Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[C:8]([OH:12])([CH3:11])([CH3:10])[CH3:9].[NH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[C:23]([Br:24])=[CH:22][N:21]=[C:20]([NH:25][C:26]2[CH:27]=[C:28]([NH:32][C:33]([N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[O:34])[CH:29]=[CH:30][CH:31]=2)[N:19]=1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.ClCCl>[Cl:1][S:2](=[O:4])(=[O:3])[NH:5][C:6]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:7].[NH2:5][S:2]([NH:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[C:23]([Br:24])=[CH:22][N:21]=[C:20]([NH:25][C:26]2[CH:27]=[C:28]([NH:32][C:33]([N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[O:34])[CH:29]=[CH:30][CH:31]=2)[N:19]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)O
Reactant: NCCCNc1nc(Nc2cccc(NC(=O)N3CCCC3)c2)ncc1Br
Reactant: O=C=NS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Product: NS(=O)(=O)NCCCNc1nc(Nc2cccc(NC(=O)N3CCCC3)c2)ncc1Br
Temperature: 2.5 °C
Reaction time: 2.5 h
Yield: 50.8 %

Procedure:
Chloro[[(1,1-dimethylethoxy)carbonyl]amino]-sulfane dioxide was prepared by adding chlorosulfonyl isocyanate (32 mg, 0.23 mmol, 1.0 eq.) to a cooled solution of tert-butyl alcohol (17 mg, 0.23 mmol, 1.0eq.) and dichloromethane (2 mL) in an ice-water bath. The resulting mixture was stirred at 0-5° C. for 2-3 hr. The solution was then treated with a solution of N-(3-((4-((3-aminopropyl)amino)-5-bromo-2-pyrimidinyl)amino)phenyl)-1-pyrrolidinecarboxamide (100 mg, 0.20 mmol, 1eq.) and dichloromethane (5 mL). DMAP (20 mg, 0.16 mmol) was then added followed by the dropwise addition of DIEA (0.1 mL, 0.57 mmol). The mixture was stirred at RT for overnight. The reaction mixture was concentrated in vacuo. The residue was dissolved in TFA (2 mL), and purified by HPLC using acetonitrile/water to afford the title compound (30 mg).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].[CH2:10]([Br:13])[CH:11]=[CH2:12]>C(OCC)C>[Br-:13].[CH2:1]([N+:4]1([CH2:12][CH:11]=[CH2:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: C=CCN1CCCCC1
Solvent: CCOCC
Product: C=CC[N+]1(CC=C)CCCCC1
Product: [Br-]
Temperature: 5 °C
Reaction time: 24 h

Procedure:
213 9 of piperidine dissolved in 300 mL of diethyl ether and was added to a 1 L 3-necked round-bottomed flask. The mixture was cooled to 5° C. with an ice bath. While stirring, a solution of 151.2 g of allyl bromide in 60 mL of diethyl ether was added slowly to the piperidine solution. After addition was complete, the reaction mixture was allowed to stir at room temperature for 18 hours. The white precipitate formed was removed by filtration. Ether was removed from the filtrate at room temperature using a rotary evaporator. The residual liquid was fractionally distilled yielding 108 g of N-allylpiperidine. To a 500 mL 3-necked round-bottomed flask was added 40.1 9 of N-allylpiperidine dissolved in 50 mL of diethyl either. After cooling to 5° C. with an ice bath, a solution of 38.7 g of allyl bromide in 30 mL of diethyl ether was added slowly. After completion of addition of allyl bromide the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 24 hours. The solid residue thus formed was collected by filtration and was washed twice with 1.5 L of diethyl ether. The washed solid was dried under vacuum yielding 44 9 of N,N-diallylpiperidinium bromide as a white solid.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[H][H].[F:16][C:17]1[CH:29]=[CH:28][C:20]2[N:21](C)[C:22](=O)[O:23][C:24](=O)[C:19]=2[CH:18]=1.Cl>CC(N(C)C)=O>[CH2:6]([O:5][C:3]([C:2]1[C:1](=[O:9])[N:21]([CH3:22])[C:20]2[C:19]([C:24]=1[OH:23])=[CH:18][C:17]([F:16])=[CH:29][CH:28]=2)=[O:4])[CH3:7]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: [H][H]
Reactant: Cn1c(=O)oc(=O)c2cc(F)ccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(O)c2cc(F)ccc2n(C)c1=O
Temperature: 90 °C
Yield: 58.3 %

