Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)#[N:2].[CH3:18][S:19]Cl.[CH3:21][S:22]SC.ClCl>C(Cl)Cl>[C:1]([C:3]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:8])=[C:18]([SH:19])[CH:7]=1)#[N:2].[C:1]([C:3]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][C:9]([S:22][CH3:21])=[C:8]([OH:12])[CH:7]=1)#[N:2]
Reactant: N#Cc1cc(F)ccc1Oc1cccc(O)c1
Reactant: CSSC
Reactant: CSCl
Agent: ClCl
Solvent: ClCCl
Product: CSc1ccc(Oc2ccc(F)cc2C#N)cc1O
Product: Cc1ccc(Oc2ccc(F)cc2C#N)cc1S
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
3-(2-Cyano-4-fluorophenoxy)phenol (0.1 mole) and methylene chloride (200 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and addition funnel. The mixture is stirred until dissolved and cooled to about -20° C. A solution of methyl sulfenyl chloride freshly prepared by reacting dimethyl disulfide (0.15 mole) with chlorine (0.18 mole) in methylene chloride (100 ml) is then added dropwise to the reaction vessel over a period of about 40 minutes. After the addition is completed stirring is continued for 30 minutes with cooling and 30 minutes at room temperature. After this time the reaction mixture is washed with water (200 ml) with 5% aqueous sodium bicarbonate (200 ml) and again with water (200 ml). The washed solution is then dried by passing it through a phase separator. The dried solution is stripped of solvent under reduced pressure and the residue chromatographed using a clay column and hexane/ethyl acetate as the eluant. The fractions containing the product are combined and stripped of solvent to yield the desired product 5-(2-cyano-4-fluorophenoxy) 2-(methylthio)phenol as the residue.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:9]=[C:10]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:4]2[N:3]=1.[F-].[Cs+].[CH2:19]([N:26]1[CH2:33][CH2:32][CH:31]2[CH:27]1[CH2:28][NH:29][CH2:30]2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CS(C)=O>[CH2:19]([N:26]1[CH2:33][CH2:32][CH:31]2[CH2:30][N:29]([C:2]3[CH:7]=[C:6]([NH2:8])[N:5]4[N:9]=[C:10]([C:12]5[O:13][CH:14]=[CH:15][CH:16]=5)[N:11]=[C:4]4[N:3]=3)[CH2:28][CH:27]12)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(CN2CCC3CNCC32)cc1
Reactant: Nc1cc(Cl)nc2nc(-c3ccco3)nn12
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Product: Nc1cc(N2CC3CCN(Cc4ccccc4)C3C2)nc2nc(-c3ccco3)nn12
Temperature: 120 °C
Reaction time: 8 h

Procedure:
5-Chloro-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrimidin-7-ylamine (0.5 mmol; see WO 99/43678 A1) was dissolved in 4 mL of DMSO along with 2-benzyl-2,7-diazabicyclo[3.3.0]octane (2 mmol; see U.S. Pat. No. 5,071,999) and 0.7 mmol of CsF. The reaction mixture was stirred at 120° C. for 8 hours. It was then cooled to room temperature and purified by preparative HPLC to afford the title compound. 1H NMR (400 Hz, DMSO-d6) 7.60 (d, J=1.0 Hz, 1H), 7.28 (br s, 2H), 7.22 (d, J=3.6 Hz, 1H), 7.0-7.2 (m, 5H), 6.68 (dd, J=3.6 Hz, 1.0 Hz, 1H) 5.2 (s, 1H), 3.8 (br s, 2H), 2.2-3.2 (m, 10H). m/z: 402 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:17]([CH3:18])=[CH:16][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.O[C:20]([CH3:24])([CH3:23])[C:21]#[N:22].[O:25]1[CH2:30]CC(=O)C[CH2:26]1>CC(N(C)C)=O>[F:1][C:2]1[C:17]([CH3:18])=[CH:16][C:5]2[N:6]([CH:10]3[CH2:11][CH2:12][N:13]([C:20]4([C:21]#[N:22])[CH2:24][CH2:30][O:25][CH2:26][CH2:23]4)[CH2:14][CH2:15]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: O=C1CCOCC1
Reactant: Cc1cc2c(cc1F)[nH]c(=O)n2C1CCNCC1
Reactant: CC(C)(O)C#N
Solvent: CC(=O)N(C)C
Product: Cc1cc2c(cc1F)[nH]c(=O)n2C1CCN(C2(C#N)CCOCC2)CC1
Temperature: 65 °C

