Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([NH:13][C:14](=[O:26])[CH2:15][O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[NH:11][CH:12]=1.[C:27]([OH:30])(=[O:29])[CH3:28]>>[C:27]([O:30][C:15](=[O:16])[CH3:14])(=[O:29])[CH3:28].[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([NH:13][C:14](=[O:26])[CH2:15][O:16][C:17]2[C:18]([CH3:25])=[CH:19][C:20]([CH3:24])=[CH:21][C:22]=2[CH3:23])[NH:11][CH:12]=1
Reactant: CC(=O)O
Agent: Cc1cc(C)c(OCC(=O)Nc2nc(-c3ccccc3N)c[nH]2)c(C)c1
Product: CC(=O)OC(C)=O

Procedure:
To a mixed solution of acetic acid (10 mL) and acetic anhydride (5 mL), N-[4-(2-aminophenyl)-1H-imidazol-2-yl]-2-(mesityloxy)acetamide (Compound 19) (350 mg, 1.0 mmol) obtained in Example 19 was added, and the mixture was stirred for 16 hours at room temperature. The solvent was distilled off under reduced pressure, the resulting residue was dissolved in chloroform (50 mL), and the mixture was washed with 10% aqueous sodium carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, and then distilled under reduced pressure. The resulting residue was dissolved in 10% ammonia/methanol solution (10 mL), and the mixture was stirred for 6 hours at room temperature. To the reaction solution, chloroform (50 mL) was added, and the mixture was washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, and then distilled under reduced pressure. The resulting crystals were dispersed in diethyl ether, collected by filtration and dried to give 250 mg of the title compound (yield 91%) expressed by the following formula (Ex. 20).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([I:23])[CH:15]=[C:16]([CH2:21]Cl)[CH:17]=3)[N:12]([CH3:24])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([I:23])[CH:15]=[C:16]([CH2:21][N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[CH:17]=3)[N:12]([CH3:24])[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)cc(I)c21
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Temperature: 25 °C
Yield: 73 %

Procedure:
A solution of N-(4-chlorobenzyl)-6-(chloromethyl)-8-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide (3.95 g), N,N-diisopropylethylamine (1.79 mL), and morpholine (0.96 mL) in anhydrous DMF (149 mL) is heated at 65° C. for 1-2 h. The reaction is allowed to cool to room temperature, then poured into H20 (300 mL) to precipitate the product. The solid is filtered, adsorbed onto silica, and chromatographed (eluent 100% CH2Cl2 (0.5% CH2Cl2 (1L), 1% MeOH in CH2Cl2 (1L), 1.5% MeOH in CH2Cl2 (1 L), 2% MeOH in CH2Cl2 (1L), 2.5% MeOH in CH2Cl2 (2L)). Product-containing fractions are combined and condensed to afford 3.17 g (73%) of the desired product as a white solid.
Reaction SMILES: [C:1]([C:3]1([CH2:16][CH:17]2[CH2:19][CH2:18]2)[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1)#[N:2].[ClH:20]>O1CCOCC1>[ClH:20].[CH:17]1([CH2:16][C:3]2([C:1]#[N:2])[CH2:4][CH2:5][NH:6][CH2:7][CH2:8]2)[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(CC2CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#CC1(CC2CC2)CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A sample of tert-butyl 4-cyano-4-(cyclopropylmethyl)piperidine-1-carboxylate (I-2, 3.6 g, 13.6 mmol) was treated with HCl (40 mL of a 4.0 M solution in dioxane) and stirred at room temperature for 2 h before being concentrated under reduced pressure to afford 4-(cyclopropylmethyl)-piperidine-4-carbonitrile hydrochloride (I-3, M+H+=165.1) which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:9].[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:9][C:3]1[CH:4]=[C:5]([NH2:6])[CH:7]=[CH:8][C:2]=1[C:14]1[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=1
Reactant: Nc1ccc(Br)c(Cl)c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2ccc(Cl)cc2)c(Cl)c1
Temperature: 25 °C

