Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:4][CH2:3]1.[Li+].[OH-].[H][H]>C1COCC1.O>[CH3:1][C:2]1([CH3:29])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:23][CH:24]=3)=[CH:7][C:6]=2[C:5]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:4][CH2:3]1
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C(C)(C)C)=CCC3(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
A solution of 24.0 mg (0.06 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl]benzoate (Compound 71) and 6.5 mg (0.16 mmol) of LiOH-H2 0 in 3 mL THF/water (3:1, v/v) was stirred overnight (22 hours) at room temperature. The reaction mixture was extracted with Et2O and the layers were separated. The aqueous layer was acidified with HCl (1M aqueous solution) and then extracted with EtOAc. The organic phase was dried over Na2 SO4 and concentrated in vacuo to give the title compound as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[F-:10].[K+]>CN1CCCC1=O.O>[F:10][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: N#Cc1ccc(Br)cn1
Reactant: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1ccc(F)cn1
Temperature: 175 °C
Reaction time: 18 h

Procedure:
The mixture of 5-bromo-pyridine-2-carbonitrile (0.50 g, 2.73 mmol), and KF (0.48 g, 8.20 mmol) in 10 ml of 1-methyl-2-pyrrolidinone was stirred at 175° C. for 18 h, cooled to RT, diluted with H2O, extracted with EtOAc, the combined organic portions were washed with H2O, brine, dried with Na2SO4, filtered, condensed, the crude compound was purified by flash column chromatography (5 to 20% of EtOAc in hexanes). The titled compound was obtained as an off-white solid.
Reaction SMILES: [CH3:1]ON(C)C(=O)CC(C)C.[F:11][C:12]([C:17]1[CH:18]=[C:19]2[NH:25][CH2:24][C:23]([CH3:27])([CH3:26])[C:20]2=[N:21][CH:22]=1)([F:16])[CH2:13][CH2:14][CH3:15]>>[F:11][C:12]([C:17]1[CH:18]=[C:19]2[NH:25][CH2:24][C:23]([CH3:26])([CH3:27])[C:20]2=[N:21][CH:22]=1)([F:16])[CH2:13][CH:14]([CH3:1])[CH3:15]
Reactant: CCCC(F)(F)c1cnc2c(c1)NCC2(C)C
Reactant: CON(C)C(=O)CC(C)C
Product: CC(C)CC(F)(F)c1cnc2c(c1)NCC2(C)C

Procedure:
Prepared starting from N-Methoxy-3,N-dimethyl-butyramide in an analogous fashion to 6-(1,1-difluoro-butyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (see Preparations 264 and 116. MS: [M+H]+=255.
Reaction SMILES: ClCCl.[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[C:20]([OH:21])=[C:19]([O:22][CH3:23])[C:18]([O:24][CH3:25])=[CH:17][C:16]=1[CH3:26].[O:27]=O>C1C=C(C=NCCN=CC2C([O-])=CC=CC=2)C([O-])=CC=1.[Co+2]>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[C:20](=[O:21])[C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[C:17](=[O:27])[C:16]=1[CH3:26]
Reactant: O=O
Reactant: COc1cc(C)c(CCCCCCCCCCO)c(O)c1OC
Agent: [Co+2]
Agent: [O-]c1ccccc1C=NCCN=Cc1ccccc1[O-]
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCO)=C(C)C1=O
Reaction time: 72 h

Procedure:
To a dichloromethane solution (30 ml) of 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methylphenol (1.4 g) is added bis(salicylidene)ethylenediiminocobalt(II) (0.06 g), and the mixture is stirred in oxygen streams at 20° C. and atmospheric pressure for 72 hours. After the reaction has been completed, the reaction mixture is passed through a bed of a small quantity of silica gel (about 15 g) to remove the catalyst. The solvent is then distilled off and the residue is recrystallized from ether-hexane (1:4). The above procedure yields 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (1.01 g) as orange-yellow needles melting at 51° C.-52° C.
Reaction SMILES: C(O[CH2:5][C@@H:6]([C@@H:12]1[CH2:16][O:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C(=O)C)[C:18]=2[CH3:27])=[N:13]1)[O:7]S(C)(=O)=O)(=O)C.CO.[C:30]([NH:34][C:35]([C@@H:37]1[CH2:46][C@H:45]2[C@H:40]([CH2:41][CH2:42][CH2:43][CH2:44]2)[CH2:39][NH:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31].C(=O)([O-])[O-].[K+].[K+]>O>[C:30]([NH:34][C:35]([C@@H:37]1[CH2:46][C@H:45]2[C@H:40]([CH2:41][CH2:42][CH2:43][CH2:44]2)[CH2:39][N:38]1[CH2:5][C@H:6]([C@@H:12]1[CH2:16][O:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[C:18]=2[CH3:27])=[N:13]1)[OH:7])=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1
Reactant: CC(=O)OC[C@H](OS(C)(=O)=O)[C@@H]1COC(c2cccc(OC(C)=O)c2C)=N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1c(O)cccc1C1=N[C@H]([C@H](O)CN2C[C@H]3CCCC[C@H]3C[C@H]2C(=O)NC(C)(C)C)CO1
Temperature: 50 °C
Reaction time: 5.5 h