Procedure:
A mixture of 5-fluoro-6-methyl-1-piperidin-4-yl-1,3-dihydro-2H-benzimidazol-2-one (D30, 0.6 g, 2.4 mmol), 2-hydroxy-2-methylpropanenitrile, (380 mg, 4.8 mmol), tetrahydro-4H-pyran-4-one (480 mg) magnesium sulphate (1.4 g) and N,N-dimethylacetamide (2.4 ml) were stirred at 65° C. under a slow stream of argon. Extra 2 ml DMA was added and stirred for a further 4 hours. The mixture was partitioned between dichloromethane and water. The dichloromethane layer was separated, dried by passing through a 3 g hydromatrix cartridge. The solvent was removed and the title compound was obtained as a off white solid from ether (617 mg). M+ 359.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH:31]([CH3:35])[CH2:32][CH2:33][OH:34])[C:20]([NH:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:21])=[CH:15][CH:14]=1>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:34][CH2:33][CH2:32][CH:31]([CH3:35])[CH:19]([C:16]2[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=2)[C:20]([NH:22][NH:23][C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])=[O:21])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CC(CCO)C(C(=O)NNC(=O)OC(C)(C)C)c1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC(C)C(C(=O)NNC(=O)OC(C)(C)C)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 44.3 %

Procedure:
p-Toluenesulfonyl chloride (321 mg) was added to a solution of tert-butyl N′-[2-(4-fluorophenyl)-5-hydroxy-3-methylpentanoyl]hydrazinecarboxylate (520 mg) in pyridine (6 mL). The reaction solution was stirred at room temperature for 12 hours and then concentrated under reduced pressure. Ethyl acetate and brine were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 335 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9]([CH3:15])([CH3:14])[C:10]2=[O:13])=[CH:5][CH:4]=1.[BH4-].[Na+].O>CO.ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9]([CH3:15])([CH3:14])[CH:10]2[OH:13])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)C(C)(C)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)C(O)C(C)(C)CC2
Reaction time: 0.25 h

Procedure:
To a solution of 7-methoxy-2,2-dimethyl-3,4-dihydro-2H-naphthalen-1-one (1.42 g, 6.81 mmol) in methanol (15 mL) and dichloromethane (5 mL) is added NaBH4 (1.04 g, 27.25 mmol) in one portion. After 15 min, water is added and the organic solvents are evaporated in vacuo. The aqueous layer is extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered, and concentrated to give 7-methoxy-2,2-dimethyl-3,4-dihydro-2H-naphthalen-1-ol, which is used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:5][N:6]([CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[C:7]([C:9]1[N:10]=[CH:11][N:12]([CH3:14])[CH:13]=1)=[O:8].[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[F:24][C:23]1[C:2]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:3][C:4]([CH2:5][N:6]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:7]([C:9]2[N:10]=[CH:11][N:12]([CH3:14])[CH:13]=2)=[O:8])=[CH:21][CH:22]=1
Reactant: Cn1cnc(C(=O)N(Cc2ccc(F)c(Br)c2)C2CCOCC2)c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: Cn1cnc(C(=O)N(Cc2ccc(F)c(-c3ccccc3)c2)C2CCOCC2)c1
Yield: 33.6 %