Procedure:
Neat diethyl malonate (1.27 g, 8.4 mmol) was added slowly to a suspension of sodium hydride (60% in mineral oil, 372 mg, 9.3 mmol) in dimethylacetamide under N2 atmosphere. The mixture was stirred at room temperature until the evolution of hydrogen gas ceased, then the mixture was heated to 90° C. for 30 min. and cooled to room temperature. A solution of Compound 38 (1.8 g, 9.3 mmol) in dimethylacetamide was added slowly and the mixture heated overnight at 120° C. The mixture was cooled to room temperature, poured into ice water, and acidified by cold 10% HCl. The solids formed were filtered and washed several times by water to yield 1.3 g (53%) of white solids. M.P. 131° C. 1H NMR (DMSO-d6): δ 1.30 (t, J=6.9 Hz, 3H), 3.54 (s, 3H), 4.31 (q, J=6.9 Hz, 2H), 7.56 (dd, J=4.6, 9.3 Hz, 1H), 7.64 (dd, J=2.9, 9.1 Hz, 1H), 7.76 (dd, J=2.9, 9.3 Hz, 1H), 12.80 (s, 1H). EIMS m/z 266 (M+1), 288 (M+23).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([OH:11])[CH2:7][S:8][C:9]=1[CH3:10])=[O:4].S(Cl)(Cl)(=O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:11])=[CH:7][S:8][C:9]=1[CH3:10])=[O:4]
Reactant: COC(=O)C1=C(C)SCC1O
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1c(O)csc1C
Yield: 75 %

Procedure:
17.4 Parts of 3-hydroxy-5-methyl-dihydrothiophene-4-carboxylic acid methyl ester are dissolved in 100 parts by volume of methylene chloride. 14.9 parts of sulfuryl chloride in 20 parts by volume of methylene chloride are added in the course of 30 minutes at 10° C., whilst passing nitrogen into the mixture. The end product is isolated from the reaction mixture by the method described in Example 1c. 12.9 parts (75% of theory) of 3-hydroxy-5-methyl-thiophene-4-carboxylic acid methyl ester of boiling point 67°-70° C./0.025 mbar are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:22](N)[CH2:23][NH2:24].[S]>O>[NH:5]1[CH2:22][CH2:23][N:24]=[C:4]1[C:3]1[C:2]([NH2:1])=[C:9]([O:10][CH3:11])[C:8]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[CH:7][CH:6]=1
Reactant: COc1c(OCCCN2CCOCC2)ccc(C#N)c1N
Reactant: NCCN
Agent: [S]
Solvent: O
Product: COc1c(OCCCN2CCOCC2)ccc(C2=NCCN2)c1N
Yield: 43 %

Procedure:
To a degassed mixture of 2-amino-3-methoxy-4-(3-morpholin-4-ylpropoxy)benzonitrile (6.5 g, 22.2 mmol) and ethylene diamine (40 mL) was added sulfur (1.8 g, 55.4 mmol). The mixture was stirred at 100° C. for 3 h at which time water was added to the reaction mixture. The precipitate that was formed was collected and washed with water and then dried overnight under vacuum to provide the title compound (3.2 g, 43%): HPLC MS RT=1.25 min, MH+=335.2; 1H NMR (DMSO-d6) δ: 7.15 (1H, d), 6.86 (2H, br s), 6.25 (1H, d), 4.02 (2H, t), 3.66 (3H, s), 3.57 (8H, m), 2.46 (2H, t), 2.44 (4H, m), 1.89 (2H, quint.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[CH3:20])[NH2:16]>>[F:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:17]=[CH:18][C:19]=1[CH3:20]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Cc1ccc(N)cc1F
Product: Cc1ccc(Nc2ccccc2CC(=O)O)cc1F