Procedure:
4-bromo-3-chloroaniline (3.0 g, 14.5 mmol), (4-chlorophenyl)boronic acid (2.7 g, 17.4 mmol), Pd(dppf)Cl2 (1.2 g, 1.5 mmol), and K2CO3 (4.0 g, 29.1 mmol) were dissolved in 1,4-dioxane (60 mL) and water (15 mL) and the resulting mixture was heated to 80° C. After 16 h the resulting mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([CH3:11])[C:3]=1[C:12]#[N:13].[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>ClCCl.N1C=CC=CC=1>[CH2:7]([N:6]1[C:2]([NH:1][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[F:14])=[C:3]([C:12]#[N:13])[C:4]([CH3:11])=[N:5]1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCn1nc(C)c(C#N)c1N
Reactant: O=C(Cl)c1ccccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCn1nc(C)c(C#N)c1NC(=O)c1ccccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 24.7 %

Procedure:
5-Amino-1-butyl-3-methyl-1H-pyrazole-4-carbonitrile (10.0 g, 56 mmole) was dissolved in a mixture of dichloromethane/pyridine (45 ml/15 ml) and cooled to 0° C. 2-fluorobenzoyl chloride (8.87 g, 56 mmole) was added dropwise and the reaction mixture was stirred for 1 hour at 0° C., and at room temperature overnight. The solvent was removed under vacuum. The residue was taken up in ethyl acetate, washed with diluted hydrochloric acid, 0.1 M sodium hydroxide, and water, and dried over sodium sulfate (anh). The solvent was removed and the solid triturated in 30% ethyl acetate/hexanes. The product was filtered to obtain 4.16 g product (yield: 24%).
Reaction SMILES: CS(O[C@H]1CCN(CC2C=CC(C)=CC=2)C1=O)(=O)=O.[F:20][C@H:21]1[C@H:26]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([F:34])[CH:28]=2)[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]1.CCN(C(C)C)C(C)C>C(#N)C>[F:34][C:29]1[CH:28]=[C:27]([C@@H:26]2[CH2:25][CH2:24][NH:23][CH2:22][C@H:21]2[F:20])[CH:32]=[CH:31][C:30]=1[OH:33]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(O)c(F)c2)[C@H](F)C1
Agent: Cc1ccc(CN2CC[C@H](OS(C)(=O)=O)C2=O)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Oc1ccc([C@@H]2CCNC[C@H]2F)cc1F
Temperature: 80 °C
Reaction time: 16 h
Yield: 41 %

Procedure:
A solution of (S)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl methanesulfonate (0.106 g, 0.375 mmol, from example 112, step D) in acetonitrile (1 mL) was added to a mixture of 2-fluoro-4-((3S,4S)-3-fluoropiperidin-4-yl)phenol (0.04 g, 0.188 mmol, from step E) and DIPEA (0.098 mL, 0.563 mmol) in acetonitrile (2 mL) heated at 80° C. The reaction mixture was then stirred at 80° C. for 16 h. The mixture was allowed to cool to rt and then concentrated in vacuo. The residue was purified using preparative LC/MS (Waters XBridge C18, 19×150 mm, 5 μm; Guard Column: Waters XBridge C18, 19×10 mm, 5 μm; Mobile Phase A: 5:95 acetonitrile:water with 10 mM NH4OAc; Mobile Phase B: 95:5 acetonitrile:water with 10 mM NH4OAc; Gradient: 15-60% B over 25 min, followed by a 10 min hold at 60% B and 5 min hold at 100% B; Flow: 15 mL/min). Fractions containing the desired product were combined concentrated in vacuo using a Genevac centrifugal evaporator to the titled compound of Example 115 (31 mg, 0.077 mmol, 41% yield) as pale yellow solid. LC-MS (M+H)+ 401; 1H NMR: (400 MHz, DMSO-d6) d=7.19-7.06 (m, 5H), 6.95-6.84 (m, 2H), 4.70-4.48 (m, 1H), 4.41-4.24 (m, 2H), 3.55 (s, 1H), 3.48-3.29 (m, 3H), 2.76-2.63 (m, 2H), 2.62-2.52 (m, 1H), 2.28 (s, 4H), 2.16-2.03 (m, 1H), 1.89 (s, 3H), 1.79-1.54 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[O:8].[F:9][C:10]([Si](C)(C)C)([F:12])[F:11].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:9][C:10]([F:12])([F:11])[CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[OH:8]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccccn1)C(F)(F)F
Yield: 126.7 %