Procedure:
A mixture of N-(3-bromo-4-fluorobenzyl)-1-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazole-4-carboxamide (150 mg), phenylboronic acid (92 mg), tetrakis(triphenylphosphine)palladium (50 mg), potassium carbonate (110 mg), DMF (2 mL) and ethanol (1 mL) was subjected to reaction in a microwave reactor (150° C., 10 min). Water was added to the reaction mixture, followed by extraction with ethyl acetate and concentrating under reduced pressure. The resulting residue was purified by TLC (silica gel) (chloroform:methanol=10:1) to give the titled compound (50 mg).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][CH:24]([CH:27]=O)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[N+:29]([C:32]1[CH:40]=[C:39]2[C:35]([CH2:36][CH2:37][NH:38]2)=[CH:34][CH:33]=1)([O-:31])=[O:30].C(O)(=O)C>ClCCl.C(OCC)(=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][CH:24]([CH2:27][N:38]2[C:39]3[C:35](=[CH:34][CH:33]=[C:32]([N+:29]([O-:31])=[O:30])[CH:40]=3)[CH2:36][CH2:37]2)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CN2CCc3ccc([N+](=O)[O-])cc32)C1
Reaction time: 2 h

Procedure:
91.5 mmol (19.4 g) of solid sodium triacetoxyborohydride are added slowly, at 20° C., to a solution of 60.8 mmol (12.1 g) of 1-(tert-butyloxycarbonyl)-3-formylpyrrolidine, 60.8 mmol (10 g) of 6-nitroindoline and 60.8 mmol (3.65 g) of acetic acid in 100 ml of dichloromethane. After 2 hours stirring, the reaction mixture is diluted with ethyl acetate. The organic phase is washed with water until pH=8, and the aqueous phase is then extracted with dichloromethane. After removal of the solvent by evaporation, the expected product is obtained.
Reaction SMILES: N[C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].N([O-])=O.[Na+].C([O-])([O-])=O.[Na+].[Na+].[ClH:20]>>[Cl:20][C@@H:2]([C@@H:3]([CH3:4])[CH2:5][CH3:6])[C:7]([OH:9])=[O:8]
Reactant: Cl
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [Na+]
Product: CC[C@H](C)[C@H](Cl)C(=O)O
Yield: 70 %

Procedure:
To a cooled (0° C.) solution of L-Isoleucine (40 g) dissolved in HCl (5N, 750 ml) was added dropwise a solution of sodium nitrite (35 g in 100 ml water). The reaction was stirred overnight at room temperature (˜23° C.), Na2CO3 (31 g) slowly added and the reaction mixture extracted with EtOAc (3×150 ml). The combined organic extracts washed with water, half saturated brine, dried over MgSO4, filtered and concentrated. The product a yellowish oil was distilled under reduced pressure (5 torr, bp=111° C.) to afford a colorless oil (32 g) obtained in 70% yield. (see FIG. 6).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][C:8](=O)[C:7]=2[CH:12]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:20][C:21](=[O:23])[CH3:22])C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:20][C:21]([CH3:22])=[O:23])[C:7]=2[CH:12]=1
Reactant: COc1ccc2c(c1)C(=O)CO2
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc2occ(CC(C)=O)c2c1

Procedure:
A mixture of 5-methoxy-benzofuran-3 (2H)-one (1.64 g, 10 mmol) and 1-triphenylphosphoranylidene-2-propanone (4.77 g, 15 mmol) was refluxed in toluene (100 ml) for 48 hrs. At the end, reaction mixture was concentrated and loaded over silica-gel column. The column was eluted with hexane (500 ml) and later with 25% ethyl acetate. The product, 1-(5-methoxy-1-benzofuran-3-yl)acetone, was obtained as a red oil. Yield: 1.1 g (53%); (M+H): 205.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:10]=2)[CH:7]=1.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1)#[CH:18]>>[N:11]1([C:9]2[N:10]=[C:5]3[N:4]=[CH:3][C:2]([C:18]#[C:17][C:19]4[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=4)=[CH:7][N:6]3[N:8]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: Brc1cnc2nc(N3CCOCC3)nn2c1
Reactant: C#Cc1cccc(C)c1
Product: Cc1cccc(C#Cc2cnc3nc(N4CCOCC4)nn3c2)c1