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3-fluoro-4-methylaniline to yield 2-[(3-fluoro-4-methylphenyl)amino]phenylacetic acid.
Reaction SMILES: [NH2:1][CH:2]([C:6]#[N:7])[C:3]([NH2:5])=[O:4].C[O-].[Na+].[C:11]([OH:14])(=O)C.[CH3:15][C:16]([CH:18]=O)=O>CO>[CH3:11][O:14][C:6]1[C:2]([C:3]([NH2:5])=[O:4])=[N:1][CH:15]=[C:16]([CH3:18])[N:7]=1
Reactant: CC(=O)C=O
Reactant: CC(=O)O
Reactant: N#CC(N)C(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(C)cnc1C(N)=O
Temperature: 20 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
Under argon, 6 g (60.5 mmol) of 2-amino-2-cyanoacetamide was initially charged in 67 g of methanol. 1.67 g (9.3 mmol) of sodium methoxide solution (30%) was added and the mixture was stirred for at 20° C. 2 hours. After nuetralization with 0.558 g (9.3 mmol) of acetic acid, 11.55 g (64.1 mmol) of methylglyoxal solution (40%) was added. The mixture was stirred at 20° C. for 2 hours and then at 50° C. for 2 hours. The solvent was distilled off and the 3-methoxy-5-methylpyrazine-2-carboxamide was purified by column chromatography (eluent: ethyl acetate/methanol 4:1). This gave 5 g of 3-methoxy-5-methylpyrazine-2-carboxamide. The yield was 50 percent. Other data concerning the title product was:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9].F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:12][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=2)[CH:5]=[N:6][C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1cnc(C(F)(F)F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=Cc1ccc(Oc2cnc(C(F)(F)F)c(Cl)c2)cc1
Temperature: 85 °C
Reaction time: 18 h
Yield: 7.3 %

Procedure:
5-Chloro-6-(trifluoromethyl)pyridin-3-ol (Preparation 83, 250 mg, 1.266 mmol) was added to a solution of 4-fluorobenzaldehyde (150 mg, 1.209 mmol) and potassium carbonate (260 mg, 1.881 mmol) in DMSO (5 mL). The mixture was stirred at 85° C. for 18 hours, then at 125° C. for 72 hours. The mixture was diluted with EtOAc (15 mL) and washed with water (2×10 mL). The organic layer was dried over sodium sulfate, filtrated and concentration in vacuo. The crude oil was purified by silica gel chromatography eluting with 0 to 20% EtOAc in heptane to yield the title compound as a yellow oil (26.5 mg, 70%):
Reaction SMILES: [OH:1][C@H:2]([C@@H:8]([NH:15][C:16]([O:18]C(C)(C)C)=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH:23]1[CH:24]=[CH:25][C:26]2N(O)N=[N:29][C:27]=2C=1.FC(F)(F)[C:35]([OH:37])=[O:36]>C(Cl)Cl>[C:35]([NH:29][C@H:27]([C:16]([NH:15][CH:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH:2]([OH:1])[CH2:3][C:4]([O:6][CH3:7])=[O:5])=[O:18])[CH2:26][CH2:25][CH2:24][CH3:23])([O:37][C:9]([CH3:14])([CH3:10])[CH3:8])=[O:36]
Reactant: On1nnc2ccccc21
Reactant: COC(=O)C[C@H](O)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)NC(c1ccccc1)C(O)CC(=O)OC
Reaction time: 0.25 h