Procedure:
According to Reference Example 8-12, by use of 2-pyridinecarboxaldehyde (500 μL, 5.26 mmol), (trifluoromethyl)trimethylsilane (932 μL, 6.31 mmol), tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 526 μL, 0.526 mmol) and tetrahydrofuran (10 mL), the mixture was stirred and reacted at room temperature for 10 minutes. Then, purification by silica gel column chromatography (chloroform/methanol=9/1) was performed to give 2-(2,2,2-trifluoro-1-hydroxyethyl)pyridine (Compound CN) (1.18 g, yield: quantitative).
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1(O)C=CC=CC=1.COC.[Si]=O.[O-2].[Ba+2]>[O-2].[Fe+2].[O-2].[V+5].[O-2].[O-2].[O-2].[O-2].[V+5].O>[C:6]1([OH:7])[C:5]([CH3:9])=[CH:4][CH:3]=[CH:2][C:1]=1[CH3:8]
Reactant: Oc1ccccc1
Reactant: Cc1ccccc1O
Agent: [Fe+2]
Agent: [V+5]
Agent: COC
Solvent: O
Product: Cc1cccc(C)c1O

Procedure:
A mixture of o-cresol and phenol, dimethyl ether and water in a molar ratio of 1:2:2.6 were reacted as described in Example 1. The catalyst contained iron oxide, vanadium oxide, silicon oxide and barium oxide in a molar ratio of 100:2:10:0.1. After working up, 2.6-xylenol was obtained with a selectivity of 99%.
Reaction SMILES: BrCC([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[C:11]1([NH2:18])C=CC=C[C:12]=1[NH2:17].C([O-])(=O)C.[Na+]>C(O)C>[N:17]1[C:6]2[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:18]=[CH:11][CH:12]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Nc1ccccc1N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: c1ccc2nccnc2c1
Reaction time: 8 h

Procedure:
To a magnetically stirred solution of the appropriate alpha-bromoacetophenone (1 eq) in 200 ml of ethanol was added the appropriate 1,2-phenylenediamine (2.4 eq), followed by addition of solid sodium acetate (3 eq). The resultant solution was warmed to reflux and stirred overnight with an air atmosphere. The product formed precipitates, and so the reaction was vacuum filtered, and the solids washed with 50 ml cold ethanol followed by washing with 50 ml 0.1 N HCl. The product was carried on without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[C:14](#[N:16])C.ClS(N=C=O)(=O)=O.CN(C)C=O>CCOC(C)=O.C(OCC)(=O)C.CCCCCC>[C:14]([C:9]1[N:8]([NH:7][C:6](=[O:13])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:12]=[CH:11][CH:10]=1)#[N:16]
Reactant: CC(C)(C)OC(=O)Nn1cccc1
Reactant: CC#N
Agent: O=C=NS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nn1cccc1C#N
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A 2L, 3-neck RB was fitted w/stir bar, N2 inlet, rubber septum low-temp. thermometer and ice/acetone cooling bath. Pyrrol-1-yl-carbamic acid tert-butyl ester (99.0 g, 0.543 mol) was added to the reactor, dissolved w/anhydrous acetonitrile (700 mL) and the stirred solution was cooled to 0° C. Chlorosulfonyl isocyanate (49.7 mL, 0.57 mol) was added dropwise via syringe (maintaining an internal temp. below 5° C.); after ˜20 minutes a suspension was observed. After 45 minutes N,N-dimethylformamide (anhydrous, 100 μL) was added dropwise via addition funnel (keeping internal temp. below 5° C.) and the reaction mixture became a solution. Stirring @0° C. was continued for 45 minutes, then the reaction was allowed to warm to RT; monitoring by TLC (silica gel, 1:3 ethyl acetate/hexane, UV, ninydrin stain) of a quenched sample indicated that the reaction had progressed to completion. The mixture was poured onto ice (˜2 L) and stirred with addition of EtOAc (2 L). The layers were separated and the organic layer was dried over magnesium sulfate. The dried solution was filtered through a pad of 30/40 Magnesol and the filtrate was concentrated to dryness in vacuo, then the residue was dissolved in a minimum volume of dichloromethane and chromatographed on a plug of silica gel, eluting with ethyl acetate/hexane, 0-50% ethyl acetate. The clean, product-containing fractions were combined and concentrated to dryness in vacuo, to afford the desired product as a white solid, 69.8 g (62%). A somewhat impure fraction provided additional material, 16.8 g (15%), bringing the total recovery to 86.6 g, (77%). 1H-NMR (CD3OD): 7.01 (dd, 1H, J=3.0, 1.6 Hz), 6.82 (dd, 1H, J=4.4, 1.7 Hz), 6.19 (dd, 1H, J=4.2, 2.9 Hz), 4.88 (s, 1H, H2O+NH—), 1.50 (br s, 9H, HN-BOC); MS: LC/MS (+esi), m/z=207.9 [M+H]
Reaction SMILES: C1N2CN3CN(C2)C[N:2]1C3.Cl[CH2:12][C:13]([NH:15][C:16]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:17]=1[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O)=[O:14].N>CO>[Cl:30][C:27]1[CH:28]=[CH:29][C:16]2[NH:15][C:13](=[O:14])[CH2:12][N:2]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17]=2[CH:26]=1
Reactant: O=C(CCl)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: C1N2CN3CN1CN(C2)C3
Agent: N
Solvent: CO
Product: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 624.3 %