Procedure:
The crude product of Example 3, (2R)-1-acetoxy-2-((4S)-2-(3-acetoxy-2-methylphenyl)-4,5-dihydrooxazol-4-yl)-2methanesulfonyloxyethane, 18′ (1.98 kg, 3.30 mol) was suspended in a mixed solvent of methanol (6.50 L) and water (6.50 L), and (3S, 4aS, 8aS)-decahydroisoquinoline-3-carboxylic acid t-butylamide, 642 g, 2.62 mol) and potassium carbonate (1.36 kg, 9.81 mol) were successively added, which was followed by stirring at 50° C. for 5.5 hours. Water (6.50 L) was added to cool the reaction mixture to room temperature and the resulting crystals were collected by filtration. These crude crystals were again suspended in water (6.50 L), stirred, washed and collected by filtration. The obtained crystals were re-suspended in methyl isobutyl ketone (10.0 L) and the suspension was subjected to azeotropic dehydration. The resulting slurry was cooled to room temperature and crystals were collected by filtration to give 902 g (1.07 mol) of the title compound, as colorless crystals.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.C(=O)(O)[O-].[Na+].[SH:24][C:25]1[N:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]2=[N:28][N:29]=1.Cl>O.CC(C)=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:24][C:25]3[N:26]4[CH:33]=[CH:32][CH:31]=[CH:30][C:27]4=[N:28][N:29]=3)[CH2:15][S:14][C@H:9]12
Reactant: Sc1nnc2ccccn12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3nnc4ccccn34)CS[C@H]12
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
2.72 g (0.01 mol) of 7-aminocephalosporanic acid was suspended in 18 ml of water, and a suspension of 2.1 g (0.025 mol) of sodium bicarbonate in 20 ml of water was added dropwise thereto over a period of time of 10 minutes. The inside temperature of the reactor was then increased to 50° C., and a suspension of 1.81 g (0.0125 mol) of 3-mercaptopyrido[2,1-c]-s-triazole in 35 ml of acetone was added dropwise thereto over a period of time of 10 minutes. The resulting mixture was refluxed for 4 hours at a stable inside temperature of the reactor of 63° C. followed by ice cooling the mixture. After the inside temperature of the reactor reached 4° C., the mixture was adjusted to a pH of 3.6 with 6 N hydrochloric acid. One hour after the stirring, the precipitated crystals were filtered and dried over phosphorus pentoxide under reduced pressure to obtain 2.31 g (yield: 61%) of the tilted compound having a melting point (decomposition) of 173° to 175° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([CH:11]=O)[C:5]=2[CH:4]=[CH:3]1.[CH3:13][NH2:14].[BH4-].[Na+].O>CO>[CH3:13][NH:14][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][N:2]2[CH3:1]
Reactant: Cn1ccc2c(C=O)cccc21
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNCc1cccc2c1ccn2C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
1-Methyl-1H-indole-4-carbaldehyde (427 mg, 2.68 mmol) was dissolved in anhydrous methanol (12 mL). Methylamine (1.07 mL of 33% solution in ethanol, 8.59 mmol) was added and the reaction was stirred for 3 h. The solution was concentrated to a yellow oil and then dissolved in anhydrous methanol (12 mL). Sodium borohydride (104 mg, 2.74 mmol) was added and the mixture was stirred overnight at room temperature. Water (10 mL) was added and the solution was concentrated. Sodium hydroxide (20 mL, 1N) was added and the aqueous layer was extracted with ethyl acetate (3×30 mL). Combined organic layers were dried over Na2SO4, filtered and concentrated to afford N-methyl(1-methyl-1H-indol-4-yl)methanamine (432 mg, 92%) as a yellow oil: 1H NMR (400 MHz, DMSO-d6) δ 7.29-7.26 (m, 2H), 7.10-7.06 (m, 1H), 7.00-6.98 (m, 1H), 6.51 (d, J=3.2 Hz, 1H), 3.87 (s, 2H), 3.76 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[N+:13]([O-])([O-])=O.[NH4+:17].[CH:18](/[CH:25]=[CH:26]/O)=[CH:19]\[C:20]([C:22]([OH:24])=[O:23])=O>C1(C)C=CC=CC=1>[N:17]1[CH:26]=[CH:25][CH:18]=[CH:19][C:20]=1[C:22]([OH:24])=[O:23].[NH4+:13]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(O)C(=O)/C=C/C=C/O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: O=C(O)c1ccccn1

