Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C([Li])CCC.F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-])=O>O1CCCC1>[F:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:16]1[C:17]([NH2:22])=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Cc1ccc(N)c(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(Nc2ccccc2N)c(F)c1
Temperature: 22 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
A solution of 2-fluoro-4-methylaniline (6.8 mL, 60 mmol) in tetrahydrofuran (200 mL) was cooled to −78° C. and treated with n-butyllithium (26 mL of a 2.5 M solution in hexanes, 66 mmol) and stirred for 1 h. A solution of 2-fluoronitrobenzene (6.3 mL, 60 mmol) in tetrahydrofuran (20 mL) was added dropwise over 5 min, and the reaction mixture was stirred at −78° C. for 0.5 h, then warmed to 22° C. After 16 h, the reaction mixture was concentrated, diluted with ethyl ether (200 mL), washed with 2 M hydrochloric acid (200 mL), dried (Na2SO4), and concentrated to a black oil. A solution of this black oil in a mixture of methanol (100 mL) and ethyl acetate (100 mL) was treated with 10% palladium on carbon (1 g) and stirred under a hydrogen atmosphere at 65 psi for 2 h, and then the reaction mixture was filtered, and concentrated. Flash chromatography (SiO2, 10→100% dichloromethane/hexanes) provided N-(2-fluoro-4-methylphenyl)benzene-1,2-diamine (7.0 g) as an orange solid:
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11](Cl)=[O:12])=[C:6]2[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:3]=1.[CH3:21][S:22]([C:25]1[CH:26]=[C:27]([NH2:31])[CH:28]=[CH:29][CH:30]=1)(=[O:24])=[O:23]>>[CH3:21][S:22]([C:25]1[CH:26]=[C:27]([NH:31][C:11]([C:10]2[CH:9]=[N:8][N:7]3[C:2]([Cl:1])=[CH:3][C:4]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=4)=[N:5][C:6]=23)=[O:12])[CH:28]=[CH:29][CH:30]=1)(=[O:23])=[O:24]
Reactant: O=C(Cl)c1cnn2c(Cl)cc(-c3ccc(Cl)cc3)nc12
Reactant: CS(=O)(=O)c1cccc(N)c1
Product: CS(=O)(=O)c1cccc(NC(=O)c2cnn3c(Cl)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-chloro-5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride and 3-methanesulfonyl-phenylamine according to general procedure II. Pale-yellow solid. MS (ISP) 461.3 [(M+H)+]; mp 253-255° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[CH:18]=[C:19]([CH:28]([NH2:30])[CH3:29])[CH:20]=[CH:21][C:22]=1[O:23][C:24]([F:27])([F:26])[F:25]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:30]([CH:28]([C:19]3[CH:20]=[CH:21][C:22]([O:23][C:24]([F:25])([F:26])[F:27])=[C:17]([CH3:16])[CH:18]=3)[CH3:29])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(C(C)N)ccc1OC(F)(F)F
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)ccc1OC(F)(F)F
Yield: 71 %

Procedure:
The title compound is prepared in 71% yield (562 mg, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (550 mg, 2.15 mmol, Step-1 of Intermediate-1) and 1-(3-methyl-4-(trifluoromethoxy)phenyl)ethanamine hydrochloride (550 mg, 2.15 mmol, Amine-80, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.Br[CH2:39][C:40]([N:42]1[CH2:47][CH2:46][CH2:45][C:44]([CH3:49])([CH3:48])[CH2:43]1)=O>>[CH3:48][C:44]1([CH3:49])[CH2:45][CH2:46][CH2:47][N:42]([CH2:40][CH2:39][O:10][C:8]2[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=3[C@H:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:6][CH:7]=2)[CH2:43]1
Reactant: CC1(C)CCCN(C(=O)CBr)C1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc([C@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCN3CCCC(C)(C)C3)cc2)c1
Yield: 101.7 %

Procedure:
Synthesized from pivalic acid (S)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-bromo-1-(3,3-dimethylpiperidin-1-yl)ethanone (19 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (11 mg) was obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8](=[O:12])[N:7]([CH3:13])[CH:6]=1)=[O:4].[OH-].[Na+]>CO>[CH3:13][N:7]1[C:8](=[O:12])[C:9]([CH3:11])=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6]1
Reactant: COC(=O)c1cc(C)c(=O)n(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C(=O)O)cn(C)c1=O
Temperature: 100 °C