Procedure:
A mixture of methanol (550 mls), hexamethylenetetramine (14.1 g., 0.1 mol) and 2-chloroacetamido-5-chlorobenzophenone (308.2 g., 1.0 mol) was stirred and saturated with ammonia at room temperature. The mixture was heated slowly to reflux with a steady stream of ammonia bubbling through the solution. Refluxing was continued for 24 hours. The flow of ammonia was interrupted and the crystal slurry obtained was cooled to room temperature. The product, filtered, washed with methanol (2 × 125 ml) and hot water (4 × 500 ml), and dried gave 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (169 g., 62.3%) melting at 213° to 215° C.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].CO.[N:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH2:18][CH3:19])=[CH:13][CH:12]=1>CCOC(C)=O.O>[N:11]1[CH:16]=[CH:15][C:14]([C:17](=[N:2][OH:3])[CH2:18][CH3:19])=[CH:13][CH:12]=1
Reactant: NO
Reactant: CCC(=O)c1ccncc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CCC(=NO)c1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
Hydroxylamine hydrochloride (2.8 g, 40.7 mmol) and sodium acetate (3.3 g, 40.7 mmol) were added to 20 mL of methanol and the resulting white slurry was stirred at room temperature for 30 min. 1-(Pyridin-4-yl)propan-1-one (5.0 g, 37.0 mmol) was added and the mixture was stirred at room temperature for 20 hours. Water (50 mL) and EtOAc (50 mL) were added and the organic layer was separated. The aqueous layer was basified with solid sodium bicarbonate and extracted with additional EtOAc. The combined organic layer was washed with saturated NaHCO3 solution and dried over MgSO4. The solvent was evaporated in vacuo to give 5.3 g of the title compound. MS: (+) m/z 151.36 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:18]=[C:17]2[N:8]([C:9](=[S:19])[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=32)[N:7]=1)=O)C.[BH4-].[Li+].Cl>O>[OH:3][CH2:4][C:6]1[CH:18]=[C:17]2[N:8]([C:9](=[S:19])[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=32)[N:7]=1
Reactant: CCOC(=O)c1cc2c3ccccc3[nH]c(=S)n2n1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Product: OCc1cc2c3ccccc3[nH]c(=S)n2n1
Reaction time: 20 h

