Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:15]=[CH:14][C:13]=1[F:25].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:15]=[CH:14][C:13]=1[F:25]
Reactant: CCOC(=O)CBr
Reactant: Cc1c(O)ccc(F)c1NCc1cc(-c2cccc(F)c2)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To a solution of 4-fluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]-2-methyl-phenol (200 mg, 0.58 mmol, 1.0 eq) in DMF (6 mL) was added Cs2CO3 (283 mg, 0.87 mmol, 1.5 eq). The reaction mixture was stirred for 1 h at room temperature, then ethyl 2-bromoacetate (117 mg, 0.70 mmol, 1.2 eq) was added. The reaction mixture was stirred for a further 1 h then poured into water and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography to give the title compound as an oil (200 mg, 80%).
Reaction SMILES: [Na].[Cl:2][C:3]1[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20](OC)=[O:21])[CH:14]=2)=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:24]([OH:27])([CH3:26])[CH3:25]>>[Cl:2][C:3]1[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]([O:27][CH:24]([CH3:26])[CH3:25])=[O:21])[CH:14]=2)=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: CC(C)O
Reactant: COC(=O)c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Agent: [Na]
Product: CC(C)OC(=O)c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A small piece of sodium was added to a solution of 4.0 g of 3-chloro-2-(4-chloro-3-methoxycarbonylphenyl)-5-trifluoromethylpyridine in 20 ml of anhydrous isopropanol, followed by stirring at 0° C. for 20 hours. The solvent was then removed. The residue was taken up in 50 ml of water. The aqueous phase was extracted three times with 50 ml of tert-butyl methyl ether each time. The combined organic phases were dried over sodium sulfate and concentrated. Yield: 2.5 g (58%) of a colorless oil;
Reaction SMILES: [C:1]([Si:5]([CH3:12])([CH3:11])[O:6][CH2:7][C@@H:8]1[CH2:10][O:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:13][C:14]1[CH:15]=[CH:16][C:17]2[O:22][CH2:21][C:20](=[O:23])[NH:19][C:18]=2[CH:24]=1>CC#N>[C:1]([Si:5]([CH3:12])([CH3:11])[O:6][CH2:7][C@@H:8]([OH:9])[CH2:10][NH:13][C:14]1[CH:15]=[CH:16][C:17]2[O:22][CH2:21][C:20](=[O:23])[NH:19][C:18]=2[CH:24]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc2c(c1)NC(=O)CO2
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CO1
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OC[C@@H](O)CNc1ccc2c(c1)NC(=O)CO2
Temperature: 50 °C
Reaction time: 6 h
Yield: 49.5 %

Procedure:
To a solution of tert-butyl-dimethyl-((S)-1-oxiranylmethoxy)-silane (commercial; 13.0 g, 69 mmol) in MeCN (220 mL) was added LiClO4 (22 g, 207 mmol). 6-amino-4H-benzo[1,4]oxazin-3-one (commercial; 11.45 g, 64 mmol) was added and the mixture was stirred at 50° C. for 6 h. The solvent was removed in vacuo and the residue was purified by CC (DCM/MeOH/NH4OH 1000/25/2 to 1000/100/2) to afford the title intermediate as a pale brown foam (11.16 g, 44% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH:15]=O.C([O-])(=O)C.[NH4+].[N+:22]([CH2:25][CH3:26])([O-:24])=[O:23]>>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH:15]=[C:25]([N+:22]([O-:24])=[O:23])[CH3:26]
Reactant: CC[N+](=O)[O-]
Reactant: COc1cc(C=O)c(OC)c2ccccc12
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1cc(C=C(C)[N+](=O)[O-])c(OC)c2ccccc12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Step A (0.8 g, 2.93 mmol) in nitroethane (10 mL) was added ammonium acetate (0.45 g, 5.84 mmol). The mixture was stirred at 60° C. overnight. The excess nitroethane was removed and the residue purified by flash chromatography (silica gel, ethyl acetate/hexane: 0.5/9.5) to give 0.5 g of a yellow solid: 1H NMR (DMSO-d6) δ 2.45 (s, 3H, CH3), 3.84 (s, 3H, OCH3), 4.00 (s, 3H, OCH3), 6.95 (s, 1H, Ar—H), 7.65 (m, 2H, Ar—H), 8.10 (m, 2H, Ar—H), 8.29 (s, 1H, CH═).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([F:23])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([N+:12]([O-])=O)[CH:6]=1.O.Cl>C(O)(C)C>[Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([F:23])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([NH2:12])[CH:6]=1
Reactant: Cc1ccc(Oc2c(F)cc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: Cc1ccc(Oc2c(F)cc(C(F)(F)F)cc2Cl)cc1N
Yield: 78.5 %