Procedure:
1,5-Dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester C-1 (2.60 g; 14.35 mmol) is suspended in MeOH. Sodium hydroxide (1 M solution, 45 ml; 45.00 mmol) is added and the reaction mixture is heated up to 100° C. (Drysyn, reflux) for 2 h. MeOH is removed under reduced pressure and 1N HCl (46 ml) is added to the solution, precipitation occurs. The precipitate is filtered off and dried under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[Cl:12][C:13]1[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=1.[H-].[Na+]>COCCOC>[Cl:12][C:13]1[N:14]=[N:15][C:16]([CH2:10][C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[O:11])=[CH:17][CH:18]=1
Reactant: CC(=O)c1ccc(F)cc1F
Reactant: Clc1ccc(Cl)nn1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(Cc1ccc(Cl)nn1)c1ccc(F)cc1F
Temperature: 50 °C
Reaction time: 4 h
Yield: 57 %

Procedure:
The 1-(2,4-difluorophenyl)ethanone (Apollo, 1.00 g, 6.40 mmol) and 3,6-dichloropyridazine (0.95 g, 6.4 mmol) in DME (10 mL) were treated with NaH (0.512 g, 12.8 mmol, 60% dispersion in oil) then warmed at about 50° C. in an oil bath. The mixture was stirred for about 4 h then sodium hydride (0.26 g, 6.4 mmol, 60% dispersion in oil) and 3,6-dichloropyridazine (0.48 g, 3.2 mmol) were added. The reaction was heated for about 0.5 h and then quenched with acetic acid and water. The mixture was extracted with EtOAc then purified by flash chromatography on silica with EtOAc as an eluent to give the title compound (0.98 g, 57%): LC/MS (Table 1, Method a) Rt=2.34 min; MS m/z: 269.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[OH:22])[CH2:2][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][CH2:17][CH3:18].[CH2:53](Cl)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.[OH-].[Na+]>[Cl-].C([N+](C)(C)C)CCCCCCCCCCCCCCC>[CH2:53]([O:22][CH:21]([CH2:20][O:19][CH2:1][CH2:2][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][CH2:17][CH3:18])[CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: CCCCCCCCCCCCCCCCCCOCC(O)COCCOCCOCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: ClCc1ccccc1
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Product: CCCCCCCCCCCCCCCCCCOCC(COCCOCCOCCO)OCc1ccccc1
Yield: 90 %

Procedure:
7.2 g (10 millimole) of 1-O-octadecyl-3-O-[2-[2-(2-trityloxyethoxy)ethoxy]ethyl]glycerol, 2.5 g (20 millimole) of benzyl chloride, 4 g (50 millimole) of 50% sodium hydroxide, 160 mg (0.5 millimole) of cetyltrimethylammonium chloride were treated by following a procedure similar to that described in Working Example 10, to give 5.1 g (88%) of the above-captioned compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH2:9])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>N1C=CC=CC=1>[C:7]([C:6]1[CH:5]=[N:4][CH:3]=[C:2]([OH:1])[CH:10]=1)#[N:9]
Reactant: NC(=O)c1cncc(O)c1
Solvent: O
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1cncc(O)c1
Temperature: 0 °C
Reaction time: 20 h
Yield: 70 %

Procedure:
5-Hydroxynicotinamide (0.69 g, 5 mmol) prepared by the method described in International Patent Publication No. 8606628 was dissolved in pyridine (50 ml). Trifluoroacetic anhydride (2.52 g, 12 mmol) was added, and the mixture was stirred at 0° C. for 20 hours. The reaction mixture, to which water (20 ml) was added, was concentrated under reduced pressure and extracted with chloroform (50 ml×3). The chloroform layer was washed with water (50 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (Wako Gel C-200, 20 g; eluted with chloroform:methanol=100:1) to give 3-cyano-5-hydroxypyridine (0.42 g, 3.5 mmol) (Yield 70%).
Reaction SMILES: [O:1]1[CH:3]([CH3:4])[CH:2]1[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH3:24])[CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1.[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[OH:1][CH:3]([CH2:4][NH:28][CH:25]([CH3:27])[CH3:26])[CH2:2][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH3:24])[CH:18]=3)[N:13]=2)=[CH:10][CH:11]=1
Reactant: CC(C)N
Reactant: COc1ccc2nc(-c3ccc(OC4OC4C)cc3)[nH]c(=O)c2c1
Product: COc1ccc2nc(-c3ccc(OCC(O)CNC(C)C)cc3)[nH]c(=O)c2c1

