Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[OH:23][C@@H:24]([CH:28]([CH3:30])[CH3:29])[C:25](O)=[O:26]>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][C:25](=[O:26])[CH:24]([OH:23])[CH:28]([CH3:30])[CH3:29])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Reactant: CC(C)[C@H](O)C(=O)O
Product: CCCC(NC(=O)C(O)C(C)C)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was coupled with (S)-2-hydroxy-3-methyl-butyric acid to afford the title compound:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([OH:29])=O)([CH3:26])[CH3:25])[CH2:14][C:13](=[O:30])[NH:12][CH:11]3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:5]2=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:70][O:71][NH3+:72].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27](=[O:29])[NH:72][O:71][CH3:70])([CH3:26])[CH3:25])[CH2:14][C:13](=[O:30])[NH:12][CH:11]3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CO[NH3+]
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CONC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.6 %

Procedure:
To a mixture of racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (30 mg, 0.05 mmol), EDCI (20 mg, 0.1 mmol), HOBt (16 mg, 0.1 mmol) and DIPEA (40 mg, 0.3 mmol) in THF (1 mL) was added o-methylhydroxylamine hydrochloride (22 mg, 0.25 mmol). The mixture was stirred at room temperature overnight and purified by prep-HPLC to give the title compound as a white solid (11 mg).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](Cl)=[O:9])(=[O:4])=[O:3].[CH2:14]1[NH:19][CH2:18][CH2:17][N:16]2[CH2:20][CH2:21][CH2:22][C@@H:15]12.[F:23][C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26]>ClCCl>[F:23][C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH:26][S:2]([C:5]1[CH:13]=[CH:12][CH:11]=[C:7]([C:8]([N:19]2[CH2:18][CH2:17][N:16]3[CH2:20][CH2:21][CH2:22][C@H:15]3[CH2:14]2)=[O:9])[CH:6]=1)(=[O:4])=[O:3]
Reactant: C1C[C@H]2CNCCN2C1
Reactant: Nc1ccccc1F
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Product: O=C(c1cccc(S(=O)(=O)Nc2ccccc2F)c1)N1CCN2CCC[C@H]2C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 3-(chlorosulfonyl)benzoyl chloride (0.521 g, 2.18 mmol) in anhydrous dichloromethane (10 mL) was added (S)-octahydropyrrolo[1,2-α]pyrazine (0.250 g, 1.98 mmol) in dichloromethane (4 mL) slowly over 10 minutes at room temperature. The mixture was stirred at room temperature for 5 hours. Then 2-fluoroaniline (1.54 g, 13.87 mmol) was added. The mixture was stirred at room temperature overnight and then concentrated. The residue was purified by chromatography on silica gel (dichloromethane, then methanol/dichloromethane=1:10) to give the titled compound.
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH2:12][C@@H:13]([CH3:23])[C:14]([O:16][CH2:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:15].[P:24](Cl)(Cl)(=[O:36])[O:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1.C(Cl)[Cl:40]>>[Cl:40][C:27]1[CH:28]=[CH:29][C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:26]=1[O:25][P:24](=[N:12][C@@H:13]([CH3:23])[C:14]([O:16][CH2:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])=[O:36]
Reactant: O=P(Cl)(Cl)Oc1cccc2ccccc12
Reactant: C[C@H](N)C(=O)OCCC(C)(C)C
Reactant: ClCCl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: C[C@H](N=[P+]([O-])Oc1c(Cl)ccc2ccccc12)C(=O)OCCC(C)(C)C
Yield: 91 %

Procedure:
Using the general procedure for synthesizing naphthyl (aminoacid ester) phosphorochloridates the tosylate salt of (S)-3,3-dimethylbutyl 2-aminopropanoate (2.00 g, 5.79 mmol), naphthalen-1-yl phosphorodichloridate (1.51 g, 5.79 mmol) and TEA (1.61 mL, 11.58 mmol) in 30 mL of dry DCM, were combined to give (2S)-3,3-dimethylbutyl 2-(chloro(naphthalen-1-yloxy)phosphorylamino)propanoate in 91% yield (2.10 g), as a clear, yellow, thick oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7](Cl)=[O:8].[NH2:14][C:15]1[CH:37]=[CH:36][C:18]([C:19]([N:21]2[CH2:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[CH2:24][C:23]3[CH:32]=[CH:33][CH:34]=[CH:35][C:22]2=3)=[O:20])=[CH:17][CH:16]=1>>[CH:32]1[C:23]2[CH2:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[CH2:27][N:21]([C:19]([C:18]3[CH:17]=[CH:16][C:15]([NH:14][C:7]([C:6]4[S:5][C:4]5[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=5[C:2]=4[Cl:1])=[O:8])=[CH:37][CH:36]=3)=[O:20])[C:22]=2[CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1sc2ccccc2c1Cl

Procedure:
As described for Example 9, 3-chlorobenzo[b]-thiophene-2-carbonyl chloride is reacted with 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine to give the product. Recrystallization from dichloro-methane-hexane gives crystals, m.p. 252°-254° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[CH3:17][C:18]([C:20]1[O:24][C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[C:21]=1[CH3:29])=[O:19].[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]\[C:33]([OH:35])=[O:34].C([O:41][CH2:42][CH3:43])(=O)C>>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]\[C:33]([OH:35])=[O:34].[CH3:17][C:18]([C:20]1[O:24][C:23]2[CH:25]=[CH:26][CH:27]=[C:28]([O:34][CH2:33][C@@H:42]([OH:41])[CH2:43][N:14]3[CH2:15][CH2:16][CH:11]([C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH:1]=4)[CH2:12][CH2:13]3)[C:22]=2[C:21]=1[CH3:29])=[O:19]
Reactant: CCOC(C)=O
Reactant: CC(=O)c1oc2ccccc2c1C
Reactant: c1ccc2cc(C3CCNCC3)ccc2c1
Agent: O=C(O)/C=C\C(=O)O
Product: CC(=O)c1oc2cccc(OC[C@@H](O)CN3CCC(c4ccc5ccccc5c4)CC3)c2c1C

Procedure:
By the reactions in the same manner as in Example 3 using (S)-4-glycidyloxy-3-methylbenzo(b)furan-2-yl methyl ketone (0.60 g) obtained in Starting Material Synthesis Example 72 and 4-(naphthalen-2-yl)piperidine (0.51 g), (S)-4-(2-hydroxy-3-(4-naphthalen-2-yl)piperidino)propyloxy)-3-methylbenzo(b)furan-2-yl methyl ketone (1.1 g) was obtained as a brown oil. This was dissolved in ethyl acetate and maleic acid (0.25 g) was added. The precipitated crystals were recrystallized from a mixed solvent of isopropanol-ethyl acetate to give the title compound (0.82 g) as pale-yellow crystals, melting point 163–164° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH:8]([CH2:13][C:14]([OH:16])=[O:15])[CH2:7]1.Cl.[CH3:22]O>>[CH3:22][O:15][C:14](=[O:16])[CH2:13][CH:8]1[C:9](=[O:12])[CH2:10][CH2:11][N:6]([CH2:5][C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]=2[Cl:2])[CH2:7]1
Reactant: O=C(O)CC1CN(Cc2ccccc2Cl)CCC1=O
Reactant: CO
Agent: Cl
Product: COC(=O)CC1CN(Cc2ccccc2Cl)CCC1=O

Procedure:
A solution of 30 g. of this hydrochloride in 300 cc. methanol saturated with gaseous hydrogen chloride is stirred at ambient temperature for 3 hours. The reaction mixture is then evaporated in a vacuum at a temperature below 50° C. and the residue is poured into water, rendered basic by the addition of sodium bicarbonate and extracted with methylene chloride. The organic extracts are washed with water, dried with anhydrous sodium sulphate and evaporated to dryness. The yellow resin obtained is used, without further purification, for the following stage.
Reaction SMILES: [CH3:1][C:2]1([CH2:5][C:6]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:11][C:10](=[O:12])[N:9]([C:13]([C:16]3[N:17]=[N:18][N:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:20]=3)([CH3:15])[CH3:14])[CH2:8][CH2:7]2)[CH2:4][O:3]1.O.OO.[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1>[OH:3][C:2]([CH3:4])([CH3:1])[CH2:5][C:6]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:11][C:10](=[O:12])[N:9]([C:13]([C:16]2[N:17]=[N:18][N:19]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:20]=2)([CH3:15])[CH3:14])[CH2:8][CH2:7]1
Reactant: CC1(CC2(c3ccccc3)CCN(C(C)(C)c3cn(-c4ccccc4)nn3)C(=O)O2)CO1
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)CC1(c2ccccc2)CCN(C(C)(C)c2cn(-c3ccccc3)nn2)C(=O)O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
A stirred solution of crude 6-((2-methyloxiran-2-yl)methyl)-6-phenyl-3-(2-(1-phenyl-1H-1,2,3-triazol-4-yl)propan-2-yl)-1,3-oxazinan-2-one (8.4 mg, 0.018 mmol) in dry THF (1 mL) was cooled in an ice bath and 1 M LiEt3BH in THF (0.1 mL, 0.1 mmol) was added. The mixture was stirred for 45 min in the ice bath. Water (1 mL) and 30% H2O2 (0.2 mL) were added. The mixture was stirred for 0.5 h and solid Na2S2O3 (˜200 mg) was added. The mixture was stirred for 0.5 h and applied to a 10-mL ChemElut cartridge. The cartridge was eluted with EtOAc (50 mL) and the eluate was concentrated to leave a residue which was purified by prep HPLC to afford the title compound (2.5 mg, 42% over 2 steps). LC-MS Method 1 tR=1.57 min, m/z=435.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:18](=[O:20])[CH3:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(N)cc1Cl
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(C)=O)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
A solution of 3-chloro-4-methoxyphenylamine (6.3 g) and triethylamine (4.04 g) in dichloromethane (100 mL) was chilled in an ice bath, acetyl chloride (3.45 g) was added dropwise and the mixture was stirred at ambient temperature overnight. The reaction mixture was extracted with water (2×30 mL) and brine (2×30 mL) and the organic layer was dried with magnesium sulfate. The drying agent was removed by filtration and the filtrate was evaporated to give N-(3-chloro-4-methoxyphenyl)acetamide (7.45 g) as a dark oil, which solidified on standing. MS: 200 (M+H)+.
Reaction SMILES: [NH2-].[Na+].Cl[C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[C:6]([CH3:11])[N:5]=1.[NH2:12][C:13]1[S:14][C:15]([C:18]([NH:20][C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:28])=[O:19])=[CH:16][N:17]=1.Cl>O.C1COCC1>[Cl:10][C:8]1[N:7]=[C:6]([CH3:11])[N:5]=[C:4]([NH:12][C:13]2[S:14][C:15]([C:18]([NH:20][C:21]3[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:28])=[O:19])=[CH:16][N:17]=2)[CH:9]=1
Reactant: Cc1cccc(Cl)c1NC(=O)c1cnc(N)s1
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(Cl)cc(Nc2ncc(C(=O)Nc3c(C)cccc3Cl)s2)n1
Temperature: 7.5 °C
Reaction time: 0.21 h

Procedure:
Into a RBF 6.6 g of Sodium Amide was added at 30-35° C. under N2 atmosphere and stirring was done for 10-15 minutes. Then the reaction mass was cooled to 5-10° C. and 120.0 mL THF and 7.92 g 4,6-Dichloro-2-methyl pyrimidine were added to the reaction mass. Addition of 10.0 g 2-amino-N-(2-chloro-6-methyl phenyl)-5-thiazole carboxamide was then performed into the reaction mass. The reaction mass was stirred for ˜40 mins at 30-35° C. to get clear solution which was transferred to an addition dropper. At temperature of 5-10° C., the reaction mass was slowly added over 30 minutes, into another RBF having 40.0 mL THF. At the same temperature, the reaction mass was stirred for 1.0-1.5 hrs. Then the reaction mass temperature was increased to 30-35° C., where stirring was performed for 3 to 4 hrs. On completion of the reaction as verified by TLC, the reaction mass was cooled slowly to a temperature of 0-5° C. Then the reaction mass pH was adjusted to 3-4 by addition of 22.4 mL HCl and 240 mL water over 10-15 mins. The reaction mass was then stirred for 2.0-2.5 hrs at 0-5° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][C:9]([CH2:12][CH3:13])=[C:10]([CH3:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17](Cl)=[O:18].C(N(CC)CC)C>ClCCCl.ClCCl>[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17]([NH:1][C:2]1[C:7]2[O:8][C:9]([CH2:12][CH3:13])=[C:10]([CH3:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:18]
Reactant: CCc1oc2c(N)cccc2c1C
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: CCc1oc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1C
Temperature: 70 °C
Reaction time: 3 h
Yield: 35.8 %

Procedure:
A mixture of 7-amino-2-ethyl-3-methylbenzo[b]furan (858 mg), 2,6-dichlorobenzoyl chloride (1.23 g) and triethylamine (1.23 g) in 1,2-dichloroethane (17 ml) was stirred for 3 hours at 70° C. The mixture was diluted with dichloromethane, washed with diluted hydrochloric acid and brine, dried over sodium sulfate, and evaporated in vacuo to give a solid. The residue solid was crystallized from a mixture of ethanol (20 ml) and water (2 ml) to give 7-(2,6-dichlorobenzoylamino)-2-ethyl-3-methylbenzo[b]furan (610 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:9])[C:5](Cl)=[N:6][CH:7]=1.[OH-].[Na+].O.[CH2:13]([SH:16])[CH2:14][CH3:15]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([Cl:9])[C:5]([S:16][CH2:13][CH2:14][CH3:15])=[N:6][CH:7]=1
Reactant: Clc1cc(Br)cnc1Cl
Reactant: CCCS
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCSc1ncc(Br)cc1Cl
Temperature: 20 °C
Reaction time: 4 h

Procedure:
A mixture of 5-bromo-2,3-dichloropyridine (4.47 g, 19.7 mmol) and NaOH (867 mg, 21.7 mmol) in DMSO (50 mL) was treated with sufficient H2O to effect dissolution. n-PrSH (1.96 mL, 21.7 mmol) was added, then the reaction was stirred at 20° C. for 4 h. The mixture was poured onto crushed ice (200 g) and then extracted with CH2Cl2 (2×100 mL). The combined CH2Cl2 extracts were washed with H2O (3×100 mL) and brine (3×100 mL), before being dried (MgSO4). Filtration, solvent evaporation, and column chromatography (IH) provided 5-bromo-3-chloro-2-propylsulfanylpyridine: m/z (ES+)=268.0 [M+H]+. Step 2: Reaction of this bromopyridine (2.73 g, 10.2 mmol) with (Z)-methyl 3-cyclopentyl-2-iodoacrylate (1.84 g, 6.6 mmol), according to the cross-coupling conditions described in Step 2 of Preparation 9, gave (E)-methyl 2-(5-chloro-6-propylsulfanylpyridin-3-yl)-3-cyclopentylacrylate: m/z (ES+)=340.1 [M+H]+. Step 3: Saponification of this ester (770 mg, 2.3 mmol), using a similar protocol to that described by Step 2 of Preparation 3, furnished the title compound: δH (CDCl3): 1.05 (t, 3H), 1.40-1.85 (m, 10H), 2.45-2.60 (m, 1H), 3.20 (t, 2H), 7.15 (d, 1H), 7.40 (d, 1H), 8.15 (d, 1H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Br.BrCC1OC(C(F)(F)F)=CC=1.[F:24][C:25]1[C:30]([C:31]#[N:32])=[CH:29][C:28]2[C:33]3([CH2:43][O:44][C:27]=2[CH:26]=1)[C:41]1[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=1)[NH:35][C:34]3=[O:42].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1>>[F:24][C:25]1[C:30]([C:31]#[N:32])=[CH:29][C:28]2[C:33]3([CH2:43][O:44][C:27]=2[CH:26]=1)[C:41]1[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=1)[N:35]([CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[C:2]([F:12])([F:11])[F:1])[C:34]3=[O:42]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: N#Cc1cc2c(cc1F)OCC21C(=O)Nc2ccccc21
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: N#Cc1cc2c(cc1F)OCC21C(=O)N(Cc2ccccc2C(F)(F)F)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 2-(trifluoromethyl)benzyl bromide to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, and 6-fluoro-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, 6-fluoro-2′-oxo-1′-[2-(trifluoromethyl)benzyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile was obtained (55%): mp 193-195° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.76-7.73 (m, 1H), 7.53-7.39 (m, 2H), 7.27-7.22 (m, 1H), 7.17-7.07 (m, 3H), 7.01-6.99 (m, 1H), 6.82-6.79 (m, 1H), 6.70-6.67 (m, 1H), 5.27-5.09 (m, 3H), 4.90-4.87 (m, 1H); MS (ES+) m/z 419.0 (M−19).
Reaction SMILES: [Na+].[Na+].[O:3]=[C:4]([CH2:8][CH2:9][C:10]([O-:12])=[O:11])[C:5]([O-:7])=[O:6].[Br-].[C:14]1([S+:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O.ClCCl>[O:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:5]([OH:7])=[O:6].[C:27]1([S+:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1.[C:27]1([S+:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C([O-])CCC(=O)C(=O)[O-]
Agent: [Br-]
Agent: [Na+]
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: O=C(O)CCC(=O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-ketoglutaric acid disodium salt (0.4 g, 2.1 mmol) was dissolved in 6 mL of water. Triphenylsulfonium bromide (1.4 g, 4.1 mmol) was dissolved in 12 mL dichloromethane. The salt solution was added dropwise to the triphenylsulfonium bromide solution and the mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness (or on oil stage) on a rotary evaporator. The product obtained from evaporation was washed with ethyl ether and dissolved using an excess amount of dichloromethane and filtered. After the evaporation of dichloromethane, the pure compound was obtained as a white solid.
Reaction SMILES: [O-]O.[C:3]1([CH:9]([CH3:11])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(=O)=[O:13].S(=O)(=O)(O)O>O>[CH3:10][C:9]([CH3:11])([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[OH:13].[CH3:11][C:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[CH2:10]
Reactant: O=S=O
Reactant: CC(C)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [O-]O
Solvent: O
Product: C=C(C)c1ccccc1
Product: CC(C)(O)c1ccccc1

Procedure:
In accordance with the present invention, this is accomplished by an improvement in the process for obtaining phenol from cumene hydroperoxide, which has been obtained by liquid-phase oxidation of cumene with molecular oxygen, which involves forming a reaction mixture by continuously feeding the cumene hydroperoxide into a decomposer wherein the incoming hydroperoxide is diluted by cumene hydroperoxide decomposition products previously formed therein, maintaining the reaction mixture at elevated temperature, feeding to the reaction mixture a decomposition catalyst selected from the group consisting of sulfur dioxide and sulfuric acid, withdrawing reaction mixture from the decomposer, removing the decomposition catalyst from the product withdrawn from the decomposer, and fractionally distilling the resulting organic products to separately recover an acetone fraction, a phenol fraction and one or more by-product fractions, which improvement comprises, in combination (a) maintaining the reaction mixture in the decomposer at a temperature in the range of from 65° to 105° C.; (b) feeding the decomposition catalyst to the reaction mixture in amount of from 0.002 to 0.02 percent by weight of the cumene hydroperoxide feed; (c) conducting the decomposition reaction in the absence of added water so that the reaction mixture does not contain more than about 0.5 percent by weight of water, based on the weight of the reaction mixture; (d) withdrawing reaction mixture from the decomposer at cumene hydroperoxide concentrations not exceeding about 0.5 percent by weight, based on the weight of the reaction mixture; and (e) adding a base to the product withdrawn from the decomposer in excess of amount required to neutralize the decomposition catalyst and sufficient to adjust the pH of the product to from 5 to 9; so that dehydration of dimethyl phenyl carbinol to form alpha-methylstyrene is substantially avoided during the decomposition and distillation steps.
Reaction SMILES: C(=O)(OC)[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6](Br)=[CH:5][C:4]=1[CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.CC1(C)C(C)(C)OB([C:29]2[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH:34]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O.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>[CH:13]1([C:4]2[C:3]([OH:2])=[CH:8][C:7]([N+:9]([O-:11])=[O:10])=[C:6]([C:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH:30]=3)[CH:5]=2)[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(Br)cc1C1CCCC1
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: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(C3CCCC3)c(O)cc2[N+](=O)[O-])CC1
Temperature: 90 °C
Yield: 75.6 %

Procedure:
4-Bromo-2-cyclopentyl-5-nitrophenyl methyl carbonate (700 mg, 2.03 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (629 mg, 2.03 mmol), Pd(PPh3)4 (235 mg, 0.20 mmol), and Cs2CO3 (1325 mg, 4.07 mmol) were combined in DMF (10 mL) and heated at 90° C. for 4 h under N2 atmosphere. The reaction was diluted with water and extracted with dichloromethane (3×10 mL). The organic fractions were combined, dried over MgSO4, filtered and concentrated. Purification by silica gel chromatography (0-100% ethyl acetate/hexanes) yielded tert-butyl 4-(5-cyclopentyl-4-hydroxy-2-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (596 mg, 77% yield). LC/MS m/z 389.4 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([CH2:8][N:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[C:15](OS(C(F)(F)F)(=O)=O)[CH:16]=3)[N:11]=[C:10]2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:7])[CH2:3][CH2:2]1.O[C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1.[C:44]([O-])([O-])=[O:45].[K+].[K+]>CC(C)=O.O.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>[CH:1]1([CH2:4][NH:5][C:6](=[O:7])[CH2:8][N:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:37]4[CH:38]=[CH:39][CH:40]=[C:35]([CH2:44][OH:45])[CH:36]=4)[CH:16]=3)[N:11]=[C:10]2[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:2][CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: O=C(Cn1c(-c2ccccc2)nc2ccc(OS(=O)(=O)C(F)(F)F)cc2c1=O)NCC1CC1
Reactant: OB(O)c1cccc(O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(Cn1c(-c2ccccc2)nc2ccc(-c3cccc(CO)c3)cc2c1=O)NCC1CC1
Temperature: 60 °C
Yield: 68 %

Procedure:
To trifluoromethanesulfonic acid 3-[(cyclopropylmethylcarbamoyl)methyl]-4-oxo-2-phenyl-3,4-dihydroquinazolin-6-yl ester (100 mg, 0.2 mmol) in acetone (2 mL) and water (1 mL) was added 3-hydroxyphenyl boronic acid (60 mg, 0.4 mmol), K2CO3 (excess), and tetrakis(triphenylphosphine)palladium (23 mg, 10 mol %). The solution was heated at 60° C. for 1 h. The resulting mixture was cooled to room temperature and the solid material collected by filtration, washed with acetone and dried in vacuo to give N-cyclopropylmethyl-2-[6-(3-hydroxymethylphenyl)-4-oxo-2-phenyl-4H-quinazolin-3-yl]acetamide (60 mg, 0.14 mmol, 68%).