Procedure:
A culture of strain CEL 2052 (ATCC 39636), growing continuously on 20 mM glucose and 8.5 mM nitrate, is induced with toluene in the absence of ammonium ions. 2-Hydroxymuconic semialdehyde is observed to accumulate rapidly at a rate which would produce 0.082 g/gdw/hr of picolinic acid if excess ammonium ions had been present. Instead, growth is inhibited immediately and the culture washes out at a dilution rate of 0.12 hr-1.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5](F)=[O:6].[CH3:14][OH:15]>C(N(CC)CC)C>[Br:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([O:15][CH3:14])=[O:6]
Reactant: O=C(F)c1cc(F)c(F)c(Br)c1F
Reactant: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(F)c(F)c(Br)c1F
Reaction time: 1 h

Procedure:
772 g of 3-bromo-2,4,5-trifluoro-benzoylfluoride are added dropwise with ice-cooling to a mixture of 1460 ml of methanol and 340 g of triethylamine. Stirring is carried out at room temperature for 1 hour. The reaction mixture is concentrated, the residue is taken up in water and methylene chloride, and the aqueous phase is again extracted by shaking with methylene chloride. After drying the organic phase over sodium sulphate, it is concentrated and the residue is distilled in vacuo. 752.4 g of methyl 3-bromo-2,4,5-trifluoro-benzoate of boiling point 122° C./20 mbar are obtained.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:10][C:11]([C@@H:13]3[C@@H:15]([CH2:16][CH2:17][CH2:18][CH3:19])[O:14]3)=[O:12])=[CH:4][C:3]=2[O:2]1.[N-:20]=[N+:21]=[N-:22].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>CO>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:10][C:11](=[O:12])[C@@H:13]([OH:14])[C@@H:15]([N:20]=[N+:21]=[N-:22])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:4][C:3]=2[O:2]1
Reactant: CCCC[C@H]1O[C@@H]1C(=O)Nc1ccc2c(c1)OCO2
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: CO
Product: CCCC[C@H](N=[N+]=[N-])[C@H](O)C(=O)Nc1ccc2c(c1)OCO2
Yield: 70.1 %

Procedure:
30 ml of a methanol suspension containing 484 mg (1.84 mmol) of (2S-trans)-N-[(3,4-methylenedioxy)phenyl]-3-butyl-oxiranecarboxamide, 239 mg (3.68 mmol) of sodium azide and 228 mg (1.89 mmol) of anhydrous magnesium sulfate was refluxed for 5 hours. After the temperature of the reaction mixture was returned to room temperature, the reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the concentrate, and the resulting mixture was washed successively with water, and then, with a saturated NaCl solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 395 mg (Yield: 70%) of the title compound.
Reaction SMILES: [CH2:1]([S:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])[C:2]#[CH:3].[C:10]([C:14]1([CH2:18]O)[CH2:17][O:16][CH2:15]1)([CH3:13])([CH3:12])[CH3:11]>>[C:10]([C:14]12[CH2:15][O:16][C:7]([CH2:6][CH2:5][S:4][CH2:1][C:2]#[CH:3])([O:9][CH2:18]1)[O:8][CH2:17]2)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)C1(CO)COC1
Reactant: C#CCSCCC(=O)O
Product: C#CCSCCC12OCC(C(C)(C)C)(CO1)CO2