Procedure:
0.519 g (0.0019 mole) of 5,6-dihydro-5-thioxopyrazolo-[1,5-c]quinazoline-2-carboxylic acid ethyl ester is suspended in 10 ml distilled tetrahydrofuran and treated with 0.1 g (0.004 mole) of 85% lithium borohydride at room temperature. After 20 hours of stirring, the reaction mixture is cooled to 0°, 4.5 ml of 1N hydrochloric acid is added and stirring is continued for 30 minutes. 25 ml of water is added and the product is filtered off after 10 minutes and dried.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:20]([O:22][C:23](=[O:30])[C@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH2:25])[CH3:21].C(Cl)(Cl)Cl.C1(C)C=CC(S(ON=C(C#N)C(OCC)=O)(=O)=O)=CC=1>C(N(CC)CC)C>[CH2:20]([O:22][C:23](=[O:30])[C@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH:25][C:13](=[O:15])[C@@H:12]1[CH2:16][CH2:17][CH2:18][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:21]
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CCOC(=O)C(C#N)=NOS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 4.1 %

Procedure:
N-Benzyloxycarbonyl-L-proline (1.25 g) and L-leucine ethyl ester hydrochloride (1.0 g) are suspended into chloroform (10 ml), and therein is dissolved triethylamine (1.4 ml). To the solution is added ethyl 2-(p-toluenesulfonyloxyimino)-2-cyanoacetate (1.5 g) and the mixture is stirred at room temperature for 16 hours. After reaction, the reaction mixture is extracted with ethyl acetate. The exatract is washed with water, 1 N aqueous sodium hydrogen carbonate, water, 1 N hydrochloric acid and water in order and then dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off and the residual oily substance (1.6 g) is dissolved in chloroform and then the mixture is subjected to a silica gel column chromatography (developer: chloroform). The first fraction thus obtained is concentrated and the resulting residue is crystallized from ether-petroleum ether to give N-(N-benzyloxycarbonyl-L-prolyl)-L-leucine ethyl ester (80 mg), melting point: 60°-64° C. The product is identified with an authentic sample by infrared spectrum.
Reaction SMILES: [Na+:1].[NH2:2][C:3]1[S:4][CH:5]=[C:6](/[C:8](=[N:26]/[O:27][CH2:28][C:29]([O:31]CC2C=CC([N+]([O-])=O)=CC=2)=[O:30])/[C:9]([NH:11][C@H:12]2[C@@H:15]([CH2:16][O:17][C:18](=[O:20])[NH2:19])[N:14]([S:21]([O-:24])(=[O:23])=[O:22])[C:13]2=[O:25])=[O:10])[N:7]=1>[Pd]>[Na+:1].[NH2:2][C:3]1[S:4][CH:5]=[C:6](/[C:8](=[N:26]/[O:27][CH2:28][C:29]([OH:31])=[O:30])/[C:9]([NH:11][C@H:12]2[C@@H:15]([CH2:16][O:17][C:18](=[O:20])[NH2:19])[N:14]([S:21]([O-:24])(=[O:22])=[O:23])[C:13]2=[O:25])=[O:10])[N:7]=1
Reactant: NC(=O)OC[C@@H]1[C@H](NC(=O)/C(=N\OCC(=O)OCc2ccc([N+](=O)[O-])cc2)c2csc(N)n2)C(=O)N1S(=O)(=O)[O-]
Agent: [Pd]
Agent: [Na+]
Product: NC(=O)OC[C@@H]1[C@H](NC(=O)/C(=N\OCC(=O)O)c2csc(N)n2)C(=O)N1S(=O)(=O)[O-]
Yield: 54.8 %

Procedure:
270 mg (0.43 mmol) of (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[(p-nitrobenzyloxycarbonyl)methoxy]imino]acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid sodium salt are dissolved in 30 ml of methanaol and the solution is hydrogenated over 150 mg of 5% palladium-on-silica gel. The catalyst is filtered off and the solvent is evaporated. The residue is taken up in 2.5 ml of water and washed twice with ethyl acetate. The aqueous phase is chromatographed (reverse-phase using water as the eluting agent). There are obtained 115 mg (54%) of (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(carboxymethoxy)imino]acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid sodium salt.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: NCc1ccccc1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Clc1nc(NCc2ccccc2)c2[nH]cnc2n1
Temperature: 60 °C
Yield: 96.3 %