Procedure:
The title compound, a brown solid, MS: m/e=320.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyrimidine (example 47, step 1) and ethynyl-3-methylbenzene.
Reaction SMILES: [H-].[Na+].[CH2:3]1[CH2:7][O:6][CH2:5][CH2:4]1.C[C:9]([C:11]1[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[C:13]([F:19])[CH:12]=1)=[O:10].C(O)(=[O:22])C>C(OC(=O)OCC)C>[Cl:17][C:16]1[CH:15]=[C:14]([Cl:18])[C:13]([F:19])=[CH:12][C:11]=1[C:9]([CH2:4][C:5]([O:6][CH2:7][CH3:3])=[O:22])=[O:10]
Reactant: C1CCOC1
Reactant: CC(=O)c1cc(F)c(Cl)cc1Cl
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(=O)OCC
Product: CCOC(=O)CC(=O)c1cc(F)c(Cl)cc1Cl
Temperature: 25 °C

Procedure:
A 250 ml flame dried round bottom flask is equipped with a pressure equalizing addition funnel, magnetic stirring bar, and gas inlet. The flask is charged with a 50% sodium hydride-in-oil suspension (3.74 g, 78.0 mmol) along with 20 ml of dry THF. The slurry of NaH is cooled to 0° C. with an ice bath and a solution of 2,4-dichloro-5-fluoroacetophenone (7.8 g, 37.6 mmol) in 100 ml of diethylcarbonate (100 ml) is added slowly (dropwise) to the slurry of NaH. After the addition is complete the mixture is stirred at room temperature until gas evolution ceases (30 minutes). The deep red-orange solution is then heated to 80° C. for 1.5 hours. The reaction mixture is poured into an ice-cold water (250 ml) solution containing acetic acid (8 ml). The mixture is extracted (3×150 ml) with ether, dried over Na2SO4, and concentrated to an orange oil. The oil is distilled at high vacuum (1 mmHg 133°-135° C.). 7.9 g of ethyl 2,4-dichloro-5-fluorobenzoylacetate is obtained as a light yellow oil.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].N[C@@H](C(O)=O)CO.[NH2:14][C@H:15](C(O)=O)[C@@H:16]([CH3:18])O>>[NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH2:3][CH2:18][CH2:16][CH2:15][NH2:14]
Reactant: C[C@@H](O)[C@H](N)C(=O)O
Reactant: C[C@H](N)C(=O)O
Agent: N[C@H](CO)C(=O)O
Product: NCCCC[C@H](N)C(=O)O

Procedure:
Ser: Ala, (N-methyl)Ser, D-Ser, Thr
Reaction SMILES: C(OC([NH:11][C@:12]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][C:16](=[O:18])[NH:15][C:13]1=[O:14])=O)C1C=CC=CC=1.O.[H][H]>C(O)C.[Pd]>[NH2:11][C@:12]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][C:16](=[O:18])[NH:15][C:13]1=[O:14]
Reactant: CCOC(=O)[C@@]1(NC(=O)OCc2ccccc2)CC(=O)NC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CCOC(=O)[C@@]1(N)CC(=O)NC1=O
Temperature: 35 °C
Reaction time: 33 h
Yield: 86.7 %