Procedure:
4-t-Butyl-1-[2-(prop-2-ynylthio)ethyl]-2,6,7-trioxabicyclo[2.2.2]octane was prepared from 3-(prop-2-ynylthio)propionic acid and 3-t-butyl-3-hydroxymethyloxetane using methodology described in Example I.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([F:11])=[C:9]([Br:12])[C:8]([CH3:13])=[C:7]([C:14]#[N:15])[C:6]=1[NH2:16])(=O)[CH3:2].O.[C:18]1(C)C=CC(S(O)(=O)=O)=C[CH:19]=1>C1(C)C=CC=CC=1>[Br:12][C:9]1[C:10]([F:11])=[C:5]2[O:4][C:1]([CH:2]3[CH2:19][CH2:18]3)=[N:16][C:6]2=[C:7]([C:14]#[N:15])[C:8]=1[CH3:13]
Reactant: CC(=O)Oc1c(N)c(C#N)c(C)c(Br)c1F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(Br)c(F)c2oc(C3CC3)nc2c1C#N

Procedure:
2-Amino-5-bromo-3-cyano-6-fluoro-4-methylphenyl acetate (I-76) (7.95 g, 25.38 mmol) was dissolved in toluene (80 ml), p-toluenesulfonic acid monohydrate (1.60 g, 20 wt. %) was added, followed by stirring under reflux for 19 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1O.[OH-].[Na+].Cl[C:13]([O:15][CH3:16])=[O:14]>O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)Cl
Reactant: Oc1ccc(F)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1ccc(F)cc1Cl
Yield: 125.6 %

Procedure:
2-Chloro-4-fluorophenol (83.4 g) was added to a solution of sodium hydroxide (27.7 g) in water (450 ml), and methyl chloroformate (69.2 g) was dropwise added thereto at a temperature of below 10° C. Precipitated crystals were collected by filtration and washed with water to give methyl (2-chloro-4-fluorophenyl)formate (134.8 g). M.P., 69°-71° C.
Reaction SMILES: [CH2:1]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]=2[S:7][C:6]=1[CH:18]=O)[CH:2]([CH3:4])[CH3:3].[C:20]([C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH:30][C:31]([O:33][CH3:34])=[O:32])=[C:25]([CH3:35])[CH:24]=1)(=[O:22])[CH3:21]>>[CH2:1]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:15])[F:16])=[CH:13][C:8]=2[S:7][C:6]=1[CH:18]=[CH:21][C:20]([C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH:30][C:31]([O:33][CH3:34])=[O:32])=[C:25]([CH3:35])[CH:24]=1)=[O:22])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1c(C=O)sc2cc(C(F)(F)F)ccc12
Reactant: COC(=O)C=Cc1ccc(C(C)=O)cc1C
Product: COC(=O)C=Cc1ccc(C(=O)C=Cc2sc3cc(C(F)(F)F)ccc3c2CC(C)C)cc1C

Procedure:
The titled compound was prepared from the above-mentioned 3-isobutyl-6-(trifluoromethyl)benzothiophen-2-carboxaldehyde (250 mg, 0.873 mmol) and methyl 3-(4-acetyl-2-methylphenyl)acrylate (191 mg, 0.875 mmol) in a procedure similar to that of Example 7 (1) as a yellow crystal (250 mg, yield 71%).
Reaction SMILES: [OH-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4]1.Br[CH2:16][CH:17]1[CH2:19][CH2:18]1>CC(C)=O.O>[CH:17]1([CH2:16][N:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:12]([OH:14])=[O:13])=[CH:4]2)[CH2:19][CH2:18]1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: BrCC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1cn(CC2CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Powdered sodium hydroxide (10 g) was added cautiously to a stirred solution of indole-3-carboxylic acid (5 g) and (bromomethyl)cyclopropane (10 g) in dry acetone (50 ml). The mixture was stirred for 24 hours at room temperature then diluted with water (250 ml) and washed with dichloromethane (2×100 ml). The aqueous phase acidified to pH 2 and the precipitate isolated and dried (6.3 g), m.p. 157° C.; δH (360 MHz, CDCl3) 0.02-0.04 (2H, m, CH2), 0.18-0.28 (2H, m, CH2), 0.83-0.89 (1H, m, CH), 3.57 (2H, d, J=7 Hz, NCH2), 6.7-6.8 (2H, m, H-5, H-6), 6.9 (1H, d, J=7 Hz, H-7), 7.55 (1H, s, H-2), 7.72 (1H, d, J=7 Hz, H- 4); m/z 215 (M+, 100%), 174 (60), 144 (40).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](O)=[O:7])#[N:2].C1(C)C=CC=CC=1.S(Cl)([Cl:25])=O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([Cl:25])=[O:7])#[N:2]
Reactant: CCc1cc(C(=O)O)cc(C#N)c1OC
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCc1cc(C(=O)Cl)cc(C#N)c1OC
Temperature: 60 °C
Reaction time: 14 h

