extract was dried over MgSO4 and the solvent was removed under reduced pressure. This gave 1.3 g of a colorless oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]([C:12]1[S:13][C:14]([S:32][CH3:33])=[C:15]([S:17]([C:20]2[CH:25]=[C:24]([O:26]C(C)(C)C)[CH:23]=[C:22]([Br:31])[CH:21]=2)(=[O:19])=[O:18])[CH:16]=1)=[O:11]>C(Cl)Cl>[CH3:8][O:9][C:10]([C:12]1[S:13][C:14]([S:32][CH3:33])=[C:15]([S:17]([C:20]2[CH:25]=[C:24]([OH:26])[CH:23]=[C:22]([Br:31])[CH:21]=2)(=[O:18])=[O:19])[CH:16]=1)=[O:11]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cc(Br)cc(OC(C)(C)C)c2)c(SC)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(S(=O)(=O)c2cc(O)cc(Br)c2)c(SC)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.1 %

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of 4-(3-bromo-5-tert-butoxy-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester ((Example 12: step c) 240 mg, 0.5 mmol) in DCM (5 mL). The solution was stirred at rt for 2 h and the solvents were removed in vacuo, yielding 214 mg of an oil (quantitative) which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].[C:10]([Cu])#[N:11]>CN(C=O)C.O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]#[N:11])=[C:3]([CH3:9])[CH:4]=1
Reactant: N#C[Cu]
Reactant: Cc1cc(F)ccc1Br
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(F)ccc1C#N
Yield: 60 %

Procedure:
A mixture of 2-bromo-5fluorotoluene (3.5 g, 18.5 mmol) and CuCN (2 g, 22 mmol) in DMF (100 mL) was refluxed for 24 hours. The reaction was diluted with water and extracted with hexane. The organics were dried over MgSO4 and the solvent removed to give product 31 (yield 60%). 1H-NMR (400 MHz, CDCl3): δ 7.60 (dd, J=5.6, 8.8 Hz, 1H), 6.93-7.06 (m, 2H), 2.55 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:38]([NH:42][C:43]([C@@H:45]1[CH2:50][NH:49][CH2:48][CH2:47][NH:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>>[C:38]([NH:42][C:43]([C@@H:45]1[CH2:50][N:49]([C:32]([N:12]2[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=[C:11]2[C:8]2[CH:9]=[N:10][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][C:7]=2[O:35][CH2:36][CH3:37])=[O:33])[CH2:48][CH2:47][NH:46]1)=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)NC(=O)[C@@H]1CNCCN1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN[C@H](C(=O)NC(C)(C)C)C1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with (S)-piperazine-2-carboxylic acid tert-butylamide (Wako) to give the title compound. HR-MS (ES, m/z) calculated for C38H49Cl2N6O3 [(M+H)+] 707.3238, observed 707.3239.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([CH2:9][C:10]#[N:11])[N:3]=1>CCOC(C)=O.CO.[Pd]>[N:3]1[CH:2]=[CH:7][CH:6]=[N:5][C:4]=1[CH2:9][C:10]#[N:11]
Reactant: N#CCc1nc(Cl)cc(Cl)n1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: N#CCc1ncccn1
Reaction time: 2.5 h
Yield: 60.1 %

Procedure:
To a solution of 2-(4,6-dichloropyrimidin-2-yl)acetonitrile (4.10 g, 21.8 mmol) and TEA (6.07 ml, 43.6 mmol) in EtOAc/MeOH (1/1, 80 mL) was added 10% Pd/C (800 mg) and the solution was vigorously stirred for 2.5 h under H2 atmosphere (1 atm). The reaction was filtered through celite and washed the celite with MeOH. The combined filtrates were concentrated under reduced pressure and purified by flash chromatography (SiO2, 40-6% EtOAc/flexanes, gradient elution) to provide 2-(pyrimidin-2-yl)acetonitrile (1.56 g, 13.1 mmol, 60%) as a pale red liquid.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:13]1([C:18]([C:20]2[CH:21]=[C:22]([C@@H:26]([CH3:30])[C:27](O)=[O:28])[CH:23]=[CH:24][CH:25]=2)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.[CH3:31][S:32]([NH2:35])(=[O:34])=[O:33].C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH:13]1([C:18]([C:20]2[CH:21]=[C:22]([C@@H:26]([CH3:30])[C:27]([NH:35][S:32]([CH3:31])(=[O:34])=[O:33])=[O:28])[CH:23]=[CH:24][CH:25]=2)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CS(N)(=O)=O
Reactant: C[C@@H](C(=O)O)c1cccc(C(=O)C2CCCC2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: C[C@@H](C(=O)NS(C)(=O)=O)c1cccc(C(=O)C2CCCC2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 790 %

Procedure:
1,1′-Carbonyldiimidazole (0.5 g, 3.06 mmol) was added to a solution of (R)-2-[3-cyclopentanoyl)phenyl]propionic acid (II) (0.68 g, 2.78 mmol) in dry CH2Cl2 (8 mL) and the resulting mixture was left stirring at room temperature for 90 min. Methanesulfonamide (0.26 g, 2.78 mmol) and DBU (0.43 mL, 2.78 mmol) were added and the mixture was left stirring fur further 16 h at room temperature. The organic phase was washed with 0.5N HCl (2×10 mL), with 5% NaH2PO4 (3×10 mL) and with water (2×10 mL). After drying with Na2SO4, solvent was removed under vacuum and the crude was purified by flash chromatography (eluent mixture CH2Cl2/MeOH 95:5). Pure N—[(R)-2-(3-cyclopentanecarbonylphenyl)propionyl]methanesulfonamide 22 was isolated as colourless oil (0.67 g, 2.09 mmol). Yield 790%.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][O:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)([CH3:9])[CH3:8])[CH2:3][OH:4].[N:17]#[C:18]Br>>[F:16][C:13]1[CH:12]=[CH:11][C:10]([C:7]([CH3:9])([O:6][CH2:5][C@H:2]2[CH2:3][O:4][C:18]([NH2:17])=[N:1]2)[CH3:8])=[CH:15][CH:14]=1
Reactant: CC(C)(OC[C@H](N)CO)c1ccc(F)cc1
Reactant: N#CBr
Product: CC(C)(OC[C@H]1COC(N)=N1)c1ccc(F)cc1