Procedure:
4-(2-Chloro-6-fluoro-4-trifluoromethylphenoxy)-2-nitrotoluene (5.57 g) and reduced iron powder (9.7 g) were suspended in isopropanol (73 cm3) and water (16 cm3) and concentrated hydrochloric acid (0.83 cm3) added. The mixture was stirred under reflux for 7 hours, cooled slightly and filtered through Hyflo. The filter pad was washed through with hot ethanol. The combined filtrate was evaporated to dryness, dissolved in ethyl acetate and washed with brine. The organic phase was dried (MgSO4), filtered and the filtrate evaporated to dryness to give a brown oil which was purified by flash chromatography (CHCl3) to give 4-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)-2-aminotoluene (4 g) as a pale brown oil. M+ =320
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9](=[O:18])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].C(OCC)(=O)C>[C:12]1([CH2:11][CH2:10][C:9](=[O:18])[CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(CCc1ccccc1)CCc1ccccc1
Yield: 80 %

Procedure:
1,5-Diphenyl-1,4-pentadien-3-one (20b, 1.00 g, 4.3 mmol) and palladium on activated carbon (0.25 g, 5%) were combined in ethyl acetate (50 ml). The mixture was placed under a hydrogen atmosphere (60 psi) on a Parr apparatus for 2 hr at room temperature. The resulting mixture was filtered through celite and the solvent evaporated to afford an oil. The crude oil was chromatographed on silica gel with ethyl acetate/hexane to give 0.82 g (80%) of a clear oil; 1H NMR: δ 2.76 (t, 4H, J=7.6 Hz), 2.97 (t, 4H, J=7.4 Hz), 7.30 (m, 10H); 13C NMR: δ 29.6, 44.2, 125.8, 128.0, 128.2, 140.7, 208.4.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:9]=[CH:8][NH:7][N:6]=1)([CH3:4])[CH3:3].[H-].[Na+].CS(O)(=O)=O.O[CH:18]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[C:19]1=[O:33].O>CN(C)C=O>[CH3:1][C:2]([C:5]1[CH:9]=[CH:8][N:7]([CH:18]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=3)[C:19]2=[O:33])[N:6]=1)([CH3:4])[CH3:3]
Reactant: O=C1C(O)CCN1c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)c1cc[nH]n1
Agent: CS(=O)(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccn(C2CCN(c3cccc(C(F)(F)F)c3)C2=O)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-(1,1-dimethylethyl)1H-pyrazole (0.22 g, 1.8 mmol) in N,N-dimethylformamide (20 mL) under nitrogen at room temperature was added 60% sodium hydride in mineral oil (90 mg, 2.16 mmol). After the addition, the mixture was stirred at room temperature for ˜15 minutes, and 3-hydroxy-1-[3-(trifluoromethyl)phenyl]-2-pyrrolidinone methanesulfonate (0.5 g, 1.8 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight and then poured into water (˜100 mL). The aqueous layer was extracted twice with ethyl acetate (˜30 mL each; brine solution was added to separate the two layers). The organic extracts were combined, dried over MgSO4 and filtered. The filtrate was concentrated and the residue purified by column chromatography (silica gel, ˜20% ethyl acetate/80% hexanes) to give the title compound, a compound of this invention, as a yellow solid (300 mg) melting at 76–78° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]=[C:10]([C:13]([OH:15])=[O:14])[CH:9]=[CH:8]2.C(N(CC)CC)C.[C:23]([O:27][C:28](ON=C(C1C=CC=CC=1)C#N)=[O:29])([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[C:28]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]=[C:10]([C:13]([OH:15])=[O:14])[CH:9]=[CH:8]2)([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29]
Reactant: NCc1cccc2ccc(C(=O)O)cc12
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1cccc2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 68 %

Procedure:
Part D--A solution of 8-aminomethyl-2-naphthoic acid (0.50 g, 0.00025 mol) and triethylamine (0.038 mL, 0.028 g, 0.000275 mol) in aqueous tetrahydrofuran (50%, 5 mL) was added, portionwise as a solid, 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (0.068 g, 0.000275 mol). All was stirred at ambient temperature over 5 hours. The solution was concentrated to half volume and extracted with diethylether. The aqueous layer was then acidified to a pH of 1.0 using hydrochloric acid (1N) and then extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure to give the title compound, N-(BOC)-8-aminomethyl-2-naphthoic acid (0.050 g, 0.00017 mol) as a white solid. mp=190°-191° C.; 1H NMR (DMSO) d 13.1 (bs, 1H), 8.8 (s, 1H), 8.0 (q, 2H, J=7.9 Hz), 7.9 (d, 1H, J=8.1 Hz), 7.6 (t, 1H, J=7.5 Hz), 7.65-7.55 (m, 2H), 4.6 (d, 2H, J=5.5 Hz), 1.4 (s, 9H).
Reaction SMILES: [O:1]=[C:2]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C([O-])(=O)C.[Na+].[Cl:18][C:19]1[CH:20]=[C:21]([N+:26]#[N:27])[CH:22]=[CH:23][C:24]=1[Cl:25]>C(O)C.O>[Cl:18][C:19]1[CH:20]=[C:21]([NH:26]/[N:27]=[C:8](\[C:2](=[O:1])[CH2:3][C:4]([O:6][CH3:7])=[O:5])/[C:9]([O:11][CH3:12])=[O:10])[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: N#[N+]c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)CC(=O)CC(=O)OC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)CC(=O)/C(=N\Nc1ccc(Cl)c(Cl)c1)C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a mixture of dimethyl 3-oxopentanedioate (3.48 g, 20 mmol) in ethanol (12 mL) and water (40 mL) at room temperature was added sodium acetate (12.0 g, 146 mmol), and was followed by the addition of 3,4-dichlorobenzenediazonium solution (20 mmol). The resulting reaction mixture was stirred at room temperature for 1 h. The product was collected by filtration, then washed with water (˜50 mL) and dried overnight under reduced pressure to yield 6.776 g (93%) of (E)-dimethyl 2-(2-(3,4-dichlorophenyl)hydrazono)-3-oxopentanedioate as a yellow solid. MS (ESI) 347 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[C:10]1([CH3:20])[C:11]([C:16]([NH:18][NH2:19])=[O:17])=[CH:12][CH:13]=[CH:14][CH:15]=1>C(O)C>[N:7]1[CH:8]=[CH:9][C:4]([C:1](=[N:19][NH:18][C:16](=[O:17])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH3:20])[CH3:2])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccncc1
Reactant: Cc1ccccc1C(=O)NN
Solvent: CCO
Product: CC(=NNC(=O)c1ccccc1C)c1ccncc1
Temperature: 25 °C
Yield: 62.9 %

Procedure:
A mixture of 3.63 gm (0.03 mole) of 4-acetylpyridine, 4.51 gm (0.03 mole) of o-toluic acid hydrazide and 100 ml of 95% ethanol is refluxed 8 hr. The hot solution is filtered. The filtrate is diluted with water to the cloud point and cooled to room temperature. The mixture is chilled in the refrigerator and the product collected, washed with water, and dried to yield 4.78 gm (63%) of the title compound having a melting point of 187.4° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Br:14]N1C(=O)CCC1=O>N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1cccc(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)Cc1cccc(CBr)c1
Temperature: 90 °C
Reaction time: 5 h
Yield: 59 %

Procedure:
Ethyl (3-methylphenyl)acetate (5.36 g) was mixed with carbon tetrachloride (80 ml), followed by heating at 90° C. N-Bromosuccinimide (5.62 g) and α,α′-azobisisobutyronitrile (250 mg) were added thereto, followed by stirring at 90° C. for 5 hours. The reaction mixture was cooled to room temperature, and then the solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain ethyl [3-(bromomethyl)phenyl]acetate (4.56 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14](=O)[C:5]=2[CH2:4][O:3]1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:14]1[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=[C:6]2[C:2]([CH3:16])([CH3:1])[O:3][CH2:4][C:5]=12
Reactant: CC1(C)OCc2c1[nH]c1ccccc1c2=O
Reactant: O=P(Cl)(Cl)Cl
Product: CC1(C)OCc2c1nc1ccccc1c2Cl
Temperature: 0 °C

Procedure:
A solution of the compound of formula VI, 3,4-dihydro-3,3-dimethylfuro[3,4-b]quinolin-9(1H)-one (6.5 g, described in Example 8), in phosphorus oxychloride (26 ml) is stirred vigorously at room temperature for one hour. The solution is added to 340 ml of crushed ice. The mixture is stirred and the precipitate is removed by filtration. The filtrate is diluted with ice-water (600 ml) and made alkaline with 30% sodium hydroxide solution (75 ml). The precipitate is collected and crystallized from petroleum ether to give the title compound, mp 108°-110° C. The hydrochloride salt of the title compound melts at 189°-194° C.
Reaction SMILES: [C:1]([O:4][CH:5]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]=[CH:19][O:20][CH3:21])=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=O)C.CS(O)(=O)=O.[C:27](=O)(O)[O-:28].[Na+]>CO>[CH3:21][O:20][CH:19]([O:28][CH3:27])[CH2:18][C:15]1[CH:16]=[CH:17][C:12]([CH:5]([O:4][CH3:1])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:13][CH:14]=1
Reactant: O=C([O-])O
Reactant: COC=Cc1ccc(C(OC(C)=O)c2ccccc2)cc1
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: CO
Product: COC(Cc1ccc(C(OC)c2ccccc2)cc1)OC

Procedure:
By the method of example 48, 1-bromo-4-(2-methoxyethenyl)benzene is lithiated and added to benzaldehyde. The crude product is acetylated with acetic anhydride in the presence of DMAP, providing alpha-(4-(2-methoxyethenyl)phenyl)benzyl acetate as a colorless oil. This ester (1.76 g) is treated with methanesulfonic acid (0.5 ml) in methanol (25 ml) at 50° for 16 hr. The acetoxy group and the enol ether are both solvolyzed in this reaction. The mixture is cooled, poured into saturated aqueous sodium bicarbonate, and extracted with three portions of ether, which are dried and evaporated to leave 1-(2,2-dimethoxyethyl)-4-((methoxy)(phenyl)methyl)benzene as a colorless oil (1.62 g). The methoxy group is hydrogenolyzed by dissolving this material in ethyl acetate (100 ml), and shaking with 10% Pd/C under 50 psi hydrogen for 60 hr. Filtration and evaporation provide 1-(2,2-dimethoxyethyl)-4-(phenylmethyl)benzene as a colorless oil (1.46 g). By the method of example 1(B&C), this is converted into the title compound, which is obtained as a pale yellow solid, mp 148°-150° after recrystallization from hexaneethyl acetate.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH:35]([CH3:37])[CH3:36]>CN(C)C=O>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH:35]([CH3:37])[CH3:36])[C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:30])(=[O:31])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1c(C(=O)N2CCS(=O)(=O)CC2)cc2cc(C(=O)N3CCN(C4CCC4)CC3)ccc21
Yield: 49 %

Procedure:
The title compound was synthesized in analogy to example 51, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone (example 202), sodium hydride and 2-bromopropane in N,N-dimethylformamide, to give the desired product as a light brown foam (49%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:29])[C:9]1[S:13][C:12]([NH:14][C:15]([C:17]2([C:20]3[CH:28]=[CH:27][C:23]4[O:24][CH2:25][O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]2)=[O:16])=[N:11][CH:10]=1.[C:30]1(C)C=CC(S(O)(=O)=O)=CC=1.CO>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:29][CH3:30])[C:9]1[S:13][C:12]([NH:14][C:15]([C:17]2([C:20]3[CH:28]=[CH:27][C:23]4[O:24][CH2:25][O:26][C:22]=4[CH:21]=3)[CH2:18][CH2:19]2)=[O:16])=[N:11][CH:10]=1
Reactant: O=C(Nc1ncc(C(O)c2ccccc2Cl)s1)C1(c2ccc3c(c2)OCO3)CC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(c1cnc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)s1)c1ccccc1Cl

Procedure:
1-Benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid [5-[(2-chloro-phenyl)-hydroxy-methyl]-thiazol-2-yl]-amide (25 mg, 0.058 mmol) was placed in 1 mL of toluene with p-toluenesulfonic acid (14 mg, 0.073 mmol). Methanol (3.0 L, 0.075 mmol) was added and the solution was subjected to microwave irradiation for 5 minutes at 150° C. The mixture was then evaporated to dryness and purified by reverse-phase preparative liquid chromatography to yield the pure product. (6.0 mg, 0.013 mol, 22%). ESI-MS m/z calc. 515.1. found; 443.3 (M+1)+ Retention time 3.72 minutes. 1H NMR (400 MHz, CD3CN) δ 1.23-1.30 (m, 2H), 1.56-1.67 (m, 2H), 3.38 (s, 3H), 5.88 (s, 1H), 5.99 (s, 2H), 6.84 (d, J=6.2 Hz, 1H), 6.92-6.98 (m, 2H), 7.26 (s, 1H), 7.33-7.38 (m, 1H), 7.41-7.48 (m, 2H), 7.62-7.71 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.[C:21]([O:25][C:26](=[O:31])[NH:27][CH2:28][CH2:29]Br)([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C(=O)C>[C:21]([O:25][C:26](=[O:31])[NH:27][CH2:28][CH2:29][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: COc1cccc(-c2[nH]c(=O)c3ccccc3c2O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cccc(-c2[nH]c(=O)c3ccccc3c2OCCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.9 %

Procedure:
To a solution of 3.79 g (14.19 mmol) of 4-hydroxy-3-(3-methoxy-phenyl)-2H-isoquinolin-1-one in N,N-dimethylacetamide (90 mL), 3.18 g (14.19 mmol) of (2-bromo-ethyl)-carbamic acid tert-butyl ester and 5.09 g (15.6 mmol) of cesium carbonate were added and the resulting mixture was stirred at room temperature for 2 hours under argon. Water was added to the reaction mixture and this was extracted twice with ethyl acetate. The combined organic layers were washed at least three times with water and then evaporated to dryness. The crude was purified by flash chromatography (eluant: ethyl acetate/hexane 1/1) to afford 3.2 g of the title compound (55%).
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([NH:9][C:10](=[O:18])OC3C=CC=CC=3)[N:6]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:5]=2)[CH2:3][CH2:2]1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][N:31]=[C:30]2[S:39][C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43].O>CS(C)=O>[CH:1]1([C:4]2[CH:8]=[C:7]([NH:9][C:10]([NH:43][C:42]3[CH:44]=[CH:45][CH:46]=[C:40]([S:39][C:30]4[C:29]5[C:34](=[CH:35][C:36]([O:37][CH3:38])=[C:27]([O:26][CH3:25])[CH:28]=5)[N:33]=[CH:32][N:31]=4)[CH:41]=3)=[O:18])[N:6]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: O=C(Nc1cc(C2CC2)nn1-c1ccccc1)Oc1ccccc1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C5CC5)nn4-c4ccccc4)c3)c2cc1OC
Temperature: 40 °C
Yield: 47 %

Procedure:
A stirred mixture of phenyl 3-cyclopropyl-1-phenyl-1H-pyrazol-5-ylcarbamate as described in Example 353A (250 mg, 0.78 mmol) and 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (prepared as described in Example 115B) (200 mg, 0.64 mmol) in DMSO (1 mL) was heated to 40° C. for 48 h. After cooling to rt, water (20 mL) was added. The resulting suspension was filtered and the collected solid purified via preparative silica gel thin-layer chromatography (eluting with a mixture of 10:10:1 ethyl acetate:dichloromethane:methanol) to give a solid which was triturated with diethyl ether (50 mL) to afford 1-(3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea (162 mg, 47%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.68 (s, 1H), 8.49 (s, 1H), 7.77 (s, 1H), 7.22-7.51 (m, 10H), 6.15 (s, 1H), 3.99 (s, 6H), 1.86 (m, 1H), 0.85-0.91 (m, 2H), 0.65-0.68 (m, 2H); LC-MS (ESI) m/z 539 (M+H)+.
Reaction SMILES: [NH:1]([CH3:13])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O)CCC.[OH-].[Na+].C(O[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(C)(C)C>O>[CH3:31][C:28]([O:27][C:26]([N:1]([C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:13])=[O:32])([CH3:29])[CH3:30]
Reactant: CN[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Product: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3.6 g of H-MePhe-OH are dissolved in a mixture of ter.-butanol, 25 ml of 10% aqueous KHCO3 solution and 5 ml of 4 N sodium hydroxide. 8 ml of di-tert.-butylcarbonate are added and the mixture stirred for 2 days at room temperature. The reaction mixture is diluted with ca. 100 ml of water and extracted with ether. The aqueous phase is acidified, with stirring to pH 2. The precipitated product is extracted with acetic acid, the extract washed with water and dried over Na2SO4. The liquid is evaporated and the product crystallised from ether/petroleum ether to yield Boc-MePHe-OH. M.P. 87°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH2:9][OH:10])[CH:3]=1.[Mn]([O-])(=O)(=O)=[O:12].[K+]>O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([OH:12])=[O:10])[CH:3]=1
Reactant: Cc1cc(C)nc(CO)c1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc(C)nc(C(=O)O)c1
Temperature: 2.5 °C
Yield: 122.3 %

Procedure:
4,6-Dimethyl-2-pyridinemethanol (7.5 g, 29.2 mmol) was added to 100 mL of water and stirred at 0-5° C. A solution of 5.3 g (32.1 mmol) of potassium permanganate in 100 mL of water was added portion-wise over 30 min while maintaining the temperature at 5-10° C. This resulted in the formation of a black solid. The mixture was stirred at 5-10° C. for an additional 30 min and then allowed to stir at room temperature for 30 min. The mixture was filtered and the manganese dioxide washed with methanol. The methanol washings were combined with the water extracts and the solvent was removed. The resulting tan solid was redissolved in water and washed with chloroform. The water layer was separated and the water removed to yield 5.4 g of 4,6-dimethyl-2-pyridinecarboxylic acid. The product was characterized by HPLC/MS.