Procedure:
(2R)-2-Benzyloxycarbonylamino-2-ethoxycarbonylsuccinimide (24.4 g, 76.2 mmol) in ethanol (73.2 ml) was heated at 60° C. to be dissolved and 5% Pd—C (2.71 g) and water (2.17 g) were added at 30-40° C. of inner temperature. After the atmosphere was substituted with nitrogen gas, hydrogen gas was introduced and the mixture was stirred at 30-40° C. for about 33 hours. When completion of the reaction was confirmed by HPLC, the reaction solution was filtered, the insoluble materials were washed with sprayed ethanol (20 ml×2) and the filtrate was concentrated. The resulting crystals were recrystallized from ethanol (24.4 ml) and the precipitated crystals were filtered, washed with sprayed ethanol (15 ml) and dried in vacuo at room temperature to give (2R)-2-amino-2-ethoxycarbonylsuccinimide (12.3 g). Yield 86.7%, HPLC 99.7%, Optical purity 100% e.e.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([NH2:16])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:17][C:18]1[N:19]([CH:27]([CH3:31])[C:28](O)=[O:29])[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH:13]([CH3:14])[CH3:15])=[C:11]([NH:16][C:28](=[O:29])[CH:27]([N:19]3[CH:20]=[C:21]([C:23]([F:24])([F:26])[F:25])[N:22]=[C:18]3[CH3:17])[CH3:31])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)c1c(N)cnn1-c1ccc(F)cc1
Reactant: Cc1nc(C(F)(F)F)cn1C(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C(F)(F)F)cn1C(C)C(=O)Nc1cnn(-c2ccc(F)cc2)c1C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.3 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-isopropylpyrazol-4-amine (0.03 g, 0.14 mmol) in DMF (1.0 mL) was added 2-[2-methyl-4-(trifluoromethyl)imidazol-1-yl]propanoic acid (0.031 g, 0.14 mmol), followed by diisopropylethylamine (0.042 g, 0.32 mmol) and HATU (0.057 g, 0.15 mmol). After stirring at room temperature for 1 h, the reaction was diluted with water and the aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude product was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.0145 g, 0.034 mmol, 25%). 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J=0.6 Hz, 1H), 7.46 (q, J=1.2 Hz, 1H), 7.33-7.24 (m, 2H), 7.21-7.11 (m, 2H), 6.63 (s, 1H), 4.92 (q, J=7.3 Hz, 1H), 2.93 (m, 1H), 2.49 (s, 3H), 1.89 (d, J=7.3 Hz, 3H), 1.04 (dd, J=10.3, 7.2 Hz, 6H); MS: (ES) m/z calculated for C20H21F4N5O [M+H]+ 424.2, found 424.0.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:11]1[C:16]([CH:17]([CH2:22][CH2:23][CH3:24])[C:18]([O:20][CH3:21])=[O:19])=[C:15]([CH3:25])[N:14]=[C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:12]=1.ClCCl.C([Zn])C1C=CC=CC=1>O1CCCC1.O.[Cl-].[Zn+2].[Cl-]>[CH2:1]([C:11]1[C:16]([CH:17]([CH2:22][CH2:23][CH3:24])[C:18]([O:20][CH3:21])=[O:19])=[C:15]([CH3:25])[N:14]=[C:13]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Agent: [Zn]Cc1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.8 %

Procedure:
To a cooled (0° C.) solution of anhydrous zinc chloride (0.060 mg; 0.439 mmol) in tetrahydrofuran (0.8 mL) under nitrogen atmosphere was added dropwise a benzylmagnesium chloride solution (1M in THF) (0.408 mL; 0.408 mmol). After 15 min, the solution was allowed to warm up to room temperature for 10 min. To an argon purged reaction tube was added methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.100 g; 0.314 mmol), (1,1′-Bis(diphenylphosphino)ferrocene)-dichloropalladium(II) complex with dichloromethane (0.015 g; 0.022 mmol) and tetrahydrofuran (3 mL). The milky benzylzinc solution was added dropwise, the mixture was stirred at room temperature for 30 min and then heated at 65° C. for 20 h. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organics were washed with a solution of ethylenediaminetetraacetic acid, water, brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-20%) in heptane furnished 0.095 g (81%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][NH:12][C:13]1[N:18]=[CH:17][C:16]([C:19]([O:21]C)=[O:20])=[C:15]([O:23][CH3:24])[CH:14]=1.[OH-].[K+]>O1CCCC1.CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][NH:12][C:13]1[N:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[C:15]([O:23][CH3:24])[CH:14]=1
Reactant: COC(=O)c1cnc(NCc2ccc(OC)cc2OC)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CNc2cc(OC)c(C(=O)O)cn2)c(OC)c1
Reaction time: 15 h
Yield: 80.1 %