Procedure:
In analogy to example 1d, (R)-2-amino-3-[1-(4-fluoro-phenyl)-1-methyl-ethoxy]-propan-1-ol was reacted with cyanogen bromide to give (S)-4-[1-(4-fluoro-phenyl)-1-methyl-ethoxymethyl]-4,5-dihydro-oxazol-2-ylamine. Colourless oil. MS (ISP): 253.3 ([M+H]+).
Reaction SMILES: C(OC([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21]([C:23]3[C:24](F)=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl.Cl.[NH:32]1[C:36]2=[N:37][C:38]([CH2:41][NH2:42])=[CH:39][CH:40]=[C:35]2[CH2:34][CH2:33]1>>[NH:32]1[C:36]2=[N:37][C:38]([CH2:41][NH:42][C:24]3[N:25]=[CH:26][CH:27]=[CH:28][C:23]=3[C:21]([NH:20][C:12]3[CH:11]=[C:10]4[C:15]([C:16]([CH3:19])([CH3:18])[CH2:17][NH:8][CH2:9]4)=[CH:14][CH:13]=3)=[O:22])=[CH:39][CH:40]=[C:35]2[CH2:34][CH2:33]1
Reactant: NCc1ccc2c(n1)NCC2
Reactant: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3cccnc3F)ccc2C(C)(C)C1
Agent: Cl
Product: CC1(C)CNCc2cc(NC(=O)c3cccnc3NCc3ccc4c(n3)NCC4)ccc21

Procedure:
The titled compound was prepared from 7-[(2-fluoro-pyridine-3-carbonyl)-amino]-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester and C-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-6-yl)-methylamine dihydrochloride by the method described in Example 1. MS (ES+): 429 (M+H). Calc'd. for C25H28N6O—428.54.
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:21][O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:5]([NH:7][CH:8]1[C:19](=[O:20])[N:10]2[C:11]([C:16]([OH:18])=[S:17])=[C:12]([CH3:15])[CH2:13][S:14][C@H:9]12)=[O:6].[NH2:29][C:30]([NH2:32])=[S:31].C([O-])(=O)C.[Na+]>O1CCCC1.O>[NH2:32][C:30]1[S:31][CH:2]=[C:3]([C:4](=[N:21][O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:5]([NH:7][CH:8]2[C:19](=[O:20])[N:10]3[C:11]([C:16]([OH:18])=[S:17])=[C:12]([CH3:15])[CH2:13][S:14][C@H:9]23)=[O:6])[N:29]=1
Reactant: NC(N)=S
Reactant: COC(=O)CON=C(C(=O)CCl)C(=O)NC1C(=O)N2C(C(O)=S)=C(C)CS[C@H]12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CON=C(C(=O)NC1C(=O)N2C(C(O)=S)=C(C)CS[C@H]12)c1csc(N)n1
Reaction time: 3 h
Yield: 73.4 %

Procedure:
A mixture of 7-[4-chloro-2-(methoxycarbonylmethoxyimino)-3-oxobutyramido]-3-methylthio-3-cephem-4-carboxylic acid (syn isomer) (2.6 g), thiourea (0.91 g) and sodium acetate (2.46 g) in tetrahydrofuran (10 ml) and water (20 ml) was stirred at 40° to 45° C. for 3 hours. Water (50 ml) was added to the reaction mixture and the resultant solution was washed with ethyl acetate. The separated aqueous layer was acidified to pH 2.2 with 10% hydrochloric acid and the acidified aqueous solution was extracted with ethyl acetate-tetrahydrofuran (8:2). The organic layer was washed with brine and dried over magnesium sulfate. The solution was evaporated and the residue was triturated with ether to give 7-[2-(2-aminothiazol-4-yl)-2-(methoxycarbonylmethoxyimino)acetamido]-3-methylthio-3-cephem-4-carboxylic acid (syn isomer) (2.0 g).
Reaction SMILES: [C:1]([C:5]1[CH:19]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[C:14][Si](C)(C)C)=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[C:1]([C:5]1[CH:19]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[CH:14])=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc2ncc(C#C[Si](C)(C)C)cn2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Product: C#Cc1cnc2cc(C(C)(C)C)nn2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-tert-Butyl-6-trimethylsilanylethynyl-pyrazolo[1,5-a]pyrimidine (example 21, step 1) (2.4 g, 8.85 mmol) was dissolved in dichloromethane (10 ml) and tetrabutylammoniumfluoride on silica gel (7.1 g, 10.6 mmol, 1.5 mmol/g) was added at room temperature. The mixture was stirred for 2 hours at room temperature and purified by flash chromatography by directly loading the mixture onto a 70 g silica gel column and eluting with heptane:ethyl acetate 100:0→40:60. The desired compound was obtained as a light yellow solid (1.45 g, 83% yield), MS: m/e=200.2 (M+H+).