Procedure:
To 3-cyano-5-ethyl-4-methoxybenzoic acid (347 mg), toluene (3.5 mL), N,N-dimethylformamide (0.01 mL) and thionyl chloride (0.15 mL) were added, and then the mixture was stirred at 60° C. for 14 hours. The solvent was distilled off under reduced pressure and then azeotroped with toluene to obtain the title compound (387 mg) as a brown oily substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:34][C@@H:35]1[CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]1[OH:41])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([S:31]([NH:34][C@@H:35]4[CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]4[OH:41])(=[O:32])=[O:33])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(N[C@@H]1CCCC[C@H]1O)c1ccccc1Br
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N[C@@H]3CCCC[C@H]3O)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 2-bromo-N-((1R,2R)-2-hydroxycyclohexyl)benzenesulfonamide. MS (ESI): mass calcd. for C22H23FN4O3S, 442.15; m/z found, 443.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.37-8.30 (m, 2H), 8.21-8.16 (m, 1H), 7.97 (m, 1H), 7.68-7.62 (m, 1H), 7.60-7.54 (m, 1H), 7.40-7.32 (m, 3H), 3.26-3.18 (m, 1H), 2.87-2.79 (m, 1H), 1.94-1.77 (m, 2H), 1.67-1.50 (m, 2H), 1.26-1.09 (m, 4H).
Reaction SMILES: C(O)C(N)(CO)C[OH:4].Cl.[NH2:10][C:11]1[N:19]=[C:18]2[C:14]([N:15]=[CH:16][N:17]2[C@@H:20]2[O:25][C@:24]([C:28]#[CH:29])([CH2:26][OH:27])[C@@H:22]([OH:23])[CH2:21]2)=[C:13](N)[N:12]=1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1O>O>[C:28]([C@:24]1([CH2:26][OH:27])[O:25][C@@H:20]([N:17]2[C:18]3[N:19]=[C:11]([NH2:10])[NH:12][C:13](=[O:4])[C:14]=3[N:15]=[CH:16]2)[CH2:21][C@@H:22]1[OH:23])#[CH:29]
Reactant: C#C[C@]1(CO)O[C@@H](n2cnc3c(N)nc(N)nc32)C[C@@H]1O
Reactant: NC(CO)(CO)CO
Agent: Cl
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: O
Product: C#C[C@]1(CO)O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@H]1O
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a Tris-HCl buffer solution (7.8 ml, pH 7.5) of Compound 28 (0.03 g, 0.103 mmol), adenosine deaminase (0.057 ml, 20 unit) was added, and the mixture was stirred for 2 hours at 40° C., followed by cooling to room temperature. The reaction mixture was applied to a reverse-phase ODS silica gel column (50 g), desalted by water (500 ml) flow, and through use of aqueous 2.5% ethanol, Compound 30 was eluted. Recrystallization from water yielded Compound 30 in an amount of 0.015 g (50%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C@@H:13]2[O:18][C:17]3[CH:19]=[CH:20][C:21]([CH:23]=O)=[CH:22][C:16]=3[O:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1.C1CCN2C(=NCCC2)CC1.[CH3:40][C:41]([O:44][C:45]([NH:47][CH:48](P(OC)(OC)=O)[C:49]([O:51][CH3:52])=[O:50])=[O:46])([CH3:43])[CH3:42]>C(Cl)Cl>[CH3:52][O:51][C:49](=[O:50])[C:48]([NH:47][C:45]([O:44][C:41]([CH3:42])([CH3:40])[CH3:43])=[O:46])=[CH:23][C:21]1[CH:20]=[CH:19][C:17]2[O:18][C@@H:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([O:6][CH2:5][C:4]4[CH:25]=[CH:26][C:27]([Cl:28])=[C:2]([Cl:1])[CH:3]=4)[CH:8]=3)[CH2:14][O:15][C:16]=2[CH:22]=1
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)P(=O)(OC)OC
Reactant: O=Cc1ccc2c(c1)OC[C@H](c1cccc(OCc3ccc(Cl)c(Cl)c3)c1)O2
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)C(=Cc1ccc2c(c1)OC[C@H](c1cccc(OCc3ccc(Cl)c(Cl)c3)c1)O2)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.7 %

Procedure:
(S)-2-[3-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxine-6 carbaldehyde (2.1 g) was dissolved in 8 mL dry DCM under nitrogen at rt and DBU (1.61 g) was added by syringe. A solutuion of Boc-phosphonoglycine trimethyl ester (1.58 g) in 4 mL of dry DCM was added to the reaction mixture and stirred at rt. for 12 hours. Reaction mixture was directly loaded on to silica gel column (40% hexanes in DCM to DCM) gave 1.8 g pure product. 1H NMR (400 MHz, CDCl3): 7.55 (d, 1H), 7.46 (d, 1H), 7.32-7.38 (m, 1H), 7.18-7.28 (m, 3H), 7.10-7.15 (m, 1H), 6.94-7.06 (m, 4H), 5.13 (m, 1H), 5.03 (s, 2H), 4.36 (m, 1H), 4.01 (m, 1H), 3.84 (s, 3H), 1.44 (s, 9H). LCMS (m/z): 587.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C:15]#[N:16])(=O)=O)=CC=1.[CH3:25][NH:26][CH3:27].C(N(CC)CC)C>C(O)C>[C:15]([CH2:14][C@H:13]([NH:17][C:18](=[O:19])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:12][N:26]([CH3:27])[CH3:25])#[N:16]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](CC#N)NC(=O)OC(C)(C)C)cc1
Reactant: CNC
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)C[C@H](CC#N)NC(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
To a solution in ethanol (20 mL) of the compound (1.32 g) obtained in step (1) above, dimethylamine (about 50%, aqueous solution, 3.92 mL) and triethylamine (519 μL) were added and the mixture was stirred at 80° C. for an hour. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. To the resulting residue, a saturated aqueous solution of sodium hydrogencarbonate was added and extraction was conducted with ethyl acetate. The combined organic layers were washed with saturated brine and after passage through a phase separator, they were concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=99:1-95:5) to give tert-butyl [(2S)-1-cyano-3-(dimethylamino)propan-2-yl]carbamate as a pale yellow oil (340 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][O:20][CH3:21])[C:9]([O:11][CH2:12][CH3:13])=[O:10].[N+:22]([O-])([OH:24])=[O:23]>CC(O)=O>[CH3:21][O:20][CH2:19][CH2:18][O:17][C:16]1[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:14]([N+:22]([O-:24])=[O:23])[CH:15]=1
Reactant: CCOC(=O)c1ccc(OCCOC)c(OCCOC)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 94 %

Procedure:
According to the procedure described in Example 6A Step 2, to a solution of ethyl 3,4-bis(2-methoxyethoxy)benzoate (7.87 g, 26.4 mmol) in AcOH (50 mL) was added HNO3 (90%, 4 mL) and the mixture was heated at 50° C. for 5 hours, to afford ethyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate as an oil (8.531 g, 94%). 1H NMR (300 MHz, CDCl3) δ 7.51 (s, 1H), 7.12 (s, 1H), 4.37 (q, 2H), 4.25 (m, 4H), 3.80 (m, 4H), 3.45 (s, 6H), 1.35 (t, 3H); LC-MS (ESI) m/z 344 (M+H)+.
Reaction SMILES: CO[C:3](=[O:19])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:20][NH:21][C:22]([NH2:24])=[O:23].C[O-].[Mg+2].C[O-].CO>>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=2)[C:3]([NH:24][C:22]([NH:21][CH3:20])=[O:23])=[O:19])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(F)c(F)c1
Reactant: CNC(N)=O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(F)c(F)c1
Temperature: 100 °C
Yield: 9.4 %

Procedure:
A mixture of 3-cyclopentyl-2-(3,4-difluoro-phenyl)-propionic acid methyl ester (1.65 g, 6.14 mmol) and methyl urea (683 mg, 9.22 mmol) in a solution of magnesium methoxide in methanol (7.4 wt %, 16.6 mL, 12.3 mmol) was refluxed at 100° C. for 8 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate) afforded 1-[3-cyclopentyl-2-(3,4-difluoro-phenyl)-propionyl]-3-methyl-urea (180 mg, 9.4%) as a white solid: mp 111-113° C.; EI-HRMS m/e calcd for C16H20F2N2O2 (M+) 310.1493, found 310.1499.