Procedure:
Methyl 6-[(2,4-dimethoxyphenyl)methylamino]-4-methoxypyridine-3-carboxylate (1.16 g) was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and methanol (10 mL). An aqueous potassium hydroxide solution (1 M, 7 mL) was added to the solution at room temperature. The reaction solution was stirred for 15 hours, and the organic solvent was then distilled off under reduced pressure. The obtained residue was diluted with water, and hydrochloric acid (1 M, 7.5 mL) was then added thereto. The resulting suspension was filtered, and the product collected by filtration was washed with water and dried under reduced pressure to obtain the title compound (0.890 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:13])=[O:12])=[C:5]2[S:14]([N:17]1[C:21](O)=[CH:20][CH:19]=[C:18]1O)(=[O:16])=[O:15].ClC1C=C(C=CC=1)C(OO)=[O:29].O1CCCC1>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:13])=[O:12])=[C:5]2[S:14]([N:17]1[CH2:18][C@@H:19]2[C@@H:20]([O:29]2)[CH2:21]1)(=[O:16])=[O:15]
Reactant: NC(=O)c1[nH]c2ccc(Br)cc2c1S(=O)(=O)n1c(O)ccc1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: NC(=O)c1[nH]c2ccc(Br)cc2c1S(=O)(=O)N1C[C@@H]2O[C@@H]2C1
Reaction time: 3 h

Procedure:
To a stirring suspension of 5-bromo-3-(2,5-dihydroxy-1H-pyrrol-1-ylsulfonyl)-1H-indole-2-carboxamide (10 mg, 0.027 mmol, 1.0 equiv.) in 2 mL of acetone was added m-chloroperoxybenzoic acid (6.5 mg, 0.038 mmol, 1.4 equiv.). After stirring for 3 hours, 3 mL of tetrahydrofuran and m-chloroperoxybenzoic acid (6.5 mg, 0.038 mmol, 1.4 equiv.) were added. After stirring an additional 72 hours, more m-chloroperoxybenzoic acid (13 mg, 0.076 mmol, 2.8 equiv.) was added and, after 3 hours, the solvent was removed in vacuo. The title compound was obtained after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. ESI+MS: 385.96 [M+H]+.
Reaction SMILES: Cl.[Br:2][CH2:3][CH2:4][C:5]1([CH3:22])[CH:9]([C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11])[N:8]2[C:18](=[O:21])[CH:19]([NH2:20])[C@H:7]2[S:6]1.C(N(CC)CC)C.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]1[C:41]([C:42](Cl)=[O:43])=[C:40]([CH3:45])[O:39][N:38]=1>C(Cl)Cl>[Br:2][CH2:3][CH2:4][C:5]1([CH3:22])[CH:9]([C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11])[N:8]2[C:18](=[O:21])[CH:19]([NH:20][C:42]([C:41]3[C:37]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[Cl:30])=[N:38][O:39][C:40]=3[CH3:45])=[O:43])[C@H:7]2[S:6]1
Reactant: Cc1onc(-c2ccccc2Cl)c1C(=O)Cl
Reactant: CC1(CCBr)S[C@@H]2C(N)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2Cl)c1C(=O)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)C(C)(CCBr)S[C@H]12
Reaction time: 33 h
Yield: 70.2 %

Procedure:
A solution of 2,2,2-trichloroethyl 2-bromoethyl-2-methyl-6-aminopenam-3-carboxylate hydrochloride (6.95 g) and triethylamine (3.0 g) in dried methylene chloride (100 ml) was cooled at -25° C. To this solution was added dropwise a solution of 3-(2-chlorophenyl)-5-methylisoxazole-4-carbonyl chloride (4.5 g) in dried methylene chloride (30 ml), and the mixture was stirred for 33 hours at the same temperature. After the reaction was completed, the reaction mixture was post-treated in the similar manner as described in Example 1 to give oily 2,2,2-trichloroethyl 2-bromoethyl-2-methyl-6-[3-(2-chlorophenyl)-5-methylisoxazole-4-carboxamido]penam-3-carboxylate (6.75 g).