Procedure:
To a suspension of 2,6-dichloropurine (110 mg, 0.52 mmol) in n-butanol (3 mL), benzylamine (57 mg, 0.52 mmol) and triethylamine (72 mg, 0.79 mmol) was added. The mixture was stirred and heated at 60° C. for 15 min. The resulting precipitate was filtered, washed with water (20 mL) and methanol (10 mL), and air-dried overnight. Compound 4 (130 mg, 95%) was obtained as an off-white solid: mp 262° C.; EI/MS (m/z (relative %)): 259 (19, M+.), 260 (14), 261 (17%), 106 (100), 91 (77); 1H NMR (400 MHz, DMSO) δ 8.15 (s, 1H), 7.25-7.34 (m, 5H), 4.66 (d, J=6 Hz, 2H); 13C NMR (100 MHz, DMSO) δ 155.0 (s) 153.1 (s), 150.7 (s), 140.2 (d, 1JC—H=200 Hz), 139.6 (s), 128.5 (d, 1JC—H=158 Hz, 127.5 (d, 1JC—H=157 Hz), 127.0 (d, 1JC—H=158 Hz) 118.1 (s), 43.4 (t, 1JC—H=139 Hz).
Reaction SMILES: [C:1]1([CH:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12](C(OCC)=O)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C.O.C(OCC)(=O)C>[C:20]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)N1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
4-(Diphenylmethoxy)-1-(ethoxycarbonyl)piperidine (4a) (11.45 g, 33.7 mmol) was dissolved in ethanol (72 mL). A cold solution of sodium hydroxide (8.2 g, 205 mmol) in water (12 mL) was added slowly and a small amount of heat was detected. The mixture was heated at reflux for 17 h and then cooled to room temperature. The mixture was subsequently diluted with water (100 mL) and ethyl acetate (100 mL) and stirred for 0.5 h to dissolve the resultant solid. The organic and aqueous layers were separated and the organic layer was washed with water (100 mL). The separate aqueous layers were extracted with ethyl acetate (100 mL) and the organic layers were combined, dried with Na2SO4, filtered and concentrated to yield 7.88 g (87.5%) of 5 as a viscous yellow oil. The structure was confirmed by 1H NMR.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][N:22]2[C@@H:26]([CH3:27])[C@@H:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:24][C:23]2=[O:34])[CH:6]=1.FC1C=CC(B(O)O)=CC=1>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:7]2[CH:6]=[C:5]([CH2:4][C:3]([OH:35])=[O:2])[CH:10]=[CH:9][C:8]=2[O:11][CH3:12])=[C:15]([CH2:21][N:22]2[C@@H:26]([CH3:27])[C@@H:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:24][C:23]2=[O:34])[CH:16]=1
Reactant: COC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Agent: OB(O)c1ccc(F)cc1
Product: COc1ccc(CC(=O)O)cc1Oc1ccc(Br)cc1CN1C(=O)O[C@H](c2ccccc2)[C@@H]1C

Procedure:
Prepared according to the procedure described in Example 19, Step 3, using the following starting materials: {3-[4-bromo-2-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid methyl ester and 4-fluorobenzeneboronic acid.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][N:22]2[C@@H:26]([CH3:27])[C@@H:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:24][C:23]2=[O:34])[CH:6]=1.COC1C=CC=CC=1B(O)O>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:7]2[CH:6]=[C:5]([CH2:4][C:3]([OH:35])=[O:2])[CH:10]=[CH:9][C:8]=2[O:11][CH3:12])=[C:15]([CH2:21][N:22]2[C@@H:26]([CH3:27])[C@@H:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:24][C:23]2=[O:34])[CH:16]=1
Reactant: COC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Agent: COc1ccccc1B(O)O
Product: COc1ccc(CC(=O)O)cc1Oc1ccc(Br)cc1CN1C(=O)O[C@H](c2ccccc2)[C@@H]1C

Procedure:
Prepared according to the procedure described in Example 19, Step 3, using the following starting materials: {3-[4-bromo-2-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid methyl ester and 2-methoxyphenylboronic acid.