Procedure:
This compound was prepared analogous to Example 4 from 2-[4-(1,2-epoxy-propoxy)-phenyl]-6-methoxy-3,4-dihydro-quinazolin-4-one and isopropylamine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:10]C(OCC1C=CC=CC=1)=O)[CH2:5][C:6]([F:9])([F:8])[CH3:7].C([SiH](CC)CC)C>[Pd].CO>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH2:10])[CH2:5][C:6]([F:9])([F:8])[CH3:7]
Reactant: COC(=O)[C@H](CC(C)(F)F)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: CC[SiH](CC)CC
Solvent: CO
Product: COC(=O)[C@@H](N)CC(C)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
In a flask under argon was placed (S)-2-benzyloxycarbonylamino-4,4-difluoro-pentanoic acid methyl ester (626 mg, 2.08 mmol), methanol (8 mL) and 10% palladium on activated carbon (100 mg). Triethylsilane (3 mL) was added slowly and the mixture stirred at 25° C. for 30 min. Another portion of 10% palladium on activated carbon (100 mg) and triethylsilane (3 mL) was added and the mixture was stirred for 30 min. A third portion of 10% palladium on activated carbon (100 mg) and triethylsilane (3 mL) was added and the mixture was stirred for 30 min. The mixture was filtered to remove the catalyst and the solids washed with methanol. The filterate was concentrated in vacuo, azeotroped with toluene, dissolved in dichloromethane and concentrated in vacuo with silica gel (2 g). Purification by Biotage flash chromatography (Aspire 40 g column, 100% ethyl acetate) afforded (S)-2-amino-4,4-difluoro-pentanoic acid methyl ester (151 mg) as a clear colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[O:14][C:15]3[CH2:25][C:20]4(OCC[O:21]4)[CH2:19][CH2:18][C:16]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.C1COCC1.Cl.C(=O)([O-])O.[Na+]>O.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[O:14][C:15]3[CH2:25][CH:20]([OH:21])[CH2:19][CH2:18][C:16]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:11][CH2:12]1
Reactant: Clc1cc(-c2nc3c(o2)CC2(CC3)OCCO2)ccc1OCC1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: OC1CCc2nc(-c3ccc(OCC4CC4)c(Cl)c3)oc2C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
To 2-(3-chloro-4-(cyclopropylmethoxy)phenyl)-4,7-dihydro-5H-spiro[1,3-benzoxazole-6,2′-[1,3]dioxolane] (10.0 g) in a mixed solvent of THF (50 mL)-methanol (25 mL)-water (25 mL) was added 6 M hydrochloric acid (27.6 mL), and the mixture was stirred at 70° C. for 1 hr. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. To the organic layer was added sodium tetrahydroborate (1.05 g), and the mixture was stirred at room temperature for 20 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (6.61 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([OH:14])([CH3:13])[C:9]([F:12])([F:11])[F:10])[CH:5]=[N:6][CH:7]=1.[B:15]1(B2OC(C)(C)C(C)(C)O2)[O:19]C(C)(C)C(C)(C)[O:16]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C([O-])(=O)C.[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:10][C:9]([F:12])([F:11])[C:8]([C:4]1[CH:3]=[C:2]([B:15]([OH:19])[OH:16])[CH:7]=[N:6][CH:5]=1)([OH:14])[CH3:13]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: CC(O)(c1cncc(Br)c1)C(F)(F)F
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CC(O)(c1cncc(B(O)O)c1)C(F)(F)F
Temperature: 80 °C

Procedure:
A vial containing the title compound from Example 55 Step A [enantiomer B (0.647 g, 2.40 mmol)], bis(pinacolato)diboron (1.22 g, 4.79 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.439 g, 0.479 mmol), tricyclohexylphosphine (0.269 g, 0.958 mmol) and potassium acetate (0.705 g, 7.19 mmol) in 1,4-dioxane (12 mL) was flushed with nitrogen, sealed tightly and heated to 80° C. overnight. The reaction was then passed through a syringe filter and concentrated under reduced pressure to provide the title compound: LCMS m/z 235.95 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.CCN(CC)CC.[CH2:19]([NH2:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH:25][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CCCCCCN
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCCCNc1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Yield: 90.9 %

Procedure:
To a solution of 3,4-difluoronitrobenzene (3.18 g, 20 mmol) in EtOAc (50 mL) were added Et3N (2.43 g, 24 mmol) and hexan-1-amine (2.02 g, 20 mmol). The reaction mixture was refluxed overnight, then cooled to rt and concentrated in vacuo to give the title compound as yellow oil (4.37 g, 91%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[C:5]([S:16]([NH:19]C(C)(C)C)(=[O:18])=[O:17])=[CH:4][N:3]=1>FC(F)(F)C(O)=O>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[C:5]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:4][N:3]=1
Reactant: Cc1cccc(Nc2nc(N)ncc2S(=O)(=O)NC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(Nc2nc(N)ncc2S(N)(=O)=O)c1
Yield: 66.3 %