Procedure:
In 10 ml of pure trifluoroacetic acid was dissolved at 0° C. 1 g (0.0032 mol) of methyl (3S,4S)-3-hydroxy-4-(N-BOC-amino)-4-phenylbutanoate partially in racemic form. After 15 min. at 0° C., the acid was rapidly evaporated off under reduced pressure wlthout heatlng. Then the vapor had disappeared, the salt so obtained was suspended in methylene chloride at 0° C. and therewere successively added 1.06 g (0.0032 mol) of BOC-Nle-ObSU, 0.620 g (0.004 mol) of HOBt and then a sufficient amount of NEM to bring the pH of the solution to 6-7. The reaction medium was heated to room-temperature in 2 h, while controling the pH, and then stirred for 12 to 15 h. The solvent was evaporated off at room-temperature using a Buchi evaporator and the peptide was extracted by means of ethyl acetate. The organic phase was then washed with 4 fractions of a dilute aqueous solution of sodium carbonate, 2 fractions of water, 4 fractions of a dilute aqueous solution of potassium hydrogenosulphate then with 2 fractions of water and only one fraction of an aqueous solution of sodium chloride. The medium was dried on magnesium sulphate and purified by chromatography on silicagel while eluting with a 1/1 mixture of methylene chloride/ethyl acetate. After triturating in an ethyl ether/hexane mixture, 0.629 g of methyl 4-(N-BOC-norleucylamino)-3-hydroxy-4-phenylbutanoate was obtained.
Reaction SMILES: [CH2:1]([N:9]1[C:18](=[O:19])[C:17]2[N:16]([CH3:20])[CH:15]=[N:14][C:13]=2[N:12]([CH3:21])[C:10]1=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].C[N+]1([O-])CC[O:26]CC1.[OH2:30].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)(C)(C)C.CC(C)=O.[Os](=O)(=O)(=O)=O>[OH:30][CH:7]([CH2:8][OH:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][N:9]1[C:18](=[O:19])[C:17]2[N:16]([CH3:20])[CH:15]=[N:14][C:13]=2[N:12]([CH3:21])[C:10]1=[O:11]
Reactant: O
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CC(C)=O
Product: Cn1cnc2c1c(=O)n(CCCCCCC(O)CO)c(=O)n2C
Yield: 63 %

Procedure:
A solution of 1-(7-octenyl)-3,7-dimethylxanthine (1.00 g, 4.5 mmol), 4-methylmorpholine-N oxide (553 mg, 4.7 mmol), and a 2.5% solution of osmium tetroxide in t-butanol (3 drops) in acetone (25 mL) and water (20 mL) was stirred for 4 days. After addition of a saturated aqueous solution of sodium hydrosulfite (10 mL) and 30 minutes of continued stirring, the reaction mixture was added to water (50 mL) and extracted with 20% ethanol/dichloromethane (3×50 mL). Evaporation of the solvent under vacuum yielded an off-white residue. The residue was recrystallized in ethanol, yielding 726 mg (63% yield) 1-(7,8-dihydroxyoctyl)-3,7-dimethylxanthine (inventive compound no. 1538) as a white solid.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[Cl:6][C:7]([C:13]([C:18]#N)=[CH:14][N:15](C)C)=[N:8][CH:9]=[N+:10]([CH3:12])[CH3:11].C1(C=CC=C(O)C=1O)[OH:21]>O.C(O)C>[Cl:6][C:7]([N:8]=[CH:9][N:10]([CH3:12])[CH3:11])=[C:13]([CH:18]=[O:21])[C:14]#[N:15]
Reactant: Oc1cccc(O)c1O
Reactant: CN(C)C=C(C#N)C(Cl)=NC=[N+](C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCO
Product: CN(C)C=NC(Cl)=C(C#N)C=O
Temperature: 0 °C
Yield: 8968.5 %

Procedure:
31.4 g of N-(3-chloro-4-cyano-5-dimethylamino-2-aza-2,4-pentadienylidene)-N,N-dimethyl ammonium perchlorate and 0.1 g of pyrogallol are stirred in a mixture of 140 ml of water and 200 ml of ethanol for one hour at 25° to 30° C. Precipitaion of reaction products is completed by addition of 500 g of ice. Vacuum filtration is then carried out. This is followed by washing with cold water. Drying is effected at 20°C over P2O5. 13.2 g (71.2%) of 3-chloro-5-dimethylamino-2-formyl-4-aza-2,4-pentadienenitrile, with a melting point of 145° to 147°C (with decomposition), are thus obtained in the form of pale needles.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:6]1)=[O:4].[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC.C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:23][C:22]3[CH:25]=[CH:26][C:19]([F:18])=[CH:20][CH:21]=3)=[CH:15][CH:16]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CC(=O)N(c2ccc(O)cc2)C1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)C1CC(=O)N(c2ccc(OCc3ccc(F)cc3)cc2)C1
Temperature: 90 °C
Reaction time: 3 h
Yield: 98.2 %

Procedure:
A solution of 5.0 g (21.3 mmol) of (RS)-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester [Example 2 b)] in 200 ml of 2-butanone is treated with 3.55 ml (27.6 mmol) of 4-fluorobenzyl-bromide and 5.88 g (42.5 mmol) of potassium carbonate and the mixture is stirred at 90° C. for 3 hours. For the working-up, the reaction mixture is diluted with ethyl acetate and extracted with water. The organic phase is separated, dried over sodium sulfate and evaporated under reduced pressure. For purification, the material obtained is chromatographed on silica gel using a 98:2-mixture dichloromethane and methanol as the eluent. There are obtained 7.18 g (98% of theory) of (RS)-1-[4-(4-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methyl ester as a white solid. MS: m/e=344 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@@H:28]([C:35]([CH3:37])=[CH2:36])[CH2:29][C:30]([O:32]CC)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].CCO.C1COCC1.[OH-].[Na+]>>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@@H:28]([C:35]([CH3:37])=[CH2:36])[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: C=C(C)[C@@H](CC(=O)OCC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: C=C(C)[C@@H](CC(=O)O)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Reaction time: 18 h
Yield: 74.8 %

Procedure:
To a stirred solution of 15.6 (0.044 g, 0.087 mmol) in EtOH (2.00 mL, 0.087 mmol) and THF (2.00 mL, 0.087 mmol) at 23° C. was added a solution of 1M sodium hydroxide (1.00 mL, 1.0 mmol). Stirring was continued for 18 hours. The resulting reaction was concentrated in vacuo. 1N HCl was added to pH 1, the resulting mixture was extracted EtOAc, dried over MgSO4, and concentrated. The crude product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford compound 15 (31 mg, 74% yield) as a colorless oil. MS ESI (neg.) m/e: 951.4 (2M−H)+, 475.1 (M−H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([Cl:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][O:25][C:26]1[C:31]([NH2:32])=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[NH2:32][C:31]1[CH:30]=[C:29]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([Cl:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)[CH:28]=[N:27][C:26]=1[O:25][CH3:24]
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N
Reactant: Cn1cc(-n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)c(Cl)n1
Product: COc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2Cl)c(=O)n4C)cc1N

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(3-chloro-1-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate K) and 2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-ylamine (Stage 89.1.1) to give the title compound as an off-white solid. (HPLC: tR 2.45 min (Method A); M+H=436 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.38 (s, 1H), 8.11-8.07 (m, 1H), 7.80-7.75 (m, 1H), 7.48-7.42 (m, 2H), 7.03-7.00 (m, 1H), 5.15-5.07 (s, br, 2H), 4.00 (s, 3H), 3.90 (s, 3H), 3.59 (s, 3H))
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:15]2[O:14][C:13]3[C:16]([CH:22]=[O:23])=[C:17]([OH:21])[CH:18]=[C:19]([CH3:20])[C:12]=3[C:11](=[O:24])[O:10][C:9]=2[C:8]([CH3:25])=[C:7]([OH:26])[CH:6]=1)=[O:4].[C:27]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:15]2[O:14][C:13]3[C:16]([CH:22]=[O:23])=[C:17]([OH:21])[CH:18]=[C:19]([CH3:20])[C:12]=3[C:11](=[O:24])[O:10][C:9]=2[C:8]([CH3:25])=[C:7]([O:26][CH3:27])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(O)c(C)c2c1Oc1c(C=O)c(O)cc(C)c1C(=O)O2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1cc(OC)c(C)c2c1Oc1c(C=O)c(O)cc(C)c1C(=O)O2
Yield: 84 %