Procedure:
A solution of 2-amino-N-(1,1-dimethylethyl)-4-[(3-methylphenyl)amino]-5-pyrimidinesulfonamide (0.90 gm, 0.0027 mol) in trifluoroacetic acid (10 mL) was heated to reflux for 1 hour. After cooling, the solvent was evaporated in vacuo and the resulting solid triturated with ether to give 0.50 g, 67% of product, m.p. 213°-215° C., as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:4][C:3]=1[OH:14].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]1[C:31]2[C:26](=[N:27][CH:28]=[N:29][C:30]=2[Cl:32])[N:25]([CH3:33])[N:24]=1>CN(C)C=O>[Cl:32][C:30]1[N:29]=[CH:28][N:27]=[C:26]2[N:25]([CH3:33])[N:24]=[C:23]([CH2:22][O:14][C:3]3[CH:4]=[C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[N:9]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])[C:31]=12
Reactant: Cc1noc(-c2ccc(C)c(O)c2)n1
Reactant: Cn1nc(CBr)c2c(Cl)ncnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccc(C)c(OCc3nn(C)c4ncnc(Cl)c34)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-methyl-5-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenol (72.0 mg, 0.0.379 mmol) and potassium carbonate (64.2 mg, 0.455 mmole) in dimethylformamide was stirred at room temperature for 30 minutes before 3-bromomethyl-4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (89.8 mg, 0.280 mmol, Example 5) was added. The reaction was stirred at room temperature overnight and then concentrated under reduced pressure to remove dimethylformamide. The residue was dissolved in ethyl acetate, washed with water, dried and concentrated. The crude product was purified by flash chromatography (silica gel, hexanes-ethyl acetate, 90/10 to 60/40) to give pure 4-chloro-1-methyl-3-[2-methyl-5-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenoxymethyl]-1H-pyrazolo[3,4-d]pyrimidine as a white solid. (Yield 41.0 mg).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]1([CH2:15][C:16]([OH:18])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:19]1(=[O:24])[CH2:23][CH2:22][CH2:21][CH2:20]1.CCOC(C)=O>C1COCC1.CCCCCC.CCOC(C)=O.O>[OH:24][C:19]1([CH:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:16]([OH:18])=[O:17])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C1CCCC1
Reactant: O=C(O)Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)C(c1ccccc1)C1(O)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a dry 250 mL round bottom flask containing 2 M lithium diisopropyl amide in THF (2 eq.) in THF (164 mL) at 0° C., was added phenyl acetic acid (3.5 g, 25.71 mmol). The mixture was then stirred at ambient temperature for 30 minutes. The reaction mixture was cooled to −78° C. and cyclopentanone (commercially available from Sigma-Aldrich, Milwaukee, Wis.) (2.73 mL, 30.85 mmol, 1.2 eq.) in THF (90 mL) was added dropwise. The mixture was then stirred at −78° C. and allowed to warm to ambient temperature over 3 hours. The progress of the reaction was monitored by TLC (TLC eluent: 30% EtOAc in hexane). The reaction mixture was poured into an EtOAc/water mixture and the aqueous layer was extracted with EtOAc. The aqueous layer was then acidified with dilute hydrochloric acid and extracted with DCM. The DCM solution was washed with brine and then concentrated to provide the product. The product (3.5 g) thus obtained was used in the next step without any further purification.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:39]=[CH:40][C:41]=1[O:42]C(=O)C)[CH2:8][N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:12][CH:11]([NH:26][C:27]([C:29]2[NH:30][C:31]3[C:36]([CH:37]=2)=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])[C:10]1=[O:38])(=O)C.CO.C(=O)([O-])[O-].[K+].[K+].Cl>O.C(OCC)(=O)C.O1CCCC1>[OH:4][C:5]1[CH:6]=[C:7]([CH:39]=[CH:40][C:41]=1[OH:42])[CH2:8][N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:12][CH:11]([NH:26][C:27]([C:29]2[NH:30][C:31]3[C:36]([CH:37]=2)=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])[C:10]1=[O:38]
Reactant: CC(=O)Oc1ccc(CN2C(=O)C(NC(=O)c3cc4ccccc4[nH]3)N=C(c3ccccc3)c3ccccc32)cc1OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(NC1N=C(c2ccccc2)c2ccccc2N(Cc2ccc(O)c(O)c2)C1=O)c1cc2ccccc2[nH]1
Reaction time: 1 h
Yield: 62.8 %

Procedure:
A mixture of (3RS)-1-(3,4-diacetoxybenzyl)-1,3-dihydro-3-(2-indolylcarbonylamino)-5-phenyl-2H-1,4-benzodiazepine-2-one (287 mg), methanol (5 ml), tetrahydrofuran (5 ml), water (1 ml) and 1N aqueous potassium carbonate (5 ml) was stirred for 1.0 hour at 0°-5° C. and then adjusted to pH 1-2 with 6N hydrochloric acid. Ethyl acetate (50 ml) and water (50 ml) were added to the mixture under stirring. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel with an eluent of a mixture of chloroform and ethyl acetate (4:1) to give (3RS)-1-(3,4-dihydroxybenzyl)-3-(2-indolylcarbonylamino)-5-phenyl-2H-1,4-benzodiazepine-2-one (155 mg).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.Br[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]>C(Cl)Cl>[CH2:10]([O:9][C:7](=[O:8])[CH2:6][NH:4][CH:1]1[CH2:3][CH2:2]1)[CH3:11]
Reactant: NC1CC1
Reactant: CCOC(=O)CBr
Solvent: ClCCl
Product: CCOC(=O)CNC1CC1
Temperature: 25 °C

Procedure:
Cyclopropylamine (12.1 mL, 175 mmol) and TEA (42 mL, 385 mmol) were combined at 0° C. in 350 mL CH2Cl2, then ethyl bromoacetate (19.4 mL, 175 mmol) was added dropwise. The reaction was warmed to RT for 3 h, then diluted with additional CH2Cl2, washed with water, sat. NaHCO3, and brine, dried (Na2SO4), filtered and concentrated. Flash filtration (silica, 30% EtOAc/hexane) provided 7-2 as a light yellow oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:4]=[CH2:5].I[CH3:16]>O1CCCC1.O>[CH2:3]([O:6][N:7]([CH3:16])[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:4]=[CH2:5]
Reactant: CI
Reactant: C=CCONC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCON(C)C(=O)OC(C)(C)C
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 97.1 %

Procedure:
Sodium hydride (NaH, 60% dispersion in mineral oil; 390 mg, 9.7 mmol, 1.1 equiv) was added to a stirred solution of tert-butyl 2-propenyloxycarbamate (2.0 g, 8.8 mmol, 1.0 equiv) in tetrahydrofuran (THF; 23 mL) at 0° C. The resulting bubbling white mixture was warmed to 23° C. and stirred for 15 minutes (min). Iodomethane (660 μL, 11 mmol, 1.2 equiv) was added and the resulting colorless solution was stirred at 23° C. for 18 h. The reaction mixture was diluted with H2O (100 mL) and extracted with CH2Cl2 (3×75 mL). The combined organic layers were dried over magnesium sulfate (MgSO4), gravity filtered, and concentrated by rotary evaporation to afford a yellow oil (1.6 g, 99%): 1H NMR (300 MHz, CDCl3) δ 5.98 (m, 1H), 5.37-5.24 (m, 2H), 4.33 (dt, J=6, 1 Hz, 2H), 3.10 (s, 3H), 1.49 (s, 9H).
Reaction SMILES: [CH2:1](O)[C@H:2]1[O:7][C@H:6]([O:8][C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H:5](O)[C@@H:4](O)[C@@H:3]1O.P([O-])([O-])([O-])=O.[OH-].[K+]>CCCCCCCCCCCC>[C:6]([OH:7])(=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCCCCCCCC
Product: CCCCCCCCCCCC(=O)O
Temperature: 30 °C
Reaction time: 72 h

Procedure:
Components for the fermentation medium described in Example 1 as well as 50 g. sucrose were dissolved in 1 liter distilled water and adjusted to pH 5.5. Fifty milliliters of the medium were placed in a 500 ml shaking flask and inoculated with 2 loopsful of the Debaryomyces phaffii strain used in Example 1, and growth was maintained at 30° C. for 26 hours. The obtained culture broth was centrifuged in order to separate the cells (about 1 g dry weight). A reaction solution was prepared by mixing 100 ml of 0.5 M phosphate buffer (pH 7.0) with 10 ml of normal dodecane. A reaction was carried out between this reaction solution and the filtered cells at 30° C. for 72 hours. The reaction products were basified to pH 10 with potassium hydroxide and were analyzed using the same process as in Example 1. As a result, 5.3 mg/L of lauric acid and 4.1 mg/L of 1,10-decane dicarboxylic acids were produced in the reaction medium. For this experiment, the medium, substrate, and the equipment were autoclaved previously so that the experiment could be carried out under sterile conditions.