Procedure:
1 mmol of 4-Formyl-3,8-dihydroxy-1,9-dimethyl-11-oxo-11H-dibenzo[b,e][1,4]dioxepine-6-carboxylic acid methyl ester was dissolved in 3 mL of acetone, 1 mmol K2CO3 was added and stirred for several minutes. Then, 1 mmol of CH3I in acetone was added from a pressure-equalizing dropping funnel. The reaction mixture was monitored by TLC. Upon completion, the reaction mixture was filtered to remove K2CO3 and evaporated by a rotatory evaporator to remove acetone. The residue was purified by column chromatography to give 4-formyl-3-hydroxy-8-methoxy-1,9-dimethyl-11-oxo-11H-dibenzo[b,e][1,4]dioxepine-6-carboxylic acid methyl ester (84%).
Reaction SMILES: [Cl:1][CH:2]([Cl:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]=[C:13]=[O:14])(=[O:11])=[O:10].[NH2:16][C:17]1[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[N:18]=1>C(#N)C>[Cl:15][CH:2]([Cl:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH:12][C:13]([NH:16][C:17]1[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[N:18]=1)=[O:14])(=[O:11])=[O:10]
Reactant: O=C=NS(=O)(=O)c1ccccc1C(Cl)Cl
Reactant: Cc1cc(C)nc(N)n1
Solvent: CC#N
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C(Cl)Cl)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-(Dichloromethyl)benzenesulfonyl isocyanate, prepared from 10 mmol of sulfonamide as described in the synthesis of Example 1, was treated with acetonitrile and 2-amino-4,6-dimethylpyrimidine (1.23 g). The mixture was stirred at room temperature for 18 hrs, cooled, and filtered to provide 1.08 g of white solid, mp 195°-197° (Dec).
Reaction SMILES: C([NH:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)[CH2:12][C:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1)C1C=CC=CC=1>C(O)C.C1COCC1.[Pd]>[NH2:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)[CH2:12][C:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)C1(Cc2cccc(NCc3ccccc3)c2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)C1(Cc2cccc(N)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6.98 g (22.43 mmol) of tert-butyl 1-[3-(benzylamino)benzyl]cyclopropanecarboxylate were dissolved in 50 ml of ethanol and 50 ml of THF, and 0.48 g (0.45 mmol) of palladium (10% on carbon) were added. At RT, the mixture was stirred under an atmosphere of hydrogen at atmospheric pressure for 2 h. The reaction mixture was then filtered off with suction through kieselguhr, the residue was washed with THF and the filtrate was concentrated. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 3.66 g (65.9% of theory) of the title compound.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:9]=[CH:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=1>C1COCC1>[OH:9][CH:10]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: Br[Mg]c1ccccc1
Reactant: COC(=O)Cc1cccc(CCCC=O)c1
Solvent: C1CCOC1
Product: COC(=O)Cc1cccc(CCCC(O)c2ccccc2)c1
Temperature: 23 °C

Procedure:
A 1.0 M solution of PhMgBr (1 equiv, 0.45 mmol) was added dropwise to a solution of methyl 2-(3-(4-oxobutyl)phenyl)acetate (1 equiv, 100 mg, 0.45 mmol) in THF (2 mL) at 0° C. The reaction was then allowed to warm to 23° C. over 1 h. The reaction was quenched by the addition on sat. aq. NH4Cl (10 mL). The aqueous phase was separated and extracted with EtOAc (2×5 mL). The organic layers were then combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 0-50% EtOAc in hexanes to afford methyl 2-(3-(4-hydroxy-4-phenylbutyl)phenyl)acetate in 78 mg (58%) as a clear translucent oil. LRMS: 298.4 (calc) 321.2 (found